Tap Vol 6 Issue 16

Myeloma, Lymphoma, Leukemia 1, 5, 37–39, 60, 61 | Breast Cancer

17, 40, 87, 88, 104

| Coriolus Versicolor

VOLUME 6, ISSUE 16

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SEPTEMBER 10, 2015

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

Journal Spotlight

Adding Elotuzumab to Lenalidomide Plus Dexamethasone Improves Progression-Free Survival in Refractory Multiple Myeloma

Our Patients Are the True Heroes of Cancer Research

By Julie M. Vose, MD, MBA, FASCO

By Matthew Stenger

I

n an interim analysis of the phase III ELOQUENT-2 trial reported in The New England Journal of Medicine, Sagar Lonial, MD, of Emory University School of Medicine, Meletios Dimopoulos, MD, of National and Kapodistrian University of Athens, and colleagues found that the addition of elotuzumab to lenalidomide (Revlimid)/dexamethasone significantly increased progression-free survival in patients with relapsed or refractory multiple myeloma.1 Elotuzumab is an immunostimulatory monoclonal antibody targeting signaling lymphocytic activation molecule F7 (also known as SLAM7, SLAMF7, and CS1). Bone marrow myeloma cells (approximately 95%) express SLAM7, as do natural killer cells. Elotuzumab directly activates natural killer cells and mediates antibody-dependent cell-mediated cytotoxicity via the CD16 pathway.

Study Details In this open-label trial conducted at 168 sites worldwide, 648 patients were randomly assigned between June 2011 and November 2012 to receive elotuzumab plus lenalidomide/dexamethasone (n Sagar Lonial, MD = 321) or lenalidomide/ dexamethasone alone (n = 325). Elotuzumab was given intravenously at 10 mg/kg on days 1, 8, 15, and 22 during 28-day cycles, along with lenalidomide at 25 mg/d on days 1 to 21 and dexamethasone orally at 40 mg during the week without elotuzumab and intravenously at 8 mg plus 28 mg orally on the day of elotuzumab administration. Patients in the control group continued on page 37

Oncology Worldwide

Charting a New Course: From Clinical Investigator to University President

By Jo Cavallo hat first intrigued Fadlo R. Khuri, MD, FACP, about the prospect of becoming the 16th President of the American University of Beirut (AUB) in Lebanon was the chance to give back to an institution and a country that had given him so much. Born in Boston, Massachusetts, in 1963, Dr. Khuri was raised

in Beirut and followed his great grandfathers, paternal grandfather, father—Raja N. Khuri, MD, later served as Dean of the AUB Medical School—and mother in attending AUB, but he left the university in 1982, during the country’s raging civil war, to study at Yale University in New Haven, Connecticut.

“I didn’t leave because of the war,” said Dr. Khuri.

There is no question that the “I left because I was attracted to explore aspects of American University of Beirut casts a Yale in terms of exposure very large shadow and has a major to a broader liberal arts impact on the political discourse in the education while preparing for medical school, which region, the development of modern would have been more difengineering and knowledge, and ficult at AUB at that time.”

After graduating from medical technology and research.

Yale, Dr. Khuri earned his —Fadlo R. Khuri, MD, FACP

Send your comments to editor@ASCOPost.com

continued on page 121

Dr. Vose is President of ASCO, the Neuman M. and Mildred E. Harris Professional Chair and Chief of the Oncology/Hematology Division in the Department of Internal Medicine at the University of Nebraska Medical Center, and the Associate Director of Clinical Research at the Fred & Pamela Buffett Cancer Center in Omaha.

MORE IN THIS ISSUE

A Conversation With Fadlo R. Khuri, MD, FACP

W

A

few weeks ago, I read an op-ed1 in The New York Times written by Stan Collender, a patient with Merkel cell carcinoma, a rare and aggressive type of skin cancer. In his article, he described his participation in a clinical trial for a new drug he is hoping will stem progression of his cancer and the need for more patients to enroll in clinical studies so effective new medications can be approved and quickly get into the hands of patients who need them. Without clinical trials, wrote Mr. Collender, promising new drugs won’t be tested, and progress against cancer will be slowed.

Oncology Meetings Coverage Debates and Didactics in Hematology and Oncology �������������������� 3–6 Best of ASCO �������������������� 14–17, 20–22 World Congress of Psycho-oncology ������������������������������ 24–27 National Cancer Policy Forum �������� 35–36 New Orleans Summer Cancer Meeting ��������������� 40–43, 45–46 S. Vincent Rajkumar, MD, on Myeloma ����38 Oncology Worldwide ������������������������ 47, 67 Direct From ASCO �������������������������� 55–58 Women in Oncology: Carolyn D. Runowicz, MD, FASCO ��������������������������� 76

continued on page 65

A Harborside Press® Publication

The ASCO Post | SEPTEMBER 10, 2015

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Conor Lynch, Executive Editor Conor@harborsidepress.com James O. Armitage, MD Editor-in-Chief

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PAGE 3

Debates and Didactics in Hematology and Oncology Thoracic Oncology

Positioning Targeted and Immunotherapy-Based Approaches in Lung Cancer

By Caroline Helwick

W

ith immunotherapy changing the face of lung cancer, is there still a place for targeted therapy? Two experts from Emory University debated this issue at the 2015 Debates and Didactics in Hematology and Oncology Conference held in Sea Island, Georgia.

Fadlo Khuri, MD, was recently named President of the American University of Beirut in Lebanon, and Suresh S. ­R amalingam, MD, is Professor and Director of Medical Oncology at Emory.

Targeting Driver Mutations “In my view,” Dr. Khuri maintained, “when you have highly characterized genomic drivers, you are going to go with genomically targeted therapy.”

Lung cancer exhibits at least three targetable mutations, at least one of which is harbored by almost two-thirds of patients with adenocarcinomas. Half or more of these patients will respond to targeted agents, with a duration of benefit that can be “quite striking,” Dr. Khuri said.

Numerous benefits remain unique to targeted agents, he said, including the opportunity to target specific drivers of oncogene-addicted tumors, high response rates, reliability and availability of biomarkers in genomic testing, a favorable cost-benefit ratio, and an understanding of mechanisms of resistance.

The prognosis of non–small cell lung cancer (NSCLC) dramatically changed with the discovery of mutations in the epidermal growth factor (EGFR). The ability to target such tumors with tyrosine kinase inhibitors led to a “sea change” in the management of EGFRmutated patients. EGFR inhibitors became and remain the first-line standard of care, he said.

The emergence of resistance has been the Achilles heel of targeted ther-

apy, but drugs in development are tackling that problem, especially by overcoming the hallmark T790M mutation.

About half the patients whose disease progresses demonstrate this alteration.

“We now have impressive data showing that we understand this mutation, its biology, and its prognosis, and we have developed treatments that target T790M,” he said.

ment, including ceritinib (Zykadia) and alectinib, are effective in more than 50% of crizotinib-treated patients. The dual ALK/EGFR inhibitor AP26113 is also active in patients with secondary resistance to ALK, he noted.

BRAF, the third driver mutation that can be targeted, is identified in 1% to 2% of patients. Monotherapy with dabrafenib (Tafinlar) yielded a disease

If you know you have a driver mutation, you go with targeted therapy. But without a known mutation, in the second-line setting, you go with nivolumab, which is dramatically superior to docetaxel.

—Fadlo Khuri, MD, FACP

Patients with the T790M mutation almost invariably respond to the thirdgeneration EGFR inhibitor AZD9291.

In a study of 138 mutation-positive patients, the disease control rate was 95%.1 Similar agents are in development, including rociletinib (CO-1686), which has produced responses in almost 60% of T790M-mutated patients.2 The ALK fusion gene represents the other “success story” of targeted management. Showing striking activity (doubling of progression-free survival) in the 5% of patients with NSCLC who have this alteration, the ALK inhibitor crizotinib (Xalkori) was rapidly approved.3 Resistance to crizotinib is also being tackled as more is learned about the mechanisms of resistance to ALK inhibitors, which differ from those observed with EGFR inhibitors. Thirdgeneration ALK inhibitors in develop-

control rate of 56% at 12 weeks and a median duration of response of 11.8 months in previously treated patients.4 It may be even more effective when combined with trametinib (Mekinist), Dr. Khuri said.

A Place for Immunotherapy Since targeted therapy is limited to mutation subsets, there is a place for immunotherapy, especially as second-line therapy, Dr. Khuri acknowledged. “If you know you have a driver mutation, you go with targeted therapy. But without a known mutation, in the secondline setting, you go with nivolumab [Opdivo], which is dramatically superior to docetaxel,” he said.

“No question, there is no more exciting science than cancer immunotherapy. Especially with combination immunotherapy, we may see dramatic, durable responses,” he acknowledged.

However, Dr. Khuri pointed out that the benefits may be accompanied by more toxicity (especially with combinations) than is seen with targeted therapy. “One of the most evident toxicities is to the bank account!” he added.

For a median progression-free survival of 6.9 months, nivolumab monotherapy costs more than $100,000. For a median progression-free survival of 11.4 months, the cost approaches $300,000, according to some calculations.

“In my view, this is probably more than the market can bear,” Dr. Khuri commented. Coupled with a 20% copay for patients, “this will be unsustainable.”

Dr. Ramalingam pointed out that as good as targeted therapy is, this approach has never cured a patient with lung cancer. “Immunotherapy is going to, by far, have a stronger impact on lung cancer than targeted treatment has had so far,” he maintained. “Immunotherapy improves survival, and this cannot be said for targeted agents.”

In addition, he added, immunotherapy can be applied to all-comers, and that unlike targeted therapy, its effect is not preferential to persons who have a little to no smoking history (ie, not the average patient). Immunotherapy addresses the “garden variety lung cancer,” which is smoking-derived tumors with high mutational burdens, he indicated.

Dr. Ramalingam further reminded listeners that although 65% of patients have a driver mutation, 25% of them will be in KRAS, “which still begs for a treatment option.” Targeted treatments, he pointed out, “are therefore used in a small percentage of our patients.”

Additional obstacles to the use of targeted therapies are the emergence of resistance, for which current options are limited, and their failure to be effective continued on page 4

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For conference exhibitor or sponsorship opportunities, contact David Horowitz at 631-935-7658 or email at david@harborsidepress.com

The ASCO Post | SEPTEMBER 10, 2015

PAGE 4

Debates and Didactics in Hematology and Oncology Approaches to Lung Cancer continued from page 3

earlier in the disease course. However, targeted agents do have the edge over immunotherapy in terms of response rates, he acknowledged, but added that when patients do respond to immunotherapy, their benefits can be durable.

Survival Benefits With Immunotherapy “We also now have overall survival data showing immunotherapy to be superior,” said Dr. Ramalingam.

In a phase I study of nivolumab in refractory NSCLC,5 2-year survival was 24%, and at 3 years, 18% of heavily pretreated patients remained free from progression, he noted. “To be alive 3 years later is very exciting for patients who have run out of options,” added Dr. Ramalingam.

In the phase III CheckMate 017 trial in previously treated squamous cell carcinoma, nivolumab significantly improved overall survival over docetaxel in the second-line setting.6 The hazard ratio of 0.59 compares favorably with that seen with targeted agents vs chemotherapy in the front line, “and this is second line,” he added. “First-line data will be out in a year or so, and if this is a sign of what’s to come, we are in for an exciting time.”

The possibility of long-term survival is further illustrated by a study led by Dr. Ramalingam of nivolumab in refractory patients with squamous cell carcinoma.7 Although the response rate was only 14%, almost all responders had ongoing responses, whether or not they continued on nivolumab.

“That tells us the power of immunotherapy,” he commented. “With targeted therapy, the median progression-free survival is 10 to 13 months. With these patients, we haven’t reached the median

duration of response.”

Activity in nonsquamous histology also has shown that the anti–PD-1 (programmed cell death protein 1) antibodies are not “one-trick ponies,” he continued. Although it yielded a slightly lower hazard ratio (0.73), nivolumab improved survival over docetaxel as second-line treatment of nonsquamous patients in the phase III CheckMate 057 study.8 “These two trials show that immunotherapy trumps targeted therapy in the second line,” he maintained.

results, high expressers (≥ 50% staining) had a response rate of 52%, a median progression-free survival of 12.5 months, and a median overall survival that had not been reached.

The anti–PD-1/PD-L1 agents may be even more effective in combination with other agents. In early-phase studies, pembrolizumab plus chemotherapy has yielded a disease control rate of 100%, with relatively good tolerability, he added.

In conclusion, Dr. Ramalingam maintained that immunotherapy offers

Immunotherapy is going to have a stronger impact on lung cancer than targeted treatment has had so far.

Immunotherapy improves survival, and this cannot be said for targeted agents.

—Suresh S. Ramalingam, MD

Beyond Nivolumab Strong data are also emerging for anti–PD-1/PD-L1 (its ligand) agents other than nivolumab. In the phase II POPLAR trial, atezolizumab significantly improved overall survival vs docetaxel in patients with strong PD-L1 expression; the response rate was 38%, and median overall survival was not reached.9 Although such findings suggest that PD-L1 expression may help select patients, noted Dr. Ramalingam, “These drugs work even in PD-L1–negative patients. Their outcomes are at least as good as with chemotherapy, and we need to bear this in mind in terms of selecting patients.”

Impressive outcomes were also achieved among PD-L1–positive patients receiving pembrolizumab (Keytruda) in KEYNOTE-001.10 In updated

the best chance of long-term survival in advanced lung cancer and a means of changing the biology of this disease. n Disclosure: Dr. Khuri reported no potential conflicts of interest. Dr. Ramalingam has served on advisory boards for and has received honoraria from AstraZeneca, Bristol-Myers Squibb, Merck, and Genentech.

References 1. Jänne PA, Yang JC, Kim DW, et al: AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. N Engl J Med 372:1689-1699, 2015.

2. Sequist LV, Soria JC, Goldman JW, et al: Rociletinib in EGFR-mutated non-small cell lung cancer. N Engl J Med 372:17001709, 2015.

3. Shaw AT, Kim DW, Nakagawa K, et al: Crizotinib versus chemotherapy in ad-

vanced ALK-positive lung cancer. N Engl J Med 368:2385-2394, 2013.

4. Planchard D, Kim TM, Mazières J, et al: Dabrafenib in patients with BRAF V600E-mutant advanced non-small cell lung cancer: A multicenter, open-label phase II trial (BRF113928). 2014 ESMO Congress. Abstract LBA38_PR. Presented September 29, 2014.

5. Brahmer J, Horn L, Antonia S: Nivolumab in patients with non-small cell lung cancer: Overall survival and long-term safety in phase 1 trial. 2013 IASLC 15th World Conference on Lung Cancer. Abstract MO 18.03.

6. Spigel DR, Reckamp KL, Rizvi NA, et al: A phase III study (CheckMate 017) of nivolumab vs docetaxel in previously treated advanced or metastatic squamous cell non-small cell lung cancer. 2015 ASCO Annual Meeting. Abstract 8009. Presented May 29, 2015.

7. Rizvi NA, Mazières J, Planchard D, et al: Activity and safety of nivolumab, an antiPD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): A phase 2, single-arm trial. Lancet Oncol 16:257-265, 2015.

8. Paz-Ares, L, Horn L, Borghaei H, et al: Phase III, randomized trial (CheckMate 057) of nivolumab versus docetaxel in advanced non-squamous cell non-small cell lung cancer. 2015 ASCO Annual Meeting.

Abstract LBA109. Presented May 29, 2015.

9. Spira AI, Park K, Mazières J, et al: Efficacy, safety and predictive biomarker results from a randomized phase II study comparing MPDL3280A vs docetaxel in 2L/3L NSCLC (POPLAR). 2015 ASCO Annual Meeting. Abstract 8010. Presented May 29, 2015.

10. 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.

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PAGE 5

Debates and Didactics in Hematology and Oncology Hematology

Indolent Lymphoma: A More Complex Malignancy Than Once Thought

By Caroline Helwick

W

ith a growing number of options for follicular lymphoma, clinicians may wonder whether there is one best regimen. James O. Armitage, MD, FACP, FRCP, Professor of Medicine at the University of Nebraska, Omaha— and Editor-in-Chief of The ASCO Post— tackled this question and offered recommendations at the 2015 Debates and Didactics in Hematology and Oncology in Sea Island, Georgia, an annual conference sponsored by Emory University.

Approach to Treatment Follicular lymphoma is actually a more complex malignancy than is often believed, according to Dr. Armitage. “It’s becoming increasingly clear that follicular lymphoma is complex and that the relationship between tumor cells and surrounding cells is important.”

Of note, some patients with grade 3 follicular lymphoma have a disease course more like diffuse large B-cell lymphoma. This is important to recognize, because it should dictate a more aggressive treatment, he said. “If you want to cure these patients, you’d better treat them with a [diffuse large Bcell lymphoma]-type regimen,” he recommended, adding that he typically treats all grade 3 follicular lymphomas this way.

The other important question is how aggressively to treat stage I (ie, localized) follicular lymphoma. This early disease will respond well to radiotherapy alone. Studies have uniformly shown that almost half of patients treated with radiotherapy alone are continuously free of disease at 10 years. “Based on this, we usually treat localized follicular lymphoma with involved-field radiotherapy alone,” he said.

A Role for ‘Watch and Wait’?

Given the excellent long-term outcomes with rituximab (Rituxan), is there a place for observation in indolent disease?

The Nebraska Lymphoma Study Group documented the 10-year overall survival rate for patients treated between 1982 and 2000 (ie, before the approval of rituximab) as approximately 50%. This rose to about 75% after the year 2000, he noted.

“Since our current treatment is so good, is it appropriate to watch and wait? Some think not, because of the impact of rituximab on the natural history of lymphoma,” Dr. Armitage noted.

He maintained that observation can be appropriate for patients who are ­asymptomatic and either do not want therapy or are elderly and frail. The caveat is that close monitoring is mandatory; delaying treatment may decrease survival, though this remains unproven, he said.

“You must be willing to observe these patients closely. Seeing them every 6 months is not enough. I see patients monthly at first, then every 3 months at most. If you are going to watch and wait, you cannot ignore these patients!”

CHOP-R vs CVP-R There are many active regimens for patients with disseminated follicular ­lymphoma.

“There are patients for whom rituximab alone is reasonable, but for rituximab-containing combinations, which is best?” Dr. Armitage asked.

mide, mitoxantrone, and rituximab).2 CHOP-R, therefore, is more active than CVP-R, and because of toxicity, fludarabine-based regimens are rarely used in the United States. The bigger question is whether to use CHOP-R or B-R, he said.

CHOP-R vs B-R The German NHL1 trial appeared to show superiority of B-R over CHOPR, based on a longer progression-free survival (P = .0281).3 But the results of NHL1 were not substantiated by the U.S.-based BRIGHT trial, which compared B-R to CHOP-R/CVP-R.4 Among the follicular/indolent lymphoma cohort, the complete remission rate with B-R was much lower (27%) than it was in NHL1 (44%).

“When the U.S. group tried to reproduce the NHL1 study, they found no difference in the regimens,” he said.

For most patients, relapse is a horrible thing, so I offer maintenance therapy because I know this will increase the time before we need to treat again, if ever. Maintenance keeps patients in remission longer, but we don’t know if it keeps them alive longer.

—James O. Armitage, MD, FACP, FRCP

He discussed as options CHOP-R (cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab), CVP-R (cyclophosphamide, vincristine, prednisone, and rituximab), B-R (bendamustine [Treanda] and rituximab), fludarabine-based regimens, and lenalidomide [Revlimid] plus rituximab.

An Italian study compared three regimens and found that complete remission rates were higher for CHOPR (74%) than for CVP-R (67%) and fludarabine/mitoxantrone/rituximab (72%).1 Progression-free survival at 3.5 years was also longer with CHOPR (68% vs 52% and 63%, respectively).

The PRIMA study showed that CHOPR produced higher complete remission rates than CVP-R and progression-free survival similar to that associated with FCM-R (fludarabine, cyclophospha-

The toxicity profiles of the two regimens, however, do differ in ways that may be important to patients. There is more vomiting and hypersensitivity reaction with bendamustine but more alopecia and neuropathy with CHOP-R.5 The lack of alopecia with bendamustine has popularized its use, he added.

Comparability between the two regimens was further demonstrated in a matched-pair analysis reported from The University of Texas MD Anderson Cancer Center.6 After six cycles, complete remission rates were 91% with CHOP-R and 93% with B-R; 2-year progression-free survival was 82% and 85%, respectively; and 2-year overall survival was 99% and 94%, respectively. Although the CHOP-R group contained more patients with high-risk criteria, patient

outcomes were no worse, he noted.

“I think both of these regimens work, and one regimen is not better than the other. Both are better than CVP-R, and fludarabine is too toxic,” Dr. Armitage concluded.

The New Option: R2 The newest option is rituximab/lenalidomide, the so-called R-squared or R2 regimen. R2 produced a very high complete remission rate (87%) in an MD Anderson series; 93% of evaluable patients became positron-emission tomography (PET)-negative, and the 2-year progression-free survival rate was 89%.7 In a multi-institutional study, the complete remission rate was lower (72%), but 2-year progression-free survival remained high (89%).8 In a 154-patient study, European investigators also reported a lower complete remission rate (36%).9 “As more patients are treated, the results are sometimes not as good as the original report, and this is common,” Dr. Armitage commented.

“There has been no comparative trial, but this regimen might offer a similar likelihood to CHOP-R and B-R for keeping low-grade follicular lymphoma patients well.”

Deciding on a Regimen All things considered, Dr. Armitage weighs the treatment options by asking the following questions: Is the patient fit? How old is the patient? Is the patient symptomatic? What side effects is the patient willing to accept?

Patients who are not generally healthy are more likely to receive rituximab alone. Patients who are ill from cancer are most likely to benefit from CHOP-R or B-R. Elderly patients are more likely to receive B-R than CHOP-R. Side effects should be weighed and patient preferences ­considered.

Optimal Treatment Duration?

Dr. Armitage emphasized that the aim of treatment is to achieve a complete remission. “It’s not okay to just treat the patient for a while and make him feel better. We know there is a huge survival advantage to achieving a complete remission,” he said.

A recent pooled analysis of three trials of patients receiving at least six continued on page 6

The ASCO Post | SEPTEMBER 10, 2015

PAGE 6

Debates and Didactics in Hematology and Oncology Indolent Lymphoma continued from page 5

cycles of chemotherapy plus rituximab confirmed the value of achieving a negative PET/computed tomography (CT) scan after induction.10 The hazard ratios associated with having a positive PET/CT were 3.9 for progression-free survival (P < .0001) and 6.7 for overall survival (P = .0002).

More uncertain is the value of maintenance rituximab in this setting. The PRIMA study “convincingly showed” that maintenance will prolong remission (hazard ratio = 0.50, P < .0001), but it did not demonstrate improved survival.2 The U.S.-based RESORT study, on the other hand, showed no difference in “time to treatment failure” between patients on the maintenance arm and those being observed only. This was defined as progression within 6 months of the last rituximab dose, no response to rituximab retreatment, initiation of alternative therapy, or inability to complete protocol therapy.11 The investigators concluded that intermittent treatment was as effective as maintenance rituximab. In Dr. Armitage’s opinion, the study’s median follow-up of 3.8 years may be too short to determine true differences in outcomes.

“You have to decide how important it is to the patient to be continuously well,” he commented. “For most patients, relapse is a horrible thing, so I offer maintenance therapy because I know this will increase the time before we need to treat again, if ever. Maintenance keeps patients in remission longer, but we don’t know if it keeps them alive longer.” n

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

References 1. Federico M, Luminari S, Dondi A, et al: R-CVP versus R-CHOP versus R-FM for the initial treatment of patients with advanced-stage follicular lymphoma: Results of the FOLL05 trial conducted by the Fondazione Italiana Linfomi. J Clin Oncol 31:1506-1513, 2013.

2. Salles G, Seymour JF, Offner F, et al: Rituximab maintenance for 2 years in patients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): A phase 3, randomized controlled trial. Lancet 377:42-51, 2011.

3. Rummel MJ, Niederle N, Maschmeyer G, et al: Bendamustine plus rituximab versus CHOP plus rituximab as firstline treatment for patients with indolent and mantle-cell lymphomas: An open-

label, multicenter, randomized, phase 3 non-inferiority trial. Lancet 381:12031210, 2013.

4. Flinn I, van der Jagt R, Kahl B, et al: An open-label, randomized study of bendamustine and rituximab compared with rituximab, cyclophosphamide, vincristine, and prednisone (R-CVP) or rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone in first-line treatment of advanced indolent non-Hodgkin’s lymphoma or mantle cell lymphoma: The BRIGHT study. 2012 ASH Annual Meeting. Abstract 902. Presented December 11, 2012.

5. Macdonald D, van der Jagt R, Burke JM, et al: Different safety profiles of firstline bendamustine-rituximab, R-CHOP, and R-CVP in an open-label, randomized study of indolent non-Hodgkin lymphoma and mantle cell lymphoma: The BRIGHT study. 2013 ASCO Annual Meeting. Abstract 8565. Presented May 31, 2013.

6. Phansalkar K, Ahmed M, Fowler N, et al: R-bendamustine vs R-CHOP as initial treatment for advanced stage low grade follicular lymphoma: A matched-pair analysis.

2014 ASH Annual Meeting. Abstract 3048.

Presented December 7, 2014.

7. Fowler NH, Neelapu SS, Hagemeister FB, et al: Lenalidomide and rituximab for untreated indolent lymphoma: Final

results of a phase II study. 2012 ASH Annual Meeting. Abstract 901. Presented December 11, 2012.

8. Martin P, Jung S, Johnson J, et al: CALGB 50803 (Alliance): A phase II trial of lenalidomide plus rituximab in patients with previously untreated follicular lymphoma. 2014 ASCO Annual Meeting. Abstract 8521. Presented May 30, 2014.

9. Kimby E, Martinelli G, Ostenstad B, et al: Rituximab plus lenalidomide improves the complete remission rate in comparison with rituximab monotherapy in untreated follicular lymphoma patients in need of therapy: Primary endpoint analysis of the randomized phase 2 trial SAKK 35/10.

2014 ASH Annual Meeting. Abstract 799.

Presented December 9, 2014.

10. Trotman J, Luminari J, Boussetta S, et al: Prognostic value of PET-CT after first-line therapy in patients with follicular lymphoma: A pooled analysis of central scan review in three multicenter studies. Lancet Haematol 1(1):e17-e27, October 2014.

11. Kahl B, Hong F, Williams ME, et al: Results of Eastern Cooperative Oncology Group protocol E4420 (RESORT): A randomized phase III study comparing two different rituximab dosing strategies for low tumor burden follicular lymphoma. 2011 ASH Annual Meeting. Abstract LBA-6. Presented December 13, 2011.

Don’t Miss These Important Reports in This Issue of The ASCO Post Louise Morrell, MD, on Genetic Testing in Breast Cancer see page 40

Mark Pegram, MD, on Tumor Complexity and Technology see page 41

Pasquale W. Benedetto, MD, on High Cure Rates in Germ Cell Tumors see page 44

Peter Agre, MD, on a New Lung Cancer Vaccine Collaboration see page 47

Georgina V. Long, MD, on Dabrafenib Plus Trametinib in BRAF V600-Mutant Melanoma see page 60

Charles Prober, MD, on Online Medical Education see page 72

Carolyn D. Runowicz, MD, FASCO, on Her Career in Gynecologic Cancer Treatment see page 76

Patricia Ganz, MD, and others on Mobile App for Breast Cancer Survivors see page 88

Laura J. Esserman, MD, MBA, on Postmastectomy Pain see page 104

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The ASCO Post | SEPTEMBER 10, 2015

PAGE 14

Best of ASCO® Gastrointestinal Oncology

Colorectal Liver Metastases: Thumbs Up for Radiofrequency Ablation, Jury Still Out for Selective Internal Radiotherapy

By Alice Goodman

T

wo “firsts” in studies of colorectal liver metastases were highlighted at the 2015 ASCO Annual Meeting: the first prospective randomized trial to evaluate radiofrequency ablation plus chemotherapy1 and the first large randomized phase III trial to study liver-directed selective internal radiation therapy.2 Radiofrequency ablation plus chemotherapy appeared to have clear benefit in this setting, whereas the results for selective internal radiotherapy in first-line therapy are currently less conclusive. Daniel G. Haller, MD, of Abramson Cancer Center at the University of Pennsylvania, discussed both trials at Best of ASCO® 2015 in Boston.

Radiofrequency Ablation Plus Chemotherapy Unresectable liver metastases treated with radiofrequency ablation plus chemotherapy improved long-term overall and progression-free survival compared with chemotherapy alone in patients with metastatic colorectal cancer, according to the results of the randomized phase II study of the EORTC NCRI CCSG-ALM Intergroup 40004 (CLOCC).

“This is the first study to prospectively evaluate radiofrequency ablation plus chemotherapy. This study showed that radiofrequency plus chemotherapy is clearly superior to systemic ­[chemo] therapy in terms of progression-free survival and overall survival in colorectal cancer patients with inoperable liver metastases. This is a no-brainer, and this study is unlikely to ever be repeated,” said Dr. Haller, who reviewed CLOCC and other important studies in gastrointestinal (colorectal) cancer selected for the Best of ASCO 2015.

Between 2002 and 2007, the study

enrolled patients with colorectal cancer who had up to nine liver metastases and no extrahepatic disease. A total of 119 patients were randomized to receive chemotherapy alone or radiofrequency ablation plus chemotherapy. In both arms, chemotherapy consisted of 6 months of FOLFOX (leucovorin, fluorouracil, oxaliplatin), and bevacizumab (Avastin) was added in 2005. In both arms, resection was allowed if chemotherapy converted unresectable metastases to resectable.

frequency ablation arm vs 40.5 months in the chemotherapy-alone arm. Eightyear overall survival was 35.9% vs 8.9%, respectively (P = .010). A total of 92 deaths were reported: 39 in the radiofrequency ablation arm and 53 in the chemotherapy-alone arm. Progressive disease accounted for 34 and 48 deaths, respectively.

Progression-free survival was significantly superior in the radiofrequency ablation arm. With long-term followup, median progression-free survival

The goal of these treatments is to allow patients to be resected, delay biliary obstruction, [and] maintain liver function, so patients can get later lines of therapy. The timing is questionable, but I believe in the middle of chemotherapy is optimal.

—Daniel G. Haller, MD

In the radiofrequency ablation arm, 56 patients were treated with radiofrequency ablation, and 27 patients (45%) underwent hepatic resection. Of the 51 patients in the chemotherapy arm, 6 eventually underwent hepatic resection.

As reported in 2010, 30-month overall survival (primary endpoint) was 61.7% for radiofrequency ablation plus chemotherapy and 57.6% for chemotherapy alone, which was higher than expected.

At a median follow-up of 9.2 years, the difference in overall survival significantly favored the radiofrequency ablation arm (P = .01). Median overall survival was 45.6 months in the radio-

Nonsurgical Treatments for Colorectal Liver Metastases ■■ Recent studies have helped to refine the usefulness of two nonsurgical treatments of colorectal liver metastases: radiofrequency ablation plus chemotherapy and selective internal radiotherapy.

■■ Radiofrequency ablation plus chemotherapy appeared to achieve superior overall survival and progression-free survival vs chemotherapy alone.

■■ Selective internal radiotherapy plus chemotherapy did not improve progression-free survival overall but did reduce the incidence of progression in the liver.

■■ Overall survival data for selective internal radiotherapy will be analyzed across three large randomized trials, and results are expected in about 2 years.

was 16.8 months for radiofrequency ablation vs 9.9 months for chemotherapy alone (P = .025). Eight-year progression-free survival was 22% vs 2%, respectively (P = .005).

SIRFLOX Study In the randomized, phase III ­SIRFLOX study, first-line therapy for patients with unresectable liver metastases with selective internal radiotherapy added to modified FOLFOX6 plus or minus bevacizumab failed to improve overall progression-free survival compared with modified FOLFOX6 plus or minus bevacizumab (which was not part of the randomization scheme) did better than those who did not.

Selective internal radiotherapy employs yttrium-90–labelled resin microspheres or glass beads as a liver-directed therapy, and it has been approved by the U.S. Food and Drug Administration for the treatment of hepatic cell carcinoma, neuroendocrine tumors, and metastatic colorectal cancer.

SIRFLOX randomized 530 patients with nonresectable liver-only or liverdominant metastatic colorectal cancer with no prior therapy in a 1:1 ratio to receive treatment with modified FOLFOX6 plus or minus bevacizumab or modified FOLFOX6 plus selective

internal radiotherapy plus or minus bevacizumab. Patients were prestratified according to extrahepatic metastasis, degree of liver involvement, and intended use of bevacizumab.

Inclusion criteria allowed extrahepatic metastases as follows: up to five lung metastases smaller than 1 cm and lymph nodes in a single anatomic region. Less than 40% of patients had extrahepatic disease. About 50% of patients received bevacizumab.

For the primary endpoint of overall progression-free survival, there was no significant difference between the two treatment arms. “However, progression-free survival in the liver (a secondary endpoint) had interesting results,” Dr. Haller noted.

Median progression-free survival in the liver was 12.6 months for chemotherapy vs 20.5 months for selective internal radiotherapy (P = .002), representing a 7.9-month improvement and a 31% risk reduction for disease progression in the liver. Complete response in the liver was achieved in 2% of the chemotherapy arm vs 6% in the selective internal radiotherapy arm (P = .020).

“Selective internal radiotherapy did not enable more liver resections and does not convert patients or downstage them,” Dr. Haller said.

More adverse events occurred with patients treated with selective internal radiotherapy. The rate of any adverse event was 73.4% for chemotherapy and 85.4% for selective internal radiotherapy.

Grade 3 or higher adverse events follow: neutropenia, 28.5% for chemotherapy vs 40.7% for selective internal radiotherapy; febrile neutropenia, 1.9% vs 6.1%; thrombocytopenia, 2.6% vs 9.8%.

Future analysis of these data will include liver-only vs liver-dominant outcomes, depth of response, quality of life, cost-effectiveness of a single treatment of selective internal radiotherapy vs systemic treatment, and overall survival.

“Selective internal radiotherapy achieved an 8-month improvement in progression-free survival in the liver, but it is not clear what this means for the lifespan of the patient. Selective internal radiotherapy did not add much to the overall response rate, but it was superior in the liver,” he continued.

“However, toxicities are noteworthy.” continued on page 15

ASCOPost.com | SEPTEMBER 10, 2015

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Best of ASCO® Gastrointestinal Cancer

Secondary Prevention in Metastatic Colorectal Cancer: Benefits of Vitamin D and Aspirin Explored

By Alice Goodman

T

wo low-cost, low-tech options may lead to a survival benefit in metastatic colorectal cancer, according to separate retrospective studies selected for the Best of ASCO® 2015. The first study suggested that vitamin D supplementation is worthy of investigation in this regard,1 and the second study added to existing evidence that regular use of aspirin may improve survival in colorectal cancer.2 “Various standard therapies can improve survival in metastatic colorectal cancer. What else can you do to improve survival in this disease?

The take-home message from these studies is that vitamin D levels and aspirin are lifestyle factors most consistently associated with improved outcomes among patients with colorectal cancer. There is strong supportive evidence for both of these interventions, and if confirmed, these lowcost options could have a substantial impact for the treatment of colorectal cancer,” said Daniel G. Haller, MD, of Abramson Cancer Center, University of Pennsylvania, Philadelphia, discussant of these two studies at the Best of ASCO® 2015.

Vitamin D Levels Higher plasma concentrations of plasma 25-hydroxyvitamin D [25(OH) D, vitamin D] are associated with significantly improved survival in patients with metastatic colorectal cancer treated with chemotherapy and biologics, according to a prospective pretherapy assessment of patients enrolled in CALGB/SWOG 80404, a random-

Colorectal Liver Metastases continued from page 14

SIRFLOX is the first of three studies to look at a pooled analysis of overall survival; the other two ongoing trials are FOXFIRE and FOXFIRE global.

Overall survival results of all three trials, for a total of 2,017 patients, should be available in about 2 years.

Additional Discussion “There are multiple options for treatment of metastatic disease to the liver.

They include systemic therapy, surgery, neoadjuvant therapy, liver-directed therapy, selective internal radiotherapy [SIRFLOX], and radiofrequency abla-

ized phase III trial of chemotherapy plus bevacizumab (Avastin), cetuximab ­(Erbitux), or both, prior to the KRASwild type amendment for this study.

The study included 2,334 patients randomized as follows: chemotherapy plus bevacizumab (n = 899 patients), cetuximab (902 patients), or both (533 patients). Plasma vitamin D was measured prior to receiving chemotherapy in 1,043 patients. The primary study results showed no significant difference in overall survival among the arms.

Significantly lower plasma vitamin D levels were found in male and black patients; those living in the northeast; and those with lower dietary and supplemental vitamin D intake, an Eastern Cooperative Oncology Group performance status of 1 (vs 0), tumoral RAS mutation, higher body mass index, lower levels of physical activity, and a blood draw during the winter and spring.

Patients in the highest quintile had significantly improved overall survival compared with those in the two lowest quintiles, after adjusting for pathologic and clinical prognostic factors: median of 32.6 months vs 24.5 months (P trend = .001).

Improved progression-free survival was also significantly associated with higher plasma concentrations of vitamin D: median of 12.2 months vs 10.1 months, respectively (P trend = .01). Results were consistent across subgroups.

“These results showed a 35% improvement in overall survival and a 21% improvement in median progression-free survival in the highest quintile compared to the lowest. According to a tion [CLOCC],” Dr. Haller said. “The goal of these latter treatments is to allow patients to be resected, delay biliary obstruction, [and] maintain liver function, so patients can get later lines of therapy. The timing is questionable, but I believe in the middle of chemotherapy is optimal,” he said. “[The phase II Intergroup 40004] study included patients with unresectable liver metastasis. Patients were allowed chemotherapy prior to randomization. The study had a huge bias in that there were more patients with a single liver metastasis in the radiofrequency ablation arm. In addition, about 50% of patients treated with ra-

Vitamin D Levels and Aspirin Use in Colorectal Cancer ■■ Higher levels of plasma vitamin D are associated with improved survival in patients with metastatic colorectal cancer.

■■ It is not known at present whether vitamin D supplementation can improve survival in patients with low levels of plasma vitamin D. ■■ A large population-based study found that aspirin exposure improves overall survival and progression-free survival in patients with metastatic colorectal cancer.

Forest plot, every subgroup did better with higher levels vs lower levels,” Dr. Haller noted.

Strengths of the study are that vitamin D levels were measured after diagnosis but before treatment and that there is detailed information on other prognostic factors. Patients received protocol-based therapy, and follow-up was standard.

“Limitations [of the study] include lack of data on vitamin D level before the cancer diagnosis. It is also not clear if a single measure of a single form of vitamin D is the best measure,” Dr. Haller continued.

“There is a preponderance of evidence from several countries that patients with higher vitamin D levels have improved outcomes. This is strong, consistent evidence. It is not clear, however, whether correcting vitamin D levels will lead to improved outcomes,” he noted.

Remaining questions are whether vitamin D supplementation should be given in adjuvant settings, whether vitamin D supplementation improves outcomes only in vitamin D–deficient patients, and what are the best formulations of vitamin D supplediofrequency ablation had resection, making it difficult to distinguish which patients were helped by radiofrequency ablation. Also, there were small numbers of patients, and they were highly selected,” Dr. Haller continued.

“Selective internal radiotherapy bought patients an extra 8 months of progression-free survival in the liver, but this therapy has toxicities. Analysis of overall survival and the impact of the initial large increase in liver progressionfree survival on further lines of therapy will add more data on this modality,” concluded Dr. Haller. n Disclosure: Dr. Haller is on the advisory board of Sirtex.

ments. Two randomized trials are looking at these questions.

“If these findings are confirmed, vitamin D supplementation will represent a low-cost option to further improve metastatic colorectal cancer outcomes,” he stated.

Aspirin Use Aspirin has been validated in primary prevention of colorectal cancer. A population-based, retrospective, cohort study conducted in Norway between 2004 and 2011 in an unselected cohort of 25,644 patients with colorectal cancer found that aspirin as secondary prevention was associated with improved survival. Twenty-five percent of patients (n = 6,109) were exposed to aspirin, as defined by a prescription of aspirin for more than 6 months after diagnosis of colorectal cancer.

At a median follow-up of 2.2 years, overall survival and colorectal cancer–specific survival were significantly improved in patients who took aspirin. Among those exposed to aspirin, 2,088 (34.2%) deaths were recorded, continued on page 16

References 1. Ruers T, Punt CJA, van Coevorden F, et al: Radiofrequency ablation combined with chemotherapy for unresectable colorectal liver metastases: Long-term survival results of a randomized phase II study of the EORTCNCRI CCSG-ALM Intergroup 40004 (CLOCC). 2015 ASCO Annual Meeting.

Abstract 3501. Presented May 29, 2015.

2. Gibbs P, Heinemann V, Sharma NK, et al: SIRFLOX: Randomized phase III trial comparing first-line mFOLFOX6 ± bevacizumab versus mFOLFOX6 ± selective internal radiation therapy ± bevacizumab in patients with metastatic colorectal cancer. 2015 ASCO Annual Meeting. Abstract 3502. Presented May 29, 2015.

The ASCO Post | SEPTEMBER 10, 2015

PAGE 16

Best of ASCO® Genitourinary Cancer

Optimal Timing of Hormonal Therapy for Biochemically Recurrent Prostate Cancer Remains Unclear

By Alice Goodman

T

here is no consensus as to whether it is better to treat immediately or to delay androgen-deprivation therapy in patients with a rising prostate-specific antigen (PSA) level (“biochemical relapse”) after curative therapy for prostate cancer. A phase III study, selected for the Best of ASCO® 2015, found that immediate androgen-deprivation therapy improved overall survival and time to clinical disease progression, but the results were not definitive.

This trial has several issues that make it difficult to walk away with a firm conclusion, according to Terence W. Friedlander, MD, of the University of California, San Francisco, who reviewed this trial and its implications at the Best of ASCO 2015.

py or metastasis or symptoms.

Only one-third of the planned accrual occurred, with 293 patients enrolled from September 2004 to July 2012.

Median follow-up was 5 years. Most patients had slowly progressing disease, and about two-thirds of each arm went on intermittent therapy.

Patients were randomized in a 1:1 ratio to receive immediate intervention with androgen-deprivation therapy (arm B) or delayed therapy (arm A).

About one-third of patients in arm A initiated androgen-deprivation therapy within 2 years, whereas 49% started therapy later than 4 years on trial or had not yet begun therapy.

The mean age was about 70 years at trial initiation. About two-thirds of

This study is not practice-changing.

When faced with a patient with a rising PSA following curative therapy, the physician should discuss therapeutic options incorporating the risks of treatment.

—Terence W. Friedlander, MD

Study Details About 20% to 50% of patients will relapse following definitive therapy for prostate cancer. The Timing of AndrogenDeprivation Therapy in Prostate Cancer Patients With a Rising PSA (TOAD) study sought to address the optimal timing of androgen-deprivation therapy in this setting. Men were eligible for the trial if they had a PSA doubling time of less than 12 months following curative thera-

Vitamin D and Aspirin continued from page 15

of which 1,172 (19.2%) were attributed to colorectal cancer. Among nonexposed patients, 7,595 deaths (38.9%) were recorded, of which 6,356 (33.5%) were colorectal cancer–specific. An adjusted multivariate analysis found that aspirin exposure after diagnosis of colorectal cancer was an independent risk factor associated with improved colorectal cancer–specific and overall survival (P < .001 for both ­comparisons).

Dr. Haller cited the following

patients had curative radiation therapy, and about one-third underwent surgery plus radiation as curative therapy. The relapse-free interval was less than 10 months in about one-third of patients and 10 months or longer in two-thirds.

Survival Data and Toxicity At 5 years, overall survival was about 10% higher if androgen-deprivation therapy was started immediately: 86% strengths of this study: a large population, unselected patients, high-quality validated data, complete follow-up data, no recall bias, and no lead-time bias. Study limitations are that the dose and duration of aspirin treatment are not known, and there are no data on toxicities.

Remaining questions on the use of aspirin are its optimal dose and duration and identification of molecular markers for which patients will benefit.

“The majority of studies show a positive effect on colorectal cancer–specific survival and overall survival. I think the

Androgen-Deprivation Therapy for Recurrent Prostate Cancer ■■ Immediate initiation of androgen-deprivation therapy may have a survival advantage over delayed therapy in the setting of biochemical-only recurrence following curative radiation therapy, surgery, or both, according to the results of a large collaborative trial.

■■ However, these study findings are not definitive due to poor accrual and a heterogeneous patient base.

■■ The decision as to when to initiate androgen-deprivation therapy should be individualized, based on a discussion with the patient of risks vs benefits.

vs 76%, respectively; 6-year overall survival was 81% vs 65.4%, respectively (P = .05). Nonsignificant reductions were also observed in prostate cancer–specific deaths and deaths due to all causes.

Overall, 46 deaths were reported, including 30 deaths in the delayed-therapy arm and 16 deaths in the immediate-therapy arm. “There were only 18 prostate cancer deaths in this study—6 of these deaths were in the immediate [androgendeprivation therapy] arm and 10 were in the delayed arm. It is difficult to interpret these data to know if this is a real difference,” Dr. Friedlander commented.

Progression-free survival (both distant and local) was improved with immediate therapy (P = .001) compared with delayed therapy. However, time to castration resistance did not differ between the two study arms.

A subgroup analysis suggested that intermittent androgen-deprivation therapy might be superior to continuous androgen-deprivation therapy. However, due to poor accrual, the study was underpowered to detect a difference in this and other secondary endpoints.

Adverse events related to androgendeprivation therapy were more common answer to whether aspirin should be used is a resounding yes,” he said.

Results of two ongoing trials are awaited: CLEAR (Alliance 80702 trial) in stage III colorectal cancer, which has a 2 × 2 factorial design: 3 vs 6 months of adjuvant FOLFOX (leucovorin, fluorouracil, and oxaliplatin) with or without celecoxib for 3 years; and the British Add-Aspirin trial, a randomized, double-blind, placebocontrolled trial after survival in nonmetastatic colorectal cancer. n Disclosure: Dr. Haller reported no potential conflicts of interest.

in the immediate-therapy arm than in the delayed-therapy arm: 80% vs 50%.

‘Not Practice-Changing’ “This was a challenging trial to conduct, and accrual was disappointing. It appears that overall survival may be improved by immediate vs delayed initiation of androgen-deprivation therapy, but the benefits are likely to be modest and have to be balanced with the considerable side effects of hormonal treatment,” stated Dr. Friedlander.

“This study is not practice-changing.

When faced with a patient with a rising PSA following curative therapy, the physician should discuss therapeutic options incorporating the risks of treatment,” he said. The way forward will depend on finding better ways to identify which patients need androgendeprivation therapy upfront and which ones can safely delay it. n Disclosure: Dr. Friedlander reported no potential conflicts of interest.

Reference 1. Duchesne et al: 2015 ASCO Annual Meeting. Abstract 5007. Presented May 29, 2015.

References 1. Ng K, Venook AP, Sato K, et al: Vitamin D status and survival of metastatic colorectal cancer patients: Results from CALGB/SWOG 80405 (Alliance). 2015 ASCO Annual Meeting. Abstract 3503. Presented May 29, 2015.

2. Bains S, Mahic M, Cvancarova M, et al: Impact of aspirin as secondary prevention in an unselected cohort of 25,644 patients with colorectal cancer: A population-based study. 2015 ASCO Annual Meeting. Abstract 3504. Presented May 29, 2015.

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Best of ASCO® Breast Cancer

Role of Surgery and Adjuvant Radiotherapy in the Treatment of Breast Cancer Explored

By Alice Goodman

T

wo separate retrospective studies have further refined our understanding of the respective contributions of surgery and radiotherapy in the treatment of breast cancer. However, these studies are not definitive, and “gold standard” trials are needed to arrive at definitive recommendations. Both abstracts were presented at the 2015 ASCO Annual Meeting and were discussed at the Best of ASCO® 2015 by Steven Isakoff, MD, of Massachusetts General Hospital, Boston.

A retrospective review of a large database suggested that surgery improves survival in intermediate- and high-grade ductal carcinoma in situ but does not affect survival in low-grade ductal carcinoma in situ. It may be possible to forgo surgery in low-grade ductal carcinoma in situ, but further prospective study is needed.

A retrospective meta-analysis found that adding adjuvant radiation therapy to neoadjuvant treatment improves outcomes in women with operable and nonoperable breast cancer, regardless of whether they achieve pathologic complete response to neoadjuvant therapy. In that study, women with and without pathologic complete response who did not receive radiation therapy had worse outcomes.

Surgical Management of Ductal Carcinoma in Situ Widespread use of mammography has led to increased detection of ductal carcinoma in situ. Currently, about 60,000 new cases of ductal carcinoma in situ are reported each year in the United States. An estimated 40% to 85% of these cases are low grade.

Current management of ductal carcinoma in situ is lumpectomy with radiation or mastectomy. The magnitude of the survival benefit of surgery in ductal carcinoma in situ is not well known. ­Yasuaki Sagara, MD, Research Fellow in Surgery at Brigham and Women’s Hospital in Boston, and coauthors designed a study to explore whether surgical management improves survival in women

with low-grade ductal carcinoma in situ.

The study was based on more than 96,000 cases of ductal carcinoma in situ entered in the Surveillance, Epidemiology, and End Results (SEER) database between 1988 and 2011. Of them, 57,000 cases met the inclusion criteria; 56,053 cases (98%) were managed surgically, and, for various reasons, 1,169 (2%) did not undergo surgery. These two cohorts of patients were compared.

cancer–specific survival in the high-grade group favoring surgery,” said Dr. Isakoff.

“We perform surgery in ductal carcinoma in situ to exclude the presence of invasive cancer and to reduce the likelihood of developing invasive cancer. At the time of surgery, about 20% to 25% of patients with ductal carcinoma in situ are upstaged. Radiotherapy after surgery reduces the risk of invasive recurrence in low-grade ductal carcinoma in situ

There is a linear path from ductal carcinoma in situ to increased risk of invasive cancer and then increased risk of mortality.

—Steven Isakoff, MD

The authors found that nonsurgically managed patients had a higher proportion of low-grade ductal carcinoma in situ and did not receive radiation therapy. Those treated with surgery were more likely to have high-grade ductal carcinoma in situ and to receive radiation therapy.

At a median follow-up of 72 months, 576 breast cancer–specific deaths (1%) were reported; 3,600 deaths from other causes (6.4%) were also reported.

Overall, surgically managed patients had significantly improved 10-year breast cancer–specific survival compared with the nonsurgical group: 98% vs 93%, respectively (P < .001). Overall survival was 89% vs 83%, respectively. Nuclear grade was associated with a survival benefit in the surgery group (P = .0003).

“The main message of this study is that there was no difference in 10-year breast cancer–specific survival for low-grade ductal carcinoma in situ patients who did or did not have surgery. These are relatively small numbers, but there is no discernible difference. But there is a difference in breast

Potential Benefits of Surgery and Adjuvant Radiotherapy ■■ Surgery appears to improve survival in high- and intermediate-risk ductal carcinoma in situ, but outcomes are similar for low-risk ductal carcinoma in situ with or without surgery.

■■ Adjuvant radiotherapy appears to improve locoregional control and disease-free survival regardless of whether pathologic complete response is achieved with neoadjuvant therapy.

from 30% to 12%; 7.5% of recurrences in low- or intermediate-stage patients are actually invasive cancer. There is a linear path from ductal carcinoma in situ to increased risk of invasive cancer and then increased risk of mortality,” he continued.

An ongoing, prospective, randomized trial is currently addressing the issue of whether low-risk ductal carcinoma in situ can be safely treated without surgery.

Called LORIS, the study is comparing surgery vs active monitoring in patients with low-risk ductal carcinoma in situ.

Radiotherapy Post Neoadjuvant Therapy It is controversial whether to incorporate response to neoadjuvant therapy into decision-making regarding the addition of adjuvant radiotherapy for patients with breast cancer. A pooled analysis of three GEPAR trials (GeparTrio, GeparQuattro, and GeparQuinto) was undertaken to address this question.

“Local recurrence rates after neoadjuvant and adjuvant chemotherapy have been shown to be similar if adequate local therapy is performed. Treatment response to neoadjuvant therapy is considered prognostic,” Dr. Isakoff told listeners.

The study, which was reported at the 2015 ASCO Annual Meeting by ­David Krug, MD, of the University Hospital, Heidelberg, Germany, suggests that adjuvant radiotherapy should be added regardless of whether patients achieve

pathologic complete response or not.

The pooled analysis included 3,370 patients with operable and nonoperable breast cancer for whom there were available data on the use of radiotherapy (57% of a total of 5,780 patients). Locoregional recurrence was defined as recurrence in the breast, chest wall, or regional lymph nodes.

At a median follow-up of 50.3 months, the overall recurrence rate was 8.8%. Five-year locoregional recurrencefree survival was 89.6% with radiotherapy vs 81.8% without (P < .004). Fiveyear disease-free survival was 74.5% vs 66.7%, respectively (P = .087).

“The top-line result is the general benefit of radiotherapy in locoregional recurrence and disease-free survival,” Dr. Isakoff said. “It gets more interesting when you look at subgroup results. Patients with pathologic complete response still had improvements with radiotherapy, and there was also an improvement with radiotherapy in patients who did not achieve pathologic complete response. The greatest benefit was observed in patients who had pathologic complete response and were node-negative after neoadjuvant therapy.”

For those who achieved pathologic complete response, 5-year locoregional recurrence-free survival was 94.7% with radiotherapy vs 85.8% without (P = .043); 5-year disease-free survival was 86.0% vs 60.3%, respectively (P = .004).

For those without pathologic complete response, 5-year locoregional recurrence-free survival was 88.4% with radiotherapy vs 81.1% without radiotherapy (P = .030); 5-year disease-free survival was 71.7% vs 67.4%, respectively (P = .519).

Multivariate analysis adjusted for baseline parameters, tumor stage, and pathologic complete response showed that radiotherapy was an independent risk factor for locoregional recurrencefree survival (P = .038) but not for disease-free survival (P = .728).

“Radiotherapy is an independent prognostic factor for locoregional recurrence and disease-free survival after neoadjuvant therapy. We still don’t know which patients can avoid radiotherapy.

We have to take these data with a grain of salt. Information on radiotherapy was available for only 57% of patients in these three trials. The three studies had different characteristics, making cross-study continued on page 20

• Infections: In Study 1, 1% of XTANDI patients compared to 0.3% of placebo patients died from infections or sepsis. In Study 2, 1 patient in each treatment group (0.1%) had an infection resulting in death.

• Falls (including fall-related injuries), occurred in 9% of XTANDI patients and 4% of placebo patients. Falls were not associated with loss of consciousness or seizure. Fall-related injuries were more severe in XTANDI patients, and included non-pathologic fractures, joint injuries, and hematomas.

• Hypertension occurred in 11% of XTANDI patients and 4% of placebo patients. No patients experienced hypertensive crisis.

Medical history of hypertension was balanced between arms.

Hypertension led to study discontinuation in< 1% of all patients.

Drug Interactions

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

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Effect of XTANDI on Other Drugs

Avoid CYP3A4, CYP2C9, and CYP2C19 substrates with a narrow therapeutic index, as XTANDI may decrease the plasma exposures of these drugs. If XTANDI is co-administered with warfarin (CYP2C9 substrate), conduct additional INR monitoring.

Please see adjacent pages for Brief Summary of Full Prescribing Information.

·i-As seen in the PREVAIL trial (Study 2): a multinational, double-blind, randomized, phase 3 trial that enrolled 1717 patients with metastatic CRPC that progressed on GnRH therapy or after bilateral orchiectomy, and who had not received prior cytotoxic chemotherapy. All patients continued on GnRH therapy.1• §Results from this analysis were consistent with those from the prespecified interim analysis. llln the PREVAIL trial, 27% of patients in the XTANDI arm and 30% of patients in the placebo arm received glucocorticoids for varying reasons. In the AFFIRM trial (Study 1), 48% of patients in the XTANDI arm and 4 6% of patients in the placebo arm received glucocorticoids. AFFIRM was a phase 3, multicenter, placebo-controlled, randomized trial that enrolled 1199 patients with metastatic CRPC who had previously received docetaxel.1 2

References: 1. XTANDI [package insert]. Northbrook, IL: Astellas Pharma US, Inc. 2. Beer TM, Armstrong AJ, Rathkopf DE, et al, for the PREVAIL Investigators.

Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med. 2014;371:424-433. 3. Data on file, Medivation, Inc.

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Best of ASCO® Breast Cancer Treatment continued from page 17

comparisons difficult,” Dr. Isakoff stated.

Additionally, the no-radiation group in the mastectomy patients included only 151 patients. A multivariate analysis found that radiotherapy also predicted locoregional recurrence in these patients but not disease-free survival.

An ongoing NSABP/RTOG study should shed more light on this issue.

That study includes patients with positive lymph nodes before treatment who undergo randomization to receive postmastectomy radiotherapy or not or—in the case of breast-conserving surgery— to whole-breast irradiation with or without regional nodal irradiation.

XTANDI® (enzalutamide) capsules for oral use Initial U.S. Approval: 2012 BRIEF SUMMARY OF PRESCRIBING INFORMATION The following is a brief summary. Please see the package insert for full prescribing information.

INDICATIONS AND USAGE XTANDI is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC).

CONTRAINDICATIONS Pregnancy XTANDI can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. XTANDI is not indicated for use in women. XTANDI is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss.

WARNINGS AND PRECAUTIONS Seizure In Study 1, which enrolled patients who previously received docetaxel, 7 of 800 (0.9%) patients treated with XTANDI experienced a seizure and no patients treated with placebo experienced a seizure. Seizure occurred from 31 to 603 days after initiation of XTANDI. In Study 2, 1 of 871 (0.1%) chemotherapy-naive patients treated with XTANDI and 1 of 844 (0.1%) patients treated with placebo experienced a seizure. Patients experiencing seizure were permanently discontinued from therapy and all seizure events resolved. There is no clinical trial experience re-administering XTANDI to patients who experienced seizure.

Limited safety data are available in patients with predisposing factors for seizure because these patients were generally excluded from the trials. These exclusion criteria included a history of seizure, underlying brain injury with loss of consciousness, transient ischemic attack within the past 12 months, cerebral vascular accident, brain metastases, and brain arteriovenous malformation. Study 1 excluded the use of concomitant medications that may lower the seizure threshold, whereas Study 2 permitted the use of these medications.

Because of the risk of seizure associated with XTANDI use, patients should be advised of the risk of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others. Permanently discontinue XTANDI in patients who develop a seizure during treatment.

Posterior Reversible Encephalopathy Syndrome (PRES) There have been reports of posterior reversible encephalopathy syndrome (PRES) in patients receiving XTANDI [see Adverse Reactions (6.2)]. PRES is a neurological disorder which can present with rapidly evolving symptoms including seizure, headache, lethargy, confusion, blindness, and other visual and neurological disturbances, with or without associated hypertension.

A diagnosis of PRES requires confirmation by brain imaging, preferably magnetic resonance imaging (MRI).

Discontinue XTANDI in patients who develop PRES. ADVERSE REACTIONS Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Two randomized clinical trials enrolled patients with metastatic prostate cancer that has progressed on androgen deprivation therapy (GnRH therapy or bilateral orchiectomy), a disease setting that is also defined as metastatic CRPC. In both studies, patients received XTANDI 160 mg orally once daily in the active treatment arm or placebo in the control arm. All patients continued androgen deprivation therapy. Patients were allowed, but not required, to take glucocorticoids.

The most common adverse reactions (≥ 10%) that occurred more commonly (≥ 2% over placebo) in the

“This study should help decide which patients should be treated with radiotherapy and whether radiotherapy can be avoided if the patient achieves pathologic complete response after neoadjuvant therapy,” he said.

“The data from the GEPAR meta-analysis suggest that at the moment, treatment should be based on prechemotherapy XTANDI-treated patients from the two randomized clinical trials were asthenia/fatigue, back pain, decreased appetite, constipation, arthralgia, diarrhea, hot flush, upper respiratory tract infection, peripheral edema, dyspnea, musculoskeletal pain, weight decreased, headache, hypertension, and dizziness/vertigo.

Study 1: Metastatic Castration-Resistant Prostate Cancer Following Chemotherapy Study 1 enrolled 1199 patients with metastatic CRPC who had previously received docetaxel. The median duration of treatment was 8.3 months with XTANDI and 3.0 months with placebo. During the trial, 48% of patients on the XTANDI arm and 46% of patients on the placebo arm received glucocorticoids.

Grade 3 and higher adverse reactions were reported among 47% of XTANDI-treated patients and 53% of placebo-treated patients. Discontinuations due to adverse events were reported for 16% of XTANDI-treated patients and 18% of placebo-treated patients. The most common adverse reaction leading to treatment discontinuation was seizure, which occurred in 0.9% of the XTANDI-treated patients compared to none (0%) of the placebo-treated patients. Table 1 shows adverse reactions reported in Study 1 that occurred at a ≥ 2% higher frequency in the XTANDI arm compared to the placebo arm.

Table 1. Adverse Reactions in Study 1 XTANDI Placebo N = 800 N = 399 Grade Grade Grade Grade a 3-4 1-4 3-4 1-4 (%) (%) (%) (%) General Disorders Asthenic 50.6 9.0 44.4 9.3 Conditionsb Peripheral 15.4 1.0 13.3 0.8 Edema Musculoskeletal And Connective Tissue Disorders Back Pain 26.4 5.3 24.3 4.0 Arthralgia 20.5 2.5 17.3 1.8 Musculoskeletal 15.0 1.3 11.5 0.3 Pain Muscular 9.8 1.5 6.8 1.8 Weakness Musculoskeletal 2.6 0.3 0.3 0.0 Stiffness Gastrointestinal Disorders Diarrhea 21.8 1.1 17.5 0.3 Vascular Disorders Hot Flush 20.3 0.0 10.3 0.0 Hypertension 6.4 2.1 2.8 1.3 Nervous System Disorders Headache 12.1 0.9 5.5 0.0 Dizzinessc 9.5 0.5 7.5 0.5 Spinal Cord Compression and Cauda 7.4 6.6 4.5 3.8 Equina Syndrome Paresthesia 6.6 0.0 4.5 0.0 Mental Impairment 4.3 0.3 1.8 0.0 Disordersd Hypoesthesia 4.0 0.3 1.8 0.0 Infections And Infestations Upper Respiratory 10.9 0.0 6.5 0.3 Tract Infectione Lower Respiratory 8.5 2.4 4.8 1.3 Tract And Lung Infectionf Psychiatric Disorders Insomnia 8.8 0.0 6.0 0.5 Anxiety 6.5 0.3 4.0 0.0 Renal And Urinary Disorders Hematuria 6.9 1.8 4.5 1.0 Pollakiuria 4.8 0.0 2.5 0.0 Injury, Poisoning And Procedural Complications Fall 4.6 0.3 1.3 0.0 Non-pathologic 4.0 1.4 0.8 0.3 Fractures Skin And Subcutaneous Tissue Disorders Pruritus 3.8 0.0 1.3 0.0 Dry Skin 3.5 0.0 1.3 0.0

characteristics,” Dr. Isakoff commented. n

Disclosure: Drs. Sagara and Isakoff reported no potential conflicts of interest. Dr. Krug has received travel expenses from Accuray.

References 1. Sagara Y, et al: 2015 ASCO Annual Meeting. Abstract 1006. Presented May 29, 2015.

2. Krug D, et al: 2015 ASCO Annual Meeting. Abstract 1008. Presented May 29, 2015.

Table 1. Adverse Reactions in Study 1 (cont.)

Respiratory Disorders Epistaxis 3.3 0.1 1.3

0.3

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

Study 2: Chemotherapy-naive Metastatic CastrationResistant Prostate Cancer Study 2 enrolled 1717 patients with metastatic CRPC who had not received prior cytotoxic chemotherapy, of whom 1715 received at least one dose of study drug. The median duration of treatment was 17.5 months with XTANDI and 4.6 months with placebo. Grade 3-4 adverse reactions were reported in 44% of XTANDI-treated patients and 37% of placebo-treated patients.

Discontinuations due to adverse events were reported for 6% of XTANDI-treated patients and 6% of placebo-treated patients.

The most common adverse reaction leading to treatment discontinuation was fatigue/asthenia, which occurred in 1% of patients on each treatment arm. Table 2 includes adverse reactions reported in Study 2 that occurred at a ≥ 2% higher frequency in the XTANDI arm compared to the placebo arm.

Table 2. Adverse Reactions in Study 2 Placebo XTANDI N = 844 N = 871 Grade Grade Grade Grade 1-4 3-4 3-4 1-4a (%) (%) (%) (%) General Disorders Asthenic 33.0 46.9 3.4 2.8 Conditionsb Peripheral 8.2 11.5 0.2 0.4 Edema Musculoskeletal And Connective Tissue Disorders 22.4 Back Pain 28.6 2.5 3.0 16.1 Arthralgia 21.4 1.6 1.1 Gastrointestinal Disorders 17.3 Constipation 23.2 0.7 0.4 14.3 Diarrhea 16.8 0.3 0.4 Vascular Disorders 7.8 Hot Flush 18.0 0.1 0.0 4.1 Hypertension 14.2 7.2 2.3 Nervous System Disorders 7.1 11.3 0.3 0.0 Dizzinessc 7.0 Headache 11.0 0.2 0.4 3.7 Dysgeusia 7.6 0.1 0.0 Mental 1.3 5.7 0.0 0.1 Impairment Disordersd Restless Legs 0.4 2.1 0.1 0.0 Syndrome Respiratory Disorders 8.5 11.0 0.6 0.6 Dyspneae Infections And Infestations Upper 10.5 0.0 0.0 Respiratory Tract 16.4 Infectionf Lower Respiratory 4.7 7.9 1.5 1.1 Tract And Lung Infectiong Psychiatric Disorders 5.7 Insomnia 8.2 0.1 0.0 Renal And Urinary Disorders 5.8 Hematuria 8.8 1.3 1.3 Injury, Poisoning And Procedural Complications 5.3 Fall 12.7 1.6 0.7 Non-Pathological 3.0 8.8 2.1 1.1 Fracture Metabolism and Nutrition Disorders Decreased 16.4 18.9 0.3 0.7 Appetite Investigations Weight 8.5 12.4 0.8 0.2 Decreased Reproductive System and Breast Disorders 1.4 Gynecomastia 3.4 0.0 0.0

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Best of ASCO® Head/Neck Cancer

HPV16 DNA in Post-Treatment Oral Rinses Signals Poor Prognosis in Oropharyngeal Cancer

By Alice Goodman

D

etectable oral HPV16 DNA in oral rinses post treatment for oropharyngeal cancer appears to be Table 2. Adverse Reactions in Study 2 (cont.)

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

Laboratory Abnormalities In the two randomized clinical trials, Grade 1-4 neutropenia occurred in 15% of patients treated with XTANDI (1% Grade 3-4) and in 6% of patients treated with placebo (0.5% Grade 3-4). The incidence of Grade 1-4 thrombocytopenia was 6% of patients treated with XTANDI (0.3% Grade 3-4) and 5% of patients treated with placebo (0.5% Grade 3-4). Grade 1-4 elevations in ALT occurred in 10% of patients treated with XTANDI (0.2% Grade 3-4) and 16% of patients treated with placebo (0.2% Grade 3-4). Grade 1-4 elevations in bilirubin occurred in 3% of patients treated with XTANDI (0.1% Grade 3-4) and 2% of patients treated with placebo (no Grade 3-4).

Infections In Study 1, 1% of patients treated with XTANDI compared to 0.3% of patients treated with placebo died from infections or sepsis. In Study 2, 1 patient in each treatment group (0.1%) had an infection resulting in death.

Falls and Fall-related Injuries In the two randomized clinical trials, falls including fallrelated injuries, occurred in 9% of patients treated with XTANDI compared to 4% of patients treated with placebo.

Falls were not associated with loss of consciousness or seizure. Fall-related injuries were more severe in patients treated with XTANDI and included non-pathologic fractures, joint injuries, and hematomas.

Hypertension In the two randomized trials, hypertension was reported in 11% of patients receiving XTANDI and 4% of patients receiving placebo. No patients experienced hypertensive crisis. Medical history of hypertension was balanced between arms. Hypertension led to study discontinuation in < 1% of patients in each arm.

Post-Marketing Experience The following additional adverse reactions have been identified during post approval use of XTANDI. Because these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure.

Neurological Disorders: posterior reversible encephalopathy syndrome (PRES) DRUG INTERACTIONS Drugs that Inhibit or Induce CYP2C8 Co-administration of a strong CYP2C8 inhibitor (gemfibrozil) increased the composite area under the plasma concentration-time curve (AUC) of enzalutamide plus N-desmethyl enzalutamide by 2.2-fold in healthy volunteers. Co-administration of XTANDI with strong CYP2C8 inhibitors should be avoided if possible.

If co-administration of XTANDI with a strong CYP2C8 inhibitor cannot be avoided, reduce the dose of XTANDI. The effects of CYP2C8 inducers on the pharmacokinetics of enzalutamide have not been evaluated in vivo. Coadministration of XTANDI with strong or moderate CYP2C8 inducers (e.g., rifampin) may alter the plasma exposure of XTANDI and should be avoided if possible.

Selection of a concomitant medication with no or minimal CYP2C8 induction potential is recommended.

Drugs that Inhibit or Induce CYP3A4 Co-administration of a strong CYP3A4 inhibitor (itraconazole) increased the composite AUC of enzalutamide plus N-desmethyl enzalutamide by 1.3-fold in healthy volunteers.

The effects of CYP3A4 inducers on the pharmacokinetics of enzalutamide have not been evaluated in vivo. Coadministration of XTANDI with strong CYP3A4 inducers (e.g., carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine) may decrease the plasma exposure of XTANDI and should be avoided if possible. Selection of a concomitant medication with no or minimal CYP3A4 induction potential is recommended. Moderate CYP3A4 inducers (e.g., bosentan, efavirenz, etravirine, modafinil, nafcillin) and St. John’s Wort may also reduce the plasma

a harbinger of poor prognosis and can predict recurrence. Oral HPV16 DNA rinses are a potential tool for

long-term tumor surveillance, according to a study selected for the Best of ASCO® 2015.1

exposure of XTANDI and should be avoided if possible.

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

disease have not been assessed.

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

USE IN SPECIFIC POPULATIONS

OVERDOSAGE

Pregnancy- Pregnancy Category X. Risk Summary XTANDI can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. While there are no human data on the use of XTANDI in pregnancy and XTANDI is not indicated for use in women, it is important to know that maternal use of an androgen receptor inhibitor could affect development of the fetus. Enzalutamide caused embryo-fetal toxicity in mice at exposures that were lower than in patients receiving the recommended dose. XTANDI is contraindicated in women who are or may become pregnant while receiving the drug. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss. Advise females of reproductive potential to avoid becoming pregnant during treatment with XTANDI. Animal Data In an embryo-fetal developmental toxicity study in mice, enzalutamide caused developmental toxicity when administered at oral doses of 10 or 30 mg/kg/day throughout the period of organogenesis (gestational days 6-15). Findings included embryo-fetal lethality (increased post-implantation loss and resorptions) and decreased anogenital distance at ≥ 10 mg/kg/day, and cleft palate and absent palatine bone at 30 mg/kg/day. Doses of 30 mg/kg/day caused maternal toxicity. The doses tested in mice (1, 10 and 30 mg/kg/day) resulted in systemic exposures (AUC) approximately 0.04, 0.4 and 1.1 times, respectively, the exposures in patients. Enzalutamide did not cause developmental toxicity in rabbits when administered throughout the period of organogenesis (gestational days 6-18) at dose levels up to 10 mg/kg/ day (approximately 0.4 times the exposures in patients based on AUC).

Nursing Mothers XTANDI is not indicated for use in women. It is not known if enzalutamide is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from XTANDI, a decision should be made to either discontinue nursing, or discontinue the drug taking into account the importance of the drug to the mother.

Pediatric Use Safety and effectiveness of XTANDI in pediatric patients have not been established.

Geriatric Use Of 1671 patients who received XTANDI in the two randomized clinical trials, 75% were 65 and over, while 31% were 75 and over. No overall differences in safety or effectiveness were observed between these patients and younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Patients with Renal Impairment A dedicated renal impairment trial for XTANDI has not been conducted. Based on the population pharmacokinetic analysis using data from clinical trials in patients with metastatic CRPC and healthy volunteers, no significant difference in enzalutamide clearance was observed in patients with pre-existing mild to moderate renal impairment (30 mL/min ≤ creatinine clearance [CrCL] ≤ 89 mL/min) compared to patients and volunteers with baseline normal renal function (CrCL ≥ 90 mL/min).

No initial dosage adjustment is necessary for patients with mild to moderate renal impairment. Severe renal impairment (CrCL < 30 mL/min) and end-stage renal

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

“The goal is to identify progressors early enough to intervene therapeutically. Persistent human papillomavirus (HPV) DNA is infrequent in oral rinses post treatment, but when it is present, it signals reinfection and is a useful marker for recurrence as well as survival,” said Robert L. Ferris, MD, PhD, University of Pittsburgh Cancer Institute, who discussed this study at the Best of ASCO ® 2015.

NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal studies have not been conducted to evaluate the carcinogenic potential of enzalutamide.

Enzalutamide did not induce mutations in the bacterial reverse mutation (Ames) assay and was not genotoxic in either the in vitro mouse lymphoma thymidine kinase (Tk) gene mutation assay or the in vivo mouse micronucleus assay.

Based on nonclinical findings in repeat-dose toxicology studies, which were consistent with the pharmacological activity of enzalutamide, male fertility may be impaired by treatment with XTANDI. In a 26-week study in rats, atrophy of the prostate and seminal vesicles was observed at ≥ 30 mg/kg/day (equal to the human exposure based on AUC). In 4-, 13-, and 39-week studies in dogs, hypospermatogenesis and atrophy of the prostate and epididymides were observed at ≥ 4 mg/kg/day (0.3 times the human exposure based on AUC).

Manufactured by: Catalent Pharma Solutions, LLC, St. Petersburg, FL 33716 Manufactured for and Distributed by: Astellas Pharma US, Inc., Northbrook, IL 60062 Marketed by: Astellas Pharma US, Inc., Northbrook, IL 60062 Medivation, Inc., San Francisco, CA 94105 Revised: August 2015 14L082-XTA Rx Only © 2015 Astellas Pharma US, Inc. XTANDI® is a registered trademark of Astellas Pharma Inc.

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Persistent human papillomavirus DNA is infrequent in oral rinses post treatment, but when it is present, it signals reinfection and is a useful marker for recurrence as well as survival.

—Robert L. Ferris, MD, PhD

There are two distinct types of head and neck cancer: carcinogenexposed and HPV-associated cancer.

The incidence of HPV head and neck cancer has increased dramatically over the past few decades, and it is now the cause of the vast majority of oropharyngeal cancers.

HPV oropharyngeal cancers have distinct clinical and biologic characteristics. “The prognosis is uniquely good, with about an 80% long-term survival.

About 10% to 25% progress within 2 years of first-line treatment. HPV oropharyngeal cancers have a favorable response to all types of salvage therapy,” he said.

HPV16 DNA (the type of HPV most responsible for 95% of oropharyngeal cancers) is detectable in oral rinses but only in up to two-thirds of patients. continued on page 22

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Study Details

The study enrolled 124 patients with HPV-associated oropharyngeal cancer treated with curative intent at four different centers from October 2009 to May 2013. Oral rinses were collected at baseline after diagnosis and at 9, 12, 18, and 24 months post treatment.

Ninety percent of the patients were male, 58% were never smokers, 85% were married at diagnosis, 65% had small tumors, and 70% had advanced nodal status.

At baseline, 67 patients (54%) had evidence of HPV16 in their oral rinses. Post treatment, persistent HPV16 was detected in five patients (4%) and newly detected HPV16 was found in one patient (1%). Ninetythree percent of patients were cleared of oral HPV16.

HPV typically recurs within 4

years, Dr. Ferris explained. At 33 months of follow-up, there were 14 recurrences and 6 deaths; 2-year disease-free survival was 92%, and 2-year overall survival was 98%.

Prognostic Implications The presence of HPV16 DNA post treatment was strongly associated with survival. All five patients with persistent HPV16 DNA died.

The five patients with persistent HPV16 all had recurrences; three of them died of oropharyngeal cancer.

Three patients had local recurrence, one patient had distant recurrence alone, and one patient had local and distant recurrences. The median time to first post-treatment recurrence was 7 months.

The specificity of detectable HPV16 DNA in oral rinses was 100%.

“When patients had it, they recurred.

The specificity for the test was 43%.

Some recurrences were not associ-

HPV16 DNA and Recurrent Oropharyngeal Cancer ■■ The persistence of HPV16 DNA in oral rinses post treatment is infrequent but strongly predictive for recurrence of oropharyngeal cancer, particularly local recurrence.

■■ Persistent oral HPV16 DNA (from diagnosis to post treatment) in oral rinses predicts disease-free survival and overall survival.

■■ Pretreatment oral HPV16 DNA does not appear to be a useful marker for recurrence.

■■ Detectable HPV16 DNA in post-treatment oral rinses may be useful for longterm monitoring of patients with HPV-positive oropharyngeal cancer.

ated with detectable HPV16 DNA,” Dr. Ferris told listeners.

In this study, post-treatment specimens were not collected during the first 9 months after diagnosis. Dr. Ferris questioned whether the presence of HPV16 DNA in oral rinses reflected persistent infection or reinfection.

In addition, other issues are that reproducible results were not confirmed before treatment and the rea-

sons for new infection are unclear. n Disclosure: Dr. Ferris reported no potential conflicts of interest.

Reference 1. Rettig EM, Wentz A, Posner MR, et al: Prognostic implication of persistent HPV16 DNA detection in oral rinses for HPV-positive oropharyngeal carcinoma.

2015 ASCO Annual Meeting. Abstract 6005. Presented May 29, 2015.

Announcements

IPOS Announces 2015 Award Winners at the World Congress of Psycho-Oncology

T

he International Psycho-Oncology Society (IPOS) announced four award winners at the 2015 World Congress of Psycho-Oncology, held July 28 to August 1 in Washington, DC.

Arthur M. Sutherland Award: William H. Redd, PhD Dr. Redd is Professor of Oncological Sciences at the Mount Sinai Hospital.

He is credited with introducing behavioral psychology and behavioral medicine to oncology; he identified the role of respondent and operant conditioning in the development of cancer treatment side effects, recognizing the severe conditioned aversions patients can develop as they undergo their treatments. He then went on to develop distraction and other intervention techniques to help patients counter these conditioned effects.

Bernard Fox Memorial Award: Susanne O. Dalton, MD, PhD Dr. Dalton is a Senior Researcher in Survivorship Unit of the Danish Cancer Research Council, and conducts research primarily focusing on social inequality in cancer and on physical, psychological, and socioeconomic consequences of cancer. Since 2011,

William H. Redd, PhD

Susanne O. Dalton, MD, PhD

she has been head of the Research Group on Social Inequality in Survivorship. She leads a series of studies exploring issues of cancer among patients with mental illness, and in another series, delineated the roles of sociodemographic factors in cancer survivorship. Her work has contributed significantly to the evidence base highlighting social inequalities that can exist in cancer care and recovery.

Noemi Fishman Award for Lifetime Clinical Excellence: Andrew J. Roth, MD Since 2007, Dr. Roth has been the Training Program Director for the clinical psycho- oncology fellowship training program at Memorial Sloan Kettering Cancer Center. He has pio-

Katriina Whitaker, PhD, CPsychol

neered the field of prostate cancer psycho-­ oncology, being among the first psychiatrist in the world specializing primarily in the psychiatric and psychosocial problems of men with prostate cancer. Notably, Dr. Roth was in the team that developed the “Distress Thermometer,” now widely used as a tool to identify distress in patients with cancer. He has supervised and helped train over 100 clinical fellows in psycho-oncology.

Hiroomi Kawano New Investigator Award: Katriina Whitaker, PhD, CPsychol Dr. Whittaker is currently Senior Lecturer at the University of Surrey.

Her doctoral thesis involved a novel application of theoretical models from

Andrew J. Roth, MD

the study of anxiety disorders to investigate anxiety in cancer patients, establishing the importance of involuntary thoughts, memories, and images in explaining mood disorder in these patients, and identifying an additional role for negative appraisals by patients of these experiences. She demonstrated the clinical utility of this research by using a psychological intervention specifically targeted on these maintaining processes, reducing associated distress substantially. n

See pages 24 to 27 for more on the World ­Congress of Psycho-Oncology.

ASCOPost.com | SEPTEMBER 10, 2015

PAGE 23

Announcements

Three New Officers Elected to ASTRO’s Board of Directors

T

he American Society for Radiation Oncology (ASTRO) has elected three new officers to the Board of Directors and three members to serve on the Nominating Committee.

Terms for all positions begin on October 20, 2015 at ASTRO’s 57th Annual Meeting. The new officers to the Board of Directors are:

President-Elect: Brian D. ­Kavanagh, MD, MPH, FASTRO Dr. Kavanagh is Professor and Interim Chair of the Department of Radiation Oncology at the University of Colorado School of Medicine, Denver, and an attending physician at the University of Colorado Hospital. His service to ASTRO includes his current roles as Co-Chair of the Health Policy Committee and as the ASTRO Advisor to the American Medical Association/Specialty Society RVS Update Committee. He is currently CoDirector of the ASTRO-AANS Stereotactic Radiosurgery Registry, and he has served ASTRO as a member of the Board of Directors (2011–2015) and in multiple other leadership positions. His additional service has included the Center for Medicare and Medicaid Services’ Hospital Outpatient Payment Advisory Panel and the Ambulatory Payment Classification Advisory Panel, as well as a member of the National Comprehensive Cancer Network’s (NCCN) Policy Advisory Group.

Health Policy Council Vice-Chair: Michael R. Kuettel, MD, PhD, MBA, FASTRO Dr. Kuettel is Professor and Chair of the Department of Radiation Medicine and The Barbara C. and George H. Hyde Chair in Radiation Medicine at Roswell Park Cancer Institute and State University of New York at Buffalo; he is Professor, Department of Molecular and Cellular Biophysics at Roswell Park Cancer Institute. Dr. Kuettel is Clinical Director of Radiation Oncology at Kaleida Health System. His service to ASTRO includes his current roles as Co-Chair of the Health Policy Committee and as the ASTRO Advisor to the American Medical Association/Specialty Society RVS Update Committee.

Science Council Vice-Chair: ­Daniel Low, PhD Dr. Low is Professor in Radiation Oncology and Vice-Chair of Medical Physics in the Department of Radiation Oncology at the University of California, Los Angeles. He currently serves ­ ASTRO as a member of the Funding Advocacy

Brian D. Kavanagh,MD

Michael R. Kuettel, MD

Daniel Low, PhD

and Clinical Trials Committee, the Best Practices Subcommittee, and the Multidisciplinary Quality Assurance Subcommittee.

Nominating Committee The new Nominating Committee members are Quynh-Thu Le, MD, FASTRO, Stanford University; John W. Rieke, MD, MultiCare Regional Cancer Center; and Indrin J. Chetty, PhD, MS, Henry Ford Health System. n

In EGFRm+ advanced NSCLC,

NEARLY 2 OUT OF 3 CASES OF PROGRESSION WITH FIRSTGENERATION EGFR TKIs ARE RELATED TO THE T790M MUTATION1,2 Lung cancer is the leading cause of cancer-related deaths both in the US and worldwide.3,4 For NSCLC EGFRm+ patients, the recommended frst-line treatment is EGFR tyrosine kinase inhibitors (TKIs).5

The majority of tumors will acquire EGFR TKI–resistance mutations 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 | SEPTEMBER 10, 2015

PAGE 24

World Congress of Psycho-oncology Psychosocial Care

International Psycho-Oncology Society and American Psychosocial Oncology Society Meet to Foster Psychosocial Oncology Worldwide

By Margot J. Fromer

T

he International Psycho-Oncology Society (IPOS) has partnered with the American Psychosocial Oncology Society (APOS) for the 17th World Congress of Psycho-Oncology, held in late July 2015 in Washington, DC. Its theme, “From National to Global: Implementing the Standard of Psychosocial Care in Oncology,” described the awareness that psychosocial care has become a recognized subspecialty of cancer care in the United States and many other Western countries—but regrettably this is not the case in many countries in the rest of the world, notably Africa and South America.

Luzia Travado, PhD

IPOS recently celebrated its 30th anniversary, and its more then 7,000 professional federated members work in over 60 countries to “foster the science and practice of psychosocial oncology to improve the care of people affected by cancer worldwide,” according to ­Luzia Travado, PhD, President of IPOS.

as a Human Right. Furthermore, in 2015, IPOS added this declaration to its International Standards of Quality in Cancer Care, which now include: (1) Psychosocial cancer care should be recognized as a universal human right; (2) Quality cancer care must integrate the psychosocial domain into routine care; and (3) Distress should be measured as the sixth vital sign after temperature, blood pressure, pulse, respiratory rate, and pain. This standard has been endorsed by 75 organizations worldwide and, in 2013, was codified in a revision of the World Cancer Declaration.

Writing and approving a declaration are important, but it does not necessarily translate into easing the lives of actual patients with cancer, and the vast majority of them still suffer without significant help.

Dr. Travado, Head of Psycho-oncology at Champalimaud Cancer Center, Lisbon, acknowledged that the bulk of the work lies ahead. “We have worked hard to influence national cancer policies to include psychosocial care and have succeeded in many countries, but we need to continue to pursue this goal and take further steps to turn this standard into international global clinical practice worldwide.”

Children With Cancer

William Breitbart, MD

Michelle Corove Fingeret, PhD

APOS has 450 practitioners and scientists in psychiatry, psychology, social work, nursing, clergy, and patient advocacy in this country, said its President, Michelle Corove Fingeret, PhD.

The Lisbon Declaration The IPOS Human Rights Task Force has been working since 2008 to raise awareness and support for the relevance of psychosocial care as a human right. To that end, in November 2014, at the World Congress of Psycho-Oncology in Lisbon, the IPOS Board endorsed the Lisbon Declaration: Psychosocial Cancer Care

and a clean environment.) The Lisbon Declaration stresses the need to: • Strengthen health systems to increase effective cancer control • Reduce the stigma of cancer and dispel the many myths surrounding the disease • Establish universal access to screening and early detection • Improve access to services across the cancer care continuum for all patients and all family members, who also suffer • Ensure universal availability of pain control and distress management • Improve the education and training of health-care professionals “These commitments oblige governments to provide access, by means of relevant legislation, to psychosocial care for all cancer patients,” said Dr. Breitbart.

Even more, policymakers, in the health and political arenas, must be made to understand that palliative care is to be included as a critical component of cancer care—as important as screening, early detection, and active treatment. And beyond understanding of and agreement with the fundamental right to psychosocial care is the necessity to make sufficient funds available to carry out necessary implementation.

William Breitbart, MD, Chairman, Department of Psychiatry and Behavioral Sciences, Memorial Sloan Kettering Cancer Center, New York, said that at least half of all patients with cancer experience psychosocial distress at some time during the course of their illness, and it must be addressed.

The Lisbon Declaration, which follows on the heels of the World Health Organization’s declaration of the Right to Health, is considered a landmark document to advance the human rights of all patients with cancer, especially those in underserved areas. (The human Right to Health states that everyone has the right to the highest attainable standard of physical and mental health, which includes access to all medical services, sanitation, adequate food, decent housing, healthy working conditions,

Andrea Patenaude, PhD, Director of Psychology Research and Clinical Services, Center for Cancer Genetics and Prevention, Dana-Farber Cancer Institute, and Associate Professor of Psychology at Harvard Medical School, described the human rights challenges in Africa, especially those facing children with cancer and their families.

“In many parts of the world, it is standard to deny children with cancer the right to know their diagnosis, the treatments they will receive, their current health status, and the likely outcome of their disease. They are desperately in need of concurrent psychosocial care provided by a caring, trusted adult with whom young patients can discuss their feelings and fears about the disease, its treatment, and possible separation from family,” stated Dr. Patenaude.

Basic human rights to psychosocial care, palliative care, and pain and symptom control do not exist in many parts of the world.

Even worse are the countless examples of ethical mistreatment and downright cruelty. For example, Dr. Patenaude described what has happened at the Moi Hospital

Andrea Patenaude, PhD

in the Rift Valley Province of Kenya. “We have reports that approximately half of the children of families that do not have health insurance [78% of parents of children with cancer in a recent study did not] are detained in the hospital—usually without the presence of their parents or much attention from hospital staff—after they have completed treatment until the parents pay the bill. This can last for 10 days to 2 weeks. If the child has died, the corpse is held hostage until the hospital bill is paid.”

This is a shocking and extreme denial of rights, said Dr. Patenaude, but there are many less dramatic yet equally important ethical issues in the psychosocial care of children with cancer. Gaps in the definition and understanding of minimal essential services that should be available to all children are wide and deep. As defined by the U.N. Convention on the Rights of the Child, the following items should be addressed: interventions to help children cope with the disease and its ramifications; the presence of parents during the child’s hospitalization; freedom from pain; age-appropriate explanations of what is and will be happening to the child; and interaction with peers and the opportunity to play and express emotions.

Lea Baider, PhD

Cultural Beliefs, Unmet Needs The Middle East has among the highest population growth rates in the world, which brings constant dynamic challenges. More than nine in ten people (93%) in the Middle East–North Africa region are Muslim. Lea Baider, PhD,

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PAGE 25

World Congress of Psycho-oncology Professor of Health Psychology and Director, Psychosocial Department, Assuta Medical Center, Tel Aviv, described what happens to many Muslim women in the Middle East when they get cancer.

“The most intimate events of life draw us into the health-care system and expose our own fundamental attitudes, moral values, and beliefs, as well as the beliefs and behaviors of those who love us and take care of us. Religion and belief systems affect psychological and physical health because they influence coping strategies, social and family behavior, and attitudes about health. They can— and do, among many Muslims—lead to fear, mistrust, silence in the face of illness, and the belief that cancer is a punishment visited upon women by Allah.”

Dr. Baider explained that in Muslim countries, belief systems and health rituals appear unscientific and contradictory when compared to evidence-based Western medical care. A pervasive culture of collective silence influences the way women perceive their bodies and their health. Nevertheless, to pursue any possible health change, it is vital to listen carefully to the traditional and religious values of women in Muslim societies.

Then we could create not conflicts but integration and cooperation in health care.

Daisuke Fujisawa, MD, PhD, of the Department of Neuropsychiatry and Palliative Care Center, Keio University School of Medicine, Tokyo, who spoke for Luigi Grassi, MD, Professor and Chair of Psychiatry, University of Ferrara (Italy) Section of Psychiatry, who could not attend the meeting, said that psychosocial oncology services are available in many parts of the world—but still too few.

For example, in a country in Africa, there are only 10 oncologists for every 40 million people, and patients often need to travel 600 kilometers or more to a cancer center where there are only rudimentary services. He described what these services can and should do: treat all patients with cancer; ensure the right to enjoy the highest attainable standard of physical and mental health; and provide psychosocial services and interventions in the event of illness.

From Principles to Practical Care Stephen Connor, PhD, Senior Fellow, Worldwide Hospice Palliative Care Alliance (WHPCA) and member of the World Health Organization Ad Hoc Advisory Group on Palliative and LongTerm Care, said that human rights advocacy must move from statements of principles and goals to practical clinical implementation. Efforts to advance psychosocial cancer care must be seen as a

human rights issue and therefore acted upon rather than just talked about.

Over a million people die every week around the world, he said, and 80% of them have highly restricted access to or no pain relief. An estimated 40 million people worldwide are in need of palliative care at any one time, but less than 10% receive it. More than 75% of all countries provide little or no palliative care to patients with cancer.

“The need for palliative care has never been greater and is increasing rapidly because the world’s population is aging, and the incidence of cancer and other noncommunicable diseases is increasing. This is especially true outside North America, Europe, and Australia. The unmet need is enormous,” said Dr. Connor.

Jamie Von Roenn, MD

what is important with regard to palliative care and how it can be furthered. ­Jamie Von Roenn, MD, ASCO Senior Director of Education, Science, and Professional Development, said, “We need to educate people, we need to talk about death and dying, and we need to develop a model of integrated care.”

Small cancer centers and community

The need for palliative care has never been greater and is increasing rapidly because the world’s population is aging, and the incidence of cancer and other noncommunicable diseases is increasing.

—Stephen Connor, PhD

“WHPCA’s advocacy began with the Seoul Declaration in 2005, which called for access to palliative care as a human right. The group emerged from the Seoul meeting of Asian hospice networks as an alliance of national and regional hospice and palliative care associations. A series of global summits and further declarations on palliative care were held and created a strong international association.”

WHPCA believes that no one with a life-limiting condition should live and die with unnecessary pain and distress due to lack of access to quality care. Its objectives include being a strong, sustainable, and efficient global membership organization exclusively focused on hospice and palliative care; being an effective and powerful global voice and advocate for hospice and palliative care; providing integration of palliative care into country health systems, drawing on and supporting local technical expertise; and assisting national associations to integrate palliative care into national undergraduate and postgraduate health science curricula and health and social care workers’ training programs.

Goals of Palliative Care Cokie Roberts, a journalist for National Public Radio and a survivor of breast cancer, introduced the plenary session panelists and asked them to describe their ideas about

oncology practices provide almost no palliative care at all—and that’s where 80% of cancer is treated in the United States.

Moreover, because do-not-resuscitate orders and end-of-life care are regulated by states, there is no national uniformity about how such care is to be provided— and how much choice patients have about the way they approach death.

Joanne Wolfe, MD, Chief, Division of Pediatric Palliative Care, Department of Psychosocial Oncology and Palliative Care, Dana-Farber Cancer Institute, and Director of Palliative Care at Boston Children’s Hospital, described the Pediatric Advanced Care Team (PACT) that helps children and their parents through serious illness.

“All our young patients receive interdisciplinary care (primary palliative care) early in their treatment, which is critically important when a child is diagnosed with cancer. The care team is ‘wrapped around’ the child and his or her family, so they feel protected and know they have knowledgeable and caring clinicians to whom to turn. Palliative care subspecialty consultation is reserved for more complicated cases such as the need for intensive symptom management.”

The Dana-Farber PACT team consists of clinicians who specialize in palliative care, symptom management, complemen-

tary medicine, spirituality-religion, social work, and community resources. These professionals consult with the patient, his or her parents, siblings, and the primary care team to ease pain and manage symptoms and side effects; foster communication among families and health-care providers; and coordinate inpatient, outpatient, and home-care services.

Dr. Wolfe said that caregivers at DanaFarber have found social media very useful for children with cancer. “This is how they are used to communicating with one another, and we can use these media to educate people and to disseminate whatever messages we feel will help.”

Stein Kaasa, MD, Professor of Medicine, Institute of Cancer Research and Molecular Medicine, University Hospital of Trondheim (Norway), said that providers should be encouraging patients to think about palliative care as early in their treatment as possible, rather than shying away from discussions of death, dying, and hospice care. “And there’s no reason to use euphemisms or call palliation anything other than it is. It is a good thing, so let’s not change its name,” Dr. Kaasa added.

In Norway, palliative care has its own diagnosis-related group and is integrated into the billing system in most institutions. In this country, said Dr. Wolfe, Medicare and most private insurers do not reimburse for advanced planning conversations, but they soon will. “It’s on the horizon,” he noted. In the United Kingdom, spending on palliative care is “hugely varied,” said Irene J. H ­ igginson, OBE, Director, Cicely Saunders Institute, Professor, King’s College London—the world’s first purpose-built institute for palliative care.

Dr. Higginson said that the purpose of palliative care is first to determine what patients and families need. “There are 13 or 14 common physical symptoms that we can help with, as well as innumerable psychosocial ones. This requires critical evaluation, and we must do it early. Even though we start it earlier in the UK than you do here, people still come to palliative care far too late in the course of their illness,” she explained.

Medical students at her institution spent time at a hospice, which made them more likely to recommend palliative care when they began practice. “In the United States, palliative care is being integrated into the medical curriculum, but it’s very slow,” concluded Dr. Von Roenn. She did note, however, that as it appears in medical schools, it follows in clinical practice. n Disclosure: Drs. Travado, Breitbart, Patenaude, Baider, Fujisawa, Grassi, Connor, Von Roenn, Wolfe, Kaasa, and Higginson reported no potential conflicts of interest.

The ASCO Post | SEPTEMBER 10, 2015

PAGE 26

World Congress of Psycho-oncology Supportive Care

Suicide After Cancer: Understanding the Challenges Across the Treatment Trajectory

By Margot J. Fromer

S

uicidal thoughts and impulses are among the most challenging symptoms in patients with cancer, and they may occur both during and after treatment. It has long been known that a cancer diagnosis carries an increased risk for suicide, but the problem is not widely addressed.

Suicide is one of the few remaining taboo topics of conversation among the general public, and even health professionals are unprepared to understand and respond to their patients’ suicidal thoughts. The topic of suicide after cancer was featured at the 2015 World Congress of Psycho-Oncology, held in late July in Washington, DC. Caring for suicidal patients is demanding and requires risk assessment, possibly urgent mental health care, knowledge of ways to manage symptoms, clarity about personal and professional ethics, willingness to grant patient autonomy, and recognition of legal liability. Moreover, most suicide research has focused on people with psychiatric rather than physical conditions, making it difficult to know how well it fits with patients with cancer.

Patients With Cancer May Think About It Andrew Roth, MD, a psychiatrist at Memorial Sloan Kettering Cancer Center, New York, said that he has seen many patients with cancer who, in a variety of ways, express the thought: “If I’m going to die anyway, what difference does it make if I kill myself?” It is best to help patients derive as much meaning and pleasure from life despite the cancer, which may alleviate ideas and plans for suicide, he explained.

The risk for suicide is definitely elevated in patients with cancer, said Dr. Roth. The more comorbidities a patient has, the higher the risk, often double that of the general population.

“We need to integrate principles and practices from the psychiatric setting, especially suicide screening—and especially early after initial cancer diagnosis, when the rate is higher. We want to know if a patient has a history of suicide attempts, poorly controlled pain, a poor prognosis, and physical impairment and/or loss of mobility. Is the patient elderly? Has there been a history of depression?”

Suicide ideation is not necessarily a precursor to the act itself, but it should be talked about. Dr. Roth also said it is important to ask patients with cancer whether

they have been or are now thinking about killing themselves and, if so, whether they have a plan in mind. “Asking about suicidal thoughts does not put new ideas into

anxiety among participants with a desire for death, serious suicidal ideation, and an interest in receiving assistance with suicide was 52.2%, 53.3%, and 40.1%, respectively.

Asking about suicidal thoughts does not put new ideas into someone’s mind, having never been there before. Many cancer patients think about whether it would be better not to be alive at some time or another after diagnosis.

—Andrew Roth, MD

someone’s mind, having never been there before. Many cancer patients think about whether it would be better not to be alive at some time or another after diagnosis.”

Ways to Look at Suicidal Thoughts Keith Wilson, PhD, Associate Scientist, Ottawa Hospital Research Institute and Staff Psychologist, The Ottawa Hospital Rehabilitation Centre, Canada, reported that palliative care studies have looked at suicidal concerns in three ways: a desire for death, suicidal ideation, and interest in receiving physician-assisted suicide.

Keith Wilson, PhD

All three were addressed in the Canadian National Palliative Care Survey of 381 patients with advanced cancer.

Participants were asked their thoughts about suicide, and they were interviewed to determine the presence of common mental disorders. Thirty percent acknowledged a transient desire for death, but only 12% had a genuine desire to die.

Some degree of suicidal ideation was reported by 16%, but only 4% thought of it often or knew how they would do it.

Close to 6% would have requested assisted suicide at the time of the interview.

“There was overlap across the categories but also differences,” said Dr. Wilson.

The prevalence of depression and/or

The study concluded that occasional wishes for death are common among patients with advanced cancer, but more serious concerns are often associated with depression and/or anxiety.

Therefore, said Dr. Wilson, “Expression of a desire for death or suicide by a terminally ill patient should raise a suspicion about mental health problems but is not in itself clearly indicative of them.”

ated with physical function and the late effects of treatment, the latter of which are particularly prevalent in survivors of childhood cancer. Suicidal ideation is driven by physical as well as emotional health, but it is interesting to note that 30% to 45% of survivors with suicidal ideation report no significant symptoms of depression, so screening for emotional distress alone will not always identify suicide risk.

Even if you do not have cancer any longer, if you feel bad much of the time or have major handicapping after-effects, life may not be enjoyable enough to keep going. In fact, said Dr. Recklitis, “Suicide ideation increases with a diminution of self-assessment of overall health, as well as an objective assessment of such. The risk factor is 30% to 50%, and more than half of those people do not have classic symptoms of clinical depression.” Therefore, he said, it is imperative to develop ways to identify survivors at high risk.

Identifying Survivors at Risk Suicide remains a risk for survivors, sometimes for years afterward, even if cancer has been cured or is in remission.

How can this be? Shouldn’t making it through a fatal disease confer a love of life, a sense of profound gratitude?

Apparently not, said Christopher Recklitis, PhD, Associate Professor of Pediatrics, Dana-Farber Cancer Institute and Harvard Medical School. He looked at data from cohort studies of long-term cancer survivors, and compared with the general population, he found a significant increase in suicide ideation and completed suicide. Although the risk decreases as time passes, it depends largely on the site of the cancer, gender, age, and permanent or long-term handicaps and health problems.

Newer studies have examined the relationship of survivor health outcomes with suicidality and revealed that risk is associ-

Christopher Recklitis, PhD

Donald Rosenstein, MD

Donald Rosenstein, MD, Professor of Psychiatry and Director, Comprehensive Cancer Support Program, University of North Carolina, Chapel Hill, said that even though many patients with cancer and survivors are not clinically depressed as they think about suicide, the Patient Health Questionnaire (PHQ-9) can be a useful assessment tool.

It is a nine-item scale that measures the presence and severity of symptoms of depression. The tool is short and can be administered in person, over the phone, or self-administered. Available in 30 languages, it is well validated and documented. The first eight questions are the ones usually asked of people thought to be depressed, and the last question is about suicide ideation. According to Dr. Rosenstein, however, that question “has been shown to result in fairly high false-positive rates, and so, is not a good choice for broad screening efforts within oncology.” n Disclosure: Drs. Roth, Wilson, Recklitis, and Rosenstein reported no potential conflicts of interest.

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ANTI–PD-1 EFFICACY

TO HELP FIGHT TUMORS

24% overall response rate in the 2 mg/kg arm (95% confidence interval [CI], 15–34; n=89); 1 complete response (1%) and 20 partial responses (23%).

86% of patients with an objective response (n=18/21) had ongoing responses with durations ranging from 1.4+ to 8.5+ months, which included 8 patients with ongoing responses of 6 months or longer.

Releases programmed death receptor-1 (PD-1) pathway–mediated inhibition of the immune response.

KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. This indication is approved under accelerated approval based on tumor response rate and durability of response. An improvement in survival or diseaserelated symptoms has not yet been established. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

SELECTED SAFETY INFORMATION • Immune-mediated adverse reactions occurred with KEYTRUDA, including pneumonitis, colitis, hepatitis, hypophysitis, nephritis, hyperthyroidism, and hypothyroidism.

Based on the severity of the adverse reaction, KEYTRUDA should be withheld or discontinued and corticosteroids administered. For more information regarding immune-mediated adverse reactions, please read the additional Selected Safety Information on the next page.

Please see additional Selected Safety Information on the next page and the Brief Summary of Prescribing Information on the adjacent pages.

For patients For patientswith withunresectable unresectableorormetastatic metastaticmelanoma melanomaand anddisease diseaseprogression progressionfollowing followingipilimumab ipilimumaband, and, if BRAF V600 if BRAF V600mutation mutationpositive, positive,a aBRAF BRAFinhibitor inhibitor

KEYTRUDA: KEYTRUDA: DURABILITY DURABILITY OF OF RESPONSE RESPONSE 24% 24%overall overallresponse responserate rate(complete (completeresponse+partial response+partialresponse) response) with withsingle-agent single-agentKEYTRUDA KEYTRUDA(95% (95%CI, CI,15–34) 15–34) Data Datafor for2 2mg/kg mg/kgevery every33weeks weeks(n=89) (n=89)

11%% 23 23%%

• •There Therewere wereobjective objectiveresponses responsesininpatients patientswith withand and without withoutBRAF BRAFV600 V600mutation–positive mutation–positivemelanoma. melanoma.

Complete CompleteResponse Response(CR) (CR)(n=1) (n=1)

Partial PartialResponse Response(PR) (PR)(n=20) (n=20) (%(% ofof patients) patients)

• •Similar Similaroverall overallresponse responserate rateresults resultswere wereobserved observed in in the the10-mg/kg 10-mg/kgarm. arm.

• •Patients Patientscontinued continuedtreatment treatmentwith with KEYTRUDA KEYTRUDA until until unacceptable unacceptable toxicity toxicity or or disease disease progression progression that that was wassymptomatic, symptomatic,was wasrapidly rapidlyprogressive, progressive, required required urgent urgent inter intervention, vention, occurred occurred with with aa decline decline in in performance performancestatus, status,ororwas wasconfirmed confirmedat at44to to66 weeks weeks with withrepeat repeatimaging. imaging.

Study design: AA multicenter, open-label, Study design: multicenter, open-label,randomized, randomized,dose-comparative dose-comparativestudy studycohort cohortofofthe theongoing ongoingKEYNOTE-001 KEYNOTE-001Phase Phase1b1btrial trialininpatients patientswith with unresectable or or metastatic melanoma and progression unresectable metastatic melanoma and progressionofofdisease. disease.Key Keyeligibility eligibilitycriteria criteriaincluded includedprior priortreatment treatmentwith withipilimumab ipilimumab(2(2orormore moredoses doses at at 3 mg/kg or or higher) and a BRAF oror MEK inhibitor, if BRAF 3 mg/kg higher) and a BRAF MEK inhibitor, if BRAFV600 V600mutation–positive; mutation–positive;and anddisease diseaseprogression progressionwithin within2424weeks weeksfollowing followingthe thelast lastdose dose of of ipilimumab.

Patients were randomized to toreceive ipilimumab.

Patients were randomized receive2 mg/kg 2 mg/kg(n=89) (n=89)oror1010mg/kg mg/kg(n=84) (n=84)ofofKEYTRUDA KEYTRUDAevery every3 3weeks weeksuntil untilunacceptable unacceptabletoxicity toxicityoror disease progression.

The major efficacy disease progression.

The major efficacyoutcome outcomemeasures measureswere wereconfirmed confirmedoverall overallresponse responserate, rate,asasassessed assessedbybyblinded blindedindependent independentcentral central review using Response Evaluation Criteria in in Solid review using Response Evaluation Criteria SolidTumors Tumors(RECIST (RECIST1.1), 1.1),and andduration durationofofresponse. response.Tumor Tumorresponse responsewas wasassessed assessedevery every1212weeks. weeks.

SELECTED SELECTEDSAFETY SAFETYINFORMATION INFORMATION • Pneumonitis • Pneumonitisoccurred occurredin in1212(2.9%) (2.9%)ofof411 411patients, patients,including including Grade 2 or 3 cases in in 8 (1.9%) and 1 (0.2%) Grade 2 or 3 cases 8 (1.9%) and 1 (0.2%)patients, patients,respectively, respectively, receiving KEYTRUDA. Monitor patients forfor signs and receiving KEYTRUDA. Monitor patients signs andsymptoms symptomsofof pneumonitis.

Evaluate pneumonitis.

Evaluatesuspected suspectedpneumonitis pneumonitiswith withradiographic radiographic imaging. imaging.Administer Administercorticosteroids corticosteroidsforforGrade Grade2 2ororgreater greater pneumonitis.

TRUDA pneumonitis.Withhold WithholdKEY KEY TRUDAforforGrade Grade2;2;permanently permanently discontinue KEYTRUDA forfor Grade 3 or 4 pneumonitis. discontinue KEYTRUDA Grade 3 or 4 pneumonitis.

• Colitis • Colitis(including (includingmicroscopic microscopiccolitis) colitis)occurred occurredinin4 4(1%) (1%)ofof411 411 patients, including patients, includingGrade Grade2 2oror3 3cases casesinin1 1(0.2%) (0.2%)and and2 2(0.5%) (0.5%) patients, respectively, receiving KEYTRUDA. Monitor patients, respectively, receiving KEYTRUDA. Monitorpatients patientsforfor signs and symptoms signs and symptomsofofcolitis. colitis.Administer Administercorticosteroids corticosteroidsfor for Grade 2 or greater colitis.

Withhold Grade 2 or greater colitis.

WithholdKEYTRUDA KEYTRUDAforforGrade Grade2 2oror3;3; permanently discontinue KEYTRUDA forfor Grade 4 colitis. permanently discontinue KEYTRUDA Grade 4 colitis.

• Hepatitis (including autoimmune hepatitis) occurred • Hepatitis (including autoimmune hepatitis) occurredinin2 (0.5%) 2 (0.5%)ofof 411411 patients, including a Grade 4 case in in 1 (0.2%) patient, receiving patients, including a Grade 4 case 1 (0.2%) patient, receiving KEY TRUDA. KEY TRUDA.Monitor Monitorpatients patientsforforchanges changesininliver liverfunction. function.

Administer Administercorticosteroids corticosteroidsforforGrade Grade2 2ororgreater greaterhepatitis hepatitis and, based onon severity ofof liver enzyme elevations, and, based severity liver enzyme elevations,withhold withholdoror discontinue KEYTRUDA. discontinue KEYTRUDA. • Hypophysitis occurred in in 2 (0.5%) ofof 411411 patients, including • Hypophysitis occurred 2 (0.5%) patients, includinga aGrade Grade2 2 case in in 1 and a Grade 4 case case 1 and a Grade 4 casein in1 (0.2% 1 (0.2%each) each)patient, patient,receiving receiving KEY TRUDA. KEY TRUDA.Monitor Monitorpatients patientsforforsigns signsand andsymptoms symptomsofof hypophysitis.

Administer hypophysitis.

Administercorticosteroids corticosteroidsforforGrade Grade2 2ororgreater greater hypophysitis. hypophysitis.Withhold WithholdKEYTRUDA KEYTRUDAforforGrade Grade2;2;withhold withholdoror discontinue forfor Grade 3; 3; and permanently discontinue discontinue Grade and permanently discontinueKEYTRUDA KEYTRUDA forfor Grade 4 hypophysitis.

Grade 4 hypophysitis.

• Nephritis • Nephritisoccurred occurredinin3 3(0.7%) (0.7%)patients, patients,consisting consistingofofone onecase caseofof Grade Grade2 2autoimmune autoimmunenephritis nephritis(0.2%) (0.2%)and andtwo twocases casesofofinterstitial interstitial nephritis nephritiswith withrenal renalfailure failure(0.5%), (0.5%),one oneGrade Grade33and andone oneGrade Grade4.4.

Monitor Monitorpatients patientsfor forchanges changesininrenal renalfunction. function. Administer Administer corticosteroids corticosteroidsfor forGrade Grade2 2ororgreater greater nephritis. nephritis. Withhold Withhold KEYTRUDA KEYTRUDAfor forGrade Grade2;2;permanently permanentlydiscontinue discontinueKEYTRUDA KEYTRUDAfor for Grade Grade3 3oror4 4nephritis. nephritis.

• Hyperthyroidism • Hyperthyroidismoccurred occurredinin5 5(1.2%) (1.2%)ofof411 411patients, patients,including including Grade Grade2 2oror3 3cases casesinin2 2(0.5%) (0.5%)and and1 1(0.2%) (0.2%)patients, patients,respectively, respectively, receiving receivingKEYTRUDA. KEYTRUDA.Hypothyroidism Hypothyroidismoccurred occurredinin34 34(8.3%) (8.3%)ofof411 411 patients, patients,including includinga aGrade Grade3 3case caseinin11(0.2%) (0.2%)patient, patient,receiving receiving KEY TRUDA. KEY TRUDA.Thyroid Thyroiddisorders disorderscan canoccur occuratatany anytime timeduring during treatment. treatment.Monitor Monitorpatients patientsfor forchanges changesininthyroid thyroidfunction function(at (atthe the start startofoftreatment, treatment,periodically periodicallyduring duringtreatment, treatment,and andas asindicated indicated based basedononclinical clinicalevaluation) evaluation)and andfor forclinical clinicalsigns signsand andsymptoms symptomsofof thyroid thyroiddisorders. disorders.Administer Administercorticosteroids corticosteroidsfor forGrade Grade33ororgreater greater hyperthyroidism. hyperthyroidism.Withhold WithholdKEYTRUDA KEYTRUDAfor forGrade Grade3;3;permanently permanently discontinue TRUDA for discontinueKEY KEYTRUDA forGrade Grade4 4hyperthyroidism. hyperthyroidism.Isolated Isolated hypothyroidism hypothyroidismmay maybebemanaged managed with with replacement replacement therapy therapy without withouttreatment treatmentinterruption interruptionand andwithout withoutcorticosteroids. corticosteroids.

• Other • Otherclinically clinicallyimportant importantimmune-mediated immune-mediatedadverse adverse reactions reactions can canoccur. occur.The Thefollowing followingclinically clinicallysignificant significantimmune-mediated immune-mediated adverse adversereactions reactionsoccurred occurredininless lessthan than1% 1%ofofpatients patientstreated treated with withKEYTRUDA: KEYTRUDA:exfoliative exfoliativedermatitis, dermatitis,uveitis, uveitis,arthritis, arthritis,myositis, myositis, pancreatitis, pancreatitis,hemolytic hemolyticanemia, anemia,partial partialseizures seizuresarising arisingininaapatient patient with withinflammatory inflammatoryfoci fociininbrain brainparenchyma, parenchyma,adrenal adrenalinsufficiency, insufficiency, myasthenic myasthenicsyndrome, syndrome,optic opticneuritis, neuritis,and andrhabdomyolysis. rhabdomyolysis.

KEYTRUDA responded KEYTRUDA provided provided ongoing responses in patients who responded

86%

(n=18/21) (n=18/21)

Of responses were ongoing in patients patients who who responded responded to KEYTRUDA

••Among progression of of disease disease 2.8, 2.8, 2.9, 2.9, and and 8.2 8.2 months months Among the the 21 21 patients patients with with an an objective response, 3 (14%) had progression after after initial initial response. response.

•• The durations ranging ranging from from 1.4+ 1.4+ to to 8.5+ 8.5+ months, months,which which The remaining remaining 18 18 patients patients (86%) (86%) had ongoing responses with durations included included 88 patients patients with with ongoing ongoing responses of 6 months or longer.

•• One first tumor tumor assessment assessment concurrent concurrentwith withaa Oneadditional additional patient patient developed developed 2 new asymptomatic lesions at the first 75% 75% decrease decrease in in overall overall tumor tumor burden.

—KEYTRUDA was durable durable for for 5+ 5+ months. months.

—KEYTRUDA was was continued continued and and this reduction in tumor burden was

SELECTED SELECTED SAFETY SAFETY INFORMATION INFORMATION (CONTINUED) common adverse adverse reactions reactions (reported (reported inin at at least least ••For For suspected suspected immune-mediated immune-mediated adverse reactions, ensure • The most common patients) were were fatigue fatigue (47%), (47%), cough cough (30%), (30%), nausea nausea adequate 20% of patients) adequate evaluation evaluation to to confirm confirm etiology or exclude other pruritus (30%), (30%), rash rash (29%), (29%), decreased decreasedappetite appetite(26%), (26%), causes.

(30%), pruritus causes.Based Basedon on the the severity severity of of the the adverse reaction, withhold (21%), arthralgia arthralgia (20%), (20%),and anddiarrhea diarrhea(20%).

(20%).

KEYTRUDA constipation (21%), KEYTRUDA and and administer administer corticosteroids. corticosteroids. Upon improvement of ofthe theadverse adversereaction reaction to to Grade Grade 11 or or less, initiate corticosteroid • It is not known known whether whether KEYTRUDA KEYTRUDA isis excreted excreted ininhuman humanmilk. milk. taper taper and and continue continue to to taper taper over over at least 1 month. Restart drugsare areexcreted excretedin inhuman humanmilk, milk,instruct instructwomen women Because many drugs KEYTRUDA KEYTRUDA ifif the the adverse adverse reaction reaction remains at Grade 1 or less. nursing during during treatment treatmentwith withKEYTRUDA. KEYTRUDA. to discontinue nursing Permanently Permanently discontinue discontinue KEYTRUDA KEYTRUDA for any severe or Grade 3 effectiveness of KEYTRUDA have notbeen been • Safety and effectiveness of KEYTRUDA have not immune-mediated immune-mediated adverse adverse reaction reaction that recurs and for any lifeestablished in pediatric pediatric patients. patients. threatening immune-mediated adverse reaction. threatening immune-mediated adverse ••Based Based on on its its mechanism mechanism of of action, action, KEYTRUDA may cause the Brief Brief Summary Summary of of the the Please see the fetal fetal harm harm when when administered administered to to aa pregnant woman. If used Information on on the the adjacent adjacent pages. pages.

Prescribing Information during during pregnancy, pregnancy, or or ifif the the patient patient becomes pregnant during treatment, treatment,apprise apprise the the patient patient of of the the potential hazard to a fetus. Merck Oncology Oncology Advise Advisefemales females of of reproductive reproductive potential potential to use highly effective 2014 Merck Merck Sharp Sharp && Dohme DohmeCorp., Corp., Copyright © 2014 contraception contraception during during treatment treatment and and for 4 months after the last a subsidiary of of Merck Merck & & Co., Co., Inc. Inc. dose doseof ofKEYTRUDA. KEYTRUDA. All rights reserved. reserved. ONCO-1116177-0000 ONCO-1116177-000011/14 11/14 keytruda.com keytruda.com

Questions Questions about about access for KEYTRUDA? Call Call The The Merck Merck Access Access Program at 855-257-3932.

Scan Scan here here or visit keytruda.com keytruda.com to to learn learn more.

Brief Summary of the Prescribing Information for KEYTRUDA® (pembrolizumab) for injection, for intravenous use INDICATIONS AND USAGE KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor.

This indication is approved under accelerated approval based on tumor response rate and durability of response. An improvement in survival or disease-related symptoms has not yet been established. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

CONTRAINDICATIONS None.

WARNINGS AND PRECAUTIONS Immune-Mediated Pneumonitis: Pneumonitis occurred in 12 (2.9%) of 411 melanoma patients, including Grade 2 or 3 cases in 8 (1.9%) and 1 (0.2%) patients, respectively, receiving KEYTRUDA in Trial 1. The median time to development of pneumonitis was 5 months (range 0.3 weeks–9.9 months). The median duration was 4.9 months (range 1 week–14.4 months).

Five of eight patients with Grade 2 and the one patient with Grade 3 pneumonitis required initial treatment with high-dose systemic corticosteroids (greater than or equal to 40 mg prednisone or equivalent per day) followed by a corticosteroid taper. The median initial dose of high-dose corticosteroid treatment was 63.4 mg/day of prednisone or equivalent with a median duration of treatment of 3 days (range 1–34) followed by a corticosteroid taper.

Pneumonitis led to discontinuation of KEYTRUDA in 3 (0.7%) patients. Pneumonitis completely resolved in seven of the nine patients with Grade 2–3 pneumonitis.

Monitor patients for signs and symptoms of pneumonitis. Evaluate patients with suspected pneumonitis with radiographic imaging and administer corticosteroids for Grade 2 or greater pneumonitis. Withhold KEYTRUDA for moderate (Grade 2) pneumonitis, and permanently discontinue KEYTRUDA for severe (Grade 3) or life-threatening (Grade 4) pneumonitis.

Immune-Mediated Colitis: Colitis (including microscopic colitis) occurred in 4 (1%) of 411 patients, including Grade 2 or 3 cases in 1 (0.2%) and 2 (0.5%) patients, respectively, receiving KEYTRUDA in Trial 1. The median time to onset of colitis was 6.5 months (range 2.3– 9.8). The median duration was 2.6 months (range 0.6 weeks–3.6 months). All three patients with Grade 2 or 3 colitis were treated with high-dose corticosteroids (greater than or equal to 40 mg prednisone or equivalent per day) with a median initial dose of 70 mg/day of prednisone or equivalent; the median duration of initial treatment was 7 days (range 4–41), followed by a corticosteroid taper. One patient (0.2%) required permanent discontinuation of KEYTRUDA due to colitis. All four patients with colitis experienced complete resolution of the event.

Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 or greater colitis. Withhold KEYTRUDA for moderate (Grade 2) or severe (Grade 3) colitis, and permanently discontinue KEYTRUDA for life-threatening (Grade 4) colitis.

Immune-Mediated Hepatitis: Hepatitis (including autoimmune hepatitis) occurred in 2 (0.5%) of 411 patients, including a Grade 4 case in 1 (0.2%) patient, receiving KEYTRUDA in Trial 1.

The time to onset was 22 days for the case of Grade 4 hepatitis which lasted 1.1 months.

The patient with Grade 4 hepatitis permanently discontinued KEYTRUDA and was treated with high-dose (greater than or equal to 40 mg prednisone or equivalent per day) systemic corticosteroids followed by a corticosteroid taper. Both patients with hepatitis experienced complete resolution of the event.

Monitor patients for changes in liver function. Administer corticosteroids for Grade 2 or greater hepatitis and, based on severity of liver enzyme elevations, withhold or discontinue KEYTRUDA. Immune-Mediated Hypophysitis: Hypophysitis occurred in 2 (0.5%) of 411 patients, consisting of one Grade 2 and one Grade 4 case (0.2% each), in patients receiving KEYTRUDA in Trial 1. The time to onset was 1.7 months for the patient with Grade 4 hypophysitis and 1.3 months for the patient with Grade 2 hypophysitis. Both patients were treated with high-dose (greater than or equal to 40 mg prednisone or equivalent per day) corticosteroids followed by a corticosteroid taper and remained on a physiologic replacement dose.

Monitor for signs and symptoms of hypophysitis. Administer corticosteroids for Grade 2 or greater hypophysitis. Withhold KEYTRUDA for moderate (Grade 2) hypophysitis, withhold or discontinue KEYTRUDA for severe (Grade 3) hypophysitis, and permanently discontinue KEYTRUDA for life-threatening (Grade 4) hypophysitis.

Renal Failure and Immune-Mediated Nephritis: Nephritis occurred in 3 (0.7%) patients, consisting of one case of Grade 2 autoimmune nephritis (0.2%) and two cases of interstitial nephritis with renal failure (0.5%), one Grade 3 and one Grade 4. The time to onset of autoimmune nephritis was 11.6 months after the first dose of KEYTRUDA (5 months after the last dose) and lasted 3.2 months; this patient did not have a biopsy. Acute interstitial nephritis was confirmed by renal biopsy in two patients with Grades 3–4 renal failure. All three patients fully recovered renal function with treatment with high-dose corticosteroids (greater than or equal to 40 mg prednisone or equivalent per day) followed by a corticosteroid taper.

Monitor patients for changes in renal function. Administer corticosteroids for Grade 2 or greater nephritis. Withhold KEYTRUDA for moderate (Grade 2) nephritis, and permanently discontinue KEYTRUDA for severe (Grade 3), or life-threatening (Grade 4) nephritis.

Immune-Mediated Hyperthyroidism and Hypothyroidism: Hyperthyroidism occurred in 5 (1.2%) of 411 patients, including Grade 2 or 3 cases in 2 (0.5%) and 1 (0.2%) patients, respectively, receiving KEYTRUDA in Trial 1. The median time to onset was 1.5 months (range 0.5–2.1). The median duration was 2.8 months (range 0.9 to 6.1). One of two patients with Grade 2 and the one patient with Grade 3 hyperthyroidism required initial treatment with highdose corticosteroids (greater than or equal to 40 mg prednisone or equivalent per day) followed by a corticosteroid taper. One patient (0.2%) required permanent discontinuation of KEYTRUDA due to hyperthyroidism. All five patients with hyperthyroidism experienced complete resolution of the event.

Hypothyroidism occurred in 34 (8.3%) of 411 patients, including a Grade 3 case in 1 (0.2%) patient, receiving KEYTRUDA in Trial 1. The median time to onset of hypothyroidism was 3.5 months (range 0.7 weeks–19 months). All but two of the patients with hypothyroidism were

treated with long-term thyroid hormone replacement therapy. The other two patients only required short-term thyroid hormone replacement therapy. No patient received corticosteroids or discontinued KEYTRUDA for management of hypothyroidism.

Thyroid disorders can occur at any time during treatment. Monitor patients for changes in thyroid function (at the start of treatment, periodically during treatment, and as indicated based on clinical evaluation) and for clinical signs and symptoms of thyroid disorders.

Administer corticosteroids for Grade 3 or greater hyperthyroidism, withhold KEYTRUDA for severe (Grade 3) hyperthyroidism, and permanently discontinue KEYTRUDA for life-threatening (Grade 4) hyperthyroidism. Isolated hypothyroidism may be managed with replacement therapy without treatment interruption and without corticosteroids.

Other Immune-Mediated Adverse Reactions: Other clinically important immune-mediated adverse reactions can occur.

The following clinically significant, immune-mediated adverse reactions occurred in less than 1% of patients treated with KEYTRUDA in Trial 1: exfoliative dermatitis, uveitis, arthritis, myositis, pancreatitis, hemolytic anemia, partial seizures arising in a patient with inflammatory foci in brain parenchyma, and adrenal insufficiency.

Across clinical studies with KEYTRUDA in approximately 2000 patients, the following additional clinically significant, immune-mediated adverse reactions were reported in less than 1% of patients: myasthenic syndrome, optic neuritis, and rhabdomyolysis.

For suspected immune-mediated adverse reactions, ensure adequate evaluation to confirm etiology or exclude other causes. Based on the severity of the adverse reaction, withhold KEYTRUDA and administer corticosteroids. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Restart KEYTRUDA if the adverse reaction remains at Grade 1 or less. Permanently discontinue KEYTRUDA for any severe or Grade 3 immune-mediated adverse reaction that recurs and for any life-threatening immune-mediated adverse reaction.

Embryofetal Toxicity: Based on its mechanism of action, KEYTRUDA may cause fetal harm when administered to a pregnant woman. Animal models link the PD-1/PDL-1 signaling pathway with maintenance of pregnancy through induction of maternal immune tolerance to fetal tissue. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus. Advise females of reproductive potential to use highly effective contraception during treatment with KEYTRUDA and for 4 months after the last dose of KEYTRUDA. ADVERSE REACTIONS The following adverse reactions are discussed in greater detail above.

• Immune-mediated pneumonitis.

• Immune-mediated colitis.

• Immune-mediated hepatitis.

• Immune-mediated hypophysitis.

• Renal failure and immune-mediated nephritis.

• Immune-mediated hyperthyroidism and hypothyroidism.

• Immune-mediated 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.

The data described in the WARNINGS and PRECAUTIONS section reflect exposure to KEYTRUDA in Trial 1, an uncontrolled, open-label, multiple cohort trial in which 411 patients with unresectable or metastatic melanoma received KEYTRUDA at either 2 mg/kg every 3 weeks or 10 mg/kg every 2 or 3 weeks. The median duration of exposure to KEYTRUDA was 6.2 months (range 1 day to 24.6 months) with a median of 10 doses (range 1 to 51). The study population characteristics were: median age of 61 years (range 18–94), 39% age 65 years or older, 60% male, 97% white, 73% with M1c disease, 8% with brain metastases, 35% with elevated LDH, 54% with prior exposure to ipilimumab, and 47% with two or more prior systemic therapies for advanced or metastatic disease.

KEYTRUDA was discontinued for adverse reactions in 9% of the 411 patients. Adverse reactions, reported in at least two patients, that led to discontinuation of KEYTRUDA were: pneumonitis, renal failure, and pain. Serious adverse reactions occurred in 36% of patients receiving KEYTRUDA. The most frequent serious adverse drug reactions reported in 2% or more of patients in Trial 1 were renal failure, dyspnea, pneumonia, and cellulitis.

Table 1 presents adverse reactions identified from analyses of the 89 patients with unresectable or metastatic melanoma who received KEYTRUDA 2 mg/kg every three weeks in one cohort of Trial 1. Patients had documented disease progression following treatment with ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. This cohort of Trial 1 excluded patients with severe immune-related toxicity related to ipilimumab, defined as any Grade 4 toxicity requiring treatment with corticosteroids or Grade 3 toxicity requiring corticosteroid treatment (greater than 10 mg/day prednisone or equivalent dose) for greater than 12 weeks; a medical condition that required systemic corticosteroids or other immunosuppressive medication; a history of pneumonitis or interstitial lung disease; or any active infection requiring therapy, including HIV or hepatitis B or C. Of the 89 patients in this cohort, the median age was 59 years (range 18–88), 33% were age 65 years or older, 53% were male, 98% were white, 44% had an elevated LDH, 84% had Stage M1c disease, 8% had brain metastases, and 70% received two or more prior therapies for advanced or metastatic disease. The median duration of exposure to KEYTRUDA was 6.2 months (range 1 day to 15.3 months) with a median of nine doses (range 1 to 23). Fifty-one percent of patients were exposed to KEYTRUDA for greater than 6 months and 21% for greater than 1 year.

KEYTRUDA was discontinued for adverse reactions in 6% of the 89 patients. The most common adverse reactions (reported in at least 20% of patients) were fatigue, cough, nausea, pruritus, rash, decreased appetite, constipation, arthralgia, and diarrhea.

Brief Summary of the Prescribing Information for KEYTRUDA® (pembrolizumab) for injection, for intravenous use (continued)

DRUG INTERACTIONS No formal pharmacokinetic drug interaction studies have been conducted with KEYTRUDA.

THE 1 ST FDA-APPROVED ANTI–PD-1 THERAPY USE IN SPECIFIC POPULATIONS Table 1: Adverse Reactions in ≥10% of Patients with Unresectable or Metastatic Melanoma

Pregnancy: Pregnancy Category D.

Risk Summary: Based on its mechanism of action, KEYTRUDA may cause fetal harm when In appropriate patients with advanced melanoma administered to a pregnant woman. Animal models link the PD-1/PDL-1 signaling pathway KEYTRUDA 2 mg/kg every 3 weeks N=89

Adverse Reaction

KEYTRUDA: All Grades (%)

Grade 3* (%)

with maintenance of pregnancy through induction of maternal immune tolerance to fetal tissue. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus.

Animal Data: Animal reproduction studies have not been conducted with KEYTRUDA to evaluate its effect on reproduction and fetal development, but an assessment of the effects General Disorders and Administration Site Conditions on reproduction was provided. A central function of the PD-1/PD-L1 pathway is to preserve Fatigue 47 7 pregnancy by maintaining maternal immune tolerance to the fetus. Blockade of PD-L1 Peripheral edema 17 1 signaling has been shown in murine models of pregnancy to disrupt tolerance to the fetus Chills 14 0 and to result in an increase in fetal loss; therefore, potential risks of administering KEYTRUDA Pyrexia 11 0 during pregnancy include increased rates of abortion or stillbirth. As reported in the literature, Gastrointestinal Disorders there were no malformations related to the blockade of PD-1 signaling in the offspring of Nausea 30 0 these animals; however, immune-mediated disorders occurred in PD-1 knockout mice.

Constipation 21 0 Human IgG4 (immunoglobulins) are known to cross the placenta; therefore, pembrolizumab Diarrhea 20 0 has the potential to be transmitted from the mother to the developing fetus. Based on its Vomiting 16 0 mechanism of action, fetal exposure to pembrolizumab may increase the risk of developing Abdominal pain 12 0 immune-mediated disorders or of altering the normal immune response.

Respiratory, Thoracic And Mediastinal Disorders Nursing Mothers: It is not known whether KEYTRUDA is excreted in human milk. No studies Cough 30 1 have been conducted to assess the impact of KEYTRUDA on milk production or its presence in Dyspnea 18 2 breast milk. Because many drugs are excreted in human milk, instruct women to discontinue Skin And Subcutaneous Tissue Disorders nursing during treatment with KEYTRUDA. Pruritus 30 0 Pediatric Use: Safety and effectiveness of KEYTRUDA have not been established in Rash 29 0 pediatric patients.

Vitiligo 11 0 Geriatric Use: Of the 411 patients treated with KEYTRUDA, 39% were 65 years and over.

Metabolism and Nutrition Disorders No overall differences in safety or efficacy were reported between elderly patients and Decreased appetite 26 0 younger patients.

Musculoskeletal and Connective Tissue Disorders Renal Impairment: Based on a population pharmacokinetic analysis, no dose adjustment is Arthralgia 20 0 needed for patients with renal impairment.

Pain in extremity 18 1 KEYTRUDA is indicated of patients with pharmacokinetic unresectable Hepatic Impairment: Based on a population analysis, noor dosemetastatic adjustment is Myalgia 14 for the 1 treatment needed for patients with mild hepatic impairment [total bilirubin (TB) less than or equal to ULN Back pain 12 1 melanoma and disease progression following ipilimumab and, if BRAF V600 mutation and AST greater than ULN or TB greater than 1 to 1.5 times ULN and any AST]. KEYTRUDA has Nervous System Disorders not been studied in patients withunder moderate (TB greater than 1.5 to 3 times ULN and anybased AST) positive, a BRAF inhibitor.

This indication is approved accelerated approval Headache 16 0 or severe (TB greater than 3 times ULN and any AST) hepatic impairment. on tumor response rate11and durability of response. An improvement in survival or diseaseDizziness 0 Females and Males of Reproductive Potential: Based on its mechanism of action, KEYTRUDA Blood and Lymphatic System Disorders related symptoms has not yet been established.

Continued approval this may may cause fetal harm when administered to a pregnant for woman.

Adviseindication females of Anemia 14 5 reproductive potential to use highly effective contraception during treatment with KEYTRUDA of clinical benefit in the confirmatory trials.

Psychiatric Disordersbe contingent upon verification and description and for at least 4 months following the last dose of pembrolizumab.

Insomnia 14 0 OVERDOSAGE Infections and Infestations There is no information on overdosage with KEYTRUDA. Upper respiratory tract infection 11 1 *There were no Grade 5 adverse reactions reported. Of the ≥10% adverse reactions, none was reported as Grade 4.

PATIENT COUNSELING INFORMATION

ANTI–PD-1 EFFICACY

TO HELP FIGHT TUMORS

24% overall response rate in the 2 mg/kg arm (95% confidence interval [CI], 15–34; n=89); 1 complete response (1%) and 20 partial responses (23%).

86% of patients with an objective response (n=18/21) had ongoing responses with durations ranging from 1.4+ to 8.5+ months, which included 8 patients with ongoing responses of 6 months or longer.

Releases programmed death receptor-1 (PD-1) pathway–mediated inhibition of the immune response.

Other clinically important adverse reactions observed in up to 10% of patients treated with KEYTRUDA were: Infections and infestations: sepsis Table 2: Laboratory Abnormalities Increased from Baseline in ≥20% of Patients with Unresectable or Metastatic Melanoma KEYTRUDA 2 mg/kg every 3 weeks N=89 Laboratory Test

All Grades (%)

Grades 3–4 (%)

Chemistry Hyperglycemia 40 2* Hyponatremia 35 9 Hypoalbuminemia 34 0 Hypertriglyceridemia 25 0 Increased Aspartate Aminotransferase 24 2* • Immune-mediated adverse24reactions Hypocalcemia 1 Hematology occurred with KEYTRUDA, including Anemia 55 8*

SELECTED SAFETY INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

• Inform patients of the risk of immune-mediated adverse reactions that may require corticosteroid treatment and interruption or discontinuation of KEYTRUDA, including: — Pneumonitis: Advise patients to contact their healthcare provider immediately for new or worsening cough, chest pain, or shortness of breath.

—Colitis: Advise patients to contact their healthcare provider immediately for diarrhea or severe abdominal pain.

—Hepatitis: Advise patients to contact their healthcare provider immediately for jaundice, severe nausea or vomiting, or easy bruising or bleeding.

—Hypophysitis: Advise patients to contact their healthcare provider immediately for persistent or unusual headache, extreme weakness, dizziness or fainting, or vision changes.

—Nephritis: Advise patients to contact their healthcare provider immediately for signs or symptoms of nephritis.

—Hyperthyroidism and Hypothyroidism: Advise patients to contact their healthcare provider immediately for signs or symptoms of hyperthyroidism and hypothyroidism.

• Advise patients of the importance of keeping scheduled appointments for blood work or other laboratory tests.

• Advise women that KEYTRUDA may cause fetal harm. Instruct women of reproductive potential to use highly effective contraception during and for 4 months after the last dose of KEYTRUDA.

pneumonitis, colitis, hepatitis, hypophysitis, • Advise nursing mothers not to breastfeed while taking KEYTRUDA. For more detailed information, please read the Prescribing Information. nephritis, hyperthyroidism, and hypothyroidism. uspi-mk3475-iv-1409r000 Immunogenicity: As with all therapeutic proteins, there is the potential for immunogenicity.

Based on the severity of the adverse reaction, Because trough levels of pembrolizumab interfere with the electrochemiluminescent (ECL) Revised: 09/2014 assay results, a subset analysis was performed in the patients with a concentration KEYTRUDA should be withheld or ofdiscontinued pembrolizumab below the drug tolerance level of the anti-product antibody assay. In this © 2014 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. corticosteroids For moreCopyright information analysis, none of and the 97 patients who were treated with administered.

2 mg/kg every 3 weeks tested All rights reserved. positive for treatment-emergent anti-pembrolizumab antibodies. regarding immune-mediated adverse reactions, please 11/14 read ONCO-1116177-0000 The detection of antibody formation is highly dependent on the sensitivity and specificity of the additional Selected Safety Information on the next page. the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) *Grade 4 abnormalities in this table limited to hyperglycemia, increased aspartate aminotransferase, and anemia (one patient each).

positivity in an assay may be influenced by several factors including assay methodology, sample handling,Please timing of sample concomitant medications, and underlying see collection, additional Selected Safety Information on the disease. For these reasons, comparison of incidence of antibodies to KEYTRUDA with the next page and the Brief Summary of Prescribing Information incidences of antibodies to other products may be misleading.

on the adjacent pages.

The Merck Access Program for KEYTRUDA for Injection Visit

merckaccessprogram-keytruda.com OR

Call

855-257-3932 • Speak with a dedicated representative Monday to Friday between 8 AM and 8 PM ET.

• Ask to be contacted by a field reimbursement associate.

Merck Oncology Copyright © 2014 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. All rights reserved. ONCO-1116177-0000 11/14

ASCOPost.com | SEPTEMBER 10, 2015

PAGE 27

World Congress of Psycho-oncology Geriatric Oncology

Coping With Aging and Cancer: Psychosocial Factors and Geriatric-Specific Interventions

By Margot J. Fromer

“Y

ou can’t control the wind, but you can adjust your sails,” said Mindy Greenstein, PhD, consulting psychologist and author, to begin her talk at the 2015 World Congress of Psycho-Oncology, held in July in Washington, DC. The sense of this proverb pervaded the entire session on cancer and aging.

Mindy Greenstein, PhD

Elders are the fastest-growing population of cancer patients with cancer, said Dr. Greenstein, and their needs are both similar to and different from younger ones. Older patients with cancer are in the midst of a “double whammy” in that they face a life-threatening illness within the context of life’s shortening.

Cancer and Aging: Similar yet Different Similarities between cancer and the negative aspects of aging include coping with the sword of Damocles while living a normal life; uncertainty and vulnerability; learning to make the most of the present; focusing on what is most meaningful in life; and reinforcing one’s most adaptive character strengths and virtues. The last aspect, said Dr. Greenstein, includes transcendence, temperance, wisdom, humanity, courage, and a sense of social justice. “These are characteristics that can help one get through the cancer crisis, but they also can serve as a bridge to the younger generation.”

There are two major differences between cancer and aging. First, young patients with cancer know how different their experience is from that of others their age, whereas older patients with cancer see others like them all around.

Second, older patients have had long life experiences dealing with crises of one sort or another and can use what they have learned to deal with cancer.

By and large, younger patients do not.

In many ways, said Dr. Greenstein,

coping with cancer is a lot like coping with aging, so clinicians can teach patients to use skills derived from the latter to get them through the former.

Silver Tsunami ‘Silver tsunami’ is the term being used to describe the crisis in cancer care, said Jimmie Holland, MD, Wayne E. Chapman Chair in Psychiatric Oncology, Memorial Sloan Kettering Cancer Center (Memorial), New York. It refers to people with the highest incidence of cancer (59% of all patients) and for whom there are often the fewest psychosocial resources.

Dr. Holland described two psychosocial resources she developed: Cancer and Aging Reflections of Elders (CARE) and a reading group known as the Vintage Readers Book Club.

The latter began as a group of two— Dr. Holland and her granddaughter— who decided to start a book club reading the Harvard Classics. When her granddaughter went off to college, she suggested continuing the club with some older patients with cancer, most of whom were home alone, isolated, lonely, and bored.

It began as an outgrowth of the Aging and Cancer Group at Memorial but quickly became much more popular.

Dr. Holland continued: “Many types of cancer are now treated as a chronic illness, and for older people, once treatment is finished and they accept that they’re going to survive—at least for a while—it’s just another one of the distressing vagaries of age.”

Older adults in general are often depressed (10% to 20% of them), and 5% to 6% suffer from anxiety disorders. Older patients with cancer report depression at a rate of 17% to 25% and anxiety at a rate of 21% to 28%. Although these numbers are only estimates, it is clear that getting older and having cancer at the same time is not much fun.

Help Is Available There are, however, interventions that can help to improve quality of life, including physical therapy, cognitive behavioral training, education about problems such as symptoms and side effects, spiritual guidance, and assistance with financial resources. And there is CARE, a five-session telephone psychotherapy program that helps people cope with the double whammy of aging and cancer.

The pilot study consisted of 61 patients with cancer (prostate, breast, lymphoma, lung, or gynecologic) who were

Now that the program is up and running, we may add intervention sessions, and we certainly need to do a larger and longer study, but the CARE program has a definitive role in improving the lives of older people with cancer.

—Jimmie Holland, MD

“We meet once a month over lunch to read and discuss the world’s classic literature, with special emphasis on the issues and problems of older people.

For example, we read Ben Franklin’s thoughts on happiness and Cicero’s essay, Old Age. One of the best things about these discussions is the recognition of the universality of human experience and how people learn to see themselves in a broader context.”

recruited by letter. They had to be 70 years of age or older, 6 months post diagnosis, and either in active treatment or 6 months past treatment. They also were required to have high distress and/or anxiety levels.

Master’s-level counselors conducted the telephone sessions, detailed as follows: • Session 1 is an introduction and overview in which the therapist introduces the program and listens to the patient’s story.

More on Psychosocial Oncology and Aging

F

or more on Aging, don’t miss the captivating new book, Lighter as We Go: Virtues, Character Strengths, and Aging, by Mindy Greenstein, PhD, and Jimmie Holland, MD, both of Memorial Sloan Kettering Cancer Center in New York. Available on Amazon and at other booksellers.

For more from the World Congress, don’t miss The ASCO Post Newsreels, video interviews with faculty recorded during the July 2015 World Congress of Psychooncology in Washington, DC. Visit http://video.ascopost. com/ n

• Session 2 deals with coping with losses and facing the unknowns of cancer and aging, as well as with the combined problems of illness and aging, present and future fears, concerns, and worries.

• Session 3 addresses loneliness, the diminished socializing that arises from both aging and cancer, and the stigma attached to aging in our society.

• Session 4 attempts to make peace with one’s life and acquire wisdom by coming to terms with one’s changing sense of self, contributing to the greater good, and passing on what one has learned.

• Session 5 consists of reflection and review.

After completing the pilot, people’s depression and anxiety decreased, as did loneliness. The ability to cope and plan ahead improved, as did finding meaning in life. Dr. Holland concluded: “Now that the program is up and running, we may add intervention sessions, and we certainly need to do a larger and longer study, but the CARE program has a definitive role in improving the lives of older people with cancer.” n Disclosure: Drs. Greenstein and Holland reported no potential conflicts of interest.

The ASCO Post | SEPTEMBER 10, 2015

PAGE 28

In the Clinic Hematology

Brentuximab Vedotin for Consolidation Therapy in High-Risk Hodgkin Lymphoma

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

O

n August 17, 2015, brentuximab vedotin (Adcetris) was approved for consolidation treatment post autologous hematopoietic stem cell transplantation in patients with classic Hodgkin lymphoma who are at high risk of relapse or progression.1,2

Supporting Efficacy Data Approval was based on a double-blind phase III trial (AETHERA) showing prolonged progression-free survival with brentuximab vedotin vs placebo on independent review.2,3 A total of 327 evaluable patients defined as high risk (response to front-line therapy defined as refractory, relapsed disease occurring within 12 months or relapsed disease with extranodal involvement) were randomized to receive brentuximab vedotin 1.8 mg/kg given IV over 30 minutes (n = 167) or placebo (n = 160) every 3 weeks for up to 16 cycles. All patients received best supportive care.

OF NOTE Brentuximab vedotin carries a boxed warning for progressive multifocal leukoencephalopathy, including fatality.

Patients were required to have had complete or partial response or stable disease during the most recent salvage therapy. Patients had a median age of 32 years (range = 18–76 years), most were male (53%) and white (94%), and the median number of prior systemic therapies (excluding autologous hematopoietic stem cell transplantation) was 2 (range = 2–8).

Median follow-up for progression-free survival was 22 months (range = 0–49 months). Median progression-free survival was 42.9+ months (95% confidence interval [CI] = 30.4–42.9+ months) in the brentuximab vedotin group vs 24.1 months (95% CI = 11.5 to not estimable) in the placebo group (stratified hazard ratio = 0.57, P = .001). At the time of the progression-free survival analysis, interim

analysis of overall survival showed no significant difference between the groups.

Patients in the placebo group could receive brentuximab vedotin in a separate trial after disease progression.

How It Works Brentuximab vedotin is an antibodydrug conjugate consisting of a chimeric IgG1 antibody directed against CD30 and the small-molecule microtubuledisrupting agent MMAE (monomethyl auristatin E), which is covalently attached to the antibody via a linker. Preclinical findings indicated that binding of the conjugate to CD30-expressing cells is followed by internalization of the conjugate-CD30 complex and release of MMAE via proteolytic cleavage. Binding of MMAE to tubulin disrupts the microtubule network within the cell, inducing cell-cycle arrest and apoptosis.

How It Is Given The recommended dosage for brentuximab vedotin as consolidation therapy post autologous hematopoietic stem cell transplantation is 1.8 mg/kg up to 180 mg given IV over 30 minutes every 3 weeks. Treatment should be initiated within 4 to 6 weeks after autologous hematopoietic stem cell transplantation or upon recovery from transplantation and should be continued until a maximum of 16 cycles, disease progression, or unacceptable toxicity. Infusion should be interrupted for infusion reaction and discontinued for anaphylaxis.

The starting dose of brentuximab does not need to be changed in patients with mild or moderate renal impairment, but the drug should be avoided in patients with severe renal impairment. The recommended starting dose is 1.2 mg/kg up to 120 mg in patients with mild hepatic impairment; the drug should be avoided in patients with moderate or severe hepatic impairment.

Treatment should be held for new or worsening grade 2 or 3 neuropathy until recovery to grade 1 or baseline and then restarted at 1.2 mg/kg; treatment should be discontinued for grade 4 peripheral neuropathy. Treatment should be held for grade 3 or 4 neutropenia until resolution to baseline or grade ≤ 2.

Granulocyte colony-stimulating factor (G-CSF) prophylaxis should be considered for subsequent cycles. If grade 4 neutropenia recurs despite G-CSF

Brentuximab Vedotin in High-Risk Hodgkin Lymphoma ■■ Brentuximab vedotin (Adcetris) has been approved for consolidation treatment post autologous hematopoietic stem cell transplantation in patients with classic Hodgkin lymphoma who are at high risk of relapse or progression.

■■ The recommended dosage for brentuximab vedotin as consolidation therapy post autologous hematopoietic stem cell transplantation is 1.8 mg/kg up to 180 mg given IV over 30 minutes every 3 weeks.

prophylaxis, treatment discontinuation or dose reduction to 1.2 mg/kg should be considered.

MMAE is primarily metabolized by CYP3A. Coadministration of brentuximab vedotin with the strong CYP3A4 inhibitor ketoconazole increased exposure to MMAE by approximately 34%; patients who are receiving strong CYP3A4 inhibitors (eg, ketoconazole, clarithromycin, indinavir [Crixivan], ritonavir [Norvir], boceprevir [Victrelis]) concomitantly with brentuximab vedotin should be closely monitored for adverse reactions.

Coadministration of brentuximab with the strong CYP3A4 inducer rifampin reduced exposure to MMAE by approximately 46%. Coadministration with P-glycoprotein inhibitors (eg, ketoconazole, cyclosporin A, ritonavir, verapamil) may increase exposure to MMAE, and patients receiving concomitant treatment should be closely monitored for adverse reactions.

Safety Profile In the phase III trial, the most common adverse events of any grade in the brentuximab vedotin group were neutropenia (78% vs 34% in the placebo group), peripheral sensory neuropathy (56% vs 16%), thrombocytopenia (41% vs 20%), anemia (27% vs 19%), and upper respiratory tract infection (26% vs 23%). The most common grade 3 or 4 adverse events were neutropenia (39% vs 10%), peripheral sensory neuropathy (10% vs 1%), and peripheral motor neuropathy (6% vs 1%).

Infusion-related reactions occurred in 15% (grade 3 in 1.7%) vs 2% of patients. Pulmonary toxicity occurred in 5% vs 3%.

Overall, 67% of patients receiving brentuximab vedotin had neuropathy of any grade. The median time to first onset was 14 weeks for any grade neuropathy, 27 weeks for grade 2 neuropathy, and 34 weeks for grade 3 neuropathy. The median time from onset to resolution or improvement was 23 weeks for any grade, 24 weeks for grade 2, and 25 weeks for grade 3. Complete reso-

lution occurred in 59% of patients; of 41% with residual neuropathy, 26% had partial improvement at last evaluation.

Serious adverse events occurred in 25% of the brentuximab vedotin group, with the most common being pneumonia (4%), pyrexia (4%), vomiting (3%), nausea (2%), hepatotoxicity (2%), and peripheral sensory neuropathy (2%).

The most common adverse events leading to dose delays were neutropenia (22%), peripheral sensory neuropathy (16%), upper respiratory tract infection (6%), and peripheral motor neuropathy (6%). Adverse events led to treatment discontinuation in 32% of patients, with the most common causes being peripheral sensory neuropathy (14%), peripheral motor neuropathy (7%), acute respiratory distress syndrome (1%), paresthesia (1%), and vomiting (1%).

Brentuximab vedotin carries a boxed warning for progressive multifocal leukoencephalopathy, including fatality. It also carries warnings/precautions for peripheral neuropathy, anaphylaxis and infusion reactions, hematologic toxicities, serious infections and opportunistic infections, tumor lysis syndrome, hepatotoxicity, pulmonary toxicity, serious dermatologic reactions, and embryo-fetal toxicity. Complete blood cell counts should be monitored before each dose.

Liver enzymes and bilirubin should be routinely monitored. The drug is contraindicated with concomitant bleomycin due to pulmonary toxicity. n References 1. U.S. Food and Drug Administration: Brentuximab vedotin. Available at www.fda. gov. Accessed August 27, 2015.

2. Adcetris (brentuximab vedotin) for injection prescribing information, Seattle Genetics, Inc, August 2015. Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/125388s080lbl. pdf. Accessed August 27, 2015.

3. Moskowitz CH, et al: Lancet 385:1853-1862, 2015.

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ASCOPost.com | SEPTEMBER 10, 2015

PAGE 35

National Cancer Policy Forum Technology

New Techniques in Oncologic Surgery and Radiology: Some Worth the Expense, Some Not So Much

By Margot J. Fromer

I

n recent years, patients with cancer have had the benefit of much high technology: proton-beam radiotherapy, intensity-modulated radiation therapy, various minimally invasive surgery techniques, and robots in the operating room. They all receive hype in the professional and public press, and patients and physicians demand their use. They are all more expensive—many wildly so—than the techniques they replace.

In light of this trend, a recent National Cancer Policy Forum workshop titled “Appropriate Use of Advanced Technologies for Radiation Therapy and Surgery in Oncology” sought to examine the clinical benefits and comparative effectiveness of emerging advanced technologies for cancer treatment in radiotherapy and surgery.

ating the clinical benefit of new devices is more difficult than testing new drugs due to the difference in regulatory oversights. Unlike new drugs that require clinical trials for U.S. Food and Drug Administration approval, devices often proliferate the market without evidence established in clinical trials.

Advances in Radiotherapy Radiation technology has been burgeoning of late, with intensity-modulated radiation therapy, various forms of stereotactic radiotherapy, particle beam therapy, and proton-beam radiotherapy. They all have the potential for better clinical outcomes and reduced treatment-related morbidity, but they are all significantly more expensive than older techniques. Moreover, some do not necessarily confer extra benefit.

Some of the “sexy” new machinery may be better than its older counterparts, and although there is some evidence to that effect, there is insufficient comparative research. This is especially troubling, because about half of all patients with cancer receive radiotherapy.

Ralph R. Weichselbaum, MD

“The increased cost of novel treatments without adequate assessment on patient outcomes warrants further discussion,” said Ralph R. W ­ eichselbaum, MD, Chair of Radiation and Cellular Oncology at the University of Chicago Medicine and Planning Committee CoChair of the workshop. “We need a critical assessment of the clinical [efficacy] and cost-effectiveness of emerging technologies in radiation and surgery.”

In addition, new technology often dominates discussions of value in health care, said Ya-Chen Tina Shih, PhD, Planning Committee Co-Chair.

The goal, she said, is to find the best treatments that patients and the healthcare system can afford. However, evalu-

Anthony Zietman, MD

“There are three basic principles underlying radiotherapy,” said Anthony Zietman, MD, Associate Director, Harvard Radiation Oncology and Director, Genitourinary Service, Massachusetts General Hospital: direct radiation-related complications do not occur in nonirradiated tissue; irradiating normal tissue does not benefit patients; and the therapeutic ratio can be optimized by maxi-

mizing the radiation dose to the tumor and minimizing the normal tissue dose.

Although these principles appear to clearly obvious, until recently, radiation oncologists have not been able to fully protect normal tissue, even as they did a good job irradiating tumors. Now there is proton-beam radiotherapy, the “point of the arrow,” as Dr. Zietman called it.

Traditional x-rays (photons) attenuate progressively with the depth of tissue, but they continue to deposit radiation beyond the tumor target, thus bathing normal tissue in unwanted radiation.

However, proton therapy has a precisely defined range with no radiation delivered beyond a specified point. Hence, there is no damage to normal tissue.

Although using proton-beam radiotherapy may seem like a no-brainer in theory, it may not necessarily be the case in practice. The technology is complicated, the machinery is enormous and tremendously heavy (requiring its own real estate), and the cost ranges in the hundreds of millions for its initial installation and many millions each year for its use and maintenance. Very few cancer centers have the required resources.

Proton beams are generated by a cyclotron, which accelerates hydrogen protons to two-thirds the speed of light.

The hydrogen protons are then shot through and focused by magnets toward a gantry that can rotate 360° around the patient. Inside the gantry is a nozzle that weighs 21,000 pounds. This nozzle guides the beam to the patient who, in schematic depictions, appears no bigger than a bug amid the gigantic machinery.

There are currently 14 of these behemoths in the United States, 11 are under construction, and more are in the offing.

Proton-beam radiotherapy has clinical advantages, said Dr. Zietman. The integral dose of radiation is smaller, and there is no exit dose. Therefore, it improves acute treatment tolerance, allows

delivery of higher doses of radiation, and can be integrated with systemic chemotherapy. It also reduces late effects.

It is thought that children have the most to gain from proton therapy because of the profoundly negative effects of any type of radiation on growth and development as well as a substantial risk of radiation-induced cancers over the remainder of their lives. There is, however, no classic comparative effectiveness research to prove this claims because most physicians would be uncomfortable randomizing their pediatric patients is such a trial in which the conventional radiation arm is very likely to prove inferior.

Adult indications for protons include tumors of the skull base, eyes, spine, and sacrum. “It’s not so much that the evidence is strong for these indications but rather that the alternatives are unacceptable,” said Dr. Zietman.

Randomized controlled trials of proton-beam radiotherapy in both children and adults are problematic.

There are ethical objections; trials need to be very large and very long, and the advantages are small and arrive late; and the initial investment for the technology is huge—perhaps too big for a treatment that may have limited advantages. Despite these considerations, Dr. Zietman said protonbeam radiotherapy is here to stay for a number of reasons. The treatment can be accurate, effective, and perhaps the best choice for pediatric solid tumors and some adult tumors. It rides the current minimally invasive popularity wave. Its technical and biologic advances create a “personalized” dose.

New centers are quickly being established around the world.

Money Still Matters Even if clinical research indicated that proton-beam therapy is an uncontinued on page 36

Visit The ASCO Post website at ASCOPost.com

The ASCO Post | SEPTEMBER 10, 2015

PAGE 36

National Cancer Policy Forum New Techniques in Surgery and Radiology continued from page 35

equivocally good thing, cost remains a problem. James Yu, MD, Associate Professor of Therapeutic Radiology, Yale University, said that cost has always been problematic, just not as dramatic as it is now. He noted that in 1979, the National Research Council reported expenditures of $4 billion for new technology, and no one knew whether it did any good. That sum now seems downright paltry.

James Yu, MD

The personal “financial toxicity” of health care is staggering now, he said, and the burden affects the quality of life of patients with cancer, so even though a treatment is physically safe, it can have an ultimately negative affect. “Therefore, rejecting low value or overly expensive treatments should be a top priority.”

What about Medicare, which pays for most of it? Reimbursement for intensity-modulated radiation therapy and proton-beam radiotherapy has surpassed older technologies, and the cost is passed on to taxpayers and patients. For example, in prostate cancer in 2005, three-dimensional ra-

diotherapy costs $20,588; intensitymodulated radiation therapy costs $31,574; and in 2008 the price tag for proton-beam radiotherapy is $13,753 more than intensity-modulated radiation therapy. In 2005, intensitymodulated radiation therapy cost Medicare $282 million more than three-dimensional radiotherapy for prostate cancer, though reimbursement has steadily declined over the past decade. In its place, protonbeam radiotherapy has the potential to cost Medicare hundreds of millions of dollars more than intensitymodulated radiation therapy —for prostate cancer alone.

Dr. Yu said that although about 50% of all patients with cancer require radiotherapy, only 1.6% of all National Institutes of Health cancer funding went to radiation research in 2013.

This amount should be significantly increased, he added. Moreover, insurance coverage with development of evidence is not applied evenly; therefore, all patients undergoing treatment with a new technology should be enrolled in a study.

Deciding on coverage of any device or technology requires review of high-quality studies that provide direct evidence of positive outcomes. The problem is that many, probably most, have not benefited from such studies. Although there is intense public interest in covering high-tech devices, published evidence has been suggestive of benefit but insufficient. In addition, clinical trials usually do not have enough subjects representative of the Medicare population.

David C. Miller, MD

Advances in Surgery The challenge in surgery, said David C. Miller, MD, Associate Professor of Urology, University of Michigan Medical School, Ann Arbor, is to enhance accessibility to minimally invasive procedures.

One such avenue is the popular, but not necessarily always better, da Vinci Surgical System for robotic-assisted laparoscopic surgery, cleared by the U.S. Food and Drug Administration in 2000. It carries a number of advantages: • Better visualization of the operative field: three-dimensional, high-definition, and 10x magnification.

• Greater flexibility of the robot arm’s “wrist” than a natural wrist.

• More precise movements and dampening of hand tremors.

• Improved ergonomics.

• Facilitation of laparoscopic surgery, which carries the advantages of smaller incisions, shorter hospital stay, and easier short-term recovery.

The da Vinci Surgical System enjoyed widespread and almost immediate success. For example, of the 111 surgeons in Michigan who performed 3,730 prostatectomies between March 2012 and June 2015, 93% used this system over open surgery. The robot is also used for cancer of the bladder, kidneys,

uterus, cervix, ovaries, colon, pancreas, thyroid, lung, esophagus, tonsil, and tongue base.

It’s popular, but is it really better?

No one knows for sure because although there are observational studies about its advantages, except for cystectomy, rectal excision, and radical prostatectomy, there are few randomized controlled trials. And there is no obvious reason to believe it is better for cancer control or that it provides better functional outcomes such as urinary control and erectile function, said Dr. Miller. In addition, current data are somewhat mixed regarding the benefits of robotic surgery for functional outcomes such as urinary control and erectile function.

Like proton-beam radiotherapy, the da Vinci Surgical System is often more expensive than open surgery. Each unit costs more than $1 million; annual service costs at least $150,000; the instruments are disposable and cost about $2,000 per case. At least one study estimated that this adds up to an average of $3,200 more per case than open surgery.

Is it worth it? “We don’t know yet,” said Dr. Miller. “The da Vinci has definite benefits and some unintended adverse consequences, including higher cost. Comparative clinical [efficacy] and cost-effectiveness has not been fully defined, so we need to make a greater effort to improve its performance and outcomes.” n Disclosure: Drs. Weichselbaum, Shih, Zietman, and Miller reported no potential conflicts of interest. Dr. Yu has received research funding from 21st Century Oncology LLC.

How Do You Speak With Your Patients About Their Level of Distress?

The ASCO Post Newsreels is pleased to present Jimmie C. Holland, MD, of Memorial Sloan Kettering Cancer Center, and Tammy A. Schuler, PhD, of the Association for Behavioral and Cognitive Therapies. Drs. Holland and Schuler demonstrate a dialogue between a clinician and a recently diagnosed cancer patient whose distress was discovered by the Distress Thermometer.

Watch this short video recorded during the 2015 World Congress on Psycho-oncology, July 2015, Washington, DC. Visit http://bit.ly/1UOBUUp for this demonstration and more on The ASCO Post Newsreels.

ASCOPost.com | SEPTEMBER 10, 2015

PAGE 37

Journal Spotlight Hematology

Refractory Multiple Myeloma continued from page 1

received lenalidomide at 25 mg on days 1 to 21 and oral dexamethasone at 40 mg on days 1, 8, 15, and 22.

phalan in 69% and 61%, thalidomide [Thalomid] in 48% in both, lenalidomide in 5% and 6%). Response to the most recent line of therapy was refractory for 35% in both groups, including 22% and 21% refractory to bortezomib and 9% and 11% refractory to thalidomide, and relapse in 65% in both.

Role of Elotuzumab in Myeloma ■■ The addition of elotuzumab to lenalidomide-dexamethasone significantly increased progression-free survival in patients with relapsed/refractory multiple myeloma.

■■ Benefit was observed across subgroups, including patients with resistance to their most recent therapy and those with the del(17p) variant.

Progression-Free Survival

Meletios Dimopoulos, MD

The coprimary endpoints were progression-free survival and objective response rate. The primary analysis of progression-free survival used independent review committee assessment of tumor response and censoring of data for patients who received subsequent myeloma therapy or missed assessments. Intention-to-treat analysis was performed as a supportive evaluation.

The elotuzumab and control groups were generally balanced for age (median, 67 and 66 years), sex (60% and 59% male), Eastern Cooperative Oncology Group performance status (0 for 50% and 45%, 1 for 43% and 45%, 2 for 8% and 11%), race/ethnicity (82% and 86% white, 10% Asian in both), presence of del(17p) (32% in both), presence of t(4:14) (9% and 10%), and stage (I in 44% and 42%, II in 32% in both, III in 21% in both).

The study groups were also balanced for number of previous treatments (median of 2 in both, ≥ 3 in 16% in both), previous stem cell transplantation (52% and 57%), and previous therapies (bortezomib [Velcade] in 68% and 71%, mel-

After a median follow-up of 24.5 months, median progression-free survival in the primary analysis was 19.4 months (95% confidence interval [CI] = 16.6–22.2 months) in the elotuzu­ mab group vs 14.9 months (95% CI = 12.1–17.2 months) in the control group (hazard ratio [HR] = 0.70, P < .001).

The outcome was similar in the inten-

an increased benefit of elotuzumab among patients diagnosed at least 3.5 years before study entry (median, 26.0 vs 17.3 months, HR = 0.55, P < .001).

Overall response rates were 79% vs 66% (odds ratio = 1.9, P < .001), with a complete response in 4% vs 7%. At the time of progression-free survival analysis, when 49% of prespecified

Patients with relapsed or refractory multiple myeloma who received a combination of elotuzumab, lenalidomide, and dexamethasone had a significant relative reduction of 30% in the risk of disease progression or death.

—Sagar Lonial, MD, Meletios Dimopoulos, MD, and colleagues

tion-to-treat analysis (HR = 0.68, 95% CI = 0.56–0.83). Rates of progressionfree survival were 68% vs 57% at 1 year and 41% vs 27% at 2 years in the elotuzumab and control groups, respectively.

The benefit of elotuzumab was consistent across subgroups, including patients aged 65 years and older and those with resistance to the most recent line of therapy, stage III disease, previous exposure to bortezomib or immunomodulatory drugs, previous stem cell transplantation, and those with the del(17p) variant. Multivariate analysis suggested

deaths for final overall survival analysis had occurred, 30% of the elotuzumab group and 37% of the control group had died.

Adverse Events The most common grade 3 or 4 hematologic adverse events in the elotuzumab group were lymphocytopenia (77% vs 49% in control group), neutropenia (34% vs 44%), anemia (19% vs 21%), and thrombocytopenia (19% vs 20%). The most common grade 3 or 4 nonhematologic adverse events were

fatigue (8% vs 8%) and diarrhea (5% vs 4%). Grade 3 or 4 cardiac disorders occurred in 4% and 6%, and grade 3 or 4 renal disorders occurred in 4% in both groups. Serious adverse events were reported in 65% and 57% of ­patients.

Infections were reported in 81% vs 74% of patients, with infection rates being identical in the two groups after adjustment for drug exposure (197 events per 100 patient-years). Infusion reactions were reported in 33 elotuzumab patients (10%, grade 1 or 2 in 29 and grade 3 in 4), with 70% of reactions occurring during the first dose. Infusion was interrupted in 5% of patients. Reactions resolved in all patients except 2 (1%), with both discontinuing treatment.

The investigators concluded: “Patients with relapsed or refractory multiple myeloma who received a combination of elotuzumab, lenalidomide, and dexamethasone had a significant relative reduction of 30% in the risk of disease progression or death.” n

Disclosure: The study was funded by BristolMyers Squibb and AbbVie Biotherapeutics. For full disclosures of the study authors, visit www.nejm.org.

Reference 1. Lonial S, Dimopoulos M, Palumbo A, et al: Elotuzumab therapy for relapsed or refractory multiple myeloma. N Engl J Med 373:621-631, 2015.

Elotuzumab Ushers in a New Era in Myeloma Therapy

By S. Vincent Rajkumar, MD

T

he long wait for monoclonal antibodies for the treatment of multiple myeloma is over. In the landmark ELOQUENT-2 study, reviewed in this issue of The ASCO Post, Lonial and colleagues convincingly demonstrate the effectiveness of elotuzumab, a monoclonal antibody directed against SLAMF7, in the treatment of relapsed multiple myeloma.1 The key findings of this randomized trial are straightforward: An absolute Dr. Rajkumar is Professor of Medicine, Division of Hematology, Mayo Clinic, Rochester, Minnesota.

improvement in response rate of 15%, a median improvement in progressionfree survival of 4.5 months, and no significant added toxicity were noted with the addition of elotuzumab to standard therapy. The results are clear and compelling. I believe that elotuzumab will be approved for the treatment of myeloma within the next several months and will usher in a new era in myeloma therapy.

Key Points From ELOQUENT-2 There are some key points from ELOQUENT-2 worthy of highlighting. First, elotuzumab does not pos-

sess significant single-agent activity in myeloma but yet appears to provide a meaningful therapeutic benefit in this trial when combined with lenalidomide [Revlimid]/low-dose dexamethasone. This finding raises the blinds on the increasing complexity of developing myeloma treatments. The demonstration of the clinical activity of drugs like elotuzumab, which need partner drugs to deliver synergistic benefit, requires large phase III trials and considerable risk of failure. This is in contrast to drugs like carfilzomib (Kyprolis), which have clear single-agent activity

that can garner accelerated approval based on single-arm phase II trials.

Second, the trial illustrates the limitations of using median time-toevent estimates to assess the value of a new drug in the relapsed/refractory myeloma setting. Although the median improvement in progression-free survival is modest, the true benefit of elotuzumab is best appreciated in the proportion of patients who are progression free at 2 years, where the difference is much more striking: 27% (control) vs 41% (elotuzumab). continued on page 38

The ASCO Post | SEPTEMBER 10, 2015

PAGE 38

Perspective

S. Vincent Rajkumar, MD continued from page 38

Third, I applaud the study team for designing a control arm (lenalidomide and low-dose dexamethasone) that is more in line with actual clinical practice rather than simply playing it

4 neuropathy in approximately 25% of patients. The moral of the story is that the control arm for a regulatory study does not need to be an approved regimen: It just needs to be one that is considered by investigators in the field to be a reasonable standard.

Strangely, how well elotuzumab is used in the clinic may depend largely on how another monoclonal antibody, daratumumab, fares in the approval process.

—S. Vincent Rajkumar, MD

safe and using a control arm that is unnecessarily more toxic. Thus, although the full approval of lenalidomide in relapsed myeloma was in combination with high-dose dexamethasone, the elotuzumab trial used low-dose dexamethasone based on data from a nonregulatory cooperative group trial showing that lowering the dose of dexamethasone reduced morbidity and mortality.

This approach is also in contrast to the trial supporting approval of panobinostat (Farydak), in which use of the approved dose of bortezomib (Velcade) rather than the less-toxic onceweekly schedule resulted in grade 3 or

Study Caveats There are a few important caveats in interpreting this study. The trial was not blinded, which raises some uncertainty in the progression-free survival estimates. There was no improvement in quality of life. Merely demonstrating that a drug did not worsen quality of life is simply not enough; after all, we are hoping that delaying disease progression is associated with at least some improvement in patients’ perceived quality of life. Finally, there is no evidence that patients lived longer as a result of the therapy, since no overall survival benefit has been shown so far; sur-

vival estimates are “immature”—we shall wait and see.

So, what then is the value of a new drug that appears to have benefit based solely on surrogate endpoints, with no real clinical benefit having been shown yet in terms of either quality of life or overall survival? It depends on the setting. In this case, we have a new drug that is well tolerated in the treatment of relapsed myeloma.

In this setting, progression-free survival has been consistently shown to be an excellent surrogate of clinical benefit in myeloma.

Therefore, I have no reservation in stating that the results of this trial are sufficient proof of the effectiveness of elotuzumab in relapsed myeloma.

Had this study been in the front-line or maintenance setting with an approved drug, we would need to see evidence of true clinical benefit to be enthusiastic.

Thus, the front-line elotuzumab study will be subject to greater scrutiny.

Real-World Implications What are the real-world implications of this study once the drug is approved? Strangely, how well elotuzumab is used in the clinic may depend largely on how another monoclonal antibody, daratumumab, fares in the approval process.

Daratumumab targets CD38 and, unlike elotuzumab, has substantial single-agent activity (approximately

30% in heavily pretreated patients).

This means it may secure accelerated approval based on phase II data and may be on the market at nearly the same time as elotuzumab. Time will tell. I expect that there will be competition between the two drugs. Since myeloma is incurable, I would try elotuzumab if daratumumab does not work and vice versa. It is also likely that these antibodies will be added not just to the regimens that were used in regulatory trials but to all manner of myeloma treatments, analogous to the way rituximab (Rituxan) is used in lymphoma. However, the complicating twist in myeloma is that we may have to adjudicate the clinical value of two antibodies simultaneously.

I do expect new monoclonal antibodies in myeloma to be pricey, similar to other new myeloma drugs. The cost will pose an enormous financial dilemma in the United States and elsewhere in the world, especially if it comes to pass that we wind up combining two monoclonal antibodies with carfilzomib (Kyprolis), pomalidomide (Pomalyst), and dexamethasone. n

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

Reference 1. Lonial S, Dimopoulos M, Palumbo A, et al: Elotuzumab therapy for relapsed or refractory multiple myeloma. N Engl J Med 373:621-631, 2015.

Announcements

NCI and Sage Bionetworks Present: Up for A Challenge?

Award up to $50,000

T

he National Cancer Institute (NCI) Division of Cancer Control and Population Sciences is partnering with Sage Bionetworks for “Up for a Challenge (U4C): Stimulating Innovation in Breast Cancer Genetic Epidemiology.” This prize competition aims to explore the genomic basis of breast cancer in diverse populations. Researchers who may be interested in this competition would be scientists involved in genetic epidemiology, bioinformatics, and data science.

Studies suggest that genetic factors play a role in determining who is at in-

creased risk of developing breast cancer, as well as what type of breast cancer they develop. The goal of U4C is to encourage innovative approaches to more fully explain the genetic basis of breast cancer.

Specifically, U4C aims to use innovative approaches to identify novel pathways—including new genes or combinations of genes, genetic variants, or sets of genomic features—involved in breast cancer risk in order to generate new biologic hypotheses. Through U4C, NCI aims to increase the number and diversity of researchers address-

ing a difficult problem by encouraging broader collaborations. Ideally, this will result in new insights that could help improve breast cancer prevention, screening, and/or treatment.

Newly Accessible Data U4C participants will be able to apply for controlled access to genetic epidemiologic data from thousands of breast cancer cases and controls from ethnically diverse populations. Some of these data sets are being made available to researchers for the first time for this competition.

NCI will award up to $50,000 and other prizes based on the identification of novel findings, replication of findings, innovation of approach, evidence of novel biologic hypotheses, and collaboration. U4C offers participants an opportunity to advance scientific knowledge of the causes of breast cancer, the second most common cancer in the world.

Visit the U4C website (https:// www.synapse.org/upforachallenge) for more information about the goals of U4C, applications, due dates, rules, and other frequently asked questions. n

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For men with mCRPC who progressed on ADT

In a clinical trial, patients had a median overall survival on ZYTIGA® (abiraterone acetate) of…*

More than 1,000 days.

And every day tells a story.

35.3 5.2 MONTHS IMPROVEMENT IN MEDIAN OVERALL SURVIVAL

MONTHS MEDIAN OVERALL SURVIVAL FOR ZYTIGA® plus prednisone† vs 30.1 MONTHS with placebo plus prednisone (active compound).‡

compared with placebo plus prednisone.

Co-primary end point—overall survival: hazard ratio (HR)=0.792; 95% CI: 0.655, 0.956; P=0.0151; prespecified value for statistical significance not reached.

Co-primary end point—radiographic progression-free survival: median not reached for ZYTIGA® plus prednisone vs a median of 8.28 months for placebo plus prednisone. HR=0.425; 95% CI: 0.347, 0.522; P<0.0001.

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*Study Design: ZYTIGA®, in combination with prednisone, was evaluated in a phase 3, randomized, double-blind, placebo-controlled, multicenter trial in patients with mCRPC who had not received prior chemotherapy (N=1,088). Patients were using a luteinizing hormone-releasing hormone (LHRH) agonist or were previously treated with orchiectomy. In the ZYTIGA® arm, patients received ZYTIGA® 1,000 mg orally once daily + prednisone 5 mg orally twice daily. In the placebo arm, patients received placebo orally once daily + prednisone 5 mg orally twice daily. In this study, the co-primary efficacy end points were overall survival (OS) and radiographic progression-free survival.

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IMPORTANT SAFETY INFORMATION (cont) Increased ZYTIGA® Exposures With Food—ZYTIGA® must be taken on an empty stomach. No food should be eaten for at least two hours before the dose of ZYTIGA® is taken and for at least one hour after the dose of ZYTIGA® is taken.

Abiraterone Cmax and AUC0-∞ (exposure) were increased up to 17- and 10-fold higher, respectively, when a single dose of abiraterone acetate was administered with a meal compared to a fasted state.

Hepatotoxicity—Monitor liver function and modify, withhold, or discontinue ZYTIGA® dosing as recommended (see Prescribing Information for more information). Measure serum transaminases (ALT and AST) and bilirubin levels prior to starting treatment with ZYTIGA®, every two weeks for the first three months of treatment, and monthly thereafter.

Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop.

Elevations of AST, ALT, or bilirubin from the patient’s baseline should prompt more frequent monitoring. If at any time AST or ALT rise above five times the upper limit of normal (ULN) or the bilirubin rises above three times the ULN, interrupt ZYTIGA® treatment and closely monitor liver function.

Drug Interactions—Based on of rifampin, a strong CYP3A4 i inducers during ZYTIGA® treat dosing frequency only during interaction trial, co-administra the pharmacokinetics of abira ZYTIGA® is an inhibitor of the h substrates with a narrow thera a dose reduction of the CYP2D use of ZYTIGA® with drugs tha related to the CYP2C8 substra Use in Specific Populations— (Child-Pugh Class C).

†At a prespecified interim analysis for OS, compared with 43% (234/542) of patient ‡Prednisone, as a single agent, is not appr

ADT=androgen-deprivation therapy.

Janssen Biotech, Inc. © Janssen Biotech, Inc. 2014 6/14 016819-140612

Please see brief summary of full Prescribing Information on subsequent pages.

Learn more today at

www.zytigahcp.com.

B:7.875 in T:7.625 in S:6.625 in

For men with mCRPC who progressed on ADT

In a clinical trial, patients had a median overall survival on ZYTIGA® (abiraterone acetate) of…*

More than 1,000 days.

And every day tells a story.

35.3 5.2 MONTHS IMPROVEMENT IN MEDIAN OVERALL SURVIVAL

MONTHS MEDIAN OVERALL SURVIVAL FOR ZYTIGA® plus prednisone† vs 30.1 MONTHS with placebo plus prednisone (active compound).‡

compared with placebo plus prednisone.

Co-primary end point—overall survival: hazard ratio (HR)=0.792; 95% CI: 0.655, 0.956; P=0.0151; prespecified value for statistical significance not reached.

Co-primary end point—radiographic progression-free survival: median not reached for ZYTIGA® plus prednisone vs a median of 8.28 months for placebo plus prednisone. HR=0.425; 95% CI: 0.347, 0.522; P<0.0001.

IMPORTANT SAFETY INFORMATION (cont) Increased ZYTIGA® Exposures With Food—ZYTIGA® must be taken on an empty stomach. No food should be eaten for at least two hours before the dose of ZYTIGA® is taken and for at least one hour after the dose of ZYTIGA® is taken.

Abiraterone Cmax and AUC0-∞ (exposure) were increased up to 17- and 10-fold higher, respectively, when a single dose of abiraterone acetate was administered with a meal compared to a fasted state.

Hepatotoxicity—Monitor liver function and modify, withhold, or discontinue ZYTIGA® dosing as recommended (see Prescribing Information for more information). Measure serum transaminases (ALT and AST) and bilirubin levels prior to starting treatment with ZYTIGA®, every two weeks for the first three months of treatment, and monthly thereafter.

Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop.

Elevations of AST, ALT, or bilirubin from the patient’s baseline should prompt more frequent monitoring. If at any time AST or ALT rise above five times the upper limit of normal (ULN) or the bilirubin rises above three times the ULN, interrupt ZYTIGA® treatment and closely monitor liver function. *Study Design: ZYTIGA®, in combination with prednisone, was evaluated in a phase 3, randomized, double-blind, placebo-controlled, multicenter trial in patients with mCRPC who had not received prior chemotherapy (N=1,088). Patients were using a luteinizing hormone-releasing hormone (LHRH) agonist or were previously treated with orchiectomy. In the ZYTIGA® arm, patients received ZYTIGA® 1,000 mg orally once daily + prednisone 5 mg orally twice daily. In the placebo arm, patients received placebo orally once daily + prednisone 5 mg orally twice daily. In this study, the co-primary efficacy end points were overall survival (OS) and radiographic progression-free survival.

ADT=androgen-deprivation therapy.

Janssen Biotech, Inc. © Janssen Biotech, Inc. 2014 6/14 016819-140612

Please see brief summary of full Prescribing Information on subsequent pages.

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www.zytigahcp.com. www.zytigahcp.com.

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® is a ®substrate DrugDrug Interactions—Based Interactions—Based on inon vitro in vitro data,data, ZYTIGA ZYTIGA is a substrate of CYP3A4. of CYP3A4.

In a drug In a drug interaction interaction trial, trial, co-administration co-administration of rifampin, of rifampin, a strong a strong CYP3A4 CYP3A4 inducer, inducer, decreased decreased exposure exposure of abiraterone of abiraterone by 55%. by 55%.

AvoidAvoid concomitant concomitant strong strong CYP3A4 CYP3A4 ® treatment. ® treatment. ® ® inducers inducers during during ZYTIGA ZYTIGA If a strong If a strong CYP3A4 CYP3A4 inducer inducer mustmust be co-administered, be co-administered, increase increase the ZYTIGA the ZYTIGA dosing dosing frequency frequency only only during during the co-administration the co-administration period period [see Dosage [see Dosage and Administration and Administration (2.3)].(2.3)].

In a dedicated In a dedicated drugdrug interaction interaction trial, trial, co-administration co-administration of ketoconazole, of ketoconazole, a strong a strong inhibitor inhibitor of CYP3A4, of CYP3A4, had no hadclinically no clinically meaningful meaningful effect effon ect on the pharmacokinetics the pharmacokinetics of abiraterone. of abiraterone. ® is an ® is ZYTIGA ZYTIGA inhibitor an inhibitor of theofhepatic the hepatic drug-metabolizing drug-metabolizing enzyme enzyme CYP2D6.

CYP2D6.

AvoidAvoid co-administration co-administration with with CYP2D6 CYP2D6 substrates substrates with with a narrow a narrow therapeutic therapeutic index. index.

If alternative If alternative treatments treatments cannot cannot be used, be used, exercise exercise caution caution and consider and consider ® inhibits ® inhibits a dose a dose reduction reduction of theofCYP2D6 the CYP2D6 substrate substrate drug.drug.

In vitro, In vitro, ZYTIGA ZYTIGA CYP2C8.

CYP2C8.

There There are no areclinical no clinical datadata on the on the ® ® use of use ZYTIGA of ZYTIGA with with drugsdrugs that are thatsubstrates are substrates of CYP2C8. of CYP2C8.

Patients Patients should should be monitored be monitored closely closely for signs for signs of toxicity of toxicity related related to the toCYP2C8 the CYP2C8 substrate substrate if used if used concomitantly concomitantly with with abiraterone abiraterone acetate. acetate. ® in patients ® in patients Use in Use Specifi in Specifi c Populations—Do c Populations—Do not use notZYTIGA use ZYTIGA with with baseline baseline severe severe hepatic hepatic impairment impairment (Child-Pugh (Child-Pugh ClassClass C). C).

ZYTIGA® (abiraterone acetate) Tablets Brief Summary of Prescribing Information.

INDICATIONS AND USAGE ZYTIGA is a CYP17 inhibitor indicated in combination with prednisone for the treatment of patients with metastatic castration-resistant prostate cancer.

CONTRAINDICATIONS Pregnancy: ZYTIGA can cause fetal harm when administered to a pregnant woman. ZYTIGA is not indicated for use in women. ZYTIGA is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss [see Use in Specific Populations].

WARNINGS AND PRECAUTIONS Hypertension, Hypokalemia and Fluid Retention Due to Mineralocorticoid Excess: ZYTIGA may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition [see Clinical Pharmacology (12.1) in full Prescribing Information]. In the two randomized clinical trials, grade 3 to 4 hypertension occurred in 2% of patients, grade 3 to 4 hypokalemia in 4% of patients, and grade 3 to 4 edema in 1% of patients treated with ZYTIGA [see Adverse Reactions].

Co-administration of a corticosteroid suppresses adrenocorticotropic hormone (ACTH) drive, resulting in a reduction in the incidence and severity of these adverse reactions. Use caution when treating patients whose underlying medical conditions might be compromised by increases in blood pressure, hypokalemia or fluid retention, e.g., those with heart failure, recent myocardial infarction or ventricular arrhythmia. Use ZYTIGA with caution in patients with a history of cardiovascular disease. The safety of ZYTIGA in patients with left ventricular ejection fraction <50% or New York Heart Association (NYHA) Class III or IV heart failure (in Study 1) or NYHA Class II to IV heart failure (in Study 2) was not established because these patients were excluded from these randomized clinical trials [see Clinical Studies (14) in full Prescribing Information]. Monitor patients for hypertension, hypokalemia, and fluid retention at least once a month. Control hypertension and correct hypokalemia before and during treatment with ZYTIGA. Adrenocortical Insufficiency: Adrenal insufficiency occurred in the two randomized clinical studies in 0.5% of patients taking ZYTIGA and in 0.2% of patients taking placebo. Adrenocortical insufficiency was reported in patients receiving ZYTIGA in combination with prednisone, following interruption of daily steroids and/or with concurrent infection or stress.

Use caution and monitor for symptoms and signs of adrenocortical insufficiency, particularly if patients are withdrawn from prednisone, have prednisone dose reductions, or experience unusual stress. Symptoms and signs of adrenocortical insufficiency may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with ZYTIGA. If clinically indicated, perform appropriate tests to confirm the diagnosis of adrenocortical insufficiency. Increased dosage of corticosteroids may be indicated before, during and after stressful situations [see Warnings and Precautions].

Hepatotoxicity: In the two randomized clinical trials, grade 3 or 4 ALT or AST increases (at least 5X ULN) were reported in 4% of patients who received ZYTIGA, typically during the first 3 months after starting treatment. Patients whose baseline ALT or AST were elevated were more likely to experience liver test elevation than those beginning with normal values. Treatment discontinuation due to liver enzyme increases occurred in 1% of patients taking ZYTIGA. No deaths clearly related to ZYTIGA were reported due to hepatotoxicity events.

Measure serum transaminases (ALT and AST) and bilirubin levels prior to starting treatment with ZYTIGA, every two weeks for the first three months of treatment and monthly thereafter. In patients with baseline moderate hepatic impairment receiving a reduced ZYTIGA dose of 250 mg, measure ALT, AST, and bilirubin prior to the start of treatment, every week for the first month, every two weeks for the following two months of treatment and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop.

Elevations of AST, ALT, or bilirubin from the patient’s baseline should prompt more frequent monitoring. If at any time AST or ALT rise above five times the ULN, or the bilirubin rises above three times the ULN, interrupt ZYTIGA treatment and closely monitor liver function.

Re-treatment with ZYTIGA at a reduced dose level may take place only after return of liver function tests to the patient’s baseline or to AST and ALT less than or equal to 2.5X ULN and total bilirubin less than or equal to 1.5X ULN [see Dosage and Administration (2.2) in full Prescribing Information].

The safety of ZYTIGA re-treatment of patients who develop AST or ALT greater than or equal to 20X ULN and/or bilirubin greater than or equal to 10X ULN is unknown.

Increased ZYTIGA Exposures with Food: ZYTIGA must be taken on an empty stomach. No food should be consumed for at least two hours before the dose of ZYTIGA is taken and for at least one hour after the dose of ZYTIGA

ZYTIGA® (abiraterone acetate) Tablets is taken. Abiraterone Cmax and AUC0-∞ (exposure) were increased up to 17and 10-fold higher, respectively, when a single dose of abiraterone acetate was administered with a meal compared to a fasted state. The safety of these increased exposures when multiple doses of abiraterone acetate are taken with food has not been assessed [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information].

ADVERSE REACTIONS The following are discussed in more detail in other sections of the labeling: • Hypertension, Hypokalemia, and Fluid Retention due to Mineralocorticoid Excess [see Warnings and Precautions].

• Adrenocortical Insufficiency [see Warnings and Precautions].

• Hepatotoxicity [see Warnings and Precautions].

• Increased ZYTIGA Exposures with Food [see Warnings and Precautions].

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 clinical practice.

Two randomized placebo-controlled, multicenter clinical trials enrolled patients who had metastatic castration-resistant prostate cancer who were using a gonadotropin-releasing hormone (GnRH) agonist or were previously treated with orchiectomy. In both Study 1 and Study 2 ZYTIGA was administered at a dose of 1,000 mg daily in combination with prednisone 5 mg twice daily in the active treatment arms. Placebo plus prednisone 5 mg twice daily was given to control patients.

The most common adverse drug reactions (≥10%) reported in the two randomized clinical trials that occurred more commonly (>2%) in the abiraterone acetate arm were fatigue, joint swelling or discomfort, edema, hot flush, diarrhea, vomiting, cough, hypertension, dyspnea, urinary tract infection and contusion.

The most common laboratory abnormalities (>20%) reported in the two randomized clinical trials that occurred more commonly (≥2%) in the abiraterone acetate arm were anemia, elevated alkaline phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia, elevated AST, hypophosphatemia, elevated ALT and hypokalemia.

Study 1: Metastatic CRPC Following Chemotherapy: Study 1 enrolled 1195 patients with metastatic CRPC who had received prior docetaxel chemotherapy. Patients were not eligible if AST and/or ALT ≥2.5X ULN in the absence of liver metastases. Patients with liver metastases were excluded if AST and/or ALT >5X ULN. Table 1 shows adverse reactions on the ZYTIGA arm in Study 1 that occurred with a ≥2% absolute increase in frequency compared to placebo or were events of special interest. The median duration of treatment with ZYTIGA was 8 months.

Table 1: Adverse Reactions due to ZYTIGA in Study 1 ZYTIGA with Placebo with Prednisone (N=791) Prednisone (N=394) 1 System/Organ Class All Grades Grade 3-4 All Grades Grade 3-4 Adverse reaction % % % % Musculoskeletal and connective tissue disorders Joint swelling/ discomfort2 29.5 4.2 23.4 4.1 Muscle discomfort3 26.2 3.0 23.1 2.3 General disorders Edema4 26.7 1.9 18.3 0.8 Vascular disorders Hot flush 19.0 0.3 16.8 0.3 Hypertension 8.5 1.3 6.9 0.3 Gastrointestinal disorders Diarrhea 17.6 0.6 13.5 1.3 Dyspepsia 6.1 0 3.3 0 Infections and infestations Urinary tract 11.5 infection 2.1 7.1 0.5 Upper respiratory tract infection 5.4 0 2.5 0 Respiratory, thoracic and mediastinal disorders Cough 10.6 0 7.6 0 Renal and urinary disorders Urinary frequency 7.2 0.3 5.1 0.3 Nocturia 6.2 0 4.1 0

® (abiraterone ® (abiraterone ZYTIGA acetate) Tablets ZYTIGA acetate) Tablets

® (abiraterone ® (abiraterone ZYTIGA acetate) Tablets ZYTIGA acetate) Tablets

Table 1: Adverse Reactions due todue ZYTIGA in Study 1 (continued) Table 3: Adverse Reactions in ≥5%inof≥5% Patients on theon ZYTIGA Arm inArm in Table 1: Adverse Reactions to ZYTIGA in Study 1 (continued) Table 3: Adverse Reactions of Patients the ZYTIGA StudyStudy 2 (continued) 2 (continued) ZYTIGA with with Placebo with with ZYTIGA Placebo Prednisone (N=791) (N=394) ZYTIGA with with Placebo with with Prednisone (N=791)Prednisone Prednisone (N=394) ZYTIGA Placebo 1 Grade 1 Grade Prednisone (N=542) Prednisone (N=540) 3-4 All GradeGrade 3-4 3-4 System/Organ Class ClassAll Grades Prednisone (N=542) Prednisone (N=540) 3-4Grades All Grades System/Organ All Grades 1 Grade 1 Grade ClassClass All Grades 3-4 All GradeGrade 3-4 3-4 Adverse reaction % % % System/Organ All Grades 3-4Grades All Grades Adverse reaction % % % % % System/Organ Adverse reaction % % % % % % Adverse reaction % % Injury,Injury, poisoning and and poisoning procedural procedural Vascular disorders Vascular disorders complications complications Hot flush 22.3 22.3 0.2 0.2 18.1 18.1 0.0 0.0 Hot flush 5 5 Fractures 5.9 5.9 1.4 1.4 2.3 2.3 0 Fractures 0 Hypertension 21.6 21.6 3.9 3.9 13.1 13.1 3.0 3.0 Hypertension Cardiac disorders Cardiac disorders Respiratory, thoracic and and Respiratory, thoracic 6 6 Arrhythmia 7.2 7.2 1.1 1.1 4.6 4.6 1.0 1.0 mediastinal Arrhythmia disorders mediastinal disorders Chest Chest pain orpain chest or chest CoughCough 17.3 17.3 0.0 0.0 13.5 13.5 0.2 0.2 7 7 discomfort 3.8 3.8 0.5 0.5 2.8 2.8 0 discomfort 0 Dyspnea 11.8 11.8 2.4 2.4 9.6 9.6 0.9 0.9 Dyspnea 8 8 Cardiac failurefailure 2.3 2.3 1.9 1.9 1.0 1.0 0.3 0.3 Psychiatric Cardiac disorders Psychiatric disorders 1 Adverse 1 Adverse Insomnia 13.5 13.5 0.2 0.2 11.3 11.3 0.0 0.0 eventsevents gradedgraded according to CTCAE version 3.0 3.0 Insomnia according to CTCAE version 2 Includes 2 Includes terms terms Arthritis, Arthralgia, Joint swelling, and Joint poisoning and and Arthritis, Arthralgia, Joint swelling, and stiffness Joint stiffness Injury,Injury, poisoning 3 Includes 3 Includes procedural complications terms terms Muscle spasms, Musculoskeletal pain, Myalgia, procedural complications Muscle spasms, Musculoskeletal pain, Myalgia, Musculoskeletal discomfort, and Musculoskeletal stiffness Musculoskeletal discomfort, and Musculoskeletal stiffness Contusion 13.3 13.3 0.0 0.0 9.1 9.1 0.0 0.0 Contusion 4 Includes 4 Includes terms terms Edema, EdemaEdema peripheral, PittingPitting edema, and Generalized Edema, peripheral, edema, and Generalized Falls Falls 5.9 5.9 0.0 0.0 3.3 3.3 0.0 0.0 edemaedema Infections and and Infections 5 Includes 5 Includes all fractures with the exception of pathological fracture all fractures with the exception of pathological fracture infestations infestations 6 Includes 6 Includes terms terms Arrhythmia, Tachycardia, Atrial Atrial fibrillation, Arrhythmia, Tachycardia, fibrillation, UpperUpper respiratory respiratory Supraventricular tachycardia, Atrial Atrial tachycardia, Ventricular tachycardia, Supraventricular tachycardia, tachycardia, Ventricular tachycardia, tract infection 12.7 12.7 0.0 0.0 8.0 8.0 0.0 0.0 tract infection Atrial Atrial flutter,flutter, Bradycardia, Atrioventricular block block complete, Conduction Bradycardia, Atrioventricular complete, Conduction Nasopharyngitis 10.7 10.7 0.0 0.0 8.1 8.1 0.0 0.0 Nasopharyngitis disorder, and Bradyarrhythmia disorder, and Bradyarrhythmia Renal Renal and urinary and urinary 7 Includes 7 Includes terms terms AnginaAngina pectoris, Chest Chest pain, and unstable. pectoris, pain,Angina and Angina unstable. disorders disorders Myocardial infarction or ischemia occurred more commonly in the Myocardial infarction or ischemia occurred more commonly in the Hematuria 10.3 10.3 1.3 1.3 5.6 5.6 0.6 0.6 Hematuria placebo arm than the in ZYTIGA arm (1.3% vs. 1.1% placebo arminthan the ZYTIGA arm (1.3% vs.respectively).

1.1% respectively).

Skin and subcutaneous Skin and subcutaneous 8 Includes 8 Includes terms terms Cardiac failure,failure, Cardiac failurefailure congestive, Left ventricular Cardiac Cardiac congestive, Left ventricular tissuetissue disorders disorders dysfunction, Cardiogenic shock,shock, Cardiomegaly, Cardiomyopathy, and and dysfunction, Cardiogenic Cardiomegaly, Cardiomyopathy, Rash Rash 8.1 8.1 0.0 0.0 3.7 3.7 0.0 0.0 Ejection fraction decreased Ejection fraction decreased 1 Adverse 1 Adverse eventsevents gradedgraded according to CTCAE version 3.0 3.0 according to CTCAE version Table 2Table 2 showsshows laboratory abnormalities of interest from Study 1. Grade 3-4 3-4 laboratory abnormalities of interest from Study 1. Grade 2 Includes 2 Includes terms terms EdemaEdema peripheral, PittingPitting edema, and Generalized peripheral, edema, and Generalized low serum phosphorus (7%) and (5%) occurred at a greater low serum phosphorus (7%)low andpotassium low potassium (5%) occurred at a greater edema edema than orthan equal to 5% to rate the in ZYTIGA arm. arm. or equal 5%inrate the ZYTIGA 3 Includes 3 Includes terms terms Arthritis, Arthralgia, Joint swelling, and Joint Arthritis, Arthralgia, Joint swelling, and stiffness Joint stiffness Table 2: Laboratory Abnormalities of Interest in Study 1 Table 2: Laboratory Abnormalities of Interest in Study 1 Table 4Table 4 showsshows laboratory abnormalities that occurred in greater than 15% laboratory abnormalities that occurred in greater than 15% Abiraterone (N=791) (N=394) and more frequently (>5%) (>5%) in theinZYTIGA arm compared to Abiraterone (N=791) Placebo Placebo (N=394) of patients, of patients, and more frequently the ZYTIGA arm compared to in Study 2. Grade 3-4 lymphopenia (9%), hyperglycemia (7%) and placebo in Study 2. Grade 3-4 lymphopenia (9%), hyperglycemia (7%) and Laboratory All Grades GradeGrade 3-4 All GradeGrade 3-4 3-4placebo Laboratory All Grades 3-4Grades All Grades aminotransferase (6%) occurred at a greater than 5% rate high alanine aminotransferase (6%) occurred at a greater than 5%inrate in Abnormality (%) (%) (%) (%) (%) (%) (%) (%) high alanine Abnormality the ZYTIGA arm. arm. the ZYTIGA Hypertriglyceridemia 0 Hypertriglyceridemia 62.5 62.5 0.4 0.4 53.0 53.0 0 Table 4: Laboratory Abnormalities in >15% of Patients in the in ZYTIGA Table 4: Laboratory Abnormalities in >15% of Patients the ZYTIGA High AST 30.6 30.6 2.1 2.1 36.3 36.3 1.5 1.5 High AST Arm ofArm Study 2 of Study 2 Hypokalemia 28.3 28.3 5.3 5.3 19.8 19.8 1.0 1.0 Hypokalemia Abiraterone (N=542) (N=540) Abiraterone (N=542) Placebo Placebo (N=540) Hypophosphatemia Hypophosphatemia 23.8 23.8 7.2 7.2 15.7 15.7 5.8 5.8 Laboratory GradeGrade 1-4 1-4 GradeGrade 3-4 3-4 GradeGrade 1-4 1-4 GradeGrade 3-4 3-4 Laboratory High ALT 11.1 11.1 1.4 1.4 10.4 10.4 0.8 0.8 Abnormality High ALT % % % % Abnormality % % % % High Total 0 HighBilirubin Total Bilirubin 6.6 6.6 0.1 0.1 4.6 4.6 0 Hematology Hematology 8.7 8.7 31.7 31.7 7.4 7.4 Lymphopenia 38.2 38.2 Study Study 2: Metastatic CRPC CRPC Prior Prior to Chemotherapy: Study Study 2 enrolled 1088 1088 Lymphopenia 2: Metastatic to Chemotherapy: 2 enrolled Chemistry Chemistry patients with metastatic CRPC CRPC who had prior prior cytotoxic patients with metastatic who not had received not received cytotoxic 1 1 56.6 56.6 chemotherapy.

Patients were were ineligible if ASTifand/or ALT ≥2.5X ULN and 6.5 6.5 50.9 50.9 5.2 5.2 chemotherapy.

Patients ineligible AST and/or ALT ≥2.5X ULN and Hyperglycemia Hyperglycemia patients were excluded if theyifhad patients were excluded theyliver hadmetastases. liver metastases.

High ALT 41.9 41.9 6.1 6.1 29.1 29.1 0.7 0.7 High ALT 37.3 37.3 3.1 3.1 28.7 28.7 1.1 1.1 High AST Table Table 3 shows adverse reactions on theonZYTIGA arm inarm Study 2 that2 that High AST 3 shows adverse reactions the ZYTIGA in Study occurred with with a ≥2%a absolute increase in frequency compared to 0.4 0.4 25.0 25.0 0.2 0.2 occurred ≥2% absolute increase in frequency compared to Hypernatremia Hypernatremia 32.8 32.8 placebo.

The median duration of treatment with ZYTIGA was 13.8 placebo.

The median duration of treatment with ZYTIGA wasmonths.

13.8 months. Hypokalemia 17.2 17.2 2.8 2.8 10.2 10.2 1.7 1.7 Hypokalemia on non-fasting blood blood drawsdraws Table 3: Adverse Reactions in ≥5%inof≥5% Patients on theon ZYTIGA Arm inArm in 1Based1Based on non-fasting Table 3: Adverse Reactions of Patients the ZYTIGA Study Study 2 2 Cardiovascular Adverse Reactions: In the In combined data for studies 1 and 1 and Cardiovascular Adverse Reactions: the combined data for studies failurefailure occurred more commonly in patients treatedtreated with ZYTIGA ZYTIGA with with Placebo with with 2, cardiac 2, cardiac occurred more commonly in patients with ZYTIGA ZYTIGA Placebo to patients on theonplacebo arm (2.1% versusversus 0.7%).0.7%).

GradeGrade 3-4 3-4 Prednisone (N=542) (N=540) compared to patients the placebo arm (2.1% Prednisone (N=542)Prednisone Prednisone (N=540) compared 1 Grade 1 Grade failurefailure occurred in 1.6% patients takingtaking ZYTIGA and led cardiac occurred in of 1.6% of patients ZYTIGA andtoled to 3-4 All GradeGrade 3-4 3-4cardiac System/Organ Class ClassAll Grades 3-4Grades All Grades System/Organ All Grades discontinuations and 2and deaths.

GradeGrade 3-4 cardiac failurefailure 5 treatment discontinuations 2 deaths.

3-4 cardiac Adverse reaction % % % % Adverse reaction % % % % 5 treatment occurred in 0.2% patients takingtaking placebo.

There There were were no treatment occurred in of 0.2% of patients placebo. no treatment General disorders General disorders discontinuations and one due todue cardiac failurefailure in the in placebo group.group. discontinuations anddeath one death to cardiac the placebo Fatigue 39.1 39.1 2.2 2.2 34.3 34.3 1.7 1.7 In Study Fatigue 1 and 12,and the 2, majority of arrhythmias were grade 1 or 2.1There was was In Study the majority of arrhythmias were grade or 2. There 2 2 EdemaEdema 25.1 25.1 0.4 0.4 20.7 20.7 1.1 1.1 one death associated with arrhythmia and one with sudden death death one death associated with arrhythmia andpatient one patient with sudden arms arms and no in theinplacebo arms. arms.

There There were were the ZYTIGA anddeaths no deaths the placebo Pyrexia 8.7 8.7 0.6 0.6 5.9 5.9 0.2 0.2 in theinZYTIGA Pyrexia 7 (0.5%) deathsdeaths due todue cardiorespiratory arrestarrest in theinZYTIGA arms arms and and 7 (0.5%) to cardiorespiratory the ZYTIGA Musculoskeletal and and Musculoskeletal 3 (0.3%) deathsdeaths in theinplacebo arms. arms.

Myocardial ischemia or myocardial 3 (0.3%) the placebo Myocardial ischemia or myocardial connective tissuetissue disorders connective disorders infarction led toled death in 3 patients in theinplacebo arms and deaths in infarction to death in 3 patients the placebo arms2 and 2 deaths in Joint swelling/ Joint swelling/ arms. arms.

3 the ZYTIGA 3 discomfort 30.3 30.3 2.0 2.0 25.2 25.2 2.0 2.0 the ZYTIGA discomfort Experience Post Marketing Experience Groin Groin pain pain 6.6 6.6 0.4 0.4 4.1 4.1 0.7 0.7 Post Marketing The following additional adverse reactions have been duringduring post post The following additional adverse reactions have identified been identified Gastrointestinal Gastrointestinal approval use of ZYTIGA. Because these these reactions are reported voluntarily approval use of ZYTIGA. Because reactions are reported voluntarily disorders disorders from afrom population of uncertain size, itsize, is not possible to reliably a population of uncertain it isalways not always possible to reliably Constipation 23.1 23.1 0.4 0.4 19.1 19.1 0.6 0.6 estimate Constipation their frequency or establish a causal relationship to drugtoexposure. estimate their frequency or establish a causal relationship drug exposure.

Diarrhea 21.6 21.6 0.9 0.9 17.8 17.8 0.9 0.9 Diarrhea Respiratory, Thoracic and and Mediastinal Disorders: non-infectious Respiratory, Thoracic Mediastinal Disorders: non-infectious Dyspepsia 11.1 11.1 0.0 0.0 5.0 5.0 0.2 0.2 pneumonitis.

Dyspepsia pneumonitis.

ZYTIGA® (abiraterone acetate) Tablets

ZYTIGA® (abiraterone acetate) Tablets

DRUG INTERACTIONS Drugs that Inhibit or Induce CYP3A4 Enzymes: Based on in vitro data, ZYTIGA is a substrate of CYP3A4.

In a dedicated drug interaction trial, co-administration of rifampin, a strong CYP3A4 inducer, decreased exposure of abiraterone by 55%.

Avoid concomitant strong CYP3A4 inducers during ZYTIGA treatment. If a strong CYP3A4 inducer must be co-administered, increase the ZYTIGA dosing frequency [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3) in full Prescribing Information].

In a dedicated drug interaction trial, co-administration of ketoconazole, a strong inhibitor of CYP3A4, had no clinically meaningful effect on the pharmacokinetics of abiraterone [see Clinical Pharmacology (12.3) in full Prescribing Information].

Effects of Abiraterone on Drug Metabolizing Enzymes: ZYTIGA is an inhibitor of the hepatic drug-metabolizing enzyme CYP2D6. In a CYP2D6 drug-drug interaction trial, the Cmax and AUC of dextromethorphan (CYP2D6 substrate) were increased 2.8- and 2.9-fold, respectively, when dextromethorphan was given with abiraterone acetate 1,000 mg daily and prednisone 5 mg twice daily. Avoid co-administration of abiraterone acetate with substrates of CYP2D6 with a narrow therapeutic index (e.g., thioridazine). If alternative treatments cannot be used, exercise caution and consider a dose reduction of the concomitant CYP2D6 substrate drug [see Clinical Pharmacology (12.3) in full Prescribing Information].

In vitro, ZYTIGA inhibits CYP2C8. There are no clinical data on the use of ZYTIGA with drugs that are substrates of CYP2C8. However, patients should be monitored closely for signs of toxicity related to the CYP2C8 substrate if used concomitantly with abiraterone acetate.

USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category X [see Contraindications].: ZYTIGA can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. While there are no adequate and well-controlled studies with ZYTIGA in pregnant women and ZYTIGA is not indicated for use in women, it is important to know that maternal use of a CYP17 inhibitor could affect development of the fetus. Abiraterone acetate caused developmental toxicity in pregnant rats at exposures that were lower than in patients receiving the recommended dose.

ZYTIGA is contraindicated in women who are or may become pregnant while receiving the drug. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss.

Advise females of reproductive potential to avoid becoming pregnant during treatment with ZYTIGA. In an embryo-fetal developmental toxicity study in rats, abiraterone acetate caused developmental toxicity when administered at oral doses of 10, 30 or 100 mg/kg/day throughout the period of organogenesis (gestational days 6-17). Findings included embryo-fetal lethality (increased post implantation loss and resorptions and decreased number of live fetuses), fetal developmental delay (skeletal effects) and urogenital effects (bilateral ureter dilation) at doses ≥10 mg/kg/day, decreased fetal ano-genital distance at ≥30 mg/kg/day, and decreased fetal body weight at 100 mg/kg/day. Doses ≥10 mg/kg/day caused maternal toxicity. The doses tested in rats resulted in systemic exposures (AUC) approximately 0.03, 0.1 and 0.3 times, respectively, the AUC in patients.

Nursing Mothers: ZYTIGA is not indicated for use in women. It is not known if abiraterone acetate 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 ZYTIGA, a decision should be made to either discontinue nursing, or discontinue the drug taking into account the importance of the drug to the mother.

Pediatric Use: Safety and effectiveness of ZYTIGA in pediatric patients have not been established.

Geriatric Use: Of the total number of patients receiving ZYTIGA in phase 3 trials, 73% of patients were 65 years and over and 30% were 75 years and over. No overall differences in safety or effectiveness were observed between these elderly patients and younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Patients with Hepatic Impairment: The pharmacokinetics of abiraterone were examined in subjects with baseline mild (n=8) or moderate (n=8) hepatic impairment (Child-Pugh Class A and B, respectively) and in 8 healthy control subjects with normal hepatic function. The systemic exposure (AUC) of abiraterone after a single oral 1,000 mg dose of ZYTIGA increased by approximately 1.1-fold and 3.6-fold in subjects with mild and moderate baseline hepatic impairment, respectively compared to subjects with normal hepatic function.

In another trial, the pharmacokinetics of abiraterone were examined in subjects with baseline severe (n=8) hepatic impairment (Child-Pugh Class C) and in 8 healthy control subjects with normal hepatic function. The systemic exposure (AUC) of abiraterone increased by approximately 7-fold and the fraction of free drug increased 2-fold in subjects with severe baseline hepatic impairment compared to subjects with normal hepatic function.

No dosage adjustment is necessary for patients with baseline mild hepatic impairment. In patients with baseline moderate hepatic impairment (ChildPugh Class B), reduce the recommended dose of ZYTIGA to 250 mg once daily. Do not use ZYTIGA in patients with baseline severe hepatic impairment (Child-Pugh Class C). If elevations in ALT or AST >5X ULN or total bilirubin >3X ULN occur in patients with baseline moderate hepatic impairment, discontinue ZYTIGA treatment [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information].

For patients who develop hepatotoxicity during treatment, interruption of treatment and dosage adjustment may be required [see Dosage and Administration (2.2) in full Prescribing Information, Warnings and Precautions, and Clinical Pharmacology (12.3)] in full Prescribing Information.

Patients with Renal Impairment: In a dedicated renal impairment trial, the mean PK parameters were comparable between healthy subjects with normal renal function (N=8) and those with end stage renal disease (ESRD) on hemodialysis (N=8) after a single oral 1,000 mg dose of ZYTIGA. No dosage adjustment is necessary for patients with renal impairment [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information].

OVERDOSAGE Human experience of overdose with ZYTIGA is limited.

There is no specific antidote. In the event of an overdose, stop ZYTIGA, undertake general supportive measures, including monitoring for arrhythmias and cardiac failure and assess liver function.

Storage and Handling: Store at 20°C to 25°C (68°F to 77°F); excursions permitted in the range from 15°C to 30°C (59°F to 86°F) [see USP controlled room temperature].

Based on its mechanism of action, ZYTIGA may harm a developing fetus.

Therefore, women who are pregnant or women who may be pregnant should not handle ZYTIGA without protection, e.g., gloves [see Use in Specific Populations].

PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Patient Information) • Patients should be informed that ZYTIGA and prednisone are used together and that they should not interrupt or stop either of these medications without consulting their physician.

• Patients receiving GnRH agonists should be informed that they need to maintain this treatment during the course of treatment with ZYTIGA and prednisone.

• Patients should be informed that ZYTIGA must not be taken with food and that no food should be consumed for at least two hours before the dose of ZYTIGA is taken and for at least one hour after the dose of ZYTIGA is taken. They should be informed that the tablets should be swallowed whole with water without crushing or chewing. Patients should be informed that taking ZYTIGA with food causes increased exposure and this may result in adverse reactions.

• Patients should be informed that ZYTIGA is taken once daily and prednisone is taken twice daily according to their physician’s instructions.

• Patients should be informed that in the event of a missed daily dose of ZYTIGA or prednisone, they should take their normal dose the following day. If more than one daily dose is skipped, patients should be told to inform their physician.

• Patients should be apprised of the common side effects associated with ZYTIGA, including peripheral edema, hypokalemia, hypertension, elevated liver function tests, and urinary tract infection. Direct the patient to a complete list of adverse drug reactions in PATIENT INFORMATION. • Patients should be advised that their liver function will be monitored using blood tests.

• Patients should be informed that ZYTIGA may harm a developing fetus; thus, women who are pregnant or women who may be pregnant should not handle ZYTIGA without protection, e.g., gloves. Patients should also be informed that it is not known whether abiraterone or its metabolites are present in semen and they should use a condom if having sex with a pregnant woman. The patient should use a condom and another effective method of birth control if he is having sex with a woman of child-bearing potential. These measures are required during and for one week after treatment with ZYTIGA. Manufactured by: Patheon Inc. Mississauga, Canada Manufactured for: Janssen Biotech, Inc. Horsham, PA 19044 © Janssen Biotech, Inc. 2012 Revised: May 2014 015924-140528

ASCOPost.com | SEPTEMBER 10, 2015

PAGE 39

Journal Spotlight Hematology

Novel Combination Increases Progression-Free Survival in CLL Patients Who Are Not Candidates for Fludarabine

By Matthew Stenger

I

n the phase III COMPLEMENT 1 trial reported in The Lancet, P ­ eter Hillmen, MB, ChB, of St. James’s University Hospital, Leeds, and colleagues found that the addition of the anti-CD20 antibody ofatumumab (Arzerra) to chlorambucil (Leukeran) increased progression-free survival among patients with chronic lymphocytic leukemia (CLL) who were not considered candidates for fludarabine due to older age or comorbidities.1

Binet stage (A in 35% and 31%, B in 33% and 38%, C in 32% and 31%), Eastern Cooperative Oncology Group performance status (0 for 39% and 38%, 1 for 53% and 54%), B symptoms (53% in both), and all other baseline characteristics.

Progression-Free Survival Both groups received a median of six treatment cycles. Median follow-up was 28.9 months. Median progression-

Addition of ofatumumab to chlorambucil led to clinically important improvements with a manageable side-effect profile in treatment-naive patients with chronic lymphocytic leukaemia who were elderly or had comorbidities.

—Peter Hillmen, MB, ChB

Study Details In this open-label trial, 447 patients from 16 countries were randomly assigned between December 2008 and May 2011 to receive chlorambucil at 10 mg/m2 on days 1 to 7 with (n = 221) or without (n = 226) ofatumumab every 28 days for 3 to 12 cycles.

Ofatumumab was given at 300 mg on day 1 and 1,000 mg on day 8 of cycle 1, followed by 1,000 mg on day 1 of subsequent cycles.

Patients could not be considered candidates for fludarabine-based treatment. The primary endpoint was progression-free survival on independent review in the intention-to-treat population.

The combination and chlorambucil groups were generally balanced for age (median, 69 and 70 years, 69% in both ≥ 65 years), sex (64% and 62% men),

free survival was 22.4 months (95% confidence interval [CI] = 19.0–25.2 months) in the chlorambucil/ofatumumab group vs 13.1 months (95% CI = 10.6–13.8 months) in the chlorambucil group (hazard ratio [HR] = 0.57, P < .0001).

Hazard ratios favored combination treatment in all subgroups. Combination treatment was associated with consistent benefit in patients aged < 65 years (HR = 0.54, 95% CI = 0.34– 0.85), ≥ 65 years (HR = 0.57, 95% CI = 0.43–0.76), and ≥ 75 years (HR = 0.56, 95% CI = 0.35–0.89).

Time to Next Therapy The combination group had significantly prolonged time to next therapy (median, 39.8 vs 24.7 months, HR = 0.49, P < .0001). After a median of 6 months of treatment in

both groups, the median treatmentfree period was 34 vs 19 months. Salvage therapy was used in 29% vs 44% of patients, with the most common treatment being rituximab (Rituxan) alone or in combination (17% and 31%).

Objective response rates were 82% vs 69% (odds ratio = 2.16, P = .001), with complete response in 14% vs 1%. No difference in overall survival was observed at the time of analysis, with death occurring in 15% of the combination group and 18% of the chlorambucil group (HR = 0.91, P = .666). Two-year survival was 89% vs 87% and 3-year survival was 85% vs 83%.

Adverse Events Adverse events ≥ grade 3 occurred in 50% of the combination group and 43% of the chlorambucil group, including 59% and 51% of patients aged ≥ 65 years.

Among grade ≥ 3 adverse events, neutropenia occurred in 26% vs 14% (30% vs 15% of patients aged ≥ 65 years), thrombocytopenia in 5% vs 10% (7% vs 10%), anemia in 5% vs 5% (5% vs 6%), and infection in 9% vs 12% (13% vs 15%). Grade ≥ 3 infusion-related reactions occurred in 10% of the combination group.

Adverse events led to discontinuation of study treatment in 13% of both groups and in 15% of patients aged ≥ 65 years in both groups. Death considered related to study treatment occurred during the treatment period in three patients in the chlorambucilofatumumab group and two in the chlorambucil group.

Study Implications The investigators concluded: “Addition of ofatumumab to chlorambucil led to clinically important

Improving Therapy for Chronic Lymphocytic Leukemia ■■ The addition of ofatumumab to chlorambucil significantly prolonged progression-free survival.

■■ Similar degree of benefit was observed in older and younger patients.

improvements with a manageable side-effect profile in treatment-naive patients with chronic lymphocytic leukaemia who were elderly or had comorbidities. Chlorambucil plus ofatumumab is therefore an important treatment option for these patients who cannot tolerate more intensive therapy.”

They noted: “More research is warranted to establish whether and how ofatumumab and obinutuzumab [Gazyva] differentiate from each other and from rituximab; to establish if one antibody is more suitable for a specific patient subgroup; and to explore which chlorambucil backbone regimen is the most complementary to anti-CD20 antibody therapy.” n

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

Reference 1. Hillmen P, Robak T, Janssens A, et al: Chlorambucil plus ofatumumab versus chlorambucil alone in previously untreated patients with chronic lymphocytic leukaemia (COMPLEMENT 1): A randomised, multicentre, open-label phase 3 trial. Lancet 385:1873-1883, 2015.

Childhood Cancer Awareness Month

The ASCO Post | SEPTEMBER 10, 2015

PAGE 40

New Orleans Summer Cancer Meeting Breast Cancer

Genetic Testing in Breast Cancer Offers Much Information but Poses Challenges in Interpretation

By Caroline Helwick

F

or breast cancer patients with robust family histories, medical oncologists should be testing not only for BRCA1/2 mutations, but also for large duplications and deletions as well as for PALB2 mutations.

“These [findings] have proven utility in testing breast cancer patients,” said Louise E. Morrell, MD, Medical Director of the Lynn Cancer Institute, Boca Raton, Florida, in an update on germline testing for breast cancer at the 2015 New Orleans Summer Cancer Meeting.1

Large Duplications and Deletions in BRCA Comprehensive BRCA testing includes complete sequencing of the BRCA1 and BRCA2 genes and an additional procedure to identify five common large rearrangements in the BRCA1 gene. BART—the ­BRACAnalysis Large Rearrangement Test—was introduced in 2006 and detects additional rare large genomic rearrangements in both BRCA1 and BRCA2. About 1% to 2% of individuals who meet the family history criteria for BRCA gene testing will have a mutation detected by the test. The guidelines of the National Comprehensive Cancer Network (NCCN) now recommend large rearrangement deletion and duplication testing to be included in BRCA gene testing.

“The original BRCA analysis [routine Sanger sequencing] looked for sequence errors, which is like going through sentences and finding errors.

But if you cut out a whole paragraph, sequencing doesn’t find the error. This is what large-deletion analysis finds,” she explained.

In very high-risk families, 9% of all mutations are due to large duplications and deletions. This additional testing identifies an additional 2.3% of mutations in such families, though far less among patients with more modest risk (those with triple-negative disease or only one affected family member).

“This means that for patients with a [considerable] family history who are looking for an explanation for the many cancers [in their families], there is a 2.3% chance you will find a mutation testing for large rearrangement delection duplication when tests were negative before,” she said.

Beyond BRCA “Today, oncologists will be testing for many abnormalities beyond BRCA, one being PALB2,” she said. While 10 times less frequent than BRCA, it is a genetically important factor.

PALB2 is a partner and localizer of BRCA2 and is part of the homologous DNA recombination-repair pathway. PALB2 accounts for 2.4% of familial aggregates of breast cancer and renders a 33% lifetime risk in carriers. This risk increases to 58% if the person has more than two affected first-degree relatives.

These observations appear relatively consistent across laboratories and institutions, she said.

Panels should always include the high-risk and intermediate-risk genes. High-risk alleles are rareto–very rare and impose a very high relative risk (up to 10-fold) for breast cancer. In this category are TP53, BRCA1, BRCA2, PTEN, CDH1, and STK11. Intermediate-risk alleles are rare with essentially a two- to fourfold increase in the risk of cancer.

They include BRIP1, ATM, PALB2, and CHEK2.

You will gain information if you do a panel test, but not all findings will be actionable. Be prepared for variants of unknown significance, which average one or two per test.

—Louise E. Morrell, MD

“We have learned that family history matters a lot with regard to risk associated with this mutation,” Dr. Morrelll said. “We now know that these genes and those we discover in the future should not be viewed in isolation. They need an accompanying familial phenotype to be most damaging.”

Information from 17,000 BRCA mutation carriers has been evaluated by the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). This has led to the identification of risk modifiers for these mutation carriers, which enhances the accuracy of risk prediction for the individual patient.

“We are realizing that not all patients are the same,” she said. “This may have added value to the patient who has the mutation but doesn’t want her ovaries out yet.”

Understanding Panel Testing Panel testing with next-generation sequencing is now offered by more than a dozen laboratories. Data from panel testing are being published, confirming the challenges with estimates of cancer risk and the problematic issues of variants of unknown significance and incidental findings.

Panel testing reports “actionable findings,” which are findings that could “plausibly lead to a specific medical recommendation or intervention,” she said. It does not mean that taking such action has demonstrated clinical utility, such as improvement in survival.

Panels evaluate 10 times the number of genes as single-gene testing, but they also increase the number of incidental findings and greatly multiply the number of variants of unknown significance. A variant of unknown significance is an alteration that reflects only a minor change along a gene that may be 10,000 to 15,000 nucleotides long. For example, in the sentence, “The big red dog ran out,” a variant of unknown significance might cause it to read, “The big ned dog ran out,” she explained.

“Based on this minor change, one would not necessarily expect a variant of unknown significance to have significant health consequences, but the variants of unknown significance classification means that we do not yet know,” she said. “Determining the significance of variants is proving to be a major challenge to interpreting multiplex panel testing.”

The clinician can try to make sense of a variant of unknown significance by looking at its location within a gene and its protein functionality, cosegregation with disease in affected families, prevalence in a control population, and other aspects.

Still, confusion reigns with variants of unknown significance, “and this is where we must dedicate considerable time, expertise, and resources in interpreting tests for our patients and families: the interpretaton is very challenging,” she remarked.

Other issues with panel testing create challenges for clinicians: lack of publication of the results of validation studies, lack of standardization for validation among labs, and unknown accuracy of panel tests. Labs can also differ in other ways: how they report results, their “transparency,” depth of coverage with nextgeneration sequencing, detection of large-deletion duplication, methods of defining variants of unknown significance, genes tested, and payment approaches.

Differences in interpretation may be the most confusing to clinicians and patients. “A patient can have a test at one lab, and a gene is called a mutation. Her sister can use a different lab, get the same finding, and it’s not called a mutation. We are not always getting the same interpretation of the same finding,” Dr. Morrell said.

When to Consider Panel Testing “When should we test for a panel of cancer genes? That’s a question that is not yet answered,” she indicated.

Dr. Morrell said she opts for panel testing when the results can help families understand their strong family history and when the results are likely to be actionable. “Mostly, panel testing helps future generations,” she added.

She noted that 10% of breast cancer patients with a strong family history who undergo panel testing will have a deleterious mutation, of which about 6% will be due to BRCA1 or BRCA2 and 4% due to genes other than BRCA1/2.

The panel test should include PALB2, which carries a lifetime risk of about 33% to 58%. For estrogen receptor– positive breast cancer patients, CHEK2, continued on page 41

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PAGE 41

New Orleans Summer Cancer Meeting Technology

Emerging Technology Will Help Tackle Tumor Complexity

By Caroline Helwick

E

merging laboratory technology will be “moving the bar forward” in terms of molecular markers, genomics, and gene-expression profiling, with the potential for huge payoffs to oncologists and patients, according to Mark Pegram, MD, the Susy Yuan-Huey Hung Professor of Medicine at Stanford School of Medicine, Director of the Breast Cancer Oncology Program at Stanford Women’s Cancer Center, and Co-Director of Stanford’s Translational Oncology Program in Palo Alto, California.

At the 10th Annual New Orleans Summer Cancer Meeting, Dr. Pegram described novel approaches as they might be applied in breast cancer, showing enthusiasm for their possibilities, tempered with a note of caution.1 “These are technologies emerging in the lab, and what the future may hold for their clinical application, we don’t yet know,” he said. “Hopefully, in the end, these will be useful for clinical decision-making and result in improved patient outcomes.”

Dr. Pegram also described the challenge of developing targeted therapies for rare mutations, even with these sophisticated tools.

End of the Pathologist?

“At Stanford, surgical oncology has conspired to try to eliminate the need for the pathologist,” Dr. Pegram quipped.

Virtually all the information useful to oncologists comes by way of the pathologist’s review—an established practice that might be disrupted by cutting-edge technology called selective negative ion mode desorption electrospray ionization mass spectrometry, developed at Stanford, he said. Desorption electrospray ionization mass spectrometry is an ionization technique that can image biologic samples without the need for extensive sample preparation, investigating the distribution of diagnostic lipids and metabolites directly from tiny tissue sections.

Genetic Testing continued from page 40

ATM, and TP53 should be included in the panel.

“You will gain information if you do a panel test, but not all findings will be actionable. Be prepared for variants of unknown significance, which can average one or two per test,” she said. Despite these issues,

As the developers explained in a published investigation,2 “Samples are bombarded with microdroplets that dissolve hundreds of lipids and metabolites. The splash forms secondary microdroplets that enter a mass spectrometer, providing a detailed chemical map of the distribution of molecules within the sample surface.”

Dr. Pegram added, “On a thin sample of tumor tissue you can measure, based on their molecular weight, all the biologic elements that splash out of that tumor sample. You find lipids, phospholipids, proteins, products of metabolism—everything that’s in there.”

Molecular masses of these multiple types of molecules from the tumor are compared to normal tissue and used to construct patterns that differentiate the tumor from the epithelium and stroma.

The technology may someday provide a means of interrogating tumor tissue without the need for a large surgical sample or reading by pathologist, he said.

Where Next-Generation Sequencing Falls Short Outside of a handful of breast cancer–associated genes with frequencies greater than 10%, “the sobering reality” is that most other mutations are “oneoffs” that are unique to individuals or small groups of individuals, Dr. ­Pegram noted. Next-generation sequencing may be able to identify these new targets, but developing drugs to target them will be difficult.

The HER2 kinase mutation is an example. This mutation is found in patients with HER2-negative breast cancer, especially of the lobular subtype. It occurs in the absence of gene amplification and has a frequency of only 1.6% (3% in lobular tumors).

“Because these mutations tend to occur in the kinase domain, it sounds reasonable to treat with lapatinib [Tykerb]; however, this doesn’t work,” he indicated. “These recombinant conshe added, “There’s value in collecting these data…. We should be doing all we can to gather this information.”

Dr. Morrell suggested that physicians consult the NCCN Clinical Practice Guidelines for Genetic/ Familial High-Risk Assessment2 and the National Institutes of Health ­GeneReviews3 websites for information about unfamiliar genes that are

structs of mutants do not bind to lapatinib anymore, but they do bind to the tyrosine kinase inhibitor neratinib.”

In a collaboration spearheaded by the group at Washington University in St. Louis, Dr. Pegram and colleagues are studying neratinib in a small cohort of patients with HER2 mutations. Taking into account the fraction of patients who harbor a HER2 kinase mutation, meet all eligibility criteria, and are willing to

complex heterogeneity was a discovery made in renal cell carcinoma.

Gerlinger and colleagues evaluated spatially separated samples from the primary tumor and associated metastases using exome sequencing.3 A single biopsy showed about 70 mutations that accounted for only half of all the mutations identified across multiple biopsies. Only 34% were contained in all regions.

These are technologies emerging in the lab, and what the future may hold for their clinical application, we don’t yet know. Hopefully, in the end, these will be useful for clinical decisionmaking and result in improved patient outcomes.

—Mark Pegram, MD

participate in a clinical trial, the researchers calculated the “number needed to study” neratinib in this population, concluding that in the best-case scenario, 125 patients must be screened to yield 1 enrollee. Nevertheless, the study did launch, with a low double-digit number of patients currently enrolled.

“One response to neratinib, a drug we thought would have exquisite activity,” Dr. Pegram said. This is “sobering” if it foreshadows the payoff for such endeavors, he commented.

Tackling Heterogeneity “Another conundrum in tumor genome sequencing campaigns is the degree of heterogeneity in breast cancer,” he continued. Genomes sequenced for more than 100-fold coverage will identify separate clones within the same primary tumor that have different genotypes—and this can be observed early, at ­diagnosis.

One of the first examples of this reported in test results. n

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

References 1. Morrell L: Next generation sequencing and inherited risk for cancer: BRCA, Lynch and beyond. 2015 New Orleans Summer Cancer Meeting. Dr. Peter A. Cassileth Memorial Lecture. Presented July 18, 2015.

“Breast cancer is the same,” Dr. Pegram indicated. “We are wrestling with how to accommodate this heterogeneity.”

Harnessing the Dynamic Nature of Mutations Moreover, these sequences are everchanging as a consequence of selection pressure after treatment. It may be possible, however, to turn this characteristic into a positive feature.

Vanderbilt investigators studied the molecular landscape of tumors after neoadjuvant chemotherapy in patients with triple-negative breast cancer, focusing on the molecular underpinnings of patients lacking a complete pathologic response (a possible marker of resistance). By next-generation sequencing and digital RNA expression analysis, they identified diverse molecular lesions and pathway activation in drugresistant tumor cells, compared to pretreatment biopsies; they hypothesized continued on page 42

2. National Comprehensive Cancer Network: Genetic/Familial High-Risk Assessment, Version 2.2015. Available at www.nccn.org/professionals/physician_ gls/pdf/genetics_screening.pdf. Accessed August 14, 2015.

3. Pagon RA, Adam MP, Ardinger HH, et al (eds): GeneReviews. Available at www. ncbi.nlm.nih.gov/books/NBK1116. Accessed August 14, 2015.

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New Orleans Summer Cancer Meeting Tumor Complexity continued from page 41

that these findings may mirror micrometastasis destined to recur clinically.

Ninety percent of the tumors contained a genetic alteration potentially treatable with available targeted drugs.4 “Tumors were enriched for mutations along pathways we all know— those related to DNA repair, growth factor receptor amplification, PI3K/ AKT, Ras/RAF/ERK, and cell cycle,” Dr. Pegram noted. “This suggests that with this type of analysis we may have the opportunity for personalized adjuvant treatment.”

Mutations of the estrogen receptor are further examples of the dynamic nature of mutations. Estrogen receptor mutations occur in up to 20% of metastatic tumors (vs about 1% in primary tumors). The frequency appears to be enriched with prior endocrine treatment, and there is a clear trend toward rising mutation frequency from primary disease to early metastatic disease to late metastatic disease.

“These mutations are also quite interesting,” he observed. “They cluster in the ligand-binding domain, which begs the question of whether antiestrogen therapeutics will hit them…. This could prove to be an opportunity, now that we understand that estrogen receptor mutations are not uncommon.”

‘Composite’ Look at Heterogeneity Could circulating tumor cells provide a snapshot of the tumor’s global picture? A new cell separation method that employs a microfluidic device yields live tumor cells that can not only be enumerated but analyzed for their components, such as steroid receptor, HER2, mutations, and proteins.

“In theory, this could be powerful,” Dr. Pegram commented. “We could measure the percentage of cells that are [estrogen receptor]–positive in the circulation, and if it reflects the global tumor burden, we can estimate the degree of heterogeneity of that marker and perhaps correlate that with the expectation of response to an antiestrogen, for example.”

It is actually now possible to isolate single cells and observe their makeup as well. In a collaboration with Amy Herr, PhD, of the Department of Bioengineering, University of California at Berkeley, who has pioneered a new technology, Dr. Pe-

gram’s lab is doing this, focusing on the protein content of circulating tumor cells. Using a single-cell Western blot analysis platform, researchers place individual cells into microwells, where they can be lysed and electrophoresed, producing a readout of all proteins within that cell.5 Single cells can also be subjected

to whole-exome sequencing. This may better capture “what’s in the general mix” of the tumor, as compared to a biopsy of just one site. This approach captures cell-to-cell heterogeneity; provides objective, quantitative, reproducible, digital data for archiving; and “spares precious patient tissue,” Dr. ­Pegram said. “Maybe

this is a path forward toward getting a handle on the heterogeneity of circulating tumor cells.”

Moreover, cells may not be needed at all to produce a global snapshot, as tumor-specific DNA can now be isolated from the circulation. This cellfree DNA approach can correlate the amount of circulating DNA with radio-

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PAGE 43

New Orleans Summer Cancer Meeting graphic findings, can quantitate secondsite mutations, and can be applied to any tumor type. “This could be very interesting in terms of following patients with metastatic disease,” he said.

Dr. Pegram concluded by acknowledging that the path to the development of new biomarkers is long and arduous but could ultimately lead to

better treatments and outcomes. n

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

References 1. Pegram M: Novel molecular markers, genomics, and gene expression profile: Moving forward the bar for breast cancer therapy development. 2015 New Orleans Summer

Cancer Meeting. Presented July 18, 2015.

2. Eberlin LS, Gabay M, Fan AC, et al: Alteration of the lipid profile in lymphomas induced by MYC overexpression. Proc Natl Acad Sci USA 111:10450-10455, 2014.

3. Gerlinger M, Rowan AJ, Horswell S, et al: Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med 366:883-892, 2012.

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4. Balko JM, Giltnane JM, Wang K, et al: Molecular profiling of the residual disease of triple-negative breast cancer after neoadjuvant chemotherapy identifies actionable therapeutic targets. Cancer Discov 4:232245, 2014.

5. Hughes AJ, Spelke DP, Xu Z, et al: Single-cell western blotting. Nat Methods 11:749-755, 2014.

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New Orleans Summer Cancer Meeting State-of-the-Art Management of Germ Cell Tumors Produces High Cure Rates

By Caroline Helwick

P

asquale W. Benedetto, MD, the Leonard M. Miller Professor of Medicine at the University of Miami/ Sylvester Comprehensive Cancer Center, recently spoke at the 2015 New

Orleans Summer Cancer Meeting about his approach to diagnosing and treating germ cell tumors in men.1 The ASCO Post was there to capture Dr. ­Benedetto’s insights.

The Basics Germ cell tumors derive from an ovum or spermatozoon, or precursor cells thereof. While germ cell tumors are primarily gonadal (95%), they can arise

in the mediastinum, retroperitoneum, or central nervous system, or constitute midline germ cell syndrome.

“These are curable malignancies in more than 90% of cases. Patients diag-

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New Orleans Summer Cancer Meeting Germ Cell Tumors

nosed with localized disease can be cured with surgery, but nonlocalized disease can also be cured,” Dr. ­Benedetto emphasized.

“It is incumbent upon medical oncologists to identify these tumors, especially when the presentation is not typical, and to treat intensively to achieve complete remission.”

In men, germ cell tumors are broadly divided into seminoma and nonsemino-

matous disease. The most primitive form of the latter is embryonal carcinoma. Differentiation along embryonic lines gives rise to any of the three germ layers (endo-, ecto-, or mesoderm), which in aggregate is called teratoma. Differentiation along extraembryonic lines gives rise to choriocarcinoma or yolk sac tumor.

A distinction between seminoma and

nonseminomatous lesions is important.

Seminomas are biologically indolent, whereas nonseminomas can be aggressive and more likely to metastasize.

Signs Pointing to Germ Cell Tumor “Any patient between the ages of 15 and 40 with an intratesticular mass has

germ cell tumor until proven otherwise,” he said. Other possible presentations include anterior superior mediastinal mass and localized retroperitoneal mass.

In addition, oncologists should suspect a germ cell tumor in any male patient with a midline tumor described as “poorly differentiated carcinoma” without an obvious primary (ie, midline germ cell syndrome); with elevated alpha-fetoprotein or beta–human chorionic gonadotropin (hCG); or with a tumor of unknown origin with isochromosome 12p, a molecular feature characteristic of germ cell neoplasms.

Importantly, occult disease, including recurrences, can be documented by these serum markers. Both alpha-fetoprotein and beta-hCG can be elevated in nonseminomatous lesions. In seminomas, alpha-fetoprotein is never elevated, and beta-hCG may or may not be elevated.

Staging of Germ Cell Cancers

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Germ cell tumors are limited to stage I disease in 85% of seminomas but in only 35% of nonseminomatous lesions. Fortunately, this distinction does not determine outcomes, he said.

“We can cure both these populations to the same degree. It’s simply the mechanism by which we get there or the relative need for any other treatment after the primary surgery,” Dr. Benedetto explained.

Tumors are best staged using the International Germ Cell Cancer Consensus Group classification system, which relies heavily on tumor marker levels and takes into account the presence and sites of metastases and magnitude of tumor marker elevations, risk-stratifying patients into good-, intermediate-, and poor-risk subsets. With seminomas, there is no category for “poor risk,” as all these patients “should be cured,” he added.

Understanding Tumor Markers While tumor markers are vital components of assessment, in the case of seminoma they do not define the disease stage. “There is no such thing as a seminoma with [alpha-fetoprotein] elevation,” he said. Patients labeled as having “seminoma” who have elevated alpha-fetoprotein, without an alternative explanation, undoubtedly have a nonseminomatous component to their disease and should be treated according to the algorithm for nonseminomatous disease.

A marker can only be interpreted with an understanding of its half-life, which is 5 to 7 days for alpha-fetoprotein and 2 to 3 days for beta-hCG. This information helps monitor the patient continued on page 46

The ASCO Post | SEPTEMBER 10, 2015

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New Orleans Summer Cancer Meeting Germ Cell Tumors continued from page 45

without the use of imaging.

“A single assay is uninterpretable,” he said. “If a marker is elevated a few weeks after treatment, you don’t know what it means unless you have a previous report. You need at least two points to determine whether the difference between those points is within the predicted range, according to the half-life of the marker.”

A persistently elevated tumor marker after surgery or chemotherapy is “unequivocal evidence” of disease, suggesting that the patient has not achieved a complete remission. A rising level indicates persistent, recurrent, or new disease.

equivalent to cisplatin/vinblastine/ bleomycin, is less toxic, and remains the standard of care.

• For good-risk patients, three cycles of bleomycin/etoposide/cisplatin are equivalent to four cycles, and for poor-risk patients, four cycles of bleomycin/etoposide/cisplatin are better than four cycles of cisplatin/ vinblastine/bleomycin.

• Etoposide/ifosfamide/cisplatin or upfront high-dose chemotherapy and stem cell transplantation is not better than bleomycin/etoposide/cisplatin as first-line therapy for poor-risk patients.

“Everything we do is to maximize the patient achieving a complete response,” he elaborated. “With 12 weeks of chemotherapy, we cure most patients.”

Milestones That Inform Current Treatment

Practical Treatment Tips

Dr. Benedetto described several discoveries and milestones in the treatment of these tumors that have informed the current standard of care: • The efficacy of cisplatin is critical to inducing complete remission in disseminated testis cancer; carboplatin should not be substituted.

• Intensity of treatment, not length of treatment, matters.

• Complete remissions are durable, and maintenance therapy is unnecessary.

• Risk-assessment criteria are based on the Indiana staging system, classifying disseminated disease as minimal-, moderate-, or high-risk.

• Bleomycin/etoposide/cisplatin is

Dr. Benedetto offered a number of clinical pearls for treating germ cell ­tumors: • Treat good-risk patients with 9 weeks of bleomycin/etoposide/cisplatin; treat poor-risk patients for 12 weeks.

• Maintain treatment intensity over the 21-day cycles. Do not get off schedule; do not initiate on a Wednesday unless you can treat the patient over the weekend.

• Do not hold any dose of chemotherapy for a low absolute neutrophil count, as these patients typically do not develop febrile neutropenia.

• Do not give growth factors to the average patient.

• Do not repeat computed tomography (CT) imaging during chemotherapy; simply repeat tumor marker assessments at the beginning of each cycle.

If markers are decreasing predictably, do not change treatment.

Treatment of Stage I Disease Since most patients with stage I disease are cured by the primary surgery, adjuvant chemotherapy is not warranted for most, if not all, patients. After orchiectomy, 70% of patients with nonseminomatous disease are cured.

Most of the 30% who relapse will do so within a few months, and their recur-

Caroline Helwick

even won one!) and welcomed a growing number of conventions (including the 2013 American Society of Hematology Annual Meeting). NOLA has been called the #1 Brainpower City (Forbes), the #1 Most Improved Metro Area (Wall Street Journal), the #1 Most Inspiring U.S. City (Good Magazine, 2014), and more. Katrina was a defin-

Dr. Benedetto emphasized, “CT scans in the middle of chemotherapy will only confuse you…. All you really need to know is whether tumor markers are going down with treatment.”

Postchemotherapy retroperitoneal exploration may be the key to achieving long-term remission in patients with a residual mass > 1 cm or after salvage therapy, he said.

—Pasquale W. Benedetto, MD

rences occur with good-risk features.

Therefore, they are highly, essentially universally, curable.

“There is nothing to be lost with surveillance and nothing to be gained with intervention,” Dr. Benedetto maintained. “It’s better to wait for the few patients who will relapse, and then treat them for cure with chemotherapy and avoid overtreatment of many who are destined never to have a ­recurrence.”

The only patient for whom adjuvant treatment might be considered is one

By Caroline Helwick

I

Imaging, Residual Masses

Everything we do is to maximize the patient achieving a complete response. With 12 weeks of chemotherapy, we cure most patients.

Resilient New Orleans: 10 Years After Katrina t’s been 10 years since floodwaters washed away lives in New Orleans—for most, figuratively or temporarily, but for more than 1,800, literally. We who call this place home all lost something—homes, possessions, jobs, pets, loved ones, our sanity. Mold and muck marked our days for a long time, but now, we seem somehow better for it.

Ten years later we are 10 times stronger, with sturdier levees and homes, better public schools and public housing, state-­‐of-­‐the-­‐art hospitals, greater commerce (more shops and restaurants!), and an influx of young entrepreneurs that has freshened our outlook.

We have hosted a Super Bowl (and

who may not be compliant with surveillance. His surveillance strategy involves CT scans of the abdomen only (not the lungs or pelvis) and chest x-rays.

ing moment for us. We’ve rebuilt—but upon our centuries-­‐old traditions for which we are known and loved.

In fact, there has been so much to cheer about that it’s easy to forget that not everything, and not everyone, has “come back.” They may never. And we are still plagued by problems common to other great American Cities. We still mourn. We are still in recovery But we are “irrepressible,” to quote President Obama. We have perhaps an unwarranted confidence in our future.

We will keep moving forward— but keeping an eye to the sky, of course. n Caroline Helwick is a reporter for The ASCO Post and lives in New Orleans.

Residual masses in nonseminomatous patients will be viable germ cell tumor in only 8%, teratoma in 50%, and fibrosis in 43%. Teratomas must be removed, as they can dedifferentiate and become resistant tumors.

For nonseminomas, positron-emission tomography (PET) scanning is not necessary for staging or for evaluating outcomes, as PET cannot distinguish between teratoma and cancer and cannot predict for relapse, he said. For seminoma, however, PET can predict for residual disease > 3 cm with 100% accuracy; therefore, it is useful for gauging response but not for initial staging.

Predicting, Treating Recurrences “You don’t want to need salvage therapy, since we don’t cure many patients that way. Do things right the first time,” Dr. Benedetto exhorted ­attendees.

While first-line chemotherapy is almost 100% curative, the cure rate drops to less than 40% in the second-line setting. Salvage chemotherapy should be ifosfamide-based, preferably including paclitaxel, ifosfamide, and platinum.

The use of transplant can be discussed with patients. n Disclosure: Dr. Benedetto reported no potential conflicts of interest.

Reference 1. Benedetto PW: How do I treat a patient diagnosed with a seminoma and a non-seminoma testicular cancer: State-ofthe-art management to obtain a high cure rate. 2015 New Orleans Summer Cancer Meeting. Presented July 18, 2015.

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Oncology In Worldwide Memoriam Thoracic Cancer

Roswell Park Cancer Institute Partners With Cuban Scientists to Develop Lung Cancer Vaccine

A thaw in 5 decades of enmity between the United States and Cuba could lead to scientific progress in both countries.

By Jo Cavallo

J

ust 4 months after President Barack Obama’s announcement in December 2014 that there would be an easing of the trade embargo between the United States and Cuba, a deal was struck between Roswell Park Cancer Institute in Buffalo, New York, and the Center for Molecular Immunology (CIM) in Havana, Cuba, to test a immunotherapy vaccine for non–small cell lung cancer (NSCLC) in the United States.

The vaccine, known as CimaVax EGF, was developed by CIM and has been approved for the treatment of late-stage NSCLC in Cuba and Peru.

Although not a cure, CimaVax has been shown in phase III clinical trials in stage III and IV NSCLC to extend survival between 4 and 6 months, curtail symptoms like coughing and breathlessness, and improve overall quality of life. The vaccine is now being tested in Japan and several European countries.

The agreement between Roswell Park Cancer Institute and CMI to develop CimaVax in the United States was made during the New York State Trade Mission to Cuba in April 2015, but a partnership between the two institutions has been in place since 2011, when investigators from Roswell Park and

CIM began exchanging academic and preclinical research information. Soon after, Roswell Park received a licensing agreement from the Government Center for Quality Control of Medicines, the Cuban regulatory authority, to test CimaVax in the laboratory.

Long-Term Objectives If the U.S. Food and Drug Administration (FDA) approves Roswell Park’s investigational new drug application, which is expected by early 2016, the cancer center will launch a phase I study of the vaccine to investigate toxicities, followed by a phase I study of the drug to test efficacy in patients with earlystage NSCLC. “Our hope for this vaccine longer term, beyond those early studies, is to see how effective it is in patients that don’t have as much tumor burden as stage III or IV lung cancer patients,” said Candace S. Johnson, PhD, President and CEO, Wallace Family Chair in Translational Research, and Professor of Oncology at Roswell Park Cancer Institute.

“After we finish our toxicity phase I approach, which won’t take long to complete since the drug has already

In Cuba: Doing More With Less ■■ $4 million: Science ministry’s research and development budget in 2015 ■■ $2 million: Gross domestic product per peer-reviewed scientific paper, about 3% of the U.S. amount ■■ 6,000: Approximate number of scientists in Cuba ■■ 559: Approximate number of Cubans who earned a BS in natural sciences or mathematics in 2007–2008 ■■ $36: How much most scientists in Cuba earn each month Source: Stone R: In from the cold. Science 348:746-751, 2015.

been tested in early clinical studies in Cuba, we would like to study the vaccine in patients presenting with a single malignant nodule, because even though those patients are good candidates for surgery, they are at high risk for disease recurrence. We want to see if we can elicit a more long-term response in early-stage patients.” If the studies prove successful in the treatment of lung cancer, according to Dr. Johnson, Roswell Park proposes to test CimaVax in other cancer types with epidermal growth factor receptor (EGFR) mutations, including prostate, breast, and colon cancers, and for the prevention of epithelial cancers.

CimaVax EGF works by depriving

Roswell Park Cancer Institute/Center for Molecular Immunology, Havana

tumors of epidermal growth factor by making the protein immunogenic and inducing an immune response that reduces the amount of circulating EGF protein in patients, stunting tumor progression. Targeting EGF protein, said Dr. Johnson, provides a totally different mechanism for prohibiting cancer cell growth than the tyrosine kinase inhibitors approved by the FDA in the treatment of advanced-stage NSCLC, including erlotinib, gefitinib (Iressa), and afatinib (Gilotrif), and so may produce fewer side effects.

“Because CimaVax immunizes patients to make antibodies against the EGF protein, it is inherently probably not going to have the side effects of a drug like erlotinib, where you are trying to achieve some inhibition of receptor activity,” said Dr. Johnson. “Inducing an immune response with CimaVax could have side effects like fever and chills, but actually the reports from the Cuban scientists show very little toxicity from the vaccine. We will have to sort this all out ourselves once we begin clinical studies.”

In addition to CimaVax, Cuba’s CIM has developed a second vaccine for NSCLC called racotumomab (Vaxira) and the monoclonal antibody nimotuzumab for the treatment of glioblastoma, which is being studied in both adult and pediatric patients.

Therapy for Diabetic Foot Ulcers

Members of Roswell Park Cancer Institute, including Mary Reid, PhD, Director of Cancer Screening and Survivorship (right, front), and the Center for Molecular Immunology, including Kalet León, Director of Research and Development (left, front), gather with colleagues outside the center in Havana, Cuba, after a meeting to discuss development of CimaVax EGF in November 2014.

Innovative oncology drugs are not the only Cuban-made medications attracting attention outside their shores.

Heberprot-P, a novel therapy for advanced diabetic foot ulcers, was developed 9 years ago by the Center for Genetic Engineering and Biotechnology continued on page 48

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In Memoriam Oncology Worldwide U.S.-Cuban Partnership continued from page 47

in Havana. The drug, which contains recombinant human epidermal growth factor, has been shown in clinical studies to accelerate healing of deep and complex ulcers and reduce diabetes-related amputations,1 according to some reports by between 75% and 80%. Although not available for clinical testing in the United States because of the trade embargo, Heberprot-P is being used in 26 other countries and is reported to have treated as many as 165,000 patients with diabetic foot ulcers.2

Coming in From the Cold Scientific collaborations between the United States and Cuba are not new and date as far back as the mid-19th century, when Joseph Henry, the first Secretary of the Smithsonian Institution, and naturalist Spencer Fullerton Baird, the Smithsonian’s Assistant Secretary, began exchanging letters, documents, and scientific literature with Felipe Poey, a professor of zoology and comparative anatomy at the University

Getting There From Here: What You Need to Know About Traveling to Cuba

I

n January 2015, the U.S. Department of the Treasury and the U.S. Department of Commerce announced changes related to the easing of sanctions on Cuba, which loosened some restrictions on travel for Americans, although some rules still apply. There are 12 legal categories of travel to Cuba, including for professional research and professional meetings. All authorized travelers to Cuba need a valid passport and a visa to enter the country, but it is no longer necessary to apply for a license. For information regarding the type of visa required to travel to Cuba, visit the Cuban Embassy website at www.cubadiplomatica.cu/ sicw/EN/ConsularServices.aspx.

For additional information on travel to Cuba, visit the U.S. Department of Treasury website at http://www.treasury.gov/presscenter/press-releases/Pages/ jl9740.aspx. n

of Havana and the founder of Havana’s Museum of Natural History. Other scientific partnerships followed, most notably between American physician Jesse Lazear, MD, and Cuban scientist Carlos Finlay, MD, whose groundbreaking investigations in 1900 proved that mosquitoes carry yellow fever.

By 1961, however, diplomatic ties between the two countries were severed as the Cold War heated up, and a full economic embargo, which included prohibitions on the importation of equipment and supplies and stringent travel restrictions, was imposed by the United States on Cuba. The Cuban Missile Crisis the following year cemented U.S. economic and diplomatic isolation of Cuba for the next 53 years.

Despite the embargo’s crippling economic sanctions on Cuba, which has stymied the import of computer technology and modern medical research equipment—CMI has only one flow cytometer to study cancer cells, according to Dr. Johnson—the country has maintained a thriving scientific community. This community includes 6,000 scientists3 and a universal health-care system that has reduced the infant mortality rate to 4.7 per 1,000 live births in 2014, compared with 6.17 in the United States,4 and at a fraction of the cost. According to the World Bank, in 2013, expenditure on health care per capita in the United States was $9,146, compared with $603 in Cuba.5 “The Cubans have had to do more with less [see sidebar] and have had to use their innovative minds to create solutions to achieve what they’ve wanted to,” said Dr. Johnson. “They may not have the fancy equipment that we do, but their infant mortality rate is better than ours, and if you look at the mean survival rate of their citizens, 79 years, it’s not different from ours.”

Forging New Scientific Collaborations Although the economic embargo has stifled scientific collaborations between the United States and Cuba, it has not completely eliminated them, and U.S. scientists have been traveling to Cuba in recent years, financing the trips with private or foundation funds.

“I have had the opportunity to make scientific visits to Cuba, and it is obvious that while our governments have had difficulty communicating, we have not,” said Peter Agre, MD, Bloomberg Distinguished Professor and Director of the Johns Hopkins Medical Research Institute, Department of Molecular Microbiology and Immunology, Bloomberg School of Public

Health; Past President of the American Association for the Advancement of Science; and a co-recipient of the 2003 Nobel Prize in Chemistry.

“While Cuba is desperately poor because of the embargo, the scientists there are doing remarkable work and have had some formidable success in cancer and other research, and we need to know about it,” continued Dr. Agre. “It is in our

lationship until certain steps are taken first. But science deserves a chance to move forward now,” said Sergio Jorge Pastrana, Foreign Secretary and Executive Director of the Academy of Sciences of Cuba in Havana.

“Joint research in almost any field can only work for the best aims and needs of both countries and should be favored without any prerequisites. The evidence

Cancer knows no socioeconomic boundaries, and the advances that are likely to occur from the collaboration between the scientists at Roswell Park Cancer Institute and the Cuban Center for Molecular Immunology could help all Americans and people in other countries as well.

—Peter Agre, MD

best interest to have the opportunity to meet our counterparts face-to-face, not just in occasional e-mails, and share our knowledge. Cancer knows no socioeconomic boundaries, and the advances that are likely to occur from the collaboration between the scientists at Roswell Park Cancer Institute and CMI could help all Americans and people in other countries as well. I have no doubt that the collaboration will lead to productive developments in research and maybe breakthroughs, which will translate into improved clinical care for patients with lung cancer and other diseases.”

strongly suggests that joint scientific research between Cuba and the United States can provide opportunities for progress and capacity building in both countries and elsewhere,” he added.

Mr. Pastrana continued: “There is a lot of misunderstanding between our two countries because of the policy that has been in place for more than 50 years. I only wish to assure all Americans that if they come to Cuba, they will find it is very different from the idea that has been created by misunderstanding for too long.” n

Disclosure: Drs. Agre and Pastrana reported no potential conflicts of interest.

A New Era in Détente Since the announcement in December 2014 of a policy shift toward Cuba, the United States and Cuba have reopened their embassies in Havana and Washington, DC, reestablishing diplomatic ties between the two countries. In addition, Cuba was removed from the list of nations that sponsor terrorism, signaling a new era in détente. However, until the American trade embargo is lifted, which will take an act of Congress and is unlikely to happen soon, the ability to fully engage in collaborative scientific research between the two countries will remain limited and opportunities for progress slowed.

“After more than half a century without diplomatic relations, a variety of issues will need to be resolved between the two countries, including visa obstacles and overcoming obstructed sharing of data, resources, and knowledge, and many would argue against a warmer re-

References 1. Berlanga J, Fernández JI, López, E, et al: Heberprot-P: A novel product for treating advanced diabetic foot ulcer. MEDICC Rev 15:11-15, 2013.

2. Reed G: Renewed U.S.-Cuba relations: Saving American lives and limbs? Huffington Post, posted January 24, 2015; updated March 26, 2015. Available at http://www. huffingtonpost.com/gail-reed/renewed-uscuba-relations-_b_6537518.html. Accessed August 18, 2015.

3. Stone R: In from the cold. Science 348:746-751, 2015.

4. Central Intelligence Agency: The World Factbook. Available at https://www. cia.gov/library/publications/the-worldfactbook/rankorder/2091rank.html. Accessed August 18, 2015.

5. The World Bank: Health expenditure per capita (current US$). Available at data. worldbank.org/indicator/sh.xpd.pcap. Accessed August 18, 2015.

If she has ovarian cancer

TEST FOR BRCA

If indicated* TREAT WITH LYNPARZA

Help her continue the fight with the first approved PARP inhibitor1

* INDICATION LYNPARZA is indicated as monotherapy in patients with deleterious or suspected deleterious germline BRCA mutated (as detected by an FDA-approved test) advanced ovarian cancer who have been treated with three or more prior lines of chemotherapy.

The indication is approved under accelerated approval based on objective response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

SELECT SAFETY INFORMATION Myelodysplastic syndrome/Acute Myeloid Leukemia (MDS/AML) have been confirmed in 2% of patients enrolled in both a single arm monotherapy trial (6 out of 298) and a randomized placebo controlled trial (3 out of 136). Overall, MDS/AML were reported in <1% of patients (22 out of 2,618) treated with LYNPARZA. The majority of MDS/AML cases were fatal (17 out of 22) and the duration of therapy in patients who developed secondary MDS/AML varied from <6 months to >2 years.

Monitor complete blood count testing at baseline and monthly thereafter. Do not start LYNPARZA until patients have recovered from hematological toxicity caused by previous chemotherapy (≤CTCAE Grade 1). For prolonged hematological toxicities, interrupt LYNPARZA and monitor blood counts weekly until recovery. If the levels have not recovered to CTCAE Grade 1 or less after 4 weeks, refer the patient to a hematologist for further investigations, including bone marrow analysis and blood sample for cytogenetics. If MDS/AML is confirmed, discontinue LYNPARZA.

Please see the following pages for additional Safety Information and Brief Summary of the full Prescribing Information.

LYNPARZA demonstrated an objective response rate of 34% in patients with BRCA-mutated advanced ovarian cancer who had been treated with 3 or more lines of chemotherapy1 The efficacy of LYNPARZA was investigated in a single-arm study of patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm) advanced cancer. A total of 137 patients with measurable gBRCAm-associated ovarian cancer treated with three or more prior lines of chemotherapy were enrolled. Efficacy was based on objective response rate and duration of response.1 Objective response rate was defined as a ≥30% reduction in target lesion size, according to RECIST criteria, as measured by CT or MRI and confirmed at least 4 weeks later.2

34

%

OBJECTIVE RESPONSE RATE (95% CI: 26, 42)

0

10

20

30

PERCENTAGE OF PATIENTS WHO RESPONDED TO THERAPY

• The rate of partial response was 32% and the rate of complete response was 2%1

7.9

MEDIAN DURATION OF RESPONSE

MONTHS (95% CI: 5.6, 9.6)

Please see the following pages for additional Safety Information and Brief Summary of the full Prescribing Information.

Warnings and Precautions Myelodysplastic syndrome/Acute Myeloid Leukemia Myelodysplastic syndrome/Acute Myeloid Leukemia (MDS/AML) have been confirmed in 6 out of 298 (2%) patients enrolled in a single arm trial of LYNPARZA monotherapy, in patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm) advanced cancers. In a randomized placebo controlled trial, MDS/AML occurred in 3 out of 136 (2%) patients with advanced ovarian cancer treated with LYNPARZA. Overall, MDS/AML were reported in 22 of 2,618 (<1%) patients treated with LYNPARZA. The majority of MDS/AML cases (17 of 22 cases) were fatal, and the duration of therapy with LYNPARZA in patients who developed secondary MDS/cancer-therapy related AML varied from <6 months to >2 years. All patients had previous chemotherapy with platinum agents and/or other DNA damaging agents.

Monitor complete blood count testing at baseline and monthly thereafter. Do not start LYNPARZA until patients have recovered from hematological toxicity caused by previous chemotherapy (≤CTCAE Grade 1). For prolonged hematological toxicities, interrupt LYNPARZA and monitor blood counts weekly until recovery. If the levels have not recovered to CTCAE Grade 1 or less after 4 weeks, refer the patient to a hematologist for further investigations, including bone marrow analysis and blood sample for cytogenetics. If MDS/AML is confirmed, discontinue LYNPARZA. Pneumonitis Pneumonitis, including fatal cases, occurred in <1% of patients treated with LYNPARZA. If patients present with new or worsening respiratory symptoms such as dyspnea, fever, cough, wheezing, or a radiological abnormality occurs, interrupt treatment with LYNPARZA and initiate prompt investigation.

If pneumonitis is confirmed, discontinue LYNPARZA. Embryo-Fetal Toxicity LYNPARZA can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. Olaparib was teratogenic and caused embryo-fetal toxicity in rats at exposures below those in patients receiving the recommended human dose of 400 mg twice daily. If the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus.

Advise females of reproductive potential to avoid becoming pregnant while taking LYNPARZA. If contraceptive methods are being considered, use effective contraception during treatment and for at least one month after receiving the last dose of LYNPARZA.

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

Safety and tolerability of LYNPARZA • LYNPARZA 400 mg twice daily was evaluated as monotherapy in 223 patients with BRCA-mutated advanced ovarian cancer who had 3 or more prior lines of chemotherapy in 6 clinical trials1

Adverse Reactions Reported in ≥20% of Patients1

LYNPARZA 400 MG TWICE DAILY n=223 CTCAE GRADES 1-4 (%)

CTCAE GRADES 3-4 (%)

34

18

Abdominal pain/discomfort

43

8

Decreased appetite

22

1

Nausea

64

3

Vomiting

43

4

Diarrhea

31

1

Dyspepsia

25

0

66

8

26

0

Arthralgia/musculoskeletal pain

21

0

Myalgia

22

0

BLOOD AND LYMPHATIC DISORDERS

Anemia GASTROINTESTINAL DISORDERS

GENERAL DISORDERS

Fatigue/asthenia INFECTIONS AND INFESTATIONS

Nasopharyngitis/URI MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS

Please see accompanying Brief Summary of Full Prescribing Information.

References: 1. LYNPARZA [package insert]. Wilmington, DE: AstraZeneca; 2014. 2. Eisenhauer EA, Therasse P, Bogaerts J, et al.

New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228-247.

LYNPARZA is a trademark of the AstraZeneca group of companies. ©2015 AstraZeneca. All rights reserved. 3118712 Last Updated 4/15

1

Laboratory Abnormalities

LYNPARZA 400 MG TWICE DAILY n=223 CTCAE GRADES 1-4 (%)

CTCAE GRADES 3-4 (%)

Decrease in hemoglobin (anemia)

90

15

Decrease in absolute neutrophil count (neutropenia)

25

7

Decrease in platelets (thrombocytopenia)

30

3

Decrease in lymphocytes (lymphopenia)

56

17

Mean corpuscular volume elevation

57

-

Increase in creatininea

30

2

a

Patients were allowed to enter clinical studies with laboratory values of CTCAE Grade 1.

The safety and tolerability of LYNPARZA were also evaluated in a randomized, placebo-controlled study1 â&#x20AC;˘ LYNPARZA 400 mg twice daily was evaluated as maintenance monotherapy in a randomized, placebo-controlled clinical trial of 96 patients with germline BRCA-mutated platinum-sensitive ovarian cancer who had received 2 or more lines of platinum-containing chemotherapy 1 â&#x20AC;˘ Frequently occurring adverse reactions and lab abnormalities were consistent with those seen in the 6 clinical trials, with the addition of back pain, headache, cough, rash, and dysgeusia 1

To learn more, including how to order LYNPARZA, please visit www.lynparza.com

The ASCO Post | SEPTEMBER 10, 2015

PAGE 54

Announcements

St. Jude Names Keith Perry, MBA, as Chief Information Officer

S

t. Jude Children’s Research Hospital has named Keith Perry, MBA, as Chief Information Officer (CIO) to provide strategic counsel and leadership for the hospital’s information technology initiatives.

“Our internal information tech-

Keith Perry, MBA

nology systems and operations play a critical role in the success of our institution,” said James R. Downing, MD, St. Jude President and Chief Executive Officer. “Keith’s extensive knowledge will support the utilization of new technologies and advancements to

Trim: 7.625 x 10.5

LYNPARZA™ (olaparib) capsules, for oral use Brief Summary of Prescribing Information. For complete prescribing information consult official package insert.

INDICATIONS AND USAGE Treatment of gBRCA-mutated advanced ovarian cancer Lynparza is indicated as monotherapy in patients with deleterious or suspected deleterious germline BRCA mutated (as detected by an FDA-approved test) advanced ovarian cancer who have been treated with three or more prior lines of chemotherapy.

The indication is approved under accelerated approval based on objective response rate and duration of response [see Clinical Studies (14) in the full Prescribing Information].

Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

DOSAGE AND ADMINISTRATION Patient Selection Select patients for the treatment of advanced ovarian cancer with Lynparza based on the presence of deleterious or suspected deleterious germline BRCA-mutations [see Indications and Usage (1) and Clinical Studies (14) in the full Prescribing Information].

Information on FDA-approved test for the detection of BRCA-mutations is available at http://www.fda.gov/companiondiagnostics.

Recommended Dosing The recommended dose of Lynparza is 400 mg (eight 50 mg capsules) taken twice daily, for a total daily dose of 800 mg. Continue treatment until disease progression or unacceptable toxicity.

If a patient misses a dose of Lynparza, instruct patients to take their next dose at its scheduled time.

Swallow capsule whole. Do not chew, dissolve, or open capsule. Do not take capsules which appear deformed or show evidence of leakage [see How Supplied/Storage and Handling (16.2) in the full Prescribing Information].

Dose Adjustments for Adverse Reactions To manage adverse reactions, consider dose interruption of treatment or dose reduction.

The recommended dose reduction is to 200 mg (four 50 mg capsules) taken twice daily, for a total daily dose of 400 mg.

If a further final dose reduction is required, then reduce to 100 mg (two 50 mg capsules) taken twice daily, for a total daily dose of 200 mg.

Dose Modifications for Use with CYP3A Inhibitors Avoid concomitant use of strong and moderate CYP3A inhibitors and consider alternative agents with less CYP3A inhibition. If the inhibitor cannot be avoided, reduce the Lynparza dose to 150 mg (three 50 mg capsules) taken twice daily for a strong CYP3A inhibitor or 200 mg (four 50 mg capsules) taken twice daily for a moderate CYP3A inhibitor [see Drug Interactions (7.2) in the full Prescribing Information].

CONTRAINDICATIONS None WARNINGS AND PRECAUTIONS Myelodysplastic syndrome/Acute Myeloid Leukemia Myelodysplastic syndrome/Acute Myeloid Leukemia (MDS/AML) have been confirmed in 6 out of 298 (2%) patients enrolled in a single arm trial of Lynparza monotherapy, in patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm) advanced cancers. In a randomized placebo controlled trial, MDS/AML occurred in 3 out of 136 (2%) patients with advanced ovarian cancer treated with Lynparza. Overall, MDS/AML were reported in 22 of 2,618 (<1%) patients treated with Lynparza. The majority of MDS/AML cases (17 of 22 cases) were fatal, and the duration of therapy with Lynparza in patients who developed secondary MDS/cancer-therapy related AML varied from <6 months to >2 years. All patients had previous chemotherapy with platinum agents and/or other DNA damaging agents.

Monitor complete blood count testing at baseline and monthly thereafter. Do not start Lynparza until patients have recovered from hematological toxicity caused by previous chemotherapy ( CTCAE Grade 1). For prolonged hematological toxicities, interrupt Lynparza and monitor blood counts weekly until recovery. If the levels have not recovered to CTCAE Grade 1 or less after 4 weeks, refer the patient to a hematologist for further investigations, including bone marrow analysis and blood sample for cytogenetics. If MDS/AML is confirmed, discontinue Lynparza.

Pneumonitis Pneumonitis, including fatal cases, occurred in <1% of patients treated with Lynparza. If patients present with new or worsening respiratory symptoms such as dyspnea, fever, cough, wheezing, or a radiological abnormality occurs, interrupt treatment with Lynparza and initiate prompt investigation. If pneumonitis is confirmed, discontinue Lynparza.

Embryo-Fetal Toxicity Lynparza can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. Olaparib was teratogenic and caused embryo-fetal toxicity in rats at exposures below those in patients receiving the recommended human dose of 400 mg twice daily. If the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus [see Use in Specific Populations (8.1) in the full Prescribing Information].

Advise females of reproductive potential to avoid becoming pregnant while taking Lynparza.

If contraceptive methods are being considered, use effective contraception during treatment and for at least one month after receiving the last dose of Lynparza [see Use in Specific Populations (8.6) in the full Prescribing Information].

ADVERSE REACTIONS The following adverse reactions are discussed elsewhere in the labeling: • Myelodysplastic syndrome/Acute Myeloid Leukemia [see Warnings and Precautions (5.1) in the full Prescribing Information] • Pneumonitis [see Warnings and Precautions (5.2) in the full Prescribing Information]

provide the highest quality of care for our patients and families.”

Mr. Perry joins St. Jude from the University of Texas MD Anderson Cancer Center, where he served as Associate Vice President and Deputy Chief Information Officer. n

Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Lynparza 400 mg twice daily as monotherapy, has been studied in 300 patients with gBRCA-mutated advanced ovarian cancer, and 223 of these patients had received 3 or more prior lines of chemotherapy.

In the 223 patients with gBRCA-mutated ovarian cancer who received 3 or more prior lines of chemotherapy (including 137 patients in Study 1 with measureable disease) [see Clinical Studies (14) in the full Prescribing Information] adverse reactions led to dose interruption in 40% of patients, dose reduction in 4%, and discontinuation in 7%. There were 8 (4%) patients with adverse reactions leading to death, two were attributed to acute leukemia, and one each was attributed to COPD, cerebrovascular accident, intestinal perforation, pulmonary embolism, sepsis, and suture rupture. Table 1 presents the frequency of adverse reactions reported in 20% of 223 patients (in 6 studies) with gBRCA-mutated advanced ovarian cancer who had received 3 or more prior lines of chemotherapy who were treated with Lynparza 400 mg twice daily. The median exposure to Lynparza in these patients was 158 days.

Table 1 Adverse Reactions Reported in 20% of Patients with gBRCA-Mutated Advanced Ovarian Cancer Receiving Lynparza Adverse Reaction Blood and Lymphatic disorders Anemia Gastrointestinal disorders Abdominal pain/discomfort Decreased appetite Nausea Vomiting Diarrhea Dyspepsia General disorders Fatigue/asthenia Infections and infestations Nasopharyngitis/URI Musculoskeletal and Connective Tissue disorders Arthralgia/musculoskeletal pain Myalgia

3 or more lines of prior chemotherapy Grades 1-4 Grades 3-4 N=223 N=223 % % 34

18

43 22 64 43 31 25

8 1 3 4 1 0

66

8

26

0

21 22

0 0

Table 2 presents the frequency of abnormal laboratory findings in the 223 patients with gBRCA-mutated advanced ovarian cancer who had received three or more prior lines of chemotherapy receiving Lynparza 400 mg twice daily.

Table 2 Laboratory Abnormalities Reported in Patients with gBRCA-Mutated Advanced Ovarian Cancer Receiving Lynparza Laboratory Parameter* 3 or more lines of prior chemotherapy Grades 1-4 Grades 3-4 N=223 N=223 % % Decrease in hemoglobin (anemia) 90 15 Decrease in absolute neutrophil count 25 7 (neutropenia) Decrease in platelets (thrombocytopenia) 30 3 Decrease in lymphocytes (lymphopenia) 56 17 Mean corpuscular volume elevation 57 Increase in creatinine* 30 2 * Patients were allowed to enter clinical studies with laboratory values of CTCAE Grade 1.

The following adverse reactions and laboratory abnormalities have been identified in 10 to <20% of the 223 patients receiving Lynparza and not included in the table: cough, constipation, dysgeusia, peripheral edema, back pain, dizziness, headache, urinary tract infection, dyspnea, and rash. The following adverse reactions and laboratory abnormalities have been identified in 1 to <10% of the 223 patients receiving Lynparza and not included in the table: leukopenia, stomatitis, peripheral neuropathy, pyrexia, hypomagnesemia, hyperglycemia, anxiety, depression, insomnia, dysuria, urinary incontinence, vulvovaginal disorder, dry skin/ eczema, pruritis, hypertension, venous thrombosis (including pulmonary embolism), and hot flush.

Table 3 presents adverse reactions reported in 20% of patients from a randomized trial of Lynparza 400 mg twice daily as maintenance monotherapy compared to placebo in patients with platinum sensitive, relapsed, high-grade serous ovarian cancer following treatment with 2 or more platinum-containing regimens. Table 4 presents the laboratory abnormalities in patients from this randomized trial. Of the 96 patients with gBRCAmutation, 53 received Lynparza, and 43 received placebo. The median duration on treatment with Lynparza was 11.1 months for patients with a gBRCA mutation compared to 4.4 months for patients with gBRCA mutation on placebo.

Adverse reactions led to dose interruptions in 26% of those receiving Lynparza and 7% of those receiving placebo; dose reductions in 15% of Lynparza and 5% of placebo patients; and discontinuation in 9% of Lynparza and 0% in placebo patients. One (2%) patient on Lynparza died as a result of an adverse reaction.

ASCOPost.com | SEPTEMBER 10, 2015

PAGE 55

Direct From ASCO

ASCO Guidelines: A Collaborative Effort

T

he ASCO Guidelines Program has worked with other professional societies and guideline development organizations in an effort to expand the ASCO guideline portfolio and harmonize recommended care options across prominent guideline development groups.

For ASCO, this effort began with a systematic and proactive approach in identifying guideline topics for development.

ASCO then reached out to partnering organizations to explore the development of joint guidelines where none currently exist, or to consider endorsement or adap-

Trim: 7.625 x 10.5

LYNPARZATM (olaparib) capsules Table 3 Adverse Reactions Reported in 20% of Patients with gBRCA-Mutated Ovarian Cancer in the Randomized Trial Adverse Reactions Lynparza Placebo N=53 N=43 Grades 1-4 Grades 3-4 Grades 1-4 Grades 3-4 % % % % Blood and Lymphatic disorders Anemia 25 4 7 2 Gastrointestinal disorders Abdominal pain/discomfort 47 0 58 2 Decreased appetite 25 0 14 0 Nausea 75 2 37 0 Vomiting 32 4 9 0 Diarrhea 28 4 21 2 Dyspepsia 25 0 14 0 Dysgeusia 21 0 9 0 General disorders Fatigue (including asthenia, lethargy) 68 6 53 2 Infections and infestations Nasopharyngitis/Pharyngitis/URI 43 0 16 0 Musculoskeletal and Connective tissue disorders Arthralgia/Musculoskeletal pain 32 4 21 0 Myalgia 25 2 12 0 Back pain 25 6 21 0 Nervous system disorder Headache 25 0 19 2 Respiratory, Thoracic, Mediastinal disorders Cough 21 0 14 0 Skin and Subcutaneous Tissue Dermatitis/Rash 25 0 14 0 Table 4 Laboratory Abnormalities in Patients with gBRCA-Mutated Ovarian Cancer in the Randomized Trial Laboratory parameter* Lynparza Placebo N=53 N=43 Grades 1-4 Grades 3-4 Grades 1-4 Grades 3-4 % % % % Decrease in hemoglobin 85 8 58 2 Decrease in absolute neutrophil count 32 8 23 0 Decrease in platelets 26 6 19 0 Mean corpuscular volume elevation 85 44 Increase in creatinine* 26 0 5 0 * Patients were allowed to enter clinical studies with laboratory values of CTCAE Grade 1.

DRUG INTERACTIONS Olaparib is primarily metabolized by CYP3A. Anticancer Agents Clinical studies of Lynparza in combination with other myelosuppressive anticancer agents, including DNA damaging agents, indicate a potentiation and prolongation of myelosuppressive toxicity.

Drugs that may Increase Olaparib Plasma Concentrations In patients (N=57), co-administration of itraconazole, a strong CYP3A inhibitor, increased AUC of olaparib by 2.7-fold. A moderate CYP3A inhibitor, fluconazole, is predicted to increase the AUC of olaparib by 2-fold.

Avoid concomitant use of strong CYP3A inhibitors (e.g., itraconazole, telithromycin, clarithromycin, ketoconazole, voriconazole, nefazodone, posaconazole, ritinovir, lopinavir/ ritinovir, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) and moderate CYP3A inhibitors (e.g., amprenavir, aprepitant, atazanavir, ciprofloxacin, crizotinib, darunavir/ ritonavir, diltiazem, erythromycin, fluconazole, fosamprenavir, imatinib, verapamil). If the strong or moderate CYP3A inhibitors must be co-administered, reduce the dose of Lynparza [see Dosage and Administration (2.4) in the full Prescribing Information].

Avoid grapefruit and Seville oranges during Lynparza treatment [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3) in the full Prescribing Information].

Drugs that may Decrease Olaparib Plasma Concentrations In patients (N=22), co-administration of rifampicin, a strong CYP3A inducer, decreased AUC of olaparib by 87%. A moderate CYP3A inducer, efavirenz, is predicted to decrease the AUC of olaparib by 50-60%.

Avoid concomitant use of strong CYP3A inducers (e.g., phenytoin, rifampicin, carbamazepine, St. John’s Wort) and moderate CYP3A4 inducers (e.g., bosentan, efavirenz, etravirine, modafinil, nafcillin). If a moderate CYP3A inducer cannot be avoided, be aware of a potential for decreased efficacy of Lynparza [see Clinical Pharmacology (12.3) in the full Prescribing Information].

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category D [see Warnings and Precautions (5.3) in the full Prescribing Information] Risk summary Lynparza can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. Olaparib was teratogenic and caused embryo-fetal toxicity in rats at exposures below those in patients receiving the recommended human dose of 400 mg twice daily. If this drug is used during pregnancy, or if a patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for loss of the pregnancy.

Animal Data In a fertility and early embryonic development study in female rats, olaparib was administered orally for 14 days before mating through to day 6 of pregnancy, which

tation of recommendations from recently developed evidence-based guidelines.

Guideline Advisory Groups The recent formation of Guideline Advisory Groups within ASCO is critical to the model. Advisory Groups were

2 resulted in increased post-implantation loss at a dose level of 15 mg/kg/day (with maternal systemic exposures approximately 11% of the human exposure (AUC0-24h) at the recommended dose).

In an embryo-fetal development study, pregnant rats received oral doses of 0.05 and 0.5 mg/kg/day olaparib during the period of organogenesis. A dose of 0.5 mg/kg/day (with maternal systemic exposures approximately 0.3% of human exposure (AUC0-24h) at the recommended dose) caused embryo-fetal toxicities including increased post-implantation loss and major malformations of the eyes (anophthalmia, microphthalmia), vertebrae/ribs (extra rib or ossification center; fused or absent neural arches, ribs, and sternebrae), skull (fused exoccipital) and diaphragm (hernia). Additional abnormalities or variants included incomplete or absent ossification (vertebrae/sternebrae, ribs, limbs) and other findings in the vertebrae/sternebrae, pelvic girdle, lung, thymus, liver, ureter and umbilical artery.

Some findings noted above in the eyes, ribs and ureter were observed at a dose of 0.05 mg/kg/day olaparib at lower incidence.

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

Pediatric Use The safety and efficacy of Lynparza has not been established in pediatric patients.

Geriatric Use In clinical studies of Lynparza enrolling 735 patients with advanced solid tumors [the majority (69%) of whom had ovarian cancer] who received Lynparza 400 mg twice daily as monotherapy, 148 (20%) of patients were aged 65 years. The safety profile was similar irrespective of age with the exception of AEs of CTCAE 3 which were reported more frequently in patients aged 65 years (53.4%) than those <65 years (43.4%). No individual adverse event or System Organ Class accounted for this observed difference.

Females of Reproductive Potential Lynparza can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1) in the full Prescribing Information]. Advise female patients of reproductive potential to avoid pregnancy while taking Lynparza. If contraceptive methods are being considered, use highly effective contraception during treatment with Lynparza and for at least one month following the last dose of Lynparza. Instruct patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking Lynparza.

Hepatic Impairment The effect of hepatic impairment on exposure to Lynparza has not been studied. Patients with bilirubin >1.5 X ULN and AST/ALT 2.5 X ULN ( 5 X ULN in the presence of liver metastases) were excluded from Lynparza clinical trials. There are no data in patients with baseline hepatic impairment (serum bilirubin >1.5 X ULN) [see Clinical Pharmacology (12.3) in the full Prescribing Information].

Renal Impairment Based on preliminary data, a 1.5 fold increase in mean exposure (AUC) was observed in patients with mild renal impairment (CLcr = 50-80 mL/min) compared to patients with normal renal function (CLcr >80 mL/min). No dose adjustment to the starting dose is required in patients with CLcr of 50 to 80 mL/min, but patients should be monitored closely for toxicity. There are no data in patients with moderate or severe renal impairment (CLcr <50 mL/min) or patients on dialysis [see Clinical Pharmacology (12.3) in the full Prescribing Information].

OVERDOSAGE There is no specific treatment in the event of Lynparza overdose, and symptoms of overdose are not established. In the event of an overdose, physicians should follow general supportive measures and should treat symptomatically.

17 PATIENT COUNSELING INFORMATION SEE FDA-APPROVED PATIENT LABELING (MEDICATION GUIDE) • Dosing Instructions: Inform patients on how to take Lynparza [see Dosage and Administration (2.1) in the full Prescribing Information]. Lynparza should be taken twice daily. Instruct patients that if they miss a dose of Lynparza, not to take an extra dose to make up for the one that they missed. They should take their next normal dose at the usual time. Each capsule should be swallowed whole. Do not chew, dissolve, or open the capsule. Patient should not take Lynparza with grapefruit or Seville oranges.

• MDS/AML: Advise patients to contact their healthcare provider if they experience weakness, feeling tired, fever, weight loss, frequent infections, bruising, bleeding easily, breathlessness, blood in urine or stool, and/or laboratory findings of low blood cell counts, or a need for blood transfusions. This may be a sign of hematological toxicity or a more serious uncommon bone marrow problem called ‘myelodysplastic syndrome’ (MDS) or ‘acute myeloid leukemia’ (AML) which have been reported in patients treated with Lynparza [see Warnings and Precautions (5.1) in the full Prescribing Information].

• Pneumonitis: Advise patients to contact their healthcare provider if they experience any new or worsening respiratory symptoms including shortness of breath, fever, cough, or wheezing [see Warnings and Precautions (5.2) in the full Prescribing Information].

• Pregnancy and Females of Reproductive Potential: Advise females to inform their healthcare provider if they are pregnant or become pregnant. Inform female patients of the risk to a fetus and potential loss of the pregnancy [see Use in Specific Populations (8.1) in the full Prescribing Information]. Advise females of reproductive potential to use effective contraception during treatment with Lynparza and for at least one month after receiving the last dose of Lynparza [see Warnings and Precautions (5.3) and Use in Specific Populations (8.1, 8.6) in the full Prescribing Information].

• Nursing Mothers: Advise patients not to breastfeed while taking Lynparza [see Use in Special Populations (8.3) in the full Prescribing Information].

• Nausea/vomiting: Advise patients that mild or moderate nausea and/or vomiting is very common in patients receiving Lynparza and that they should contact their healthcare provider who will advise on available antiemetic treatment options.

Distributed by: AstraZeneca Pharmaceuticals LP, Wilmington, DE 19850 3079901 12/14 Issued: 12/2014

created based on a recommendation by the guidelines team of the ASCO Leadership Development Program to the ASCO Board of Directors.

Advisory groups comprise content experts that advise ASCO’s Clinical Practice Guidelines Committee (CPGC) on the highest priority topics to consider for guideline development within a given area. There are currently seven Advisory Groups, with four focusing on specific disease sites—breast, gastrointestinal, genitourinary, and thoracic cancers—and three dedicated to topics within survivorship, supportive care, and resource stratification.

Gary H. Lyman, MD, MPH, FASCO

“Guideline advisory groups have been one of the most innovative and productive efforts to come out of the ASCO Guideline Program in the last couple of years,” said Gary H. Lyman, MD, MPH, continued on page 58

Order ASCO Answers Guides to Cancer for Your Practice

A

SCO Answers Guides to breast, colorectal, lung, and prostate cancers are designed to help newly diagnosed patients understand their disease and treatment options. These comprehensive, patient-friendly booklets contain trusted information about the diagnosis, treatment, side effects, and psychosocial effects of cancer. These guides also provide space for recording details about diagnosis and treatment plans, a feature that allows patients to easily go back and find specific information when needed. Printed copies can be purchased from the ASCO University Bookstore, in packs of 50, at cancer. net/eStore. Shipping is free, and ASCO members save 20%. n

© 2015. American Society of Clinical Oncology. All rights reserved.

The ASCO Post | SEPTEMBER 10, 2015

PAGE 56

Direct From ASCO

Journal of Clinical Oncology Special Series Issues Provide Updates on Important Topics in Oncology Practice

T

he Journal of Clinical Oncology ( JCO) annually publishes several Special Series of reviews—diseasespecific issues dedicated to providing readers with concise, authoritative updates on important topics in oncology practice. Each issue of the Special Series explores one specific area of cancer care through a collection of articles written by leaders in the field and an introductory overview authored by the issue’s Associate and Guest Editors.

For 2015, the line-up of Special Series includes:

Gastrointestinal Cancers: Where We Are and Where We Are Going • Associate Editors: Alan P. Venook, MD, and Joel E. Tepper, MD, FASCO • Guest Editor: Jeffrey A. Meyerhardt, MD, MPH Topics will include immunotherapy, radiation, diet and lifestyle, genetic screening, gastric and esophageal cancers, hepatocellular carcinoma, and more.

Advances in Head and Neck Cancer • Associate Editor: Danny Rischin, MD • Guest Editors: Quynh-Thu Le, MD, and Robert L. Ferris, MD, PhD, FACS Topics will include human papillomavirus–negative pharyngeal cancer, advances in surgery and radiotherapy, survivorship, quality of life and surveillance, nasopharyngeal cancer, nonmelanoma cutaneous head and neck cancer, and more.

Pediatric Cancer: Progress Through Collaboration • Associate Editor: Melissa M. Hudson, MD • Guest Editors: Ching-Hon Pui, MD, and William H. Meyer, MD Topics will include acute lymphoblastic leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, central nervous system tumors, osteosarcoma, Ewing sarcoma, and more.

Save the Date Genitourinary Cancers Symposium January 7–9, 2016 Moscone West Building San Francisco, California

Inaugural Cancer Survivorship Symposium: Advancing Care and Research January 15–16, 2016 San Francisco Marriott Marquis San Francisco, California

Gastrointestinal Cancers Symposium January 21–23, 2016 Moscone West Building San Francisco, California

Global Cancer Medicine • Associate Editor: Tony Mok, MD • Guest Editor: Lawrence N. Shulman, MD Topics will include structural barriers to diagnosis and treatment, resource-constrained settings, global pediatric oncology, infections and cancer, cancer genomics, and more.

The JCO Special Series on Gastrointestinal Cancers is available now at JCO. org, and the remaining three issues will be published later this year.

JCO Editor-in-Chief Stephen A. Cannistra, MD, FASCO, explained why the journal focused specifically on these four topics in cancer care.

“Gastrointestinal cancers, pediatric oncology, head and neck tumors, and global oncology were chosen for this year’s collection because each of these areas has witnessed important changes over the past several years, from novel diagnostics and treatment approaches to greater insight into disease pathogenesis,” Dr. Cannistra said. “We felt that issues on these topics would be of value

Stephen A. Cannistra, MD, FASCO

to our broad readership, which includes clinicians, clinical investigators, and patients. There should be something of interest in this year’s collection for every reader of JCO.” “The Special Series represents JCO’s ongoing effort to provide readers with a rapid, self-contained, and efficient way of updating their knowledge in a variety of diseases seen in everyday practice,” Dr. Cannistra said. n Originally printed in ASCO Daily News. © American Society of Clinical Oncology.

“Journal of Clinical Oncology to Feature Four Special Series Issues in 2015.” am.asco. org, June 1, 2015. All rights reserved.

Conquer Cancer Foundation Young Investigator Award Applications Now Open

T

he Conquer Cancer Foundation’s Young Investigator Award (YIA) provides research funding to promising physicians to support the transition from final years of training to faculty appointment and to encourage and promote quality research in clinical oncology. The online application for 2016 YIAs is open now through September 24, 2015.

The YIA is a 1-year research grant totaling $50,000, paid in two increments to the awardee’s institution.

The applicant must be a physician (MD, DO, or international equivalent) who is currently within the last 2 years of final subspecialty training at an academic medical institution at the time of grant submission. Applicants should be planning an investigative career in clinical oncology.

Areas of interest include (but are not limited to) breast cancer, cholangiocarcinoma, fibrolamellar cancer, kidney cancer, pediatrics, sarcoma, supportive care, cancer prevention, and health disparities.

To learn more about how YIAs have launched careers and led to breakthroughs in cancer research, and to submit your application, visit conquercancerfoundation.org/yia. n © 2015. American Society of Clinical Oncology. All rights reserved.

ASCOPost.com | SEPTEMBER 10, 2015

PAGE 57

Direct From ASCO

This September, Triple Your Impact

A

t the 2015 ASCO Annual Meeting, the Conquer Cancer Foundation (CCF) launched The Campaign to Conquer Cancer—a comprehensive, $150 million fundraising campaign supporting breakthrough research and sharing vital knowledge with physicians, patients, and families. In support of The Campaign, CCF Board Member Raj Mantena, RPh, announced his intention to match individual donations to CCF dollar-for-dollar, up to $1 million, for the coming year.

This September, Mr. Mantena is raising the stakes: He will match all donations two-to-one, tripling the impact of gifts made between September 1 and September 30. In light of this, CCF has set a goal to raise

Volume 7, Issue 3

May 2011

Journal of oncology Practice

$50,000 by September 30.

As with regular gifts, matching gift funds will support the Foundation mission area each donor selects.

Options include the CCF Grants and

Nancy R. Daly, MS, MPH

Awards Program, Cancer.Net and ASCO’s patient information program, CancerLinQ™ (ASCO’s rapid learning system), and more. If a do-

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

The Authoritative Resource for Oncology Practices

Report on the ASCO 2010 Provider-Payer Initiative Meeting

By Michael N. Neuss, MD, et al Subspecialization in Community Oncology: Option or Necessity?

By Dean H. Gesme, MD, et al Current Hepatitis B Screening Practices and Clinical Experience of Reactivation in Patients Undergoing Chemotherapy for Solid Tumors: A Nationwide Survey of Medical Oncologists

By Fiona L. Day, FRACP, et al Barriers to Recruitment of Rural Patients in Cancer Clinical Trials

By Shamsuddin Virani, MB, BS, et al Partners and Partnerships: Trends in Private Oncology Practice

By Thomas A. Paivanas, MHSA

www.jop.ascopubs.org

What’s Hot in

JOP

JOP.ascopubs.org Feasibility and Effectiveness of a Pilot Program to Facilitate Quality Improvement Learning in Oncology: Experience of the American Society of Clinical Oncology Quality Training Program

by Arif H. Kamal, et al

Health-Related Quality of Life of Food-Insecure Ethnic Minority Patients With Cancer

by Francesca Gany, et al

Impact of the National Cancer Institute Community Cancer Centers Program on Clinical Trial and Related Activities at a Community Cancer Center in Rural Nebraska

by Mehmet Sitki Copur, et al

Are Patients With Cancer Less Willing to Share Their Health Information? Privacy, Sensitivity, and Social Purpose

by David Grande, et al

Complications Associated With Use of Long-Term Central Venous Catheters Among Commercially Insured Women With Breast Cancer

by Allison Lipitz-Snyderman, et al

Raj Mantena, RPh, and ASCO Past President Peter Paul Yu, MD, FASCO, at the ASCO Annual Meeting.

nor does not have a particular mission area in mind, he or she can always give to CCF’s “Area of Greatest Need,” supplying triple the support where it is needed most.

No matter which mission area a donor selects, all gifts count toward The Campaign to Conquer Cancer’s $150 million goal. While Mr. Mantena’s challenge means each donation goes three times as far, it also means that each gift brings the Foundation three times closer to realizing its vision: a world free from cancer.

“We cannot thank Raj Mantena enough for his tremendous demonstration of support at this landmark moment in the Foundation’s history,” said CCF Executive Director and Chief Philanthropic Officer Nancy R. Daly, MS, MPH. “His generosity has a powerful impact on programs and resources advancing cancer prevention, treatment, and cures. We sincerely hope his matching gift challenge will inspire others to come together and give in the name of conquering cancer.”

History has shown we can—and have—made progress: The cancer death rate has dropped 20% in the past 20 years thanks, in part, to the hard work of dedicated oncology professionals. But it is critical we continue this momentum, which cannot be maintained without the support of generous donors. Thanks to Mr. Mantena, your gift this September will triple the impact advancing progress against cancer.

Donors can participate in this matching gift challenge at conquercancerfoundation.org/match, or by mailing a check to the Conquer Cancer Foundation at P.O. Box 896076, Charlotte, NC, 28289-6076. Mail donations must be postmarked by September 30, 2015 to qualify for the two-toone match period.

Will you step up to the challenge? n Originally printed in ASCO Connection. © American Society of Clinical Oncology.

“This September: Triple Your Impact.”

ASCO Connection, September 2015. All rights reserved.

The ASCO Post | SEPTEMBER 10, 2015

PAGE 58

Direct From ASCO

Join Us for the Community Research Forum Annual Meeting

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his year’s Community Research Forum Annual Meeting is right around the corner. There is an exciting lineup scheduled for the meeting, with participants and presenters representing a range of practices and types of research programs. Participants will engage with one another in breakout sessions to address topics related to conducting clinical research in a community-based practice,

including coverage analyses of clinical trials, contract negotiations, exemplary attributes of trial sites, and practical considerations for precision medicine.

The meeting will include presentations by internationally recognized speakers on personalized medicine and the challenges of molecular profiling. There will also be discussions about clinical trial opportunities.

ASCO Guidelines

ommendations in a clear and transparent manner.1 ASCO does not mandate how collaborators should create and present guidelines, as long as they primarily adhere to the IOM and CMSS standards. An organization can contract out its guideline development; produce it in-house; or have a unique development, quality appraisal, and approval process. Documents do not have to contain specific sections, nor must data be summarized in a certain format.

Collaborators typically follow the format used to publish their guideline development efforts, and the components are generally consistent across the collaborating guideline development groups.

Collaborations between ASCO and other guideline development groups can take several forms. In the traditional joint collaboration model, organizations typically share the human and/or financial resources equally, with a similar number of representatives on the guideline development panel dividing the writing responsibility.

In a more recent collaborative guideline development, one organization takes the lead, whereas others play more of a supporting role. If ASCO takes the lead, the Society provides the majority of the resources, whereas collaborators send official representatives to sit on the expert panel and approve the final guideline. If both organizations approve of the guideline, it is published as a joint effort and placed on the organizations’ websites. In this manner, guideline productivity can increase. Guidelines can reach a wider audience and have a greater impact with dual publication to their respective memberships.

“ASCO is very flexible in making collaborations work, either from having one representative on the panel to completely coproducing or endorsing other organizations’ guidelines,” said Sharon H. ­Giordano, MD, MPH, of the University of Texas MD Anderson Cancer Center, and Chair of ASCO’s CPGC.

continued from page 55

FASCO, of the Fred Hutchinson Cancer Research Cen- ter and the University of Washington. Dr. Lyman is a member of ASCO’s Board of Directors and the Chair of the Methodology Subcommittee of the CPGC. Prior to these advisory groups, guideline development typically relied on ad hoc proposals from ASCO members.

“While still encouraging member suggestions, this new organization allows for a more systematic and comprehensive approach to guideline development with a broad scope of coverage, and better prioritization,” Dr. Lyman said.

A Collaborative Approach Providing a list of prioritized guideline topics each year, along with the order in which guidelines will be developed, will facilitate collaborative efforts with other guideline development groups. Such collaborative efforts can include joint guideline development, guideline endorsement, or guideline adaptation.

The prioritized list of topics allows ASCO staff to contact other guideline development groups about possible collaboration in creating new guidelines. Joint guideline development occurs when the topics and scope of effort of two or more guideline development groups align, and there is an agreed-upon process for guideline development. Development of a joint guideline allows for a more efficient use of resources and facilitates increased guideline standardization, credibility, and dissemination.

ASCO collaborates with organizations striving to meet the standards of the Institute of Medicine (IOM) and Council of Medical Specialty Societies (CMSS).

This includes managing conflicts of interest among guideline development group members, establishing evidence-based recommendations, and presenting rec-

The Community Research Forum has also developed valuable tools for community researchers, including the ASCO Research Program Quality Assessment Tool, the ASCO Clinical Trial Workload Assessment Tool, and an online repository of resources. Please join fellow colleagues from community research sites for this great opportunity to advance clinical research. The meeting will

Sharon H. Giordano, MD, MPH

CAP Partnerships ASCO has created two joint guidelines with the College of American Pathologists (CAP) since the organizations began working together in 2008, and they have followed the traditional model of equal responsibility.

The guideline development process can take longer together than when created by either organization alone. However, the result is a document with more strength, credibility, and reach. “Even if there is additional time, it is incredibly valuable to work with clinicians on the guideline,” said Elizabeth A. Wagar, MD, of The University of Texas MD Anderson Cancer Center, and Chair of CAP’s Pathology and Laboratory Quality Center Committee.

Whereas oncologists help CAP members understand the therapeutic options based on biomarker testing, Dr. Wagar said, pathologists help the oncologists understand issues with obtaining high-quality data and clear results.

Expansion and Shortened Production Time Guideline endorsements and adaptations allow ASCO to rapidly expand its guideline portfolio, an action encouraged by the ASCO membership that will facilitate guideline integration into ASCO’s new CancerLinQ™ initiative. Once Guideline Advisory Groups receive confirmation of prioritized topics from the CPGC, literature is reviewed to see if any guidelines already

take place September 20 to 21, 2015, in ­Alexandria, Virginia.

Visit the Community Research Forum webpage at www.asco.org/ communityresearchforum to register for Meeting, and for additional information about the Forum and its resources. n © 2015. American Society of Clinical Oncology. All rights reserved.

exist on each topic from other organizations. If the guidelines are evidencebased and up-to-date—and the Guideline Advisory Group agrees with the recommendations—the group considers endorsing the guideline. If the Guideline Advisory Group agrees with most, but not all, of the recommendations of an existing guideline, it may opt to modify the guideline and produce an adapted version.

ASCO has published several endorsements and adaptations on a variety of topics over the past year, and several more endorsements are currently in press. An independent panel at ASCO adapted a pan-Canadian practice guideline concerning fatigue in adult cancer survivors in 2014.2 The adaptation process took a few months, but a de novo guideline likely would have taken at least 1 year, Dr. Lyman said.

With more than 50 completed guidelines, endorsements, and adaptations, and more than 20 topics currently in development, the ASCO Guidelines Program has worked to increase its portfolio of evidence-based clinical practice guidelines to better meet the needs of its membership and the patients they serve. n References 1. Institute of Medicine: Standards for developing trustworthy clinical practice guidelines. Available at www. iom.edu/Reports/2011/Clinical-Practice-GuidelinesWe-Can-Trust/Standards.aspx. Accessed May 13, 2015.

2. Bower JE, Bak K, Berger A, et al: Screening, assessment, and management of fatigue in adult survivors of cancer: An American Society of Clinical Oncology clinical practice guideline adaptation. J Clin Oncol 32:1840-1850, 2014.

Originally printed in ASCO Daily News. © American Society of Clinical Oncology. “ASCO Guidelines: A Collaborative Effort” am.asco. org, May 29, 2015. All rights reserved.

NC C N

GUIDELINES 速1

ASCO 速 2

esmo 3

NICE St. Gallen 4 d iag nost icS consensus g u idance 5

The ASCO Post | SEPTEMBER 10, 2015

PAGE 60

Journal Spotlight Dermatologic Oncology

Dabrafenib Plus Trametinib Improves Overall Survival vs Dabrafenib in BRAF V600–Mutant Melanoma

By Matthew Stenger

O

verall survival results of the phase III COMBI-d trial reported in The Lancet by Georgina V. Long, MD, and colleagues showed that the combination of the BRAF inhibitor dabrafenib (Tafinlar) with the MEK ­ inhibitor trametinib (Mekinist) resulted in significantly prolonged overall survival vs dabrafenib alone in BRAF V600–mutant melanoma.1 The primary analysis of the trial had shown that the combination significantly prolonged progression-free survival.2

and 34%), lactate dehydrogenase level (greater than the upper limit of normal in 36% and 33%), visceral disease (78% and 68%), and number of disease sites (at least three in 48% and 43%).

Improved Overall Survival At the final data cutoff ( January 2015), after 222 patients had died, median overall survival was 25.1 months (95% confidence interval [CI] = 19.2 months to not reached) in the combination group vs 18.7 months (95% CI

The improvement in overall survival establishes the combination of dabrafenib and trametinib as the standard targeted treatment for BRAF Val600 mutation–positive melanoma.

—Georgina V. Long, MD, and colleagues

Study Details In this double-blind trial, 423 previously untreated patients from 14 countries with BRAF V600E/K mutation–positive unresectable stage IIIC or IV melanoma were randomly assigned between May 2012 and November 2012 to receive oral dabrafenib at 150 mg twice daily and oral trametinib at 2 mg once daily (n = 211) or dabrafenib and placebo (n = 212). The primary endpoint was progression-free survival; overall survival was a secondary endpoint.

The combination and dabrafenib groups were generally balanced for age (median, 55 and 56.5 years), sex (53% and 54% male), Eastern Cooperative Oncology Group performance status (0 for 73% and 71%, 1 for 26% and 29%), BRAF mutation (V600E in 85% in both, V600K in 15% and 14%), stage (IVM1c in 67% and 65%; IIIc, IVM1a-b in 33%

= 15.2–23.7 months) in the dabrafenib group (hazard ratio [HR] = 0.71, P = .0107). Overall survival was 74% vs 68% at 1 year and 51% vs 42% at 2 years.

Consistent benefit of the combination was observed across all subgroups, with hazard ratios significantly favoring the combination among patients with Val600Glu mutation, stage IVM1c disease, baseline lactate dehydrogenase above the upper limit of normal, visceral disease, and at least three disease sites.

At the current analysis, after an additional 17 months of follow-up since the primary analysis, median progression-free survival was 11.0 months (95% CI = 8.0–13.9 months) in the combination group vs 8.8 months (95% CI = 5.9–9.3 months) in the dabrafenib group (HR = 0.67, P = .0004, unadjusted for multiple testing). Consistent benefit of the

Dabrafenib/Trametinib for Melanoma ■■ Dabrafenib plus trametinib significantly prolonged overall survival and progression-free survival in melanoma patients.

■■ Combination treatment was associated with lower rates of cutaneous squamous cell carcinoma, hyperkeratoses, skin papilloma, alopecia, and hand-foot syndrome.

combination was observed across all subgroups.

In the primary analysis, at a median follow-up of 9 months, median progression-free survival had been 9.3 vs 8.8 months (HR = 0.75, P = .0348). Overall response rates were 69% (complete response in 16%) vs 53% (complete response in 13%, P = .0014).

Subsequent Therapy A total of 29% of the combination group and 31% of the dabrafenib group continued study treatment for at least 15 days after progression. Subsequent therapy, excluding study therapy, was used in 33% and 51% of patients, in the combination and dabrafenib groups, respectively, with the most common treatments being ipilimumab (Yervoy, 18% and 28%), dacarbazine (8% and 11%), and vemurafenib (Zelboraf, 8% and 11%); anti–programmed cell death protein 1 (PD-1) treatment was received by 3% and 7%.

Adverse Events The most common treatment-related adverse events of any grade in the combination group were pyrexia (52% vs 25%), chills (28% vs 14%), fatigue (27% vs 28%), and rash (24% vs 20%), whereas those in the dabrafenib group were hyperkeratosis (33% vs 6%), fatigue (28% vs 27%), hand-foot syndrome (27% vs 6%), and alopecia (26% vs 5%). The combination group also had lower rates of cutaneous squamous cell carcinoma (3% vs 9%), and skin papilloma (1% vs 18%).

Treatment-related grade 3 adverse events occurred in 32% vs 30% of patients (grade 4 events in one combination recipient and three dabrafenib recipients), with the most common being pyrexia (7% vs 2%) in the combination group and cutaneous squamous cell carcinoma (9% vs 3%) in the dabrafenib group. New primary malignant melanomas occurred in < 1% and 2% of patients and noncutaneous treatment-emergent cancers were reported in 1% and 2%.

Treatment was discontinued due to adverse events in 11% of the combination group vs 7% of the dabrafenib group, with the most common reasons being pyrexia (2% vs 1%) and decreased ejection fraction (1% vs 1%).

The investigators concluded: “The improvement in overall survival establishes the combination of dabrafenib and trametinib as the standard targeted treatment for BRAF Val600 mutation–positive melanoma. Studies assessing dabrafenib and trametinib in combination with immunotherapies are ongoing.” n

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

References 1. Long GV, Stroyakovskiy D, Gogas H, et al: Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: A multicentre, double-blind, phase 3 randomised controlled trial. Lancet 386:444-451, 2015.

2. Long GV, Stroyakovskiy D, Gogas H, et al: Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma.

N Engl J Med 371:1877-1888, 2014.

COMBI-d Trial and the Need to Guide Progress in Melanoma Treatment Michael S. Sabel, MD, FACS, of the University of Michigan Health Systems, Ann Arbor, offers his perspective on the COMBI-d trial discussed above. See page 61.

ASCOPost.com | SEPTEMBER 10, 2015

PAGE 61

Perspective

COMBI-d Trial and the Need to Guide Progress in Melanoma Treatment

By Michael S. Sabel, MD, FACS

A

s reviewed in this issue of The ASCO Post, Long et al1 have reported the final overall survival analysis of the COMBI-d phase III trial comparing combination therapy with the BRAF inhibitor dabrafenib (Tafinlar) and the MEK inhibitor trametinib (Mekinist) to monotherapy with dabrafenib alone, confirming the superiority of combination therapy in patients with advanced melanoma harboring the BRAF V600 mutation.

As witnessed before, such combination therapy not only improves survival, but also reduces many of the complications associated with paradoxical activation of the MAPK pathway.

tion. And, while it may be tempting to compare 1-year survival data between trials, the patient populations being treated are not the same, as immunotherapy trials are often restricted to, or dominated by, patients with BRAF wild-type melanoma.

While it is important that our research efforts moving forward address these clinical questions regarding the multidisciplinary management of melanoma, we also must spend time educating patients, in both the office and the media, about the limitations of these therapies and the questions that still exist regarding their optimal use.

Further Insight While the COMBI-d study findings serve primarily to support the idea that combination therapy should be the standard targeted therapy for patients with BRAF V600 mutation– positive melanoma, the more mature survival analysis provides further insight into the rapidly changing management of advanced melanoma. It has been stated before, but cannot be overemphasized, that this is a unique and challenging period for clinicians treating patients with melanoma. After years of limited options, the rapid introduction and development of two distinct classes of systemic agents for melanoma have been extremely exciting but uniquely perplexing, as each new clinical trial raises additional questions regarding both clinical application and basic science.

In their discussion, the authors compare the progression-free and overall survival data with those from trials of single-agent immunotherapies and find that they compare favorably. This shines a light on one of the challenges facing clinicians—the most appropriate choice of therapy in patients with a BRAF V600 mutaDr. Sabel is Chief, Division of Surgical Oncology, University of Michigan Health Systems, Ann Arbor.

edge—not only the most appropriate clinical use of current drugs, but also gaining additional insight into the basic science that dictates their successes (and failures).

The triumphs of the checkpoint inhibitors ipilimumab (Yervoy), pem-

—Michael S. Sabel, MD, FACS

In addition, these are moving targets. At the same time Long et al are providing additional support for combination targeted therapy, new data are emerging supporting combination immunotherapy.

These classes of drugs are also substantially different in terms of ease of delivery, cost, expected toxicities, and the time course of response, all of which must be considered when translating clinical trial results to individual patients.

Persistent Holes in Our Knowledge These questions highlight many of the issues we have to address moving forward, particularly as ongoing trials begin to explore the combination of these two classes. With new agents being developed, many of the clinical trials are designed with a focus on comparing efficacy and establishing position. We must be diligent in assuring that ongoing research continues to address persistent holes in our knowl-

brolizumab (Keytruda), and nivolu­ mab (Opdivo) have been a tremendous boon to patients and have altered the landscape of melanoma management, but have also challenged our understanding of the interactions between the immune system and cancer.

Likewise, data such as those presented

by Long et al regarding dabrafenib and trametinib highlight ongoing questions regarding the molecular basis of melanoma.

These questions will only become more apparent as we continue to explore future combinations and shift to the adjuvant setting, where the goals of therapy and the biology of the disease can be considerably different. Our clinical research must strive not only to document moderate improvements in outcome, but to identify predictive factors that optimize patient selection and address gaps in our basic science knowledge. These might then allow us to optimize the timing and sequence of combination therapies

in concordance with how these agents function and interact and identify new potential targets for intervention. The “bench to bedside” model should more appropriately be visualized as a continuous “back and forth” between the bench and bedside.

Curbing Overenthusiasm With each newly reported success of both targeted therapies and immunotherapies, it is sometimes hard to prevent our enthusiasm and excitement from overshadowing some of the gaps in knowledge we still have.

We must also be aware that this same phenomenon is present in our patients, who are also witness to the trumpeted successes of the new systemic agents in the media.

In surgical oncology, we have seen an increasing, and concerning, trend for patients refusing surgery or seeking to greatly limit surgery, secondary to their enthusiasm for “new drugs” they read about. This includes patients declining completion node dissections as well as those refusing surgery for clinically evident stage III disease or isolated, resectable M1a disease.

While it is important that our research efforts moving forward address these clinical questions regarding the multidisciplinary management of melanoma, we also must spend time educating patients, in both the office and the media, about the limitations of these therapies and the many questions that still exist regarding their optimal use. n

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

Reference 1. Long GV, Stroyakovskiy D, Gogas H, et al: Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: A multicentre, double-blind, phase 3 randomised controlled trial. Lancet. May 29, 2015 (early release online).

Visit The ASCO Post website at ASCOPost.com

The ASCO Post | SEPTEMBER 10, 2015

PAGE 62

Announcements

Seventeen ASTRO Members Awarded Fellows Designation

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he American Society for Radiation Oncology (ASTRO) has selected 17 distinguished members to receive the ASTRO Fellows designation. The 2015 class of Fellows will receive the recognition at the Awards Ceremony at A ­ STRO’s 57th Annual Meeting on Tuesday, October 20 in San Antonio, Texas.

ASTRO Fellows designation, or FASTRO, honors those individuals who have been active or emeritus members of ASTRO for at least 15 years, given the equivalent of 10 years of service to ASTRO, and significantly added to the field of radiation oncology in the areas of research, education, patient care, and/or service and leadership.

Including the 2015 class of Fellows, 259 ASTRO members have received the FASTRO designation since the inception of the award in 2006.

2015 Fellows Class The members of the 2015 Fellows class are: May Abdel-Wahab, MD, PhD, Director of the Division of Human Health in the Department of Nuclear Sciences and Applications, International Atomic Energy Agency Kaled M. Alektiar, MD, Attending Radiation Oncologist, Memorial Sloan Kettering Cancer Center Manjeet Chadha, MD, Attending Physician and Associate Chair of the Charles and Bernice Blitman Department of Radiation Oncology, Mount Sinai Beth Israel A. Bapsi Chakravarthy, MD, Professor and Residency Program Director in the Department of Radiation Oncology, Vanderbilt University Eric L. Chang, MD, Professor and Chair of the Department of Radiation Oncology, Keck School of Medicine of University of Southern California Joel M. Cherlow, MD, PhD, Radiation Oncologist, Long Beach Radiation Oncology Medical Group and Orange County CyberKnife and Radiation Oncology Center, and Medical Director, Department of Radiation Oncology, Saddleback Memorial Hospital Martin Colman, MD, Professor and Chair of the Department of Radiation Oncology and John Sealy Distinguished Centennial Chair, The University of Texas Medical Branch, Galveston Carol A. Hahn, MD, Associate Professor, Department of Radiation Oncology, Duke Cancer Institute

James M. Larner, MD, Professor of Radiation Oncology and Chair, Department of Radiation Oncology, and Professor of Medicine, Department of Internal Medicine/ Hematology Oncology, University of ­Virginia

Robert C. Miller, MD, MBA, Professor of Radiation Oncology, Mayo Clinic Florida, and Medical Director, Mayo Clinic Operations Arnold dela Cruz Paulino, MD, Professor and Pediatric Radiation Oncology Fellowship Director, Depart-

ment of Radiation Oncology, The University of Texas MD Anderson Cancer Center Rachel Rabinovitch, MD, Professor, Departments of Radiation Oncology and Medicine, University of Colorado School of Medicine

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Announcements

C. Leland Rogers, MD, Clinical Professor, Department of Radiation Oncology, Virginia Commonwealth University David I. Rosenthal, MD, Section Chief and Director of Translational Research, Head and Neck Division of Radiation Oncology, and Professor, Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center

Richard Kenneth Valicenti, MD, MA, Professor and Chair of the Department of Radiation Oncology, University of California, Davis School of Medicine Julia White, MD, Professor, Department of Radiation Oncology, The Ohio State University Comprehensive Cancer Center

Yan Yu, PhD, MBA, Professor, ViceChair, and Director of Medical Physics, Department of Radiation Oncology, Thomas Jefferson ­University “The 17 Fellows chosen this year have demonstrated their dedication to the field of radiation oncology. Their work has impacted and benefited patients and the field of radiation oncology

in a variety of ways, including patient care, research, education, service, and leadership,” said Bruce G. Haffty, MD, FASTRO, Chair of ASTRO’s Board of ­Directors and Professor and Chairman of the Department of Radiation Oncology at Rutgers–Robert Wood Johnson Medical School and Associate Director at the Cancer Institute of New Jersey. n

The ASCO Post | SEPTEMBER 10, 2015

PAGE 64

Announcements

Massimo Cristofanilli, MD, Named Associate Director for Precision Medicine and Translational Research at Lurie Cancer Center

B

reast cancer expert Massimo ­Cristofanilli, MD, has been appointed Associate Director for Precision Medicine and Translational Research at the Robert H. Lurie Comprehensive

Cancer Center of Northwestern University and Director of Northwestern Onco-SET (Sequence, Evaluate, Treat).

Dr. Cristofanilli will also be Professor of Medicine in the Division of Hematolo-

gy-Oncology at Northwestern University Feinberg School of Medicine.

An expert in translational research and treatment of patients with inflammatory breast cancer, Dr. Cristofanilli

will be an integral part of the medical oncology team providing breast cancer patients with the most effective treatment options available at the Maggie Daley Center for Women’s Cancer Care in Prentice Women’s Hospital.

Massimo Cristofanilli, MD

As Associate Director for Precision Medicine and Director of Northwestern Onco-SET, Dr. Cristofanilli will oversee the development of Onco-SET and related clinical and research operations. The program personalizes cancer care for patients by sequencing the individual genetic profile of their tumors and evaluating the results to provide the treatments or clinical trials that will offer the greatest benefit.

Dr. Cristofanilli comes to Northwestern from Thomas Jefferson University and Hospitals, where he served as Director of Jefferson Breast Care Center and Deputy Director of Translational Research at the Kimmel Cancer Center. Previously, Dr. Cristofanilli was Chair of the Department of Medical Oncology at Fox Chase Cancer Center and Executive Director of the Morgan Welch Inflammatory Breast Cancer Program and Clinic at The University of Texas MD Anderson Cancer Center.

“We have the unprecedented opportunity to design a patient-centered, biology-driven model of cancer care combining sophisticated tissue and blood-based molecular diagnostic technologies and innovative treatments,” said Dr. Cristofanilli. “We plan to continue the establishment of strategic partnerships and to involve our patients in an educational and informative journey to advance their understanding of their disease and treatments.” n

Visit The ASCO Post website at ASCOPost.com

ASCOPost.com | SEPTEMBER 10, 2015

PAGE 65

Expert’s Corner Oncology Worldwide

Fadlo R. Khuri, MD, FACP continued from page 1

medical degree from Columbia University College of Physicians and Surgeons in New York and completed his medical residency in internal medicine at Boston City Hospital, followed by a fellowship in hematology and medical oncology at Tufts University/New England Medical Center. Dr. Khuri then began a remarkable 20-year career as one of the leading translational clinical investigators and physicians in lung and aerodigestive medical oncology, first at MD Anderson Cancer Center in Houston and for the past 13 years at Emory University School of Medicine in Atlanta.

Before starting his new position at AUB on September 1, 2015, Dr. Khuri was Deputy Director of Emory’s Winship Cancer Institute, Professor and Chair of the Department of Hematology and Medical Oncology, Executive Associate Dean for Research, and the Roberto C. Goizueta Distinguished Chair for Cancer Research at Emory.

During his tenure at Emory, Dr. Khuri was instrumental in securing a National Cancer Institute (NCI) designation for Winship Cancer Institute, the only cancer institute in Georgia to achieve an NCI designation, and was co-head of the $12.5 million NCI-funded Specialized Program of Research Excellence (SPORE) in head and neck ­cancer.

Dr. Khuri is the recipient of numerous awards, including the American Association for Cancer Research Richard and Hinda Rosenthal Memorial Award and the Nagi Sahyoun Award of the Middle East Medical Assembly for his groundbreaking research in lung and aerodigestive cancers. He has been named one of America’s Top Cancer Doctors by Castle Connolly Medical for the past 8 years. Dr. Khuri is a longtime member of ASCO and has served as a member of ASCO’s Cancer Prevention Committee, the Conquer Cancer Foundation Grants Selection Committee, the Journal of Clinical Oncology Editorial Board, and the Scientific Program Committee.

The ASCO Post talked with Dr. Khuri about his decision to leave Emory University; the new responsibilities and challenges he faces; and his goal of making AUB the premier liberal arts institution in the Middle East.

Deep Roots in Family History Please talk about the decision-making that went into changing the course of your career from leading clinical investigator and physician in the field of lung

and aerodigestive medical oncology to university president.

I was elected to the Board of Trustees of AUB in 2014, so I was aware of some of the challenges the university faced but had not initially considered the position of President when I was first approached. However, after thinking more about it and looking at what the university’s needs are and my skill set, although I’m not going to say it is a perfect fit, I liked what I could do and what I could contribute and thought it would be an important use of the substantial number of remaining years in my career.

Several areas of importance stood out to me from my very first meeting to discuss this position. AUB is an institution that has educated my great grandfathers, my grandfather, both of my parents, my wife’s grandfather, and her parents, and it is where I started, so its roots run deep in my family history.

in building communities of trust that would be valuable for that institution and for that region. So I took the plunge and less than 7 weeks after that first interview, I was informed that I was the search committee’s and the Board leadership’s first choice for President.

Innovators in Research and Education What will be your primary responsibilities as President?

My main goal is to ensure that the university continues to thrive and that the culture of progressive thought and innovation, service, and generosity to the community continues to be supported. Another goal is that the deans of the six faculties that I’ll have the privilege of overseeing, including Agriculture and Food Sciences; Arts and Sciences; Engineering and Architecture; Health Sciences; Medicine; the Suliman S. Olayan School of Business;

The most surprising thing about medicine, and oncology in particular, is how much physicians get back from their patients. We find inspiration, hope, and confidence in difficult times and the ingenuity to figure out a solution when we can’t treat someone’s disease by the book.

—Fadlo R. Khuri, MD, FACP

What I saw in AUB is an institution that has an impact on its region like no other university I know of in the world.

There are great universities in China, India, and the United States, and they counterbalance each other. I don’t mean any disrespect to the other great universities in Lebanon and in the region, but there is no question that AUB casts a very large shadow and has a major impact on the political discourse in the region, the development of modern engineering and knowledge, and medical technology and research.

Furthermore, AUB is a fundamental driver of the American liberal arts ethos in the region, and I thought I could contribute to strengthening its liberal arts curriculum with regard to my skill set

as well as university interdisciplinary programs, all get supported to the degree they need. I also want to drive the university toward becoming a major research institution, which it was well into the 1980s and has been rebuilding since the end of the Lebanese Civil War in 1990.

In the Middle East, the amount of funding support for scientific research is relatively low. We don’t have the equivalent of the National Institutes of Health to provide funding, but you can make a strategic investment in scholarship in the arts, economics, political sciences, business, and medicine. So we are going to have to be innovators in education and innovators in research without losing that liberal arts ethos that makes

AUB such a fundamental driver of the region’s moral compass.

Bold Choices What are your greatest challenges?

The university has gone through some periods of unrest, and this past year, students organized protests over increases in tuition. I would like to slow down the increase in student tuition, as I think the students have a point there, but we also have to show the value in the unique and high-quality education we provide.

We also need to invest more in making AUB a premier research institution.

I’d like to be here long enough to produce clear evidence that AUB is one of the 100 greatest and most valuable universities in the world, which, from the perspective of an American institution in a country of 4 million people and close to 2 million refugees, is not going to be easy.

I think we can get it done because the quality of our faculty and students is stellar, but we are going to have to make some bold choices and not make as many mistakes as we could otherwise afford. Still, I want to emphasize that my goal is to develop an institutional culture where people take risks, and even if there is an honest mistake, that mistake is celebrated and not castigated.

Mentor, Teacher, Supervisor Will you continue to see patients?

I’ll be seeing patients at least a couple of times a month, but I’m not going to have a private clinic; I’ll have a teaching clinic. I have superb colleagues, including at least two excellent lung and aerodigestive physicians at AUB, and they will keep the private patients.

I’d like to be a teaching attending with residents and fellows and with my colleagues and still help mentor them to develop new trials and participate in global trials of new agents, new genomic drivers, and new treatment modalities like immunotherapy.

I would like to think that my role will be even more as a mentor, teacher, and supervisor than my work at Emory. I’ve always enjoyed teaching nurse practitioners, physician assistants, residents, fellows, medical students, and international faculty, so I will have more of a teaching role at AUB.

A Team of Stars at Emory How difficult was it to give up your research program at Emory University?

In one sense, it was very difficult, and in another, it was somewhat rewarding. continued on page 66

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Expert’s Corner Fadlo R. Khuri, MD, FACP continued from page 65

It’s very rewarding because we’ve grown a team of stars at Emory who are all very good citizens, outstanding scientists, and thought leaders in the biology and treatment of cancer.

For example, the lung cancer research program at Emory is superbly led by Haian Fu, PhD [Leader, Discovery and Development Therapeutics Program], and Suresh S. ­R amalingam, MD [Director of Medical Oncology and the Lung Cancer Program]. Dr. ­R amalingam is a major leader at ASCO and the Eastern Cooperative Oncology Group, and Dr. Fu is one of the leading cancer biologists focusing on proteinprotein interactions. There are superb scientists such as Jing Chen, PhD [CoDirector of Experimental Therapeutics Program in Leukemia], Adam Marcus, PhD [Director, Integrated Cellular Imaging Shared Resource], and others as well as great clinical investigators, such as Taofeek Owonikoko, MD, PhD [Associate Professor in the Department of Hematology and Medical Oncology], who was just accepted to the ASCO Leadership Development Program. The team has a lot of depth, and I’m very proud of them.

I’m actually happy to step back and see them succeed. But I will miss going to their lab meetings and seeing the fabulous progress made by their undergraduate and graduate students, post-docs, and fellows. I am a per-

manent student and love science, so I will miss those interactions and the day-to-day, week-to-week accomplishments and delight in witnessing their discoveries. I love the idea of not just proving our scientific hypotheses but repudiating them as well and helping create new ones.

I’m realistic enough to know that I’m not going to have the bandwidth to help drive that kind of mission individually at AUB. I’m going to have to help drive it collectively. But I am keeping my collaborations with Emory, and I’ll remain part of the program project as it goes forward.

Change for the Right Reasons You spent most of your youth in Lebanon. Are you excited to be back there and in a position to make a major difference in the region?

I’m extremely excited. The real challenge in life is about being able to reinvent and redefine yourself every 10 to 15 years, and I think you should only do that if you are sure you are doing it for the right reasons. And to the best of my ability to look into my soul, I think I have made this change for the right reasons.

I want to help contribute to a new era of understanding and liberal thinking and scientific renaissance as well as a renaissance in the humanities in the region. I was very fortunate to grow up in the Near East. I had a wonderful childhood and adolescence despite the

war. I learned a lot, and a lot of what I learned is because of this university, so it is time for me to help continue that tradition and maybe accelerate it a little and give back.

The most surprising thing about medicine, and oncology in particular, is how much physicians get back from their patients. We find inspiration, hope, and confidence in difficult times and the ingenuity to figure out a solution when we can’t treat someone’s disease by the book.

Medicine is a very rewarding twoway stream, so from that perspective, I think it would be great to be able to contribute in a meaningful way to AUB and to Lebanon because they

have contributed so much to me and to my growth and will continue to contribute to my life.

I enjoy being a member of ASCO and the American Association for Cancer Research and will continue to be a member of both organizations. I will probably break my nearly perfect 20-year streak of attendance at the annual meetings but will likely come to each meeting every other year, and I will certainly attend the meetings online because it’s not just about the learning that is important to me. It is being part of the community of scholars and physicians that I do not want to lose touch with. n Disclosure: Dr. Khuri reported no potential conflicts of interest.

Don’t Miss These Important Reports in This Issue of The ASCO Post Sagar Lonial, MD, on Elotuzumab and Lenalidomide/Dexamethasone in Refractory Multiple Myeloma see page 1

Julie Vose, MD, MBA, FASCO, on the Role of the Patient in Clinical Research see page 1

Suresh S. Ramalingam, MD, on Targeted and Immunotherapeutic Approaches to Lung Cancer see page 3

James O. Armitage, MD, FACP, FRCP, on Indolent Lymphoma see page 5

Daniel G. Haller, MD, on Treatments of Colorectal Liver Metastases see page 14

Steven Isakoff, MD, on Surgery and Adjuvant Radiotherapy in Breast Cancer see page 17

Robert L. Ferris, MD, PhD, on HPV16 DNA in Post-Treatment Oropharyngeal Cancer see page 21

Andrew Roth, MD, and colleagues, on Risk of Suicide After Cancer see page 26

Jimmie Holland, MD, on Psychosocial Interventions for Older Patients With Cancer see page 27

Visit The ASCO Post online at ASCOPost.com

ASCOPost.com | SEPTEMBER 10, 2015

PAGE 67

Oncology In Worldwide Memoriam Access to Care

Access to Cancer Medicines Not Uniform Across Europe

By Caroline Helwick

A

ccess to cancer medicines—including some old standbys—is inconsistent across Europe, depriving many patients of treatments that are the standard of care elsewhere,1 according to Alexandru E. Eniu, MD, PhD, Chair of the European Society for Medical Oncology (ESMO) Emerging Countries Committee and Head of the Day Hospital Unit at the Cancer Institute Ion Chiricută, ClujNapoca, Romania.

“Inequalities exist in availability and patient costs, especially for newer, more expensive drugs, but drug shortages also affect several essential, old and inexpensive drugs, and this should be unacceptable!” Dr. Eniu said at the ASCO/ESMO Joint Session on Global Perspective on Value at the 2015 ASCO Annual Meeting.

Disparities in Cancer Outcomes “For a number of years, we have known there are important disparities in cancer outcomes across Europe,” he said. The recent EUROCARE-5 study documented the age-standardized incidence vs 5-year relative survival for breast cancer, prostate cancer, and melanoma by European region.2 Survival in Eastern Europe was generally low and below the European mean, particularly for cancers with good or intermediate prognosis, the study found.

Regarding breast cancer, for example, Eastern European countries had approximately half the risk of developing the disease compared with Northern European countries. However, their 5-year relative survival rate was only about 70%, vs 85% in Northern Europe.

Factors accounting for cancer outcome disparities are numerous, including the general population’s health and lifestyle, health-system infrastructure, cancer-care infrastructure, stage at diagnosis, cancer “workforce,” and presence or absence of screening programs.

Factors Linked to Lack of Access “Patient access and availability of cancer medication are also very important,” he said. “Without the drugs, you cannot influence the condition.”

He said the main contributors to the problem of access are the “dramatically increased pricing” by phar-

maceutical companies and the “incoherent reimbursement strategy” of the various national bodies, as they “face the problem of trying to accommodate within budgets the new drugs and new indications.”

Health professionals also contribute, in a way, by “not raising the bar high enough” in terms of the benefits demanded of expensive new drugs.

“We have to ask more from ourselves,” he suggested.

Clinical Examples of Access Variability The recent ESMO antineoplastic medicines survey shed light on the variability in access to cancer medicines across Europe, including drugs listed on the World Health Organization (WHO) Essential Medicines list (www.who.int/ medicines/publications/essentialmedicines/eml2015). The survey gathered information on new drug approval status, drug reimbursement and patient out-of-pocket costs, and actual availability of drugs (drug shortages were a critical issue at the time) across the continent, focusing on 14 solid tumor types.

Disparities in Access to Cancer Medicines in the European Union ■■ Across the 28 countries in the European Union, disparities exist in patient access to cancer medicines.

■■ The recent ESMO antineoplastic medicines survey found that the problem is not limited to expensive new drugs.

■■ In some countries, valuable drugs are not available or are only available at full cost to patients.

cancer. For example, for anti-HER2 therapy, the newer agents are not widely available or available only at full cost to patients.

A similar scenario is seen with targeted treatments for lung cancer, and for melanoma, many cutting-edge drugs are not available at all or only at full cost.

Search for Creative Solutions Although the European Medicines Agency (EMA) process is very transparent, and its decisions regarding safety and efficacy of new drugs are valid for the entire European Union, there are 28 different countries with complicated reimbursement systems. The many na-

Inequalities exist in availability and patient costs, especially for newer, more expensive drugs, but drug shortages also affect several essential, old and inexpensive drugs, and this should be unacceptable!

—Alexandru E. Eniu, MD, PhD

Dr. Eniu used tamoxifen in adjuvant breast cancer as an example of the information gathered regarding its formulary inclusion and availability. “Tamoxifen was widely available across Europe, but when we questioned how patients found the drug in the pharmacy, we found that it was not available in certain countries,” he said. “You can imagine this is a big issue. We showed that drug shortages affect several essential old and inexpensive drugs, not just new ones, and this is not an issue of resources.”

Similarly, adjuvant trastuzumab (Herceptin) is widely available across Europe, usually at no cost to patients, but some countries require preapproval, which causes weeks of delay in its use. Variability is also observed in the availability and out-of-pocket costs of drugs for metastatic breast

tional commissions and expert committees often work with “weak data” and are “replicating at a lower level” the same assessment performed by the EMA, he said.

These groups, he added, are looking for “creative and desperate strategies.” In Dr. Eniu’s own country, Romania, it took almost 8 years to approve trastuzumab in the metastatic setting. “The problem is we cannot always accommodate the cost of new drugs,” he said.

Dr. Eniu further noted that the prices proposed by pharmaceutical companies are increasing substantially, that prices are often unrelated to their magnitude of benefit, and that there is little if any transparency in how these prices are set.

He added that many drugs ranked high on ESMO’s new Magnitude of Clinical Benefit Scale (MCBS)

[see The ASCO Post, August 10, 2015, page 5] may not be available in some countries. In fact, none of the top-ranked drugs—ipilimumab (Yervoy), vemurafenib (Zelboraf ), trametinib (Mekinist), or dabrafenib (Tafinlar)—is available in Romania.

Dr. Eniu and his team will be looking at their survey data in conjunction with the WHO Essential Medicines List and the Magnitude of Clinical Benefit Scale to better understand the availability of the most critical drugs per country, and they are expanding their survey internationally.

Solutions to problems related to access must be multimodal, he said. For one thing, health professionals must be more concerned about benefit and “raise the bar,” he suggested. “You wouldn’t buy a new car if it only drives 5 mph faster. You wouldn’t consider the investment worth it.”

The Magnitude of Clinical Benefit Scale can help improve access to cancer medications by informing the process of drug prioritization when resources are limited. National bodies should find ways to reimburse for “reasonable medicines” and apply these sound principles to public policy, he said. Finally, he added, the pharmaceutical industry should strive for “Justum pretium,” ie, “the just price.” n

Disclosure: Dr. Eniu has received honoraria from and served as a consultant or advisor to AstraZeneca, Novartis, and Roche. He also has received research funding from AstraZeneca, GlaxoSmithKline, Novartis, and Roche.

References 1. Eniu AE: Disparities of cancer medicine access in Europe. 2015 ASCO Annual Meeting. ASCO/European Society for Medical Oncology (ESMO) Joint Session: Global Perspective on Value.

2. De Angelis R, Sant M, Coleman MP, et al: Cancer survival in Europe 1999-2007 by country and age: Results of EUROCARE-5—a population-based study. Lancet Oncol 15:23-34, 2014.

2 FDA APPROVALS For use both as monotherapy and in combination with paclitaxel

CYRAMZA as a single agent, or in combination with paclitaxel, is indicated for the treatment of patients with advanced or metastatic gastric or gastroesophageal (GE) junction adenocarcinoma with disease progression on or after prior fluoropyrimidine- or platinumcontaining chemotherapy.

IMPORTANT SAFETY INFORMATION FOR CYRAMZA WARNING: HEMORRHAGE, GASTROINTESTINAL PERFORATION, AND IMPAIRED WOUND HEALING Hemorrhage: CYRAMZA increased the risk of hemorrhage and gastrointestinal hemorrhage, including severe and sometimes fatal hemorrhagic events.

Permanently discontinue CYRAMZA in patients who experience severe bleeding.

Gastrointestinal Perforation: CYRAMZA can increase the risk of gastrointestinal perforation, a potentially fatal event. Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation.

Impaired Wound Healing: Impaired wound healing can occur with antibodies inhibiting the VEGF pathway. Discontinue CYRAMZA therapy in patients with impaired wound healing. Withhold CYRAMZA prior to surgery and discontinue CYRAMZA if a patient develops wound healing complications.

Warnings and Precautions

Hemorrhage • CYRAMZA increased the risk of hemorrhage and gastrointestinal hemorrhage, including severe and sometimes fatal hemorrhagic events. In study 1, which evaluated CYRAMZA as a single agent in advanced gastric cancer, the incidence of severe bleeding was 3.4% for CYRAMZA and 2.6% for placebo. In study 2, which evaluated CYRAMZA plus paclitaxel, the incidence of severe bleeding was 4.3% for CYRAMZA plus paclitaxel and 2.4% for placebo plus paclitaxel. Patients with gastric cancer receiving nonsteroid anti-inflammatory drugs (NSAIDs) were excluded from enrollment in studies 1 and 2; therefore, the risk of gastric hemorrhage in CYRAMZA-treated patients with gastric tumors receiving NSAIDs is unknown. Permanently discontinue CYRAMZA in patients who experience severe bleeding.

Arterial Thromboembolic Events (ATEs) • Serious, sometimes fatal, ATEs including myocardial infarction, cardiac arrest, cerebrovascular accident, and cerebral ischemia occurred in clinical trials including 1.7% of 236 patients who received CYRAMZA as a single agent for gastric cancer in study 1. Permanently discontinue CYRAMZA in patients who experience a severe ATE. Hypertension • An increased incidence of severe hypertension occurred in patients receiving CYRAMZA as a single agent (8%) as compared to placebo (3%) and in patients receiving CYRAMZA plus paclitaxel (15%) as compared to placebo plus paclitaxel (3%). Control hypertension prior to initiating treatment with CYRAMZA. Monitor blood pressure every 2 weeks or more frequently as indicated during treatment. Temporarily suspend CYRAMZA for severe hypertension until medically controlled. Permanently discontinue CYRAMZA if medically significant hypertension cannot be controlled with antihypertensive therapy or in patients with hypertensive crisis or hypertensive encephalopathy.

Infusion-Related Reactions (IRRs) • Prior to the institution of premedication recommendations across clinical trials of CYRAMZA, IRRs occurred in 6 out of 37 patients (16%), including 2 severe events. The majority of IRRs across trials occurred during or following a first or second CYRAMZA infusion. Symptoms of IRRs included rigors/ tremors, back pain/spasms, chest pain and/or tightness, chills, flushing, dyspnea, wheezing, hypoxia, and paresthesia. In severe cases, symptoms included bronchospasm, supraventricular tachycardia, and hypotension.

Monitor patients during the infusion for signs and symptoms of IRRs in a setting with available resuscitation equipment. Immediately and permanently discontinue CYRAMZA for grade 3 or 4 IRRs.

Gastrointestinal Perforations • CYRAMZA is an antiangiogenic therapy that can increase the risk of gastrointestinal perforation, a potentially fatal event. Four of 570 patients (0.7%) who received CYRAMZA as a single agent in clinical trials experienced gastrointestinal perforation. In study 2, the incidence of gastrointestinal perforations was also increased in patients who received CYRAMZA plus paclitaxel (1.2%) as compared to patients who received placebo plus paclitaxel (0.3%). Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation.

Impaired Wound Healing • Impaired wound healing can occur with antibodies inhibiting the VEGF pathway.

CYRAMZA has not been studied in patients with serious or nonhealing wounds.

CYRAMZA, an antiangiogenic therapy, has the potential to adversely affect wound healing. Withhold CYRAMZA prior to surgery. Resume CYRAMZA following the surgical intervention based on clinical judgment of adequate wound healing. If a patient develops wound healing complications during therapy, discontinue CYRAMZA until the wound is fully healed.

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

Reversible Posterior Leukoencephalopathy Syndrome (RPLS) • RPLS has been reported at a rate of <0.1% in clinical studies with CYRAMZA. Confirm the diagnosis of RPLS with MRI and discontinue CYRAMZA in patients who develop RPLS. Symptoms may resolve or improve within days, although some patients with RPLS can experience ongoing neurologic sequelae or death.

Proteinuria Including Nephrotic Syndrome • Monitor proteinuria by urine dipstick and/or urinary protein creatinine ratio for the development of worsening of proteinuria during CYRAMZA therapy.

Withhold CYRAMZA for urine protein levels that are ≥2 g over 24 hours.

Reinitiate CYRAMZA at a reduced dose once the urine protein level returns to <2 g over 24 hours. Permanently discontinue CYRAMZA for urine protein levels >3 g over 24 hours or in the setting of nephrotic syndrome.

Thyroid Dysfunction • Monitor thyroid function during treatment with CYRAMZA. Embryofetal Toxicity • Based on its mechanism of action, CYRAMZA can cause fetal harm when

CYRAMZA® (ramucirumab) PLUS PACLITAXEL SIGNIFICANTLY EXTENDED OVERALL SURVIVAL (OS)1 RAINBOW OS: MEDIAN - MONTHS (95% CI)*1 1.0

CYRAMZA + paclitaxel (8.5, 10.8)

OS PROBABILITY

0.8

MAJOR OUTCOME MEASURE

9.6

MONTHS

30% INCREASE IN MEDIAN OS

0.6

Hazard Ratio=0.81 (0.68, 0.96); P=0.017

0.4

7.4

0.2

MONTHS

CYRAMZA + paclitaxel Placebo + paclitaxel (6.3, 8.4)

Placebo + paclitaxel

0.0 0

2

4

6

8

10

12

14

16

18

20

22

24

26

28

TIME FROM RANDOMIZATION (MONTHS) Number at Risk

CYRAMZA 330 + paclitaxel Placebo 335 + paclitaxel

308

267

228

185

148

116

78

60

41

24

13

6

1

0

294

241

180

143

109

81

64

47

30

22

13

5

2

0

• The percentage of deaths at the time of analysis was 78% (256 patients) and 78% (260 patients) in the CYRAMZA plus paclitaxel and placebo plus paclitaxel treatment arms, respectively1 The phase III RAINBOW trial evaluated the efficacy and safety of CYRAMZA plus paclitaxel vs placebo plus paclitaxel in patients with locally advanced or metastatic gastric or GE junction adenocarcinoma with disease progression on or after prior fluoropyrimidine- and platinum-containing chemotherapy. Major efficacy outcome measure was OS. Supportive efficacy outcome measures were progression-free survival (PFS) and objective response rate (ORR). All patients were Eastern Cooperative Oncology Group performance status 0 or 1. Prior to enrollment, 97% of patients had progressed during treatment or within 4 months after the last dose of first-line chemotherapy for metastatic disease. Twenty-five percent of patients had received anthracycline in combination with platinum/ fluoropyrimidine therapy, while 75% did not. Patients were randomized 1:1 to CYRAMZA 8 mg/kg (n=330) or placebo (n=335) every 2 weeks (on days 1 and 15) of each 28-day cycle. Patients in both arms received paclitaxel 80 mg/m2 on days 1, 8, and 15 of each 28-day cycle.1,3 CI=confidence interval. *Intent-to-treat (ITT) population. † ITT population.

ORR was defined as complete plus partial response. Disease progression and tumor response were assessed by investigators in accordance with Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.2

CYRAMZA PLUS PACLITAXEL ALSO SIGNIFICANTLY DELAYED DISEASE PROGRESSION AND PROVIDED SIGNIFICANTLY GREATER ORR VS PLACEBO PLUS PACLITAXEL (SUPPORTIVE EFFICACY OUTCOME MEASURES)*1 • Median PFS with CYRAMZA plus paclitaxel was 4.4 months (95% CI: 4.2, 5.3) vs 2.9 months (95% CI: 2.8, 3.0) with placebo plus paclitaxel (hazard ratio 0.64 [95% CI: 0.54, 0.75]; P<0.001)1 - The percentage of events at the time of analysis was 85% (279 patients) and 88% (296 patients), respectively • Significantly more patients responded to CYRAMZA combined with paclitaxel (28%; 95% CI: 23, 33) than to placebo plus paclitaxel (16%; 95% CI: 13, 20) (P<0.001)†1,2

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

Most Common Adverse Reactions—Single Agent • The most commonly reported adverse reactions (all grades; grade 3/4) occurring in ≥5% of patients receiving CYRAMZA and ≥2% higher than placebo in study 1 were hypertension (16% vs 8%; 8% vs 3%), diarrhea (14% vs 9%; 1% vs 2%), headache (9% vs 3%; 0% vs 0%), and hyponatremia (6% vs 2%; 3% vs 1%).

• The most common serious adverse events with CYRAMZA in study 1 were anemia (3.8%) and intestinal obstruction (2.1%). Red blood cell transfusions were given to 11% of CYRAMZA-treated patients vs 8.7% of patients who received placebo.

• Clinically relevant adverse reactions reported in ≥1% and <5% of CYRAMZAtreated patients in study 1 were: neutropenia (4.7% vs 0.9%), epistaxis (4.7% vs 0.9%), rash (4.2% vs 1.7%), intestinal obstruction (2.1% vs 0%), and arterial thromboembolic events (1.7% vs 0%).

• Across clinical trials of CYRAMZA administered as a single agent, clinically relevant adverse reactions (including grade ≥3) reported in CYRAMZA-treated patients included proteinuria, gastrointestinal perforation, and infusionrelated reactions. In study 1, according to laboratory assessment, 8% of CYRAMZA-treated patients developed proteinuria vs 3% of placebo-treated patients. Two patients discontinued CYRAMZA due to proteinuria. The rate of gastrointestinal perforation in study 1 was 0.8% and the rate of infusionrelated reactions was 0.4%.

Most Common Adverse Reactions—Combination with Paclitaxel • The most commonly reported adverse reactions (all grades; grade 3/4) occurring in ≥5% of patients receiving CYRAMZA plus paclitaxel and ≥2% higher than placebo plus paclitaxel in study 2 were fatigue/asthenia (57% vs 44%; 12% vs 6%), neutropenia (54% vs 31%; 41% vs 19%), diarrhea (32% vs 23%; 4% vs 2%), epistaxis (31% vs 7%; 0% vs 0%), hypertension (25% vs 6%; 15% vs 3%), peripheral edema (25% vs 14%; 2% vs 1%), stomatitis (20% vs 7%; 1% vs 1%), proteinuria (17% vs 6%; 1% vs 0%), thrombocytopenia (13% vs 6%; 2% vs 2%), hypoalbuminemia (11% vs 5%; 1% vs 1%), and gastrointestinal hemorrhage events (10% vs 6%; 4% vs 2%).

• The most common serious adverse events with CYRAMZA plus paclitaxel in study 2 were neutropenia (3.7%) and febrile neutropenia (2.4%); 19% of patients treated with CYRAMZA plus paclitaxel received granulocyte colony-stimulating factors.

• Adverse reactions resulting in discontinuation of any component of the CYRAMZA plus paclitaxel combination in 2% or more patients in study 2 were neutropenia (4%) and thrombocytopenia (3%).

• Clinically relevant adverse reactions reported in ≥1% and <5% of the CYRAMZA plus paclitaxel-treated patients in study 2 were sepsis (3.1% for CYRAMZA plus paclitaxel vs 1.8% for placebo plus paclitaxel) and gastrointestinal perforations (1.2% for CYRAMZA plus paclitaxel vs 0.3% for placebo plus paclitaxel).

Drug Interactions • No pharmacokinetic interactions were observed between ramucirumab (CYRAMZA) and paclitaxel.

Use in Specific Populations • Pregnancy: Based on its mechanism of action, CYRAMZA can cause fetal harm.

Animal models link angiogenesis, VEGF, and VEGF Receptor 2 (VEGFR2) to critical aspects of female reproduction, embryofetal development, and postnatal development. There are no available data on CYRAMZA use in pregnant women to inform any drug-associated risks. No animal studies have been conducted to evaluate the effect of ramucirumab on reproduction and fetal development.

Advise females of reproductive potential of the potential risk for maintaining pregnancy, risk to the fetus, and risk to newborn and infant development, and to use effective contraception during CYRAMZA therapy and for at least 3 months following the last dose of CYRAMZA. • Lactation: Because of the potential risk for serious adverse reactions in nursing infants from ramucirumab, advise women that breastfeeding is not recommended during treatment with CYRAMZA. • Females of Reproductive Potential: Advise females of reproductive potential that based on animal data CYRAMZA may impair fertility.

Please see Brief Summary of Prescribing Information for CYRAMZA, including Boxed Warnings for hemorrhage, gastrointestinal perforation, and impaired wound healing, on next page.

RB HCP ISI 24APR2015 References: 1. CYRAMZA (ramucirumab) [package insert]. Indianapolis, IN: Eli Lilly and Company; 2015. 2. Wilke H, Muro K, Van Cutsem E, et al; for the RAINBOW Study Group.

Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol. 2014;15(11):1224-1235. 3. Data on file, Eli Lilly and Company. ONC09302014b.

RB97116

05/2015 PRINTED IN USA

© Lilly USA, LLC 2015. All rights reserved.

CYRAMZA is a trademark owned by or licensed to Eli Lilly and Company, its subsidiaries, or affiliates.

CYRAMZA® (ramucirumab) injection BRIEF SUMMARY: For complete safety, please consult the full Prescribing Information.

WARNING: HEMORRHAGE, GASTROINTESTINAL PERFORATION, AND IMPAIRED WOUND HEALING Hemorrhage: CYRAMZA increased the risk of hemorrhage and gastrointestinal hemorrhage, including severe and sometimes fatal hemorrhagic events. Permanently discontinue CYRAMZA in patients who experience severe bleeding.

Gastrointestinal Perforation: CYRAMZA can increase the risk of gastrointestinal perforation, a potentially fatal event. Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation.

Impaired Wound Healing: Impaired wound healing can occur with antibodies inhibiting the VEGF pathway. Discontinue CYRAMZA therapy in patients with impaired wound healing. Withhold CYRAMZA prior to surgery and discontinue CYRAMZA if a patient develops wound healing complications.

INDICATIONS AND USAGE Gastric Cancer CYRAMZA as a single agent, or in combination with paclitaxel, is indicated for the treatment of patients with advanced or metastatic, gastric or gastro-esophageal junction adenocarcinoma with disease progression on or after prior fluoropyrimidine- or platinum-containing chemotherapy.

CONTRAINDICATIONS None.

WARNINGS AND PRECAUTIONS Hemorrhage CYRAMZA increased the risk of hemorrhage and gastrointestinal hemorrhage, including severe and sometimes fatal hemorrhagic events. In Study 1, the incidence of severe bleeding was 3.4% for CYRAMZA and 2.6% for placebo. In Study 2, the incidence of severe bleeding was 4.3% for CYRAMZA plus paclitaxel and 2.4% for placebo plus paclitaxel. Patients with gastric cancer receiving nonsteroid anti-inflammatory drugs (NSAIDs) were excluded from enrollment in Studies 1 and 2; therefore, the risk of gastric hemorrhage in CYRAMZA-treated patients with gastric tumors receiving NSAIDs is unknown. In Study 3, the incidence of severe bleeding was 2.4% for CYRAMZA plus docetaxel and 2.3% for placebo plus docetaxel. Patients with NSCLC receiving therapeutic anticoagulation or chronic therapy with NSAIDS or other antiplatelet therapy other than once daily aspirin or with radiographic evidence of major airway or blood vessel invasion or intratumor cavitation were excluded from Study 3; therefore the risk of pulmonary hemorrhage in these groups of patients is unknown. In Study 4, the incidence of severe bleeding was 2.5% for CYRAMZA plus FOLFIRI and 1.7% for placebo plus FOLFIRI. Permanently discontinue CYRAMZA in patients who experience severe bleeding.

Arterial Thromboembolic Events Serious, sometimes fatal, arterial thromboembolic events (ATEs) including myocardial infarction, cardiac arrest, cerebrovascular accident, and cerebral ischemia occurred in clinical trials including 1.7% of 236 patients who received CYRAMZA as a single agent for gastric cancer in Study 1. Permanently discontinue CYRAMZA in patients who experience a severe ATE. Hypertension An increased incidence of severe hypertension occurred in patients receiving CYRAMZA as a single agent (8%) as compared to placebo (3%) and in patients receiving CYRAMZA plus paclitaxel (15%) as compared to placebo plus paclitaxel (3%), in patients receiving CYRAMZA plus docetaxel (6%) as compared to placebo plus docetaxel (2%), and in patients receiving CYRAMZA plus FOLFIRI (11%) as compared to placebo plus FOLFIRI (3%). Control hypertension prior to initiating treatment with CYRAMZA. Monitor blood pressure every two weeks or more frequently as indicated during treatment. Temporarily suspend CYRAMZA for severe hypertension until medically controlled. Permanently discontinue CYRAMZA if medically significant hypertension cannot be controlled with antihypertensive therapy or in patients with hypertensive crisis or hypertensive encephalopathy.

Infusion-Related Reactions Prior to the institution of premedication recommendations across clinical trials of CYRAMZA, infusion-related reactions (IRRs) occurred in 6 out of 37 patients (16%), including two severe events. The majority of IRRs across trials occurred during or following a first or second CYRAMZA infusion. Symptoms of IRRs included rigors/tremors, back pain/spasms, chest pain and/or tightness, chills, flushing, dyspnea, wheezing, hypoxia, and paresthesia. In severe cases, symptoms included bronchospasm, supraventricular tachycardia, and hypotension. Monitor patients during the infusion for signs and symptoms of IRRs in a setting with available resuscitation equipment. Immediately and permanently discontinue CYRAMZA for Grade 3 or 4 IRRs. Gastrointestinal Perforations CYRAMZA is an antiangiogenic therapy that can increase the risk of gastrointestinal perforation, a potentially fatal event. Four of 570 patients (0.7%) who received CYRAMZA as a single agent in clinical trials experienced gastrointestinal perforation. In Study 2, the incidence of gastrointestinal perforations was also increased in patients that received CYRAMZA plus paclitaxel (1.2%) as compared to patients receiving placebo plus paclitaxel (0.3%). In Study 3, the incidence of gastrointestinal perforation was 1% for CYRAMZA plus docetaxel and 0.3% for placebo plus docetaxel. In Study 4, the incidence of gastrointestinal perforation was 1.7% for CYRAMZA plus FOLFIRI and 0.6% for placebo plus FOLFIRI. Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation.

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

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

Reversible Posterior Leukoencephalopathy Syndrome Reversible Posterior Leukoencephalopathy Syndrome (RPLS) has been reported with a rate of <0.1% in clinical studies with CYRAMZA. Confirm the diagnosis of RPLS with MRI and discontinue CYRAMZA in patients who develop RPLS. Symptoms may resolve or improve within days, although some patients with RPLS can experience ongoing neurologic sequelae or death.

Proteinuria Including Nephrotic Syndrome In Study 4, severe proteinuria occurred more frequently in patients treated with CYRAMZA plus FOLFIRI compared to patients receiving placebo plus FOLFIRI. Severe proteinuria was reported in 3% of patients treated with CYRAMZA plus FOLFIRI (including 3 cases [0.6%] of nephrotic syndrome) compared to 0.2% of patients treated with placebo plus FOLFIRI. Monitor proteinuria by urine dipstick and/or urinary protein creatinine ratio for the development of worsening of proteinuria during CYRAMZA therapy.

Withhold CYRAMZA for urine protein levels that are 2 or more grams over 24 hours. Reinitiate CYRAMZA at a reduced dose once the urine protein level returns to less than 2 grams over 24 hours. Permanently discontinue CYRAMZA for urine protein levels greater than 3 grams over 24 hours or in the setting of nephrotic syndrome.

Thyroid Dysfunction Monitor thyroid function during treatment with CYRAMZA. In Study 4, the incidence of hypothyroidism reported as an adverse event was 2.6% in the CYRAMZA plus FOLFIRI treated patients and 0.9% in the placebo plus FOLFIRI treated patients. ®

CYRAMZA (ramucirumab) injection

RB-G HCP BS 29APR2015

Embryofetal Toxicity Based on its mechanism of action, CYRAMZA can cause fetal harm when administered to pregnant women.

Animal models link angiogenesis, VEGF and VEGF Receptor 2 (VEGFR2) to critical aspects of female reproduction, embryofetal development, and postnatal development. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with CYRAMZA and for at 3 least months after the last dose of CYRAMZA. ADVERSE REACTIONS Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Safety data are presented from two randomized, placebo controlled clinical trials in which patients received CYRAMZA: Study 1, a randomized (2:1), double-blind, clinical trial in which 351 patients received either CYRAMZA 8 mg/kg intravenously every two weeks or placebo every two weeks and Study 2, a double-blind, randomized (1:1) clinical trial in which 656 patients received paclitaxel 80 mg/m2 on days 1, 8, and 15 of each 28-day cycle plus either CYRAMZA 8 mg/kg intravenously every two weeks or placebo every two weeks.

Both trials excluded patients with Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 2 or greater, uncontrolled hypertension, major surgery within 28 days, or patients receiving chronic anti-platelet therapy other than once daily aspirin. Study 1 excluded patients with bilirubin ≥1.5 mg/dL and Study 2 excluded patients with bilirubin >1.5 times the upper limit of normal.

CYRAMZA Administered as a Single Agent Among 236 patients who received CYRAMZA (safety population) in Study 1, median age was 60 years, 28% were women, 76% were White, and 16% were Asian. Patients in Study 1 received a median of 4 doses of CYRAMZA; the median duration of exposure was 8 weeks, and 32 (14% of 236) patients received CYRAMZA for at least six months.

In Study 1, the most common adverse reactions (all grades) observed in CYRAMZA-treated patients at a rate of ≥10% and ≥2% higher than placebo were hypertension and diarrhea. The most common serious adverse events with CYRAMZA were anemia (3.8%) and intestinal obstruction (2.1%). Red blood cell transfusions were given to 11% of CYRAMZA-treated patients versus 8.7% of patients who received placebo.

Table 1: Adverse Reactions Occurring at Incidence Rate ≥5% and a ≥2% Difference Between Arms in Patients Receiving CYRAMZA in Study 1 CYRAMZA (8 mg/kg) Placebo N=236 N=115 Adverse Reactions (MedDRA)a System Organ Class All Grades Grade 3-4 All Grades Grade 3-4 (Frequency %) (Frequency %) (Frequency %) (Frequency %) Gastrointestinal Disorders Diarrhea 14 1 9 2 Metabolism and Nutrition Disorders Hyponatremia 6 3 2 1 Nervous System Disorders Headache 9 0 3 0 Vascular Disorders Hypertension 16 8 8 3 a

MedDRA Version 15.0.

Clinically relevant adverse reactions reported in ≥1% and <5% of CYRAMZA-treated patients in Study 1 were: neutropenia (4.7% CYRAMZA versus 0.9% placebo), epistaxis (4.7% CYRAMZA versus 0.9% placebo), rash (4.2% CYRAMZA versus 1.7% placebo), intestinal obstruction (2.1% CYRAMZA versus 0% placebo), and arterial thromboembolic events (1.7% CYRAMZA versus 0% placebo).

Across clinical trials of CYRAMZA administered as a single agent, clinically relevant adverse reactions (including Grade ≥3) reported in CYRAMZA-treated patients included proteinuria, gastrointestinal perforation, and infusion-related reactions. In Study 1, according to laboratory assessment, 8% of CYRAMZA-treated patients developed proteinuria versus 3% of placebo-treated patients. Two patients discontinued CYRAMZA due to proteinuria. The rate of gastrointestinal perforation in Study 1 was 0.8% and the rate of infusion-related reactions was 0.4%.

CYRAMZA Administered in Combination with Paclitaxel Among 327 patients who received CYRAMZA (safety population) in Study 2, median age was 60 years, 31% were women, 63% were White, and 33% were Asian. Patients in Study 2 received a median of 9 doses of CYRAMZA; the median duration of exposure was 18 weeks, and 93 (28% of 327) patients received CYRAMZA for at least six months.

In Study 2, the most common adverse reactions (all grades) observed in patients treated with CYRAMZA plus paclitaxel at a rate of ≥30% and ≥2% higher than placebo plus paclitaxel were fatigue, neutropenia, diarrhea, and epistaxis. The most common serious adverse events with CYRAMZA plus paclitaxel were neutropenia (3.7%) and febrile neutropenia (2.4%); 19% of patients treated with CYRAMZA plus paclitaxel received granulocyte colony-stimulating factors. Adverse reactions resulting in discontinuation of any component of the CYRAMZA plus paclitaxel combination in 2% or more patients in Study 2 were neutropenia (4%) and thrombocytopenia (3%).

Table 2: Adverse Reactions Occurring at Incidence Rate ≥5% and a ≥2% Difference Between Arms in Patients Receiving CYRAMZA plus Paclitaxel in Study 2 CYRAMZA plus Paclitaxel Placebo plus Paclitaxel (N=327) (N=329) Adverse Reactions (MedDRA) System Organ Class All Grades Grade ≥3 All Grades Grade ≥3 (Frequency %) (Frequency %) (Frequency %) (Frequency %) Blood and Lymphatic System Disorders Neutropenia Thrombocytopenia Gastrointestinal Disorders Diarrhea Gastrointestinal hemorrhage events

54 13

41 2

31 6

19 2

32 10

4 4

23 6

2 2

1

7

1

12 2

44 14

6 1

1

5

1

1

6

0

0

7

0

15

6

3

Stomatitis 20 General Disorders and Administration Site Disorders Fatigue/Asthenia 57 Peripheral edema 25 Metabolism and Nutrition Disorders Hypoalbuminemia 11 Renal and Urinary Disorders Proteinuria 17 Respiratory, Thoracic, and Mediastinal Disorders Epistaxis 31 Vascular Disorder Hypertension 25 ®

CYRAMZA (ramucirumab) injection

RB-G HCP BS 29APR2015

Clinically relevant adverse reactions reported in ≥1% and <5% of the CYRAMZA plus paclitaxel treated patients in Study 2 were sepsis (3.1% CYRAMZA plus paclitaxel versus 1.8% placebo plus paclitaxel) and gastrointestinal perforations (1.2% CYRAMZA plus paclitaxel versus 0.3% for placebo plus paclitaxel).

Immunogenicity As with all therapeutic proteins, there is the potential for immunogenicity. In 23 clinical trials, 86/2890 (3.0%) of CYRAMZA-treated patients tested positive for treatment-emergent anti-ramucirumab antibodies by an enzyme-linked immunosorbent assay (ELISA). Neutralizing antibodies were detected in 14 of the 86 patients who tested positive for treatment-emergent anti-ramucirumab antibodies.

The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay.

Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to CYRAMZA with the incidences of antibodies to other products may be misleading.

DRUG INTERACTIONS No pharmacokinetic interactions were observed between ramucirumab and paclitaxel.

USE IN SPECIFIC POPULATIONS Pregnancy Risk Summary Based on its mechanism of action, CYRAMZA can cause fetal harm. Animal models link angiogenesis, VEGF and VEGF Receptor 2 (VEGFR2) to critical aspects of female reproduction, embryofetal development, and postnatal development. There are no available data on CYRAMZA in pregnant women to inform any drug-associated risks. No animal studies have been conducted to evaluate the effect of ramucirumab on reproduction and fetal development. The background risk of major birth defects and miscarriage for the indicated populations are unknown. In the U.S. general population the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Advise pregnant women of the potential risk to a fetus.

Animal Data No animal studies have been specifically conducted to evaluate the effect of ramucirumab on reproduction and fetal development. In mice, loss of the VEGFR2 gene resulted in embryofetal death and these fetuses lacked organized blood vessels and blood islands in the yolk sac. In other models, VEGFR2 signaling was associated with development and maintenance of endometrial and placental vascular function, successful blastocyst implantation, maternal and feto-placental vascular differentiation, and development during early pregnancy in rodents and non-human primates. Disruption of VEGF signaling has also been associated with developmental anomalies including poor development of the cranial region, forelimbs, forebrain, heart, and blood vessels.

Lactation Risk Summary There is no information on the presence of ramucirumab in human milk, the effects on the breast-fed infant, or the effects on milk production. Human IgG is present in human milk, but published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because of the potential risk for serious adverse reactions in nursing infants from ramucirumab, advise women that breastfeeding is not recommended during treatment with CYRAMZA. Females and Males of Reproductive Potential Contraception Females Based on its mechanism of action, CYRAMZA can cause fetal harm. Advise females of reproductive potential to use effective contraception while receiving CYRAMZA and for at least 3 months after the last dose of CYRAMZA. Infertility Females Advise females of reproductive potential that based on animal data CYRAMZA may impair fertility.

Pediatric Use The safety and effectiveness of CYRAMZA in pediatric patients have not been established. In animal studies, effects on epiphyseal growth plates were identified. In cynomolgus monkeys, anatomical pathology revealed adverse effects on the epiphyseal growth plate (thickening and osteochondropathy) at all doses tested (5-50 mg/kg). Ramucirumab exposure at the lowest weekly dose tested in the cynomolgus monkey was 0.2 times the exposure in humans at the recommended dose of ramucirumab as a single agent.

Geriatric Use Of the 563 CYRAMZA-treated patients in two randomized gastric cancer clinical studies, 36% were 65 and over, while 7% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects.

Renal Impairment No dose adjustment is recommended for patients with renal impairment based on population pharmacokinetic analysis.

Hepatic Impairment No dose adjustment is recommended for patients with mild (total bilirubin within upper limit of normal [ULN] and aspartate aminotransferase [AST] >ULN, or total bilirubin >1.0-1.5 times ULN and any AST) or moderate (total bilirubin >1.5-3.0 times ULN and any AST) hepatic impairment based on population pharmacokinetic analysis. Clinical deterioration was reported in patients with Child-Pugh B or C cirrhosis who received single-agent CYRAMZA.

PATIENT COUNSELING INFORMATION • Hemorrhage: Advise patients that CYRAMZA can cause severe bleeding. Advise patients to contact their health care provider for bleeding or symptoms of bleeding including lightheadedness].

• Arterial thromboembolic events: Advise patients of an increased risk of an arterial thromboembolic event.

• Hypertension: Advise patients to undergo routine blood pressure monitoring and to contact their health care provider if blood pressure is elevated or if symptoms from hypertension occur including severe headache, lightheadedness, or neurologic symptoms.

• Gastrointestinal perforations: Advise patients to notify their health care provider for severe diarrhea, vomiting, or severe abdominal pain.

• Impaired wound healing: Advise patients that CYRAMZA has the potential to impair wound healing. Instruct patients not to undergo surgery without first discussing this potential risk with their health care provider.

• Pregnancy and fetal harm: Advise females of reproductive potential of the potential risk for maintaining pregnancy, risk to the fetus, and risk to postnatal newborn and infant development and to use effective contraception during CYRAMZA therapy and for at least 3 months following the last dose of CYRAMZA. • Lactation: Advise patients not to breastfeed during CYRAMZA treatment.

• Infertility: Advise females of reproductive potential regarding potential infertility effects of CYRAMZA Additional information can be found at www.CYRAMZAHCP.com.

DOSAGE AND ADMINISTRATION Do not administer CYRAMZA as an intravenous push or bolus.

Recommended Dose and Schedule The recommended dose of CYRAMZA either as a single agent or in combination with weekly paclitaxel is 8 mg/kg every 2 weeks administered as an intravenous infusion over 60 minutes. Continue CYRAMZA until disease progression or unacceptable toxicity. When given in combination, administer CYRAMZA prior to administration of paclitaxel.

Premedication Prior to each CYRAMZA infusion, premedicate all patients with an intravenous histamine H1 antagonist (e.g., diphenhydramine hydrochloride). For patients who have experienced a Grade 1 or 2 infusion-related reaction, also premedicate with dexamethasone (or equivalent) and acetaminophen prior to each CYRAMZA infusion.

Dose Modifications Infusion-Related Reactions (IRR) • Reduce the infusion rate of CYRAMZA by 50% for Grade 1 or 2 IRRs. • Permanently discontinue CYRAMZA for Grade 3 or 4 IRRs. Hypertension • Interrupt CYRAMZA for severe hypertension until controlled with medical management.

• Permanently discontinue CYRAMZA for severe hypertension that cannot be controlled with antihypertensive therapy.

Proteinuria • Interrupt CYRAMZA for urine protein levels ≥2 g/24 hours. Reinitiate treatment at a reduced dose of 6 mg/kg every 2 weeks once the urine protein level returns to <2 g/24 hours. If the protein level ≥2 g/24 hours reoccurs, interrupt CYRAMZA and reduce the dose to 5 mg/kg every 2 weeks once the urine protein level returns to <2 g/24 hours.

• Permanently discontinue CYRAMZA for urine protein level >3 g/24 hours or in the setting of nephrotic syndrome.

Wound Healing Complications • Interrupt CYRAMZA prior to scheduled surgery until the wound is fully healed.

Arterial Thromboembolic Events, Gastrointestinal Perforation, or Grade 3 or 4 Bleeding • Permanently discontinue CYRAMZA. For toxicities related to paclitaxel, refer to the current prescribing information.

CYRAMZA® (ramucirumab) injection

RB-G HCP BS 29APR2015

Eli Lilly and Company, Indianapolis, IN 46285, USA Copyright © 2015, Eli Lilly and Company. All rights reserved.

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The ASCO Post | SEPTEMBER 10, 2015

PAGE 72

Education in Oncology Professional Development

The Flipped Classroom: Swapping the Traditional Lecture Hall for an Online Version A Conversation With Charles Prober, MD

By Jo Cavallo

D

espite enormous advances in modern medicine and the explosion of biomedical information over the past century, the way medical education is taught in the United States is stuck in a format that does not optimize learning, according to Charles Prober, MD, Senior Associate Dean for Medical Education at Stanford School of Medicine in California.

years ago by the School of Medicine.

One recently developed course using this model in microbiology/infectious diseases was created by Stanford in collaboration with four other medical schools, including the University of California, San Francisco; the University of Washington, Seattle; Duke University, Durham, North Carolina; and the University of Michigan, Ann Arbor.

The combination of video material and the in-class activities provides students with a deeper understanding of the material and makes the course more relevant.

—Charles Prober, MD

The combination of the digitally empowered learner, the rapid expansion of biomedical knowledge, and the increasing specialization within the practice of medicine is driving the need to reimagine medical education, so lessons are more comprehensible and memorable, what Dr. Prober calls “stickier.”

Dr. Prober believes that content should be more engaging, embrace a learning strategy that can be self-paced, and designed to make better use of the fixed amount of educational time available to train new doctors.

Rather than professors delivering a series of facts to students gathered in a lecture hall, in this “flipped classroom” model of education, students acquire basic knowledge on a specific subject through a series of short—10 minutes or less—videos presented online. The video sessions can be downloaded to a student’s computer or mobile device and viewed as often as necessary to master the content in preparation for in-depth interactive classroom discussions with the professors. In this flipping of the classroom model, lessons previously taught in class are learned at home, and “homework” is performed in the classroom, with small groups of students interacting with faculty.

The flipped classroom approach to teaching is part of the Stanford Medicine Interactive Learning Initiative (smili. stanford.edu), which was launched 2

According to Dr. Prober, several medical school courses at Stanford have seen improved student attendance and course ratings since they migrated from poorly attended lectures as the primary mode of delivery to the flipped classroom approach.

Dr. Prober first described the use of the flipped classroom in medical education in 2012 in an article called “Lecture Halls Without Lectures—A Proposal for Medical Education” published in The New England Journal of Medicine.1 The model was further detailed a year later in an article he coauthored with Salman Khan, founder of the Khan Academy, Mountain View, California, called “Medical Education Reimagined: A Call to Action,” published in Academic Medicine.2 The ASCO Post talked with Dr. Prober about this new concept in higher learning and its impact on the education of medical students.

Growing Popularity Among Students Stanford first used the flipped classroom concept in its biochemistry classes.

How has it changed the way students’ learn, and what has been the reaction from students?

The core biochemistry class here was redesigned 4 years ago to follow the flipped classroom model. Historically, the course had not been well received,

as evidenced by very few students participating in organized lectures—only about 20% of students attended the lectures, and 80% found them not to be particularly compelling. Our faculty produced a series of short videos and, in parallel, designed richly interactive classroom sessions that became more patient-centered and problem-centered than the previous curriculum.

The students found the material much more relevant and compelling because it showed them why they needed to understand the information to take care of their future patients. The course immediately became more popular, with up to 90% of the students attending the optional interactive sessions.

So the students are more engaged, the material is being delivered in a more efficient fashion, the course ratings have gone up substantially, and we believe that the students are retaining the material.

I am not suggesting that there is no room in medical education for the more conventional lecture-hall settings, but to be successful, those kinds of lectures would have to be special learning opportunities for students.

The Sweet Spot for Delivering Videos How did you determine that 10 minutes is the optimal amount of time for students to grasp the material in the videos?

There is a fair amount of emerging data showing that 10 minutes of material is about right for a typical learner’s attention span. Some people even suggest that reducing the information to less than 10 minutes is beneficial, but there is a limit to how short you want to make these videos. So 6 to 10 minutes is what we think is the sweet spot for delivering videos that have imbedded within them no more than two or three learning objectives as opposed to 20 learning objectives you might have in a conventional lecture.

Expanding Content Are you producing these videos in a variety of specialties, including medical oncology?

One of our faculty members who runs our introductory courses in molecular biology is an oncologist,

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. and he has created videos for some of the more difficult to understand concepts. For example, he devised one on the Kaplan-Meier survivorship curves. So far, we have content in biochemistry, epidemiology, biostatistics, health policy, microbiology, immunology, infectious diseases, endocrinology, and cardiology. Our faculty is becoming more and more convinced that this is a strategy that may work for their students.

We are also producing videos for students in our clinical rotations. For example, one of our core clinical rotations is in surgery, and instead of presenting the information in a lecture format, members of the surgical team have created short videos of the information. After watching the videos, the students, who are in different hospitals doing their surgical rotations, then come together once a week in a central place to have an interactive classroom session about the material in the video.

Cultivating a Deeper Understanding Why is the flipped classroom method effective in helping medical students retain knowledge? continued on page 73

ASCOPost.com | SEPTEMBER 10, 2015

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Announcements

W. Kimryn Rathmell, MD, PhD, Will Direct Division of Hematology and Oncology at Vanderbilt

Jeffrey Rathmell, PhD, to Lead New Center for Immunobiology at Vanderbilt

W

J

. Kimryn Rathmell, MD, PhD, Alexander Professor for Translational Science and Associate Director for Training and Education at the University of North Carolina’s Lineberger Comprehensive Cancer Center, has been named Director of Vanderbilt’s Division of Hematology and Oncology. She began her new role as of September 1.

W. Kimryn Rathmell, MD, PhD

Dr. Rathmell is a physician-scientist whose research focuses on the genetic and molecular signals that drive renal cell carcinomas and who specializes in the treatment of patients with rare and complex kidney cancers, as well as prostate, bladder, and testicular cancers.

In her current research, Dr. Rathmell and colleagues have identified factors that are critical to transitions in the progression of kidney cancer. She has also led or participated in a number of the Cancer Genome Atlas projects.

The Flipped Classroom continued from page 72

There are several reasons. One is that the material is created to conform to a template, so there is consistency in the format regardless of the content. In a lecture situation, content can be delivered via a variety of formats, which may leave the learner confused. For example, if you have 50 minutes to deliver a lecture, some professors use up to 150 slides. This may drive a delivery pace that is difficult for many students to follow. So I think format consistency in the video presentations automatically facilitates learning.

Also, the short video format allows

At Vanderbilt, Dr. Rathmell will continue to care for patients with genitourinary malignancies, in addition to continuing research in her laboratory at Vanderbilt-Ingram Cancer Center (VICC).

“We are excited about the recruitment of Kim Rathmell, who has already demonstrated an impressive commitment to research excellence and training. Her leadership of the Division of Hematology and Oncology will contribute significantly to VICC on many levels,” said Jennifer Pietenpol, PhD, B.F. Byrd Jr Professor of Oncology and Director of VICC. Dr. Rathmell has been inducted into the Alpha Omega Alpha Honor Medical Society and the American Society of Clinical Investigators, where she currently serves on the council as Secretary/Treasurer. She has also authored more than 80 articles, has served on the editorial boards for several scientific journals, and is an Associate Editor for the Journal of Clinical Investigation.

Dr. Rathmell earned her medical degree, as well as her doctorate (in biophysics), at Stanford University. Following an internship at the University of Chicago, she completed her residency and fellowship at the University of Pennsylvania. n for efficient packaging of the information that the teacher wants to convey, and students can review the material as many times as they need to master the content. The videos allow students to learn at their own pace, on their own time. In a classroom setting, students have one shot at understanding the material being presented.

But what really allows the video material to be relevant and “to stick” is that the students can then put the principles they’ve learned online into practice in the classroom interacting with their peers and faculty.

With this method, the combination of video material and the in-class

effrey Rathmell, PhD, has been recruited to Vanderbilt University Medical Center (VUMC) to lead a new Center for Immunobiology, a structure supported by the Department of Pathology, Microbiology, and Immunology, the Department of Medicine, and Vanderbilt-Ingram Cancer Center (VICC). He took on his new role September 1.

Jeffrey Rathmell, PhD

Dr. Rathmell comes to Vanderbilt from Duke University Medical Center, where he was Associate Professor of Pharmacology and Cancer Biology, as well as of Immunology in the Duke Molecular Physiology Institute. He was additionally Director of Graduate Studies of Pharmacology. He has been named a Professor of Pathology, Microbiology, and Immunology and will serve as co-leader of the Host Tumor Interactions Research Program at VICC. His work at Vanderbilt will focus on the field of immunometabolism and activities provides students with a deeper understanding of the material and makes the course more relevant; therefore, the information is more likely to stick with students for a longer time.

One of the core elements of these videos are patient stories; students can learn some of the key concepts we are trying to teach about basic science and the pathogenesis of a specific disease.

The patient stories are powerful and help students understand the importance of learning this material.

The real test of the flipped classroom method, and it’s too soon to tell at the moment, is whether presenting

how nutrient and metabolic pathways can influence immune responses.

“Vanderbilt has great immunologists across the medical school, and the main goals of the new Center for Immunobiology will be to foster basic immunology science, which touches on many different fields and diseases, and to help build the immunology community,” said Dr. Rathmell.

“We are delighted to welcome Jeff to VICC and look forward to his contributions and leadership as we grow cancer immunology from basic and translational research to clinical investigation,” said Jennifer Pietenpol, PhD, B.F. Byrd Jr Professor of Oncology and Director of VICC. Dr. Rathmell has authored more than 90 research articles and serves as a member of the editorial board for several scientific journals.

He earned his doctorate in immunology at Stanford University and completed a graduate fellowship with the National Science Foundation during his PhD training. He undertook postdoctoral training at the Abramson Family Cancer Research Institute at the University of Pennsylvania, where he earned fellowships from the Howard Hughes Medical Institute and the Irvington Institute for Immunological Research. n medical education in this new way provides students with a superior ability to deal with clinical experiences than the traditional method of learning. So we are interested in tracking long-term outcomes. n Disclosure: Dr. Prober reported no potential conflicts of interest.

References 1. Prober CG, Heath C: Lecture halls without lectures—A proposal for medical education. N Engl J Med 366:1657-1659, 2012.

2. Prober CG, Khan S: Medical education reimagined: A call to action. Acad Med 88:1407-1410, 2013.

Visit The ASCO Post website at ASCOPost.com

The ASCO Post | SEPTEMBER 10, 2015

PAGE 74

Announcements

Iuliana Shapira, MD, Named Chief of Hematology and Oncology at SUNY Downstate

I

uliana Shapira, MD, has joined SUNY Downstate Medical Center as Chief of the Division of Hematology and Oncology. In this position, Dr. Shapira will provide leadership in the clinical, academic, and administrative aspects of the program, as well as broaden the relationship with SUNY Downstate’s affiliated institutions.

Dr. Shapira was the Jacobi Hospital Site Investigator for the Albert Einstein Minority National Cancer Institute Community Oncology Research Program Grant until March 2015.

Dr. Shapira graduated from the Carol Davila University of Medicine and Pharmacy in Bucharest, Romania. She trained in internal medicine at Saint Barnabas Medical Center in Livingston,

New Jersey, and completed a hematology-oncology fellowship at SUNY Downstate. She is board certified in internal medicine, hematology, and medical oncology. n

Iuliana Shapira, MD

Dr. Shapira was previously Associate Professor of Medicine at Hofstra North Shore-LIJ School of Medicine, where she served as Director of its Center for Cancer Genetics and Cancer Control and site Co-Investigator for numerous studies under a Cancer Community Oncology Program Grant from the National Institutes of Health.

She has served as Associate Editor of the Journal of Molecular Medicine since 2008.

Dr. Shapira is the 2016 President of the American Federation for Medical Research (AFMR) Eastern Region, Councilor for AFMR’s National Council, and a member of the Federation of American Societies for Experimental Biology National Institutes of Health Research Enterprise Evaluation Subcommittee. She is also a member of the Audit Committee of the Alliance in Clinical Trials for Oncology, serving as National Cancer Institute Clinical Trials Monitoring Branch Auditor.

She served as Chairwoman for the Clinical Competency Committee and Site Program Director for the Hematology-Oncology Fellowship Program of North Shore University Hospital.

Visit The ASCO Post website at ASCOPost.com © 2015 Genentech USA, Inc. All rights reserved. COB/092414/0002(1) Printed in USA.

ASCOPost.com | SEPTEMBER 10, 2015

PAGE 75

Announcements

Andrew S. Chi, MD, PhD, Named Head of Neuro-Oncology at NYU’s Laura and Isaac Perlmutter Cancer Center

N

ew York University (NYU) Langone Medical Center announced the appointment of physician-scientist and brain tumor specialist Andrew S. Chi, MD, PhD, as Chief of Neuro-On-

cology for its Laura and Isaac Perlmutter Cancer Center and Co-Director of the NYU Langone Brain Tumor Center.

In his new role, Dr. Chi will lead all neuro-oncology-related pro-

grams. In addition, he will co-lead the NYU Langone Brain Tumor Center in partnership with John G. ­Golfinos, MD, Chair of the Department of Neurosurgery.

IN ONCOLOGY, HAVE WE

MAXIMIZED THE POTENTIAL OF TARGETING THE MAPK PATHWAY?

Research has found that abnormal MAPK signaling may lead to increased or uncontrolled cell proliferation and resistance to apoptosis. Studies have shown that the MAPK pathway plays an important role in some cancers.1 Based on these findings, Genentech is investigating further ways to target the MAPK pathway.

Learn more at TargetMAPK.com.

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

Clinical and Investigative Expertise Dr. Chi comes to NYU from Massachusetts General Hospital, DanaFaber/Harvard Cancer Center, and Harvard Medical School, where he held the title of Assistant Professor of Neurology. His clinical work at Massachuetts General Hospital included the neuro-oncologic treatment of primary brain tumors, metastatic tumors to the central nervous system, and neurologic complications of cancer.

Andrew S. Chi, MD, PhD

In addition to his clinical expertise, Dr. Chi’s investigative work principally focuses on the identification of molecular genetic alterations that underlie the development, progression, and treatment resistance of brain tumors. By understanding the mechanism by which tumor genome alterations drive the growth of cancers, therapeutic strategies can be designed to improve outcomes for patients.

After completing his postdoctoral research at Massachusetts General Hospital, Dr. Chi began his research studies of the underlying genetic mechanisms of brain tumors in the laboratory on a team with Daniel P. ­Cahill, MD, PhD, and A. John Iafrate, MD, PhD, where they advanced the understanding of the molecular genetics of gliomas and uncovered novel molecular targets for the treatments for brain tumors.

Dr. Chi earned his medical degree and doctorate in biochemistry and molecular biology from Chicago Medical School.

He completed his residency in neurology at Harvard Medical School, based at Massachusetts General Hospital and Brigham and Women’s Hospital, serving his final year as Chief Resident.

“I am thrilled to join NYU Langone and to work with the respected faculty at the Perlmutter Cancer Center,” said Dr. Chi. “We share a similar vision of innovation for the Cancer Center, and I am confident that as a result of these efforts, we will see major scientific and clinical advances against these horrible diseases in the coming years.” n

The ASCO Post | SEPTEMBER 10, 2015

PAGE 76

Women in Oncology Gynecologic Cancer

How Carolyn D. Runowicz, MD, FASCO, Is Shaping the Future of Gynecologic Cancers

By Beth Howard

Carolyn D. Runowicz, MD, FASCO

C

arolyn D. Runowicz, MD, ­FASCO, has worn just about every hat in the field of oncology— clinician, professor, researcher, administrator, and even cancer survivor.

Currently the Executive Associate Dean for Academic Affairs and Professor in the Department of Obstetrics and Gynecology at the Herbert Wertheim College of Medicine at Florida International University in Miami, she has held numerous academic and professional leadership positions, conducted research in gynecologic oncology, and helped to blaze trails for other female oncologists.

A native of Willimantic, Connecticut, Dr. Runowicz attended the University of Connecticut and then headed to Thomas Jefferson Medical College in Philadelphia for her medical degree. The stage for her career in oncology was set in her first year

of medical school, when through an American Cancer Society fellowship, she “shadowed” gynecologic oncologist George C. Lewis, MD. “His passion for what he did was contagious,” said Dr. Runowicz. “He would get in early in the morning and stay until late at night, yet he never seemed tired. Every day was met with enthusiasm and vigor. I thought, wow, if I could find that same passion in my life, I would really be happy.” She also became enamored with the specialty of gynecologic oncology. “It was comprehensive care of women with cancer, from diagnosis to the end of life,” she said.

important in her training was fellowship director ­Carmel C ­ ohen, MD, Professor of Obstetrics, Gynecology, and Reproductive Medicine at Mount Sinai.)

A few years later, Dr. Runowicz was recruited to join Albert Einstein College of Medicine and Montefiore Medical Center to help develop a Division of Gynecologic Oncology and start a fellowship program. She had also begun conducting clinical trials in gynecologic cancers.

Fortuitous Timing It was an exciting time to be in the field. “I was privileged to be at insti-

I like to think I was always empathetic with patients, but going through cancer gave me another look into what their lives were like.

—Carolyn D. Runowicz, MD, FASCO

During her residency at Mount Sinai Hospital in New York, from 1977 to 1981, Dr. Runowicz joined the Department of Obstetrics and Gynecology, guided by Saul B. Gusberg, MD [then Distinguished Service Professor and Chairman in the Department of Obstetrics and Gynecology at Mount Sinai School of Medicine], one of the founding fathers of gynecologic oncology, and completed her fellowship in the specialty. (Also

tutions where some of the new drugs were being developed—drugs that changed how cancer was treated,” said Dr. Runowicz. “I was at Mount Sinai when platinum-based chemotherapy came out, then at Einstein when Susan B. Horwitz, PhD, [Distinguished Professor in the Department of Molecular Pharmacology] began to describe how paclitaxel worked. I had all these patients who had been on platinum-based chemotherapy, and

it stopped working. But we put them on paclitaxel and witnessed another miracle.”

Dr. Runowicz was also involved in researching cisplatin for the treatment of ovarian cancer. “It’s been amazing to see how these drugs absolutely changed how we treat cancer,” she said.

By now, Dr. Runowicz had found her own passion, but a diagnosis of breast cancer in 1992 threw her an unexpected curve ball. Because the cancer had spread to her lymph nodes, treatment included chemotherapy, radiation, and tamoxifen.

The grueling regimen took 11 months to complete, but Dr. ­Runowicz never stopped working, even as she struggled with nausea and crushing fatigue. “I didn’t realize the cumulative effect [of the treatment]. The first session of chemo was not that bad, the second was a little worse. With each time, it required an additional day to get over.

And antinausea medications were almost nonexistent then,” she said. “I like to think I was always empathetic with patients, but going through cancer gave me another look into what their lives were like.”

Hitting Her Stride In 2002, Dr. Runowicz became the Director of the Carole and Ray Neag Comprehensive Cancer Center at the University of Connecticut

Ovarian Cancer Awareness Month

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Women in Oncology Health Center to rebuild its cancer program. She had also begun taking leadership roles in several professional societies and accumulating several “firsts.” For instance, she was the first woman to head the traditionally all-male Society of Gynecologic Oncologists. “I had to tread carefully,” she said. “But it was a great experience and ­privilege.”

In 2000, Dr. Runowicz proposed a name change for the group—to the Society of Gynecologic Oncology. “I had a vision of a much larger organization that would no longer be about doctors but about the science,” she said. It took 10 years, but the group was finally renamed in 2011. “It was a name that indicated this was a serious professional organization focused on the science and not the doctors,” said Dr. Runowicz.

Dr. Runowicz was also the first gynecologic oncologist to serve on ­A SCO’s Board of Directors. Her other notable appointments include a term as President of the American Cancer Society from 2005 to 2006. In 2004, she was asked by President George W. Bush to serve as a member of the National Cancer Advisory Board for a 6-year appointment, which included two terms as its Chair.

At the same time, Dr. Runowicz managed to speak regularly on gynecologic cancers, menopause management, and breast cancer; to advocate for women’s health; and to write several books, including To Be Alive: A Woman’s Guide to a Full Life After Cancer (Henry Holt & Co, 1995), and coauthored with her husband ­Sheldon Cherry, MD, Associate Dean of Clinical Affairs and Professor of Obstetrics and Gynecology at Florida International University’s Herbert Wertheim College of Medicine, The Menopause Book: A Guide to Women’s Health After 40 (Macmillan Publishers, 1994).

Enjoying New Challenges At Florida International University, Dr. Runowicz is enjoying the challenges and rewards of helping guide the school’s fledgling medical program.

The new medical school just graduated its third class. “We’re in the building phase,” said Dr. Runowicz. “There’s a lot of enthusiasm here.”

In addition to Dr. Runowicz’ academic responsibilities at the university, she and her colleagues are investigating a promising novel therapy for ovarian cancer: intraperitoneal delivery of paclitaxel via magneto-

electric nanoparticles, which may enable researchers to overcome some of the barriers to the widespread use of intraperitoneal chemotherapy in ovarian cancer.

“The tumor opens up a pore, and the particle goes in and kills the cell,” she said. “We’ve cured ovarian cancer in a mouse model. That’s a long

way from success in humans, but it’s a start.”

Dr. Runowicz also maintains a clinical practice in Miami and feels privileged to have had the opportunity to become an oncologist and to continue to have such a varied career, from taking care of patients and conducting research to being an aca-

demician. It is clear from her extraordinary list of past accomplishments in oncology care and her work today, Dr. Runowicz has found the same passion in her career she so admired in the career of her early mentor, Dr. Lewis. n Disclosure: Dr. Runowicz reported no potential conflicts of interest.

It’s what’s inside that counts.

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As a result, a FoundationOne® comprehensive genomic profile can identify 3 times more targeted therapy options than traditional hot spot testing.1 We are more than just a test provider.

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1. Frampton GM, Fichtenholtz A, Otto GA, et al. Development and validation of a clinical cancer genomic profiling test based on massively parallel DNA sequencing. Nat Biotechnol. 2013;31(11):1023-1031. ©2015 Foundation Medicine, Inc. Foundation Medicine® and FoundationOne® are registered trademarks.

The ASCO Post | SEPTEMBER 10, 2015

PAGE 78

Through the Lens of Oncology History

A Century of Progress The text and photographs on this page are excerpted from a four-volume series of books titled Oncology Tumors & Treatment: A Photographic History, by Stanley B. Burns, MD, FACS. The photos below are from the volume titled “The Anesthesia Era: 1845–1875.” To view additional photos from this series of books, visit burnsarchive.com.

THE Anesthesia Era: 1845–1875 Hypertrophic Tumor of the Forehead, Philadelphia, Circa 1870

I

n 1869, the first periodical produced with photographs appeared in Europe. Just 1 year later, The Photographic Review of Medicine and Surgery, with original photographs, was published in America. The publication was edited by Philadelphia surgeon Frank F. Maury, MD (1840– 1879) and dermatologist Louis A. Duhring, MD (1843–1913). The journal was devoted to publishing monthly photographs and case reports of rare, unusual, or interesting patients.

Fascinating Photographs Over a 2-year period, 1870 to 1872, 48 albumen prints were published. The images presented were the most fascinating pictures of the extremes of disease; they appeared for decades thereafter as illustrations in medical texts.

Ophthalmologist Richard J. ­L evis, MD (1827–1890) is remembered for introducing the wire loop used in cataract extraction. He presented this showcased photograph with its case history entitled, “Hypertrophic Tumor of the Integument of Forehead, Eyelid & Eyebrow,” in 1870.

“The patient, a 30-year-old man, was noted at birth to have a small protuberance in the left temple. By

age 14, vision in his left eye was totally obscured. At age 30, the left eye has atrophied, and an entire quadrant of his face has been consumed by the persistent tumor. No treatment was advised.”

Progressive Deformities Neurofibromatosis, or von Recklinghausen’s disease, is a condition characterized by dermal, neural, and osseous deformities often progressing to severe and gross distortion.

History’s most famous victim and extreme example of the disease is John ­Merrick, the “Elephant Man.” Typically, the disease presents as a small elevation around the eye or temple which, left untreated, may steadily grow to enormous proportions, as seen in the photo at right.

In 1882, a student of ­ R udolf ­Virchow, MD (founder of cellular pathology), Friedrich Daniel von ­R ecklinghausen, MD (1833–1910), gave the classic description of the disease as a phakomatosis: “Café-au-lait colored spots with associated tumors of the nerves, skin, and bones that progress sometimes into the giantism of an extremity or skin deformity.”

The disease is genetically transmitted and there is no known cure for neurofibromatosis. Future therapy lies in medical genetics. The map-

ping of the human genome and the study of inherited DNA sequences have made it possible to establish the genetic linkage and chromosome map location for neurofibromatosis.

In 1987, Barker, et al detailed the

­e xact sequence (16220). n Excerpted from Oncology Tumors & Treatment: A Photographic History, by Stanley B. Burns, MD. Photographs courtesy of Stanley B. Burns, MD, and The Burns Archive.

“Café-au-lait colored spots with associated tumors of the nerves, skin, and bones that progress sometimes into the giantism of an extremity or skin deformity.”

BECAUSE YOU CAN’T DO THIS TO FL…

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A first-in-class selective inhibitor of PI3Kδ, a protein that is expressed in normal and malignant B cells

ZYDELIG is a PI3Kδ inhibitor indicated for Relapsed FL after ≥2 systemic therapies Accelerated approval was granted for FL based on overall response rate. An improvement in patient survival or disease related symptoms has not been established. Continued approval for this indication may be contingent upon verification of clinical benefit in confirmatory trials.

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

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

FL

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

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FDA approved in relapsed FL after ≥2 systemic therapies

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KINASE INHIBITOR APPROVED IN FL.

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

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

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

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

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

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

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

POWER of response

DURATION of response

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

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

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

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

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S:9.5” ZYDELIG® (idelalisib) tablets, for oral use Brief Summary of full Prescribing Information. See full Prescribing Information. Rx Only.

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

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

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

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

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

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

• ZYDELIG is indicated for the treatment of adults with relapsed small lymphocytic lymphoma (SLL) who have received ≥2 prior systemic therapies.

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

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

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

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

Fatal and serious pneumonitis occurred in ZYDELIG-treated patients.

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

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

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

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

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

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

Dose Modifications:

Subjects with Relapsed CLL:

• Pneumonitis: discontinue ZYDELIG for any symptomatic pneumonitis

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

205858-GS-000-PI July 2014

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

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

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

© 2015 Gilead Sciences, Inc. All rights reserved.

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

All other marks are the property of their respective owners.

S:13”

DOSAGE AND ADMINISTRATION:

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

ASCOPost.com | SEPTEMBER 10, 2015

PAGE 83

Reflections

Never Say Never

By Grace Wang, MD

The following essay by Grace Wang, MD, is adapted from The Big Casino: America’s Best Cancer Doctors Share Their Most Powerful Stories, which was coedited by Stan Winokur, MD, and Vincent Coppola and published in May 2014.

The book is available on Amazon. com and thebigcasino.org.

T:13.75”

D

K came to me in 1997 with disseminated breast cancer. We talked about prognosis, and I told her that we’d never cured her disease. We discussed a clinical trial involving the experimental drug trastuzumab (Herceptin). She was a nurse and understood it was important for her to try the drug, not only for herself, but also for other patients.

“Dr. Wang! Your patient is having chills and shortness of breath,” said a nurse. It was DK. As I ran to the chemotherapy suite, I worried what could be happening. As physicians, our motto has always been, “First, do no harm.”

Yet, when you have patients with diseases that are uniformly fatal, you be-

come more interested in research trials. There aren’t other choices.

I began my career nearly 4 decades ago as an assistant professor at the University of Miami Medical School treating breast cancer patients. It was a time when many more of my patients presented with stage IV cancer.

Thanks to breast cancer awareness and screening mammograms, many more patients are being cured today, and mortality rates have dropped 30%. However, one patient dying is one patient too many. When I came into private practice, I did clinical trials but not without some resistance.

At one point, we experimented with the natural (by this time, genetically cloned) immune system modulator interleukin. It was, among laymen anyway, the latest “magic bullet” for cancer. A reporter from the local newspaper interviewed my partner, Dr. Leonard Kalman, and me about the drug. I thought the interview had gone very well. Then to our dismay, we landed on the front page of the paper. We were compared to the Laetrile (a “wonder drug” supposedly distilled from apricot pits) clinic in Mexico that actor Steve McQueen went to for his cancer.

We were not under the umbrella of an academic institution, and, to be honest, interleukin had a lot of toxicity, including plummeting blood pressure, fever, and chills. It turned out that interleukin is now recognized as a drug that helps the immune system combat kidney cancer and melanoma.

At the time, we hoped it would induce complete remissions and cure patients with other stage IV cancers. We proceeded with our trials. I became reporter-shy for many years.

Improving Breast Cancer Care Let’s return to the story about DK, the nurse with breast cancer who’d been coming to our clinic for years. In my heart, she was not cured, but even though she had diffuse bone metastases, scan after scan showed she was in a complete remission. We finally stopped the trastuzumab in 2009. Today, DK is 75 and working as a hospice nurse.

Trastuzumab was approved by the U.S. Food and Drug Administration in 1998, a landmark in the treatment of certain kinds of breast cancer.

focused on breast oncology. I go to breast cancer research conferences.

The community physician is now part of research trials underway all over the world.

Medical ‘Miracles’ To me DK is one of those medical “miracles” that now occurs daily. When I reflect on my career, I remember other amazing patients like the one who went to dental school and had treatments for metastatic breast cancer that had spread to her bones. Today, she runs her own

When it comes to my patients and their prognoses, when I’m asked if there’s a cure for cancer, I’ve learned never to say never.

—Grace Wang, MD

I made the decision to leave my position at the University of Miami Medical School partly because I thought I would be bored treating only breast cancer patients. Now that the research is so voluminous and treatments are so targeted, I have come full circle. I’m never bored treating breast cancer patients, and I’m still doing clinical trials. Over my career, research has led to miracles. For example, thanks to the development of imatinib (Gleevec), we now see complete, long-term remissions in patients with chronic myeloid leukemia.

Everyone is becoming specialized, most often as part of a diseaseoriented team. We now have breast surgeons, breast plastic surgeons, and medical and radiation oncologists, all

dental practice, her children are graduating from college, and she’s still in complete remission.

Another patient had 17 positive lymph nodes. She later adopted two babies, and she and her husband saw their children graduate from high school. She’s never had a relapse. And then there are the patients who develop new primary cancers that we pick up and are still cured because of good survivorship care.

When it comes to my patients and their prognoses, when I’m asked if there’s a cure for cancer, I’ve learned never to say never. n Dr. Wang is a medical oncologist specializing in hematology/oncology in ­ ­Miami, Florida.

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The ASCO Post | SEPTEMBER 10, 2015

PAGE 84

Book Review

A Cancer Handbook for Inquisitive Laypersons and Health-Care Professionals

By Ronald Piana

“I

was at a meeting in San Francisco in 1978 and received a call from my wife, Nancy: ‘Jack, I just came back from the doctor. He said I have a lump in my left breast.’” So begins The Cancer Solution, a new book by Jack C. ­Westman, MD, MS, Professor Emeritus of Psychiatry at the University of Wisconsin School of Medicine and Public Health, Madison. He has written more than 150 professional publications and 12 books.

Jack C. Westman, MD, MS

The lump in his wife’s breast turned out to be an adenocarcinoma, and Nancy Westman had a radical mastectomy. She was a survivor for 26 years, and then, in 2002, the cancer recurred. After a valiant and very difficult struggle, she succumbed to the

ventional treatments along with their various side effects. This common information won’t interest oncologists, and its plodding format will turn off lay readers, even those with cancer or those caring for someone with cancer. Moreover, this kind of cancer information is best delivered in pamphlets or on any of the numerous well-vetted websites.

Unwarranted Potshots More problematic is the disoriented segue Dr. Westman takes halfway through chapter 1, skipping into Lance Armstrong’s battle with metastatic testicular cancer and then into an offhanded critique of conventional cancer treatment, focusing on cisplatin, which, despite considerable side effects, had cured Lance Armstrong. “Overall, [cisplatin proved] of little long-term value, except against testicular cancer, illustrating the fact that no single chemotherapeutic agent in use at this time kills all kinds of cancer cells.” This statement is not a news flash, and it simply serves as a lead-up to the rest of the chapter, which takes unwarranted potshots at the oncology community.

The central problem with The Cancer Solution, aside from its misleading title, is that the author tries too hard to be too many things: instructor, policy wonk, historian, and all-around muckraking curmudgeon. disease in 2012. That personal struggle and loss were the seed for this book. From the day that Dr. Westman’s wife was first diagnosed with breast cancer in 1978, he began doing extensive research on the disease and the various treatment options.

Naturally, oncology has gone through a huge transformation since 1978, and Dr. Westman’s knowledge and views have also evolved during that period. His idea to construct an informative book that offers material interesting to both the lay and medical communities comes with considerable challenges, many of which, unfortunately, he doesn’t overcome.

For starters, a reader of The ASCO Post opening the book will be confronted by rather loosely constructed data detailing the main categories of cancer and a cursory look at cancer staging. There’s a description of con-

Dr. Westman makes some valid points about much-needed cost control, citing The New York Times article

by Ezekiel Emanuel titled “A Plan to Fix Cancer Care.” However, he cannot resist the temptation to criticize the oncology community, stating, “The more doctors do for patients, the more reimbursement they receive.… Oncologists typically make more money if they use newly approved drugs and the latest radiation treatments than if they use cheaper, older alternatives that work just as well.” This is a broad and rather cheap accusation that community oncologists will surely find offensive. Moreover, there are no hard data to back it up.

The author then mentions ASCO’s Quality Oncology Practice Initiative (QOPI), giving a fairly good assessment of the project’s mission and goals.

He also delivers a solid discussion about

Bookmark Title: The Cancer Solution: Taking Charge of Your Life With Cancer Author: Jack C. Westman, MD, MS Publisher: Archway Publishing Publication date: January 15, 2015 Price: $20.00; paperback, 310 pages the impending oncology workforce shortage. But once again, Dr. Westman then veers erratically into a soft-toned diatribe about oncologists’ salaries, drilling home his bone of contention, writing, “Separating cancer specialists’ income from treatment choices is important.… Instead provider incentives should be aligned toward patient-centered, coordinated care among cancer specialists….”

It becomes glaringly obvious that Dr. Westman did not spend time in busy community clinics when researching his book. Nor did he venture into the interior of the ultra-introspective oncology community’s constant evolution toward patient-centered care, data collection, and patient communication. In these efforts, oncology serves as a model for most other medical disciplines.

Important Information In the first half of chapter 3, “Navigating the Cancer,” Dr. Westman provides many simple-to-read instructions and hints for those newly entering the system, such as instructing patients how to track and maintain their own personal health record, offering suggestions and evaluations of several personal electronic health chart systems on the market. Readers are also given brief summaries about living wills, donot-resuscitate orders, and other tough but vital decision-making guides. This is important information, especially for caregivers.

In the second half of the chapter, Dr. Westman gets down to the nuts and bolts of cost, another reliable source of

information. But after a thorough trip through Medicaid tips to assessing the costs of nursing homes, Dr. Westman then wanders into thorny territory, advocating for “life panels,” which of course is a euphemism for the equally ridiculous term “death panels,” famously coined by Sarah Palin in 2009. As the oncology community knows, highquality palliative care is needed for cancer patients facing end-of-life issues.

To make his argument for life panels, Dr. Westman uses a financial planner named Bob Goldman, who told the story of his elderly mother whose life had become “more punishment than reward.” Evidently, she wanted out.

In what amounts to a disjointed argument for physician-assisted suicide, Dr. Westman decries the costs of endof-life care and seems to support Bob Goldman’s model for a life panel. He writes, “On a statutory life panel, a doctor would be held blameless. And Goldman would have no problem adding a medical ethicist and a therapist.”

Central Problem The central problem with The Cancer Solution, aside from its misleading title, is that the author tries too hard to be too many things: instructor, policy wonk, historian, and all-around muckraking curmudgeon. Thus, the book’s good sections are muddled by the author’s strong opinions, which often come out of left field. Moreover, in pedantic fashion, the author assaults the reader with subtitled chapter sections such as “A Paradigm Shift is Needed” or “Models for Treatment Directed at Cancer Cells Them-

ASCOPost.com | SEPTEMBER 10, 2015

PAGE 85

Announcements

selves” and devotes a mere 80 or 90 words to these lofty goals. It feels rushed.

Dr. Westman saves the best writing for chapters 9, 10, and 11, during which he gives compelling descriptions of immunotherapy, lifestyle issues, prevention, and complementary strategies. He also makes a solid case for more focus on discovering the etiology of a cancer and then developing ways to prevent disease or treat it at its earliest stage, as seen with successes in gastric cancer and cervical cancer.

During these sections, although they

Thomas J. Lynch Jr, MD, Leaves Yale Cancer Center

T

homas J. Lynch Jr, MD, Director of Yale Cancer Center and Physician-in-Chief of Smilow Cancer Hospital at Yale-New Haven, left Yale in August to become Chairman and Chief Executive Officer of the Massachusetts General Physicians Organization.

are highly readable and interesting, Dr. Westman will certainly get challenged by his unwavering support of several eccentric researchers in the early 1900s who asserted, “the fundamental cause of cancer is a disturbance in cell metabolism that makes a cell prefer fermentation of glucose for energy production rather than the more efficient oxidative

metabolism.… Therefore, it may be that the uncontrolled growth of cancer cells arises when they are stuck in the fermentation process.”

Dr. Westman concludes his book with a “Where Do We Go From Here?” chapter that doesn’t really add much in the way of new material on this subject.

If he maintained the same tempo and

interesting, if somewhat kooky, style and content as in his chapters on immunotherapy and complementary strategies, this would have been a better read.

As it is, The Cancer Solution may not be for all readers of The ASCO Post. That said, Dr. Westman lost his wife to cancer, and wrote a book in her honor—a noble effort. n

NOW APPROVED! For the treatment of metastatic NSCLC

A TKI for first-line use in EGFR mutation–positive patients

Indication Thomas J. Lynch Jr, MD

Dr. Lynch joined Yale Cancer Center as Director in 2009 and assumed the role of inaugural Physician-in-Chief at Smilow, which opened that year. Under his leadership, more than 130 scientists and clinicians joined the institutions, new patient volume grew from 3,500 to 9,000 through key affiliations, and participation in therapeutic clinical trials grew by 325%.

Peter Schulam, MD, PhD, Professor of Urology and Chair/Chief of Yale’s Department of Urology, will serve as the interim Director of Yale Cancer Center and Physician-in-Chief at Smilow.

Dr. Schulam joined in 2012 as inaugural Chief of the Department of Urology at Yale-New Haven Hospital and Chair of the Department at Yale School of Medicine, where he has established a multidisciplinary team in urologic oncology. He has implemented a program for MRI-fusion–guided biopsy of prostate cancer, and leads a research program focused on prostate cancer imaging. In addition, Dr. Schulam. n

IRESSA is indicated for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations as detected by an FDAapproved test.

Limitation of Use: Safety and efficacy of IRESSA have not been established in patients with metastatic NSCLC whose tumors have EGFR mutations other than exon 19 deletions or exon 21 (L858R) substitution mutations.

Important Safety Information • There are no contraindications for IRESSA • Interstitial Lung Disease (ILD): ILD occurred in patients taking IRESSA. Withhold IRESSA for worsening of respiratory symptoms.

Discontinue IRESSA if ILD is confirmed • Hepatotoxicity: Obtain periodic liver function testing. Withhold IRESSA for Grade 2 or higher for alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) elevations. Discontinue for severe hepatic impairment • Gastrointestinal Perforation: Discontinue IRESSA for gastrointestinal perforation • Diarrhea: Withhold IRESSA for Grade 3 or higher diarrhea • Ocular Disorders Including Keratitis: Withhold IRESSA for signs and symptoms of severe or worsening ocular disorders including keratitis. Discontinue for persistent ulcerative keratitis • Bullous and Exfoliative Skin Disorders: Withhold IRESSA for Grade 3 or higher skin reactions or exfoliative conditions • Embryo-fetal Toxicity: Can cause fetal harm. Advise of potential risk to a fetus and use of effective contraception • Advise women to discontinue breast-feeding during treatment with IRESSA • The most commonly reported adverse drug reactions, reported in more than 20% of the patients and greater than placebo, were skin reactions and diarrhea Please see Brief Summary of complete Prescribing Information on adjacent pages.

Learn more about IRESSA at www.iressa-usa.com.

IRESSA is a registered trademark of the AstraZeneca group of companies. ©2015 AstraZeneca. All rights reserved. 3133300 7/15

The ASCO Post | SEPTEMBER 10, 2015

PAGE 86

Announcements

Diane Simeone, MD, Named Upcoming Chair of PanCAN Scientific Board

D

iane Simeone, MD, Director of the Pancreatic Cancer Center at the University of Michigan, was recently named the Upcoming Chair of the National Scientific and Medical Advisory Board for the Pancreatic Cancer Action Network (PanCAN). Her 2-year term as

Chair runs from 2017 to 2019. Dr. Simeone will serve as Chair-Elect until then.

Dr. Simeone is the Founding Director of the University of Michigan Pancreatic Cancer Center. She also serves as the Director for the U-M Multidisciplinary Pancreatic Cancer Clinic, and

TRIM: 8.125 X 10.875 Diane Simeone, MD

IRESSA® (gefitinib) tablets for oral use Brief Summary of Prescribing Information.

For complete prescribing information consult official package insert INDICATIONS AND USAGE IRESSA is indicated for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations as detected by an FDA-approved test [see Clinical Studies (14) in the full Prescribing Information].

Limitation of Use: Safety and efficacy of IRESSA have not been established in patients with metastatic NSCLC whose tumors have EGFR mutations other than exon 19 deletions or exon 21 (L858R) substitution mutations [see Clinical Studies (14) in the full Prescribing Information].

DOSAGE AND ADMINISTRATION Patient Selection Select patients for the first-line treatment of metastatic NSCLC with IRESSA based on the presence of EGFR exon 19 deletion or exon 21 (L858R) substitution mutations in their tumor [see Indications and Usage (1) and Clinical Studies (14) in the full Prescribing Information].

Information on FDA-approved tests for the detection of EGFR mutations in NSCLC is available at: http://www.fda.gov/CompanionDiagnostics.

Recommended Dose The recommended dose of IRESSA is 250 mg orally once daily with or without food until disease progression or unacceptable toxicity.

Do not take a missed dose within 12 hours of the next dose.

Administration to Patients Who Have Difficulty Swallowing Solids Immerse IRESSA tablets in 4 to 8 ounces of water by dropping the tablet in water, and stir for approximately 15 minutes. Immediately drink the liquid or administer through a naso-gastric tube.

Rinse the container with 4 to 8 ounces of water and immediately drink or administer through the naso-gastric tube.

Dose Modification Dose Modifications for Adverse Drug Reactions Withhold IRESSA (for up to 14 days) for any of the following: Acute onset or worsening of pulmonary symptoms (dyspnea, cough, fever) [see Warnings and Precautions (5.1) in the full Prescribing Information] NCI CTCAE Grade 2 or higher in ALT and/or AST elevations [see Warnings and Precautions (5.2) in the full Prescribing Information] NCI CTCAE Grade 3 or higher diarrhea [see Warnings and Precautions (5.4) in the full Prescribing Information] Signs and symptoms of severe or worsening ocular disorders including keratitis [see Warnings and Precautions (5.5) in the full Prescribing Information] NCI CTCAE Grade 3 or higher skin reactions [see Warnings and Precautions (5.6) in the full Prescribing Information] Resume treatment with IRESSA when the adverse reaction fully resolves or improves to NCI CTCAE Grade 1.

Permanently discontinue IRESSA for: Confirmed interstitial lung disease (ILD) [see Warnings and Precautions (5.1) in the full Prescribing Information] Severe hepatic impairment [see Warnings and Precautions (5.2) in the full Prescribing Information] Gastrointestinal perforation [see Warnings and Precautions (5.3) in the full Prescribing Information] Persistent ulcerative keratitis [see Warnings and Precautions (5.5) in the full Prescribing Information] Dose Modifications for Drug Interactions Strong CYP3A4 Inducers Increase IRESSA to 500 mg daily in the absence of severe adverse drug reaction, and resume IRESSA at 250 mg seven days after discontinuation of the strong CYP3A4 inducer [see Drug Interactions (7) and Clinical Pharmacology (12.3) in the full Prescribing Information].

CONTRAINDICATIONS None.

WARNINGS AND PRECAUTIONS Interstitial Lung Disease (ILD) ILD or ILD-like adverse drug reactions (e.g., lung infiltration, pneumonitis, acute respiratory distress syndrome, or pulmonary fibrosis) occurred in 1.3% of the 2462 patients who received IRESSA across clinical trials; of these, 0.7% were Grade 3 or higher and 3 cases were fatal.

Withhold IRESSA and promptly investigate for ILD in any patient who presents with worsening of respiratory symptoms such as dyspnea, cough and fever. Permanently discontinue IRESSA if ILD is confirmed [see Dosage and Administration (2.4) and Adverse Reactions (6.1) in the full Prescribing Information].

Hepatotoxicity In patients who received IRESSA across clinical trials, 11.4% of patients had increased alanine aminotransferase (ALT), 7.9% of patients had increased aspartate aminotransferase (AST), and 2.7% of patients had increased bilirubin. Grade 3 or higher liver test abnormalities occurred in 5.1% (ALT), 3.0% (AST), and 0.7% (bilirubin) of patients. The incidence of fatal hepatotoxicity was 0.04%.

Obtain periodic liver function testing. Withhold IRESSA in patients with worsening liver function and discontinue in patients with severe hepatic impairment [see Dosage and Administration (2.4), Adverse Reactions (6.1), and Use in Specific Populations (8.7) in the full Prescribing Information].

Gastrointestinal Perforation Gastrointestinal perforation occurred in three (0.1%) of the 2462 IRESSA-treated patients across clinical trials [see Adverse Reactions (6.1) in the full Prescribing Information]. Permanently discontinue IRESSA in patients who develop gastrointestinal perforation [see Dosage and Administration (2.4) in the full Prescribing Information].

Severe or Persistent Diarrhea Grade 3 or 4 diarrhea occurred in 3% of 2462 IRESSA-treated patients across clinical trials.

Withhold IRESSA for severe or persistent (up to 14 days) diarrhea [see Dosage and Administration (2.4) and Adverse Reactions (6.1) in the full Prescribing Information].

leads the Translational Oncology Program at the University’s North Campus Research Complex. She is Past President of the American Pancreatic Association and currently serves on the National Cancer Institute Pancreatic Cancer Task Force. n

Ocular Disorders including Keratitis Ocular disorders [keratitis (0.1%), corneal erosion and aberrant eyelash growth (0.2%), conjunctivitis, blephritis and dry eye (6.7%)] occurred in the 2462 IRESSA-treated patients across clinical trials. The incidence of Grade 3 ocular disorders was 0.1% [see Adverse Reactions (6.1) in the full Prescribing Information]. Interrupt or discontinue IRESSA for severe, or worsening ocular disorders [see Dosage and Administration (2.4) in the full Prescribing Information].

Bullous and Exfoliative Skin Disorders Bullous conditions including toxic epidermal necrolysis, Stevens Johnson syndrome and erythema multiforme have been reported from treatment with IRESSA. Erythema multiforme and dermatitis bullous have been reported in two patients (0.08%) across NSCLC trials (Study 2, Study 3 and Study 4). IRESSA treatment should be interrupted or discontinued if the patient develops severe bullous, blistering or exfoliating conditions.

Embryo-fetal Toxicity Based on its mechanism of action and data from animal reproduction studies IRESSA can cause fetal harm when administered to a pregnant woman. In animal reproductive studies, oral administration of gefitinib from organogenesis through weaning resulted in fetotoxicity and neonatal death at doses below the recommended human dose. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with IRESSA and for at least two weeks following completion of therapy [see Use in Specific Populations (8.1, 8.3) in the full Prescribing Information].

ADVERSE REACTIONS The following adverse drug reactions are discussed in more detail in other sections of the labeling: Interstitial Lung Disease [see Warnings and Precautions (5.1) in the full Prescribing Information] Hepatotoxicity [see Warnings and Precautions (5.2) in the full Prescribing Information] Gastrointestinal Perforation [see Warnings and Precautions (5.3) in the full Prescribing Information] Severe or Persistent Diarrhea [see Warnings and Precautions (5.4) in the full Prescribing Information] Ocular Disorders including Keratitis [see Warnings and Precautions (5.5) in the full Prescribing Information] Bullous and Exfoliative Skin Disorders [see Warning and Precautions (5.6) in the full Prescribing Information] Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of IRESSA is based on the data from 2462 patients with NSCLC who received IRESSA 250 mg daily monotherapy in three randomized clinical studies (Study 2, Study 3 and Study 4).

Patients with a history of interstitial lung disease, drug-induced interstitial disease, radiation pneumonitis that required steroid treatment or any evidence of clinically active interstitial lung disease were excluded from these studies.

Controlled Studies: Study 2 was a randomized, multicenter, open-label trial in which 1217 patients were randomized to receive first-line treatment for metastatic NSCLC; 607 patients received IRESSA 250 mg daily and 589 patients received carboplatin/paclitaxel. The median duration of treatment with IRESSA was 5.9 months. The study population characteristics were: median age 57 years, age less than 65 years (73%), female (79%), Asian (100%), NSCLC adenocarcinoma histology (100%), never smoker (94%), light ex-smoker (6%), ECOG PS 0 or 1 (90%).

Study 3 was a randomized, multicenter, double-blind, placebo-controlled trial in which 1692 patients were randomized to receive second- or third-line treatment for metastatic NSCLC; of which 1126 patients received IRESSA 250 mg daily and 562 patients received placebo. The median duration of treatment with IRESSA was 2.9 months. The study population characteristics were: median age 62 years, age less than 65 years (60%), female (33%), Caucasian (75%), Asian (21%), NSCLC adenocarcinoma histology (48%), never smoker (22%), ECOG PS 0 or 1 (65%), PS 2 (29%), PS 3 (5%) and two or more prior therapies (51%).

Study 4 was a randomized, multicenter, open-label trial in which 1466 patients were randomized to receive second-line treatment for metastatic NSCLC; 729 patients received IRESSA 250 mg daily and 715 patients received docetaxel. The median duration of treatment with IRESSA was 2.4 months. The study population characteristics were: median age 61 years, age less than 65 years (61%), female (36%), Caucasian (79%), Asian (21%), NSCLC adenocarcinoma histology (54%), never smoker (20%), ECOG PS 0 or 1 (88%) and two or more prior therapies (16%).

The pooled safety database from the three randomized trials was used to evaluate for serious and uncommon adverse drug reactions. Common adverse reactions were evaluated in Study 3. The most frequent adverse reactions in Study 3 (incidence of >20% and greater than placebo) reported in IRESSA-treated patients were skin reactions (47%) and diarrhea (29%). The most frequent fatal adverse reactions in IRESSA-treated patients were respiratory failure (0.9%), pneumonia (0.8%), and pulmonary embolism (0.5%).

Approximately 5% of IRESSA-treated patients and 2.3% of placebo-treated patients discontinued treatment due to an adverse event. The most frequent adverse reactions that led to discontinuation in patients treated with IRESSA were nausea (0.5%), vomiting (0.5%) and diarrhea (0.4%).

Table 1 – Selected Adverse Drug Reactions Occurring with an Incidence Rate ≥5% and an Increase of >2% of IRESSA-treated Patients in Study 3 Percentage (%) of patients IRESSA (N=1126) Placebo (N=562) Adverse Reaction All Grades Grade 3 and 4 All Grades Grade 3 and 4 Skin and subcutaneous tissue disorders 47% 2% 17% 0.4% Skin reactions1 Nail disorders2 5% 0.1% 0.7% 0% Gastrointestinal disorders 29% 3% 10% 1% Diarrhea3 Vomiting 14% 1.2% 10% 0.4% Stomatitis4 7% 0.3% 4% 0.2% Metabolism and nutrition disorders Decreased appetite 17% 2.3% 14% 2.0%

ASCOPost.com | SEPTEMBER 10, 2015

PAGE 87

Patient’s Corner

I’m Living a Full and Happy Life With Stage IV Breast Cancer After 6 years on a new therapy, there is no evidence of cancer in my body.

By Janet Klein, as told to Jo Cavallo

A

fter coping with breast cancer for more than a decade, it is difficult for me to put into words exactly how grateful I am to all the doctors, nurses,

and researchers whose efforts have kept me alive for all these years. And not just alive, but thriving.

TRIM: 8.125 X 10.875had disA routine mammogram IRESSA® (gefitinib) tablets for oral use

Table 1 – Selected Adverse Drug Reactions Occurring with an Incidence Rate ≥5% and an Increase of >2% of IRESSA-treated Patients in Study 3 (cont'd.)

Percentage (%) of patients IRESSA (N=1126) Placebo (N=562) Adverse Reaction All Grades Grade 3 and 4 All Grades Grade 3 and 4 Eye disorders 6% 0% 3.2% 0% Conjunctivitis/blepharitis/dry eye5 1

Includes Acne, Acne pustular, Dermatitis, Dermatitis acneiform, Dermatitis exfoliative, Drug eruption, Dry skin, Erythema, Exfoliative rash, Folliculitis, Pruritus, Pruritus generalized, Rash, Rash erythematous, Rash generalized, Rash macular, Rash maculo-papular, Rash papular, Rash pruritic, Rash pustular, Rash vesicular, Skin exfoliation, Skin toxicity, Xeroderma 2 Includes Ingrowing nail, Nail bed infection, Nail disorder, Nail infection, Onychoclasis, Onycholysis, Paronychia 3 Includes Diarrhea, Feces soft, Frequent bowel movements 4 Includes Aphthous stomatitis, Cheilitis, Glossodynia, Mouth ulceration, Mucosal inflammation, Oral mucosal blistering, Stomatitis, Tongue disorder, Tongue ulceration 5 Includes Blepharitis, Conjunctival hyperemia, Conjunctivitis, Dry eye, Eye irritation, Eye pruritus, Eye swelling, Eyelid irritation, Eyelid edema, Eyelids pruritus

Table 2 – Treatment Emergent Laboratory Abnormalities Occurring More Frequently in IRESSA-Treated Patients in Study 3 IRESSA Placebo All Grades Grade 3 and 4 All Grades Grade 3 and 4 Adverse Reaction % % % % Alanine aminotransferase increased1 38%2 2.4% 23%2 1.4%4 Aspartate aminotransferase increased1 40%3 2.0% 25%3 1.3%5 Proteinuria 35% 4.7% 31% 3.3% 1

Patients were allowed to enter the clinical study with lab values of ALT or AST CTCAE grade 1 or 2 14% gefitinib patients and 10% placebo patients were CTC grade 1 or 2 ALT at baseline 15% gefitinib patients and 12% placebo patients were CTC grade 1 or 2 AST at baseline 4 0.2% of placebo patients were CTC grade 3 at baseline 5 0.4% of placebo patients were CTC grade 3 at baseline 2 3

The following adverse reactions have been reported with IRESSA across NSCLC trials (Study 2, Study 3 and Study 4) and are not listed elsewhere in Section 6: nausea (18%), asthenia (17%), pyrexia (9%), alopecia (4.7%), hemorrhage (including epistaxis and hematuria) (4.3%), dry mouth (2%), dehydration (1.8%), allergic reactions including angioedema and urticaria (1.1%), elevations in blood creatinine (1.5%), and pancreatitis (0.1%).

Postmarketing Experience The following adverse reactions have been identified during post-approval use of IRESSA. 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.

Renal and urinary disorders: cystitis, hemorrhagic cystitis Skin and subcutaneous tissue disorders: cutaneous vasculitis DRUG INTERACTIONS Drugs Affecting Gefitinib Exposure CYP3A4 Inducer Drugs that are strong inducers of CYP3A4 increase the metabolism of gefitinib and decrease gefitinib plasma concentrations. Increase IRESSA to 500 mg daily in patients receiving a strong CYP3A4 inducer (e.g., rifampicin, phenytoin, or tricyclic antidepressant) and resume IRESSA at 250 mg 7 days after discontinuation of the strong inducer [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3) in the full Prescribing Information].

CYP3A4 Inhibitor Drugs that are strong inhibitors of CYP3A4 (e.g., ketoconazole and itraconazole) decrease gefitinib metabolism and increase gefitinib plasma concentrations. Monitor adverse reactions when administering strong CYP3A4 inhibitors with IRESSA. Drugs Affecting Gastric pH Drugs that elevate gastric pH (e.g., proton pump inhibitors, histamine H2-receptor antagonists, and antacids) may reduce plasma concentrations of gefitinib. Avoid concomitant use of IRESSA with proton pump inhibitors, if possible. If treatment with a proton-pump inhibitor is required, take IRESSA 12 hours after the last dose or 12 hours before the next dose of the proton-pump inhibitor.

Take IRESSA 6 hours after or 6 hours before an H2-receptor antagonist or an antacid [see Clinical Pharmacology (12.3) in the full Prescribing Information].

Hemorrhage in Patients taking Warfarin International Normalized Ratio (INR) elevations and/or hemorrhage have been reported in some patients taking warfarin while on IRESSA therapy. Patients taking warfarin should be monitored regularly for changes in prothrombin time or INR. USE IN SPECIFIC POPULATIONS Pregnancy Risk Summary Based on its mechanism of action and animal data, IRESSA can cause fetal harm when administered to a pregnant woman. In animal reproductive studies, oral administration of gefitinib from organogenesis through weaning resulted in fetotoxicity and neonatal death at doses below the recommended human dose (see Animal Data). Advise pregnant women of the potential hazard to a fetus or potential risk for loss of the pregnancy.

The background risk of major birth defects and miscarriage for the indicated population is unknown; however, the background risk in the U.S. general population of major birth defects is 2-4% and miscarriage is 15-20% of clinically recognized pregnancies.

Data Animal Data A single dose study in rats showed that gefitinib crosses the placenta after an oral dose of 5 mg/kg (30 mg/m2, about 0.2 times the recommended human dose on a mg/m2 basis). When pregnant rats were treated with 5 mg/kg from the beginning of organogenesis to the end of weaning there was a reduction in the number of offspring born alive. This effect was more severe at 20 mg/kg (approximate the human clinical dose on a mg/m2 basis) and was accompanied by high

covered two small tumors in my left breast, and a tissue biopsy confirmed stage I estrogen receptor–positive breast cancer. Even though the can2

neonatal mortality soon after parturition. In rabbits, a dose of 20 mg/kg/day (240 mg/m2, about twice the recommended dose in humans on a mg/m2 basis) caused reduced fetal weight.

Lactation Risk Summary It is not known whether IRESSA is excreted in human milk. Animal studies indicate the gefitinib and its metabolites are present in rat milk at a concentration higher than those in maternal plasma.

Because of the potential for serious adverse reactions in nursing infants from IRESSA, advise women to discontinue breast-feeding during treatment with IRESSA. Data Animal Data Levels of gefitinib and its metabolites were 11-to-19-fold higher in milk than in blood, after oral exposure of lactating rats to a dose of 5 mg/kg.

Females and Males of Reproductive Potential Contraception Based on its mechanism of action and animal data, IRESSA can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1) in the full Prescribing Information].

Advise females of reproductive potential to use effective contraception during treatment with IRESSA and for at least two weeks following completion of therapy.

Infertility IRESSA may result in reduced fertility in females of reproductive potential [see Nonclinical Toxicology (13.1) in the full Prescribing Information].

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

Geriatric Use Of the 823 patients enrolled in two randomized, active-controlled clinical trials 374 patients (45%) were 65 years and older, and 93 patients (11%) were 75 years and older. No overall differences in safety were observed between patients 65 years and older and those younger than 65 years. There is insufficient information to assess for differences in efficacy between older and younger patients.

Renal Impairment Less than four percent (<4%) of gefitinib and its metabolites are excreted via the kidney. No clinical studies were conducted with IRESSA in patients with severe renal impairment.

Hepatic Impairment The systemic exposure of gefitinib was compared in patients with mild, moderate, or severe hepatic impairment due to cirrhosis (according to Child-Pugh classification) and healthy subjects with normal hepatic function (N=10/group). The mean systemic exposure (AUC0- ) was increased by 40% in patients with mild impairment, 263% in patients with moderate impairment, and 166% in patients with severe hepatic impairment. Monitor adverse reactions when IRESSA is administered to patients with moderate and severe hepatic impairment.

In a study comparing 13 patients with liver metastases and moderate hepatic impairment (addition of CTC grade of baseline AST/SGOT, ALP, and bilirubin equals 3 to 5) to 14 patients with liver metastases and normal hepatic function, the systemic exposure of gefitinib was similar [see Warnings and Precautions (5.2) in the full Prescribing Information].

OVERDOSAGE Twenty three patients were treated weekly with doses from 1500 mg to 3500 mg, and IRESSA exposure did not increase with increasing dose. Adverse events were mostly mild to moderate in severity, and were consistent with the known safety profile of IRESSA. In the event of suspected overdose, interrupt IRESSA, institute supportive care, and observe until clinical stabilization. There are no specific measures/treatments that should be taken following IRESSA overdosing.

PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labelling (Patient Information).

Interstitial Lung Disease: Advise patients to immediately contact their healthcare provider for new onset or worsening of pulmonary symptoms such as dyspnea, cough and fever [see Warnings and Precautions (5.1) in the full Prescribing Information].

Hepatotoxicity: Inform patients that they will need to undergo lab tests to monitor for liver function.

Advise patients to contact their healthcare provider to report any new symptoms indicating hepatic toxicity [see Warnings and Precautions (5.2) in the full Prescribing Information].

Gastrointestinal Perforation: Advise patients that IRESSA can increase the risk of gastrointestinal perforation and to seek immediate medical attention for severe abdominal pain [see Warnings and Precautions (5.3) in the full Prescribing Information].

Severe or Persistent Diarrhea: Advise patients to contact their healthcare provider for severe or persistent diarrhea [see Warnings and Precautions (5.4) in the full Prescribing Information].

Ocular Disorders including Keratitis: Advise patients promptly to contact their healthcare provider if they develop eye symptoms, lacrimation, light sensitivity, blurred vision, eye pain, red eye or changes in vision [see Warnings and Precautions (5.5) in the full Prescribing Information].

Bullous and Exfoliative Skin Disorders: Advise patients that IRESSA can increase the risk of bullous and exfoliative skin disorders and to seek immediately medical attention for severe skin reactions [see Warnings and Precautions (5.6) in the full Prescribing Information].

Embryo-fetal Toxicity: Advise pregnant women of the potential risk to a fetus or potential risk for loss of the pregnancy [see Warnings and Precautions (5.7) and Use in Specific Populations (8.1) in the full Prescribing Information]. Advise females of reproductive potential to use effective contraception during treatment with IRESSA and for at least two weeks following completion of therapy [see Use in Specific Populations (8.3) in the full Prescribing Information].

Lactation: Advise women to discontinue breast-feeding during treatment with IRESSA [see Use in Specific Populations (8.2) in the full Prescribing Information].

IRESSA is a trademark of the AstraZeneca group of companies. ©AstraZeneca 2015 Manufactured for: AstraZeneca Pharmaceuticals LP Wilmington, DE 19850 By: AstraZeneca UK Limited Macclesfield, Cheshire, England Product of Belgium 3148105 7/15

Issued: 07/15

cer was caught at such an early stage, and there was no evidence that it had spread, I wanted to have the best chance for a cure and opted for the most aggressive treatment my doctor offered: a contralateral prophylactic mastectomy followed by reconstructive breast surgery.

Janet Klein

After my surgery, my oncologist gave me the Oncotype DX genomic test to score, on a scale of 0 to 100, how likely it was that my cancer would recur, so we could evaluate whether adjuvant chemotherapy would be beneficial. I scored a 1, indicating that my risk of recurrence was low and that the potential harms of chemotherapy outweighed the benefits.

And just to be extra cautious, because I was 49 years old and had not yet gone through menopause, my oncologist advised 5 years of tamoxifen. Unfortunately, 4 years later, my cancer recurred in the same breast and had spread to my iliac bone. Now, I was facing stage IV disease and possibly death.

The Clinical Trial That Is Saving My Life My initial diagnosis didn’t come as a surprise to me. Both my mother and younger sister had breast cancer, and I always felt it was inevitable that I would be next in line. But when the cancer recurred, after all the indications that it wouldn’t, I was devastated and concerned about having to go through additional surgery, plus chemotherapy and radiation therapy.

Fortunately, before I had to make that decision, my oncologist told me about a new clinical trial investigating palbociclib (Ibrance), a CDK4/6 inhibitor, in combination with letrozole.

Even though I did not test positive for the BRCA gene mutation, as an extra precaution and to give myself the best shot at halting progression of my cancer, before I entered the trial, I decided to have my ovaries removed. After continued on page 88

The ASCO Post | SEPTEMBER 10, 2015

PAGE 88

Technology in Oncology ‘Share the Journey’ Mobile App Aims to Understand the Different Experiences of Breast Cancer Survivors

By Jo Cavallo

I

n March 2015, Sage Bionetworks and Apple released “Share the Journey: Mind, Body, and Wellness After Breast Cancer,” a patient-centered iPhone app that tracks five common consequences of breast cancer treatment, including fatigue, cognitive function, sleep disturbances, mood changes, and a reduction in exercise performance. Users can also customize the app to include information about sexual dysfunction and other health concerns.

The Share the Journey app is an interactive research study that aims to understand why some breast cancer survivors recover more quickly than others, why their symptoms vary, and how their symptoms can be improved.

The study is open to both healthy women and breast cancer survivors between the ages of 18 and 80 who live in the United States.

Research at UCLA’s Jonsson Comprehensive Cancer Center in Los Angeles and a collaborator on the development of the Share the Journey app.

“So often when I measure outcomes in women with breast cancer, the issue is how much is due to aging and how much is due to the cancer,” said Dr. Ganz. “The opportunity to have a large group of healthy women also complete the same instruments in a contemporaneous way may shed more light on how people either cope and improve their situation or who might be having more difficulty.”

Ann H. P ­ artridge, MD, MPH

Patricia Ganz, MD

Enrolling healthy women into the study is crucial to understanding the “human cost of breast cancer treatment,” said ­Patricia Ganz, MD, Director of Cancer Prevention and Control

A Full and Happy Life continued from page 87

just 9 months of being on the combination therapy, all evidence of my cancer was gone. I have been in the trial for the past 6 years and remain cancer-free. My doctor has told me that as long as the treatment is effective for me, I will likely continue on it as maintenance therapy for the rest of my life.

Giving Back I know that with cancer there is no guarantee remissions will last forever, especially when metastatic disease is involved, but I’m at peace. To be alive and living a full and satisfying life after a stage IV diagnosis is miraculous to me.

To express my appreciation to the oncology profession that has given me

The Share the Journey app uses an Apple open-source platform called ResearchKit. Developed by the Jonsson Comprehensive Cancer Center, Penn Medicine, Dana-Farber Cancer Institute, and Sage Bionetworks, who is the sponsor of the study, the app can be downloaded for free at the iTunes App Store (sharethejourneyapp.org). To ensure participants’ confidentiality, each user is assigned a unique, random code for data collection by the researchers.

Susan Love, MD

In addition to Dr. Ganz, Ann H. ­ artridge, MD, MPH, Clinical DirecP tor of the Breast Oncology Program at Dana-Farber Cancer Institute; Judy E. ­Garber, MD, MPH, Director, Cancer Risk and Prevention Clinic at DanaFarber Cancer Institute; Kathryn H. Schmitz, PhD, MPH, Professor of Epidemiology in Biostatistics and Epidemiology at the University of Pennsylvania Perelman School of Medicine; and Susan Love, MD, Medical Director of the Dr. Susan Love Research Foundation were also advisers on the development of the app.

Empowering Survivors Share the Journey is meant to provide women and their doctors, as well as the researchers monitoring the information, with a comprehensive, accurate accounting of participants’ daily health experiences. “This technology allows women to track the symptoms of their disease and what they think is making them feel better or worse,” said Andrew Trister, MD, PhD, MSE, Senior Physi-

I have no doubt that the combination of having a wonderful oncology team providing me with the best medical guidance and being actively engaged in my treatment decisions has kept me alive for 10 years.

—Janet Klein

so much and to contribute to important new research in breast cancer, I am participating in the Share the Journey: Mind, Body, and Wellness After Breast Cancer clinical study (sharethejourneyapp.org) [see more about the Share the Journey app above]. The study is investigating the symptoms women face after breast cancer treatment and what can be done to improve them. I’m happy to offer details

about my experience in the hope that they will provide researchers with the information needed to improve the lives of other women facing this disease.

Being an Active Participant in Cancer Care Having lived with breast cancer for so many years has also taught me the valuable lesson of how crucial it is to

cian at Sage Bionetworks and an investigator of the research study. “The study is geared toward the idea that we will be able to turn what has previously been thought of as objective responses from people—also called anecdotes—about their disease into actionable, objective signals. Ultimately, we can use those signals to fuel further research that may lead to interventions to help people better live their lives after treatment. This study allows patients to see whether their health is getting better because they take on the role of being more of a manager of their symptoms and less of a voyeur.”

Andrew Trister, MD, PhD, MSE

The app periodically asks women to answer questions about their current health and medical history; level of fatigue and mood; cognitive changes; and sleep and exercise patterns; it sends notices asking participants to complete certain tasks and surveys. The app then tracks and stores participants’ responses to the surveys; their journal entries about their symptoms; and data they input about various tasks they perbe a full participant with my oncology team in my medical care, and it’s a message I repeat over and over to other cancer survivors I meet. As wonderful and capable as oncologists and nurses are, they can’t fight a patient’s cancer by themselves; they need the patient’s help.

If patients think they can fight cancer without being fully involved in their care, they are wrong. I have no doubt that the combination of having a wonderful oncology team providing me with the best medical guidance and being actively engaged in my treatment decisions has kept me alive for 10 years. And I fully expect it will keep me alive for many more. n Ms. Klein lives in Sherman Oaks, California.

ASCOPost.com | SEPTEMBER 10, 2015

PAGE 89

Technology in Oncology formed, such as the amount of physical activity they completed in a day.

“This gives survivors the ability to know how they are doing in real time,” said Dr. Ganz. “We know from behavioral science research that very often people underestimate or overestimate how much they are walking or how much they are eating in a day. We built into this app the ability for users to monitor the number of steps they take and how many flights of stairs they climb daily. It also allows users to set goals for exercise.”

Having the ability to capture a variety of information from patients, said Dr. Ganz, can provide clinicians with a strategy to personalize treatment.

“About 25% to 30% of women have ongoing problems after breast cancer treatment ends, and that is the group we need to find better interventions for. We need to know who these women are and what their issues are. If we could identify these women early on and/or during this post-treatment data collection

and learn the integrated characteristics that will cause them to have ongoing fatigue or cognitive difficulties, we might be able to personalize strategies to treat these patients upfront or follow up with early intervention,” Dr. Ganz explained.

Furthering Breast Cancer Research The Share the Journey study will last about 6 months. Data captured in the app will then be processed and analyzed by the study investigators and reported in scientific publications. Share the Journey participants can also opt to share their coded study data with researchers outside of this study.

“We think having data from this study shared broadly with the research community will help answer questions [about the after effects of breast cancer] from previous studies and help us gain insights from other research projects,” said Dr. Trister. “I also think this type of technology could lead to greater participation in traditional clinical trials.”

Using Technology to Improve Care for Survivors The Share the Journey app is not the first digital tool Dr. Ganz has helped develop. Several years ago, in response to the recommendations in the Institute of Medicine’s 2005 report, From Cancer Patient to Cancer Survivor: Lost in Transition, which concluded that every cancer survivor should have a coordinated survivorship care plan after treatment, Dr. Ganz collaborated with others to launch Journey Forward. Her collaborators included the National Coalition for Cancer Survivorship, Anthem, Inc., Genentech, and later the Oncology Nursing Society. The app was initially designed as a web-based care plan builder for professionals and has now expanded to include resource tools for patients and survivors in the form of a downloadable medical app.

The Journey Forward app allows survivors and oncologists to create a posttreatment plan and includes a summary of the survivors’ cancer diagnosis and

treatment; a schedule for follow-up tests and surveillance; an area for psychosocial assessment; and information on managing ongoing symptoms and what to expect following treatment.

The app can be downloaded for free to both Apple iOS and Google Android mobile devices. The My Care Plan section of the app can also be downloaded in a printable PDF format. A Survivorship Library for Patients, where survivors can find information about their symptoms and care, is available on the Journey Forward website. To access the Survivorship Library for Patients and download the Journey Forward app, visit journeyforward.org.

“The information in the treatment and summary care plan in Journey Forward can help survivors start a conversation with their health-care team,” said Dr. Ganz. “It really is a way to increase patient empowerment.” n Disclosure: Dr Ganz is on the advisory board for InformedDNA. Dr. Trister reported no potential conflicts of interest.

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PAID ADVERTISEMENT

Polycythemia Polycythemia Vera: Vera:

Are AreSome SomePatients Patientsat atIncreased IncreasedRisk?

Risk?

For For Forsome some somepatients patients patientswhose whose whosehematocrit hematocrit hematocritlevels levels levelsremain remain remainelevated, elevated, elevated,and and andfor for forthose those thosewho who whocontinue continue continueto to toexperience experience experienceclinical clinical clinicalsigns signs signsand and and symptoms symptoms symptomssuch such suchas as asfatigue, fatigue, fatigue,pruritus, pruritus, pruritus,night night nightsweats sweats sweatsor or orsplenomegaly, splenomegaly, splenomegaly,PV PV PVremains remains remainsuncontrolled. uncontrolled. uncontrolled.

Overview Overview Overview

Thrombotic Thrombotic Thromboticand and andhemorrhagic hemorrhagic hemorrhagiccomplications complications complicationsare are areamong among amongthe the theleading leading leading 14 1414 causes causes causesof ofofmorbidity morbidity morbidityand and andmortality mortality mortalityassociated associated associatedwith with withPV. PV. PV. Cancer What What WhatIs Is IsPolycythemia Polycythemia PolycythemiaVera?

Vera?

Vera?

Cancer Cancerand and and 6,15 6,15 cardiovascular cardiovascularmortality mortality mortalityare are arethe the thefrequent frequent frequentcauses causes causesof ofofdeaths deaths deathsin ininPV. PV. PV.6,15 Polycythemia Polycythemia Polycythemiavera vera vera(PV) (PV) (PV)isisisaaamyeloproliferative myeloproliferative myeloproliferativeneoplasm neoplasm neoplasm(MPN) (MPN) (MPN) cardiovascular characterized characterized characterized by by by an an an overproduction overproduction overproduction of ofof When When Whenassessing assessing assessingrisks risks risksfor for formorbidity morbidity morbidity normal normal normalred red redblood blood bloodcells, cells, cells,white white whiteblood blood bloodcells cells cells and and andmortality mortality mortalityin ininpatients, patients, patients,consider consider consider 3,14,16 3,14,16 3,14,16 and and andplatelets platelets plateletsthat that thatleads leads leadsto totoan an anincreased increased increasedrisk risk risk the the the following following following : : : The The Therate rate rateof of ofdeath death death 1-4 1-4 1-4 of ofofthrombosis. thrombosis. thrombosis.

•••Elevated Elevated Elevatedhematocrit hematocrit hematocritlevels levels levels Erythrocytosis Erythrocytosis Erythrocytosis(elevated (elevated (elevated due due due to to to cardiovascular cardiovascular cardiovascular •••History History Historyof ofofthrombosis thrombosis thrombosis red red redblood blood bloodcell cell cellmass) mass) mass)isisisthe the themost most mostprominent prominent prominent Advanced Advancedage age age(≥60 (≥60 (≥60years) years) years) clinical clinical clinicalmanifestation manifestation manifestationof ofofPV, PV, PV,distinguishing distinguishing distinguishingititit events events eventsor or ormajor major majorthrombosis thrombosis thrombosis •••Advanced 55 5 •••Leukocytosis Leukocytosis Leukocytosis from from fromother other otherMPNs. MPNs. MPNs. was was wasfour four fourtimes times timeshigher higher higher •••Cardiovascular Cardiovascular Cardiovascularrisk risk riskfactors factors factors such such suchas as ashigh high highcholesterol cholesterol cholesterollevels, levels, levels, PV PV PVmay may mayoccur occur occurat atatany any anyage age agebut but butoften often oftenpresents presents presents in in in patients patients patients with with with elevated elevated elevated hypertension, hypertension, hypertension,diabetes, diabetes, diabetes,obesity obesity obesity later later laterinininlife, life, life,with with withaaamedian median medianage age ageat atatdiagnosis diagnosis diagnosisof ofof 6,7 6,7 6,7 and and andsmoking smoking smoking 60 60 60years. years. years. Approximately Approximately Approximately100,000 100,000 100,000patients patients patients hematocrit hematocrit hematocritlevels levels levelsof of of45% 45% 45% 88 8 inininthe the theUnited United UnitedStates States Statesare are areliving living livingwith with withPV. PV. PV. to to to50% 50% 50%compared compared comparedwith with with According According According to toto data data data from from from aaa large, large, large, randomized, randomized, randomized, controlled controlled controlled clinical clinical clinical trial, trial, trial, Clinical Clinical ClinicalPresentation Presentation Presentationof of ofPV PV PV those those thosewho who whomaintained maintained maintained the the the rate rate rate of ofof death death death due due due to toto cardiovascular cardiovascular cardiovascular Contributing Contributing Contributingto to toIts Its ItsDiagnosis Diagnosis Diagnosis aaahematocrit hematocrit hematocrittarget target target events events eventsor orormajor major majorthrombosis thrombosis thrombosiswas was was Janus Janus Janus kinases kinases kinases (JAKs) (JAKs) (JAKs) mediate mediate mediate cytokine cytokine cytokine 9,10 9,10 9,10 four four fourtimes times timeshigher higher higherin ininpatients patients patientswith with with signaling signaling signaling and and and growth growth growth factors. factors. factors.

An An An 222 of of of <45%. <45%. <45%. elevated elevated elevatedhematocrit hematocrit hematocritlevels levels levelsof ofof45% 45% 45% important important importantgenetic genetic geneticdiscovery discovery discoveryabout about aboutaaapoint point point to toto50% 50% 50%compared compared comparedwith with withthose those thosewho who who mutation mutation mutationin ininthe the theJanus Janus Januskinase kinase kinase222(JAK2) (JAK2) (JAK2)gene gene gene 11 1111 maintained maintained maintainedaaahematocrit hematocrit hematocrittarget target targetof ofof has has hasenhanced enhanced enhancedthe the theunderstanding understanding understandingof ofofPV. PV. PV. 22 2 <45% <45% <45%(Figure (Figure (Figure1).

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PV PV PVisisisan an anelusive elusive elusivedisease disease diseasethat that thatmay may maynot not notbe be berecognized recognized recognizedfor for foryears. years. years.

Diagnosis Diagnosis Diagnosismost most mostfrequently frequently frequentlyoccurs occurs occursby by bychance chance chancefollowing following followingaaaroutine routine routine 12 1212 examination. examination. examination.

Diagnosis Diagnosis Diagnosismay may mayalso also alsooccur occur occurafter after afteraaathrombotic thrombotic thromboticevent event event 12 1212 or ororas as asaaaresult result resultof ofofdisease-related disease-related disease-relatedsymptoms. symptoms. symptoms.

The The Thefollowing following followingimportant important importantsigns signs signsand and andsymptoms symptoms symptomswarrant warrant warrantaaaprompt prompt prompt CICI=CI=confi =confi confi dence dence dence interval; interval; interval; Hct Hct Hct ==hematocrit. =hematocrit. hematocrit.

6,7 6,7 6,7 evaluation evaluation evaluationand and andsuggest suggest suggestPV PV PV :: : Figure Figure Figure 1.1.Kaplan-Meier 1.Kaplan-Meier Kaplan-Meier curve curve curve for for for total total total cardiovascular cardiovascular cardiovascular events. events. events.

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Cardiovascular Cardiovascular Cardiovascular events events events and and and intensity intensity intensity ofoftreatment oftreatment treatment ininpolycythemia inpolycythemia polycythemia vera. vera. vera.

NNEngl NEngl Engl JJMed. JMed. Med. 2013;368(1):22-33.

2013;368(1):22-33.

2013;368(1):22-33.

Copyright Copyright Copyright ©2013 ©2013 ©2013 •••Thrombotic Thrombotic Thromboticevents events events Massachusetts Massachusetts Massachusetts Medical Medical Medical Society.

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•••Splenomegaly Splenomegaly Splenomegaly(with (with (withor ororwithout without withoutthrombocytosis thrombocytosis thrombocytosisand/or and/or and/or leukocytosis) leukocytosis) leukocytosis) Thrombosis, Thrombosis, Thrombosis,Splenomegaly Splenomegaly Splenomegalyand and andOther Other OtherDiseaseDiseaseDisease-

related related relatedSymptoms Symptoms Symptoms

In InInPV, PV, PV,aaawide wide widespectrum spectrum spectrumof ofofthrombotic thrombotic thromboticmanifestations manifestations manifestationsexists exists existsthat that that 14 1414 may may mayoccur occur occurbefore before beforethe the thedisease disease diseaseisisisdiagnosed. diagnosed. diagnosed.

Palpable Palpable Palpablesplenomegaly splenomegaly splenomegaly isisisan an animportant important importantphysical physical physicalfifinding finding ndingbecause because becauseincreased increased increasedspleen spleen spleensize size sizeisisis 12 1212 present present presentin inin30% 30% 30%to toto40% 40% 40%of ofofpatients patients patientswith with withPV. PV. PV. Additional Additional Additionalsigns signs signsand and and Prognosis Prognosis Prognosisand and andRisk Risk RiskFactors Factors Factors symptoms symptoms symptomsof ofofPV, PV, PV,which which whichmay may maycontribute contribute contributeto totoaaasubstantial substantial substantialquality-ofquality-ofquality-of17 1717 In InInaaalarge large largepopulation-based population-based population-basedstudy study studyin ininmore more morethan than than4,000 4,000 4,000patients patients patients life life lifeburden burden burdenin ininpatients patients patientswith with withPV, PV, PV,include include include:: : with with withPV, PV, PV,life life lifeexpectancy expectancy expectancywas was was36% 36% 36%lower lower lowerthan than thanthat that thatof ofofthe the thegeneral general general •••Fatigue Fatigue Fatigue 13 1313 population. population. population.

•••Pruritus Pruritus Pruritus •••Night Night Nightsweats sweats sweats

Clinical Clinical ClinicalConsiderations Considerations Considerations in in inManaging Managing ManagingPV PV PV

Clinical Clinical ClinicalNeed Need Needin in inPV PV PV

Phlebotomy Phlebotomy Phlebotomyto to tomaintain maintain maintainHct Hct Hctat at at<45% <45% <45% plus plus pluslow-dose low-dose low-doseaspirin aspirin aspirin

3,11 3,11 3,11 Therapeutic Therapeutic Therapeuticapproaches approaches approachesto totoPV PV PVfocus focus focuson on on :: : •••Controlling Controlling Controllingand and andmaintaining maintaining maintaininghematocrit hematocrit hematocritlevels levels levelsat atat<45% <45% <45% •••Treating Treating Treatingcomplications complications complicationsof ofofthrombosis thrombosis thrombosisand and andhemorrhage hemorrhage hemorrhage •••Reducing Reducing Reducingthrombotic thrombotic thromboticrisk risk riskand and andminimizing minimizing minimizingthe the therisk risk riskof ofof leukogenic leukogenic leukogenictransformation transformation transformation •••Managing Managing Managingsplenomegaly splenomegaly splenomegalyand and andother other otherdisease-related disease-related disease-related symptoms symptoms symptoms

••Poor •Poor Poor compliance compliance compliance or oror tolerance tolerance tolerance to toto frequent frequent frequent phlebotomy phlebotomy phlebotomy ••Symptomatic •Symptomatic Symptomatic or oror progressive progressive progressive splenomegaly splenomegaly splenomegaly ••High •High High risk risk risk of ofof thrombosis thrombosis thrombosis ••Severe •Severe Severe disease-related disease-related disease-related symptoms symptoms symptoms ••Progressive •Progressive Progressive myeloproliferation myeloproliferation myeloproliferation (leukocytosis (leukocytosis (leukocytosis or oror thrombocytosis) thrombocytosis) thrombocytosis)

Phlebotomy Phlebotomy Phlebotomyisisisusually usually usuallythe the thestarting starting startingpoint point pointof ofoftreatment treatment treatmentin ininpatients patients patients 2,11 2,11 2,11 with with withPV, PV, PV,in ininaddition addition additionto tototherapy therapy therapywith with withlow-dose low-dose low-doseaspirin. aspirin. aspirin. LowLowLowdose dose doseaspirin aspirin aspirinhas has hasbeen been beenshown shown shownto totoprevent prevent preventboth both botharterial arterial arterialand and andvenous venous venous 18 1818 thrombotic thrombotic thromboticcomplications complications complicationsin ininpatients patients patientswith with withPV. PV. PV. Cytoreductive Cytoreductive Cytoreductivetherapy therapy therapywith with withhydroxyurea hydroxyurea hydroxyureaor ororinterferon-alpha interferon-alpha interferon-alphamay may may also also alsobe be behelpful helpful helpfulin ininpatients patients patientswho who whohave have havediffi diffi diffi culty culty cultywith with withphlebotomy, phlebotomy, phlebotomy, who who whohave have havesymptomatic symptomatic symptomaticor ororprogressive progressive progressivesplenomegaly splenomegaly splenomegalyor ororwho who who 11 1111 experience experience experience severe severe severe symptoms. symptoms. symptoms. Although Although Although treatment treatment treatment with with with hydroxyurea hydroxyurea hydroxyureamay may maybe be betolerated tolerated toleratedby by bymost most mostpatients, patients, patients,itititisisisimportant important important to totoconsider consider considerthat that thatapproximately approximately approximately25% 25% 25%of ofofpatients patients patientswith with withPV PV PVdevelop develop develop 19, 19, 19, 20 2020 resistance resistance resistanceto totoor ororintolerance intolerance intoleranceof ofofhydroxyurea hydroxyurea hydroxyurea(Table (Table (Table1).

1).

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HU HU HUIntolerance Intolerance Intolerance

After After After12 12 12weeks weeks weeksof ofofHU HU HUat atat At At Atleast least least111of ofofthe the thefollowing: following: following: aaatotal total totaldose dose doseof ofof≥2 ≥2 ≥2g/day g/day g/dayor oror •••Neutropenia Neutropenia Neutropenia(absolute (absolute (absolute neutrophil neutrophil neutrophilcount count countof ofof at atatthe the themaximum maximum maximumtolerated tolerated tolerated 99 9 dose, dose, dose,ififif<2 <2 <2g/day g/day g/day <1.0 <1.0 <1.0xxx10 10 10/L) /L) /L) •••Need Need Needfor for forphlebotomy phlebotomy phlebotomy •••Platelet Platelet Plateletcount count countof ofof 99 9 to totomaintain maintain maintainHct Hct Hctlevel level level /L /L/L <100 <100 <100xxx10 10 10 at atat<45% <45% <45%or oror •••Hgb Hgb Hgblevel level levelof ofof<10 <10 <10g/dL g/dL g/dL •••Elevated Elevated Elevatedplatelet platelet plateletand and andwhite white white •••Leg Leg Legulcers ulcers ulcersor ororother other other blood blood bloodcell cell cellcounts counts countsor oror unacceptable unacceptable unacceptable •••<50% <50% <50%reduction reduction reductionin inin nonhematologic nonhematologic nonhematologic splenomegaly splenomegaly splenomegaly HU-related HU-related HU-relatedtoxicity toxicity toxicity Hct, Hct, Hct, hematocrit; hematocrit; hematocrit; Hgb, Hgb, Hgb, hemoglobin. hemoglobin. hemoglobin.

191919 Modifi Modifi Modifi ed ed ed from from from Barosi Barosi Barosi et etet al. al. al.

Despite Despite Despite current current current approaches, approaches, approaches, including including including phlebotomy, phlebotomy, phlebotomy, lowlowlowdose dose doseaspirin, aspirin, aspirin,interferon-alpha interferon-alpha interferon-alphaor ororcytoreductive cytoreductive cytoreductivetherapy therapy therapywith with with hydroxyurea, hydroxyurea, hydroxyurea,some some somepatients patients patientswill will willnot not notbe be beable able ableto totogain gain gainand and andmaintain maintain maintain 19,20 19,20 19,20 hematocrit hematocrit hematocritlevels levels levelsof ofof<45% <45% <45% (Figure (Figure (Figure 2).

2).

2).

For For Forsome some somepatients patients patientswhose whose whosehematocrit hematocrit hematocritlevels levels levelsremain remain remainelevated, elevated, elevated, and and andfor for forthose those thosewho who whocontinue continue continueto totoexperience experience experienceclinical clinical clinicalsigns signs signs and and and symptoms symptoms symptoms such such such as as as fatigue, fatigue, fatigue, pruritus, pruritus, pruritus, night night night sweats sweats sweats 11,20 11,20 11,20 or oror splenomegaly, splenomegaly, splenomegaly, PV PV PV remains remains remains uncontrolled. uncontrolled. uncontrolled. Recently, Recently, Recently, standardized standardized standardizedcriteria criteria criteriafor for formonitoring monitoring monitoringand and andassessing assessing assessingresponse response response in ininPV PV PVhave have havebeen been beendeveloped developed developedfor for forclinical clinical clinicalresearch. research. research.Evaluation Evaluation Evaluation of ofof response response response includes includes includes such such such parameters parameters parameters as as as resolution resolution resolution of ofof splenomegaly splenomegaly splenomegalyand and andother other otherdisease-related disease-related disease-relatedsigns, signs, signs,hematocrit hematocrit hematocritof ofof <45%, <45%, <45%,blood blood bloodcount count countremission, remission, remission,absence absence absenceof ofofthrombotic thrombotic thromboticevents events events 21 2121 and and andbone bone bonemarrow marrow marrowhistology. histology. histology.

Hydroxyurea Hydroxyurea Hydroxyurea(HU) (HU) (HU)or or orinterferon-alpha interferon-alpha interferon-alphaas as as aa a first-line first-line first-linecytoreductive cytoreductive cytoreductivetherapy therapy therapyat at atany any anyage age age

••Patients •Patients Patients are are are intolerant intolerant intolerant of ofof or oror resistant resistant resistant to toto HU HU HU

Unmet Unmet Unmetneed need needexists exists existsfor for foraaasubset subset subsetof of ofpatients patients patients not not notmanaged managed managedappropriately appropriately appropriatelyby by bycurrent current currenttreatment treatment treatment strategies strategies strategies(alone (alone (aloneor or orin inincombination) combination) combination) Hct, Hct, Hct,hematocrit. hematocrit. hematocrit. aa a

All All All patients patients patients should should should be be be managed managed managed aggressively aggressively aggressively for for for their their their generic generic generic cardiovascular cardiovascular cardiovascular risk risk risk factors. factors. factors.

HU HU HU should should should be be be used used used with with with caution caution caution in inin patients patients patients <40 <40 <40 years years years of ofof age; age; age; busulfan busulfan busulfan may may may be be be considered considered considered in inin elderly elderly elderly patients patients patients (>70 (>70 (>70 years). years). years).

111111 Figure Figure Figure 2.2.2.

AAA practical practical practical management management management algorithm. algorithm. algorithm.

Learn Learn Learnmore more moreabout about aboutunderstanding understanding understanding the the theburden burden burdenof of ofPolycythemia Polycythemia PolycythemiaVera Vera Vera at at atwww.MPNConnect.com www.MPNConnect.com www.MPNConnect.com References References References 1.1.1. Vannucchi Vannucchi Vannucchi AM, AM, AM, Guglielmelli Guglielmelli Guglielmelli P,P,P, Tefferi Tefferi Tefferi A. A.A. CA CA CA Cancer Cancer Cancer JJClin.

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Br BrBr JJHaematol.

JHaematol.

Haematol.

2010;148:961-963.

2010;148:961-963.

2010;148:961-963.

20.

20.

20. Alvarez-Larrán Alvarez-Larrán Alvarez-Larrán A, A,A, Pereira Pereira Pereira A, A,A, Cervantes Cervantes Cervantes FFet Fetet al. al.al.

Blood.

Blood.

Blood.

2012;119:1363-1369.

2012;119:1363-1369.

2012;119:1363-1369.

21.

21.

21. Barosi Barosi Barosi G, G,G, Mesa Mesa Mesa R, R,R, Finazzi Finazzi Finazzi GGG et etet al. al.al.

Blood.

Blood.

Blood.

2013;121:4778-4781.

2013;121:4778-4781.

2013;121:4778-4781.

©2015, ©2015, ©2015, Incyte Incyte Incyte Corporation.

Corporation.

Corporation.

All All All rights rights rights reserved. reserved. reserved.

EDU-1118i EDU-1118i EDU-1118i 03/15 03/15 03/15

The ASCO Post | SEPTEMBER 10, 2015

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Integrative Oncology Coriolus versicolor

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

T

he use of dietary supplements by patients with cancer has increased significantly over the past 20 years despite insufficient evidence of safety and effectiveness.

Finding reliable sources of information about 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 Coriolus versicolor for this issue because of its increasing use by patients with cancer.

Compiled by Barrie R. Cassileth, 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.

Scientific name: Coriolus versicolor Common names: Trametes versicolor, PSK, PSP, VPS, Turkey Tail, Yun Zhi, Kawaratake, Krestin

Overview

Coriolus versicolor, a mushroom found throughout the world, belongs to the class Basidiomycetes. Mushrooms are valued in traditional Oriental medicine for their health-promoting effects and are often combined

with herbs to build strength and stamina and to treat disease.

Coriolus is popularly known as a turkey tail mushroom because of its resemblance to the multicolored tail of a wild turkey. It is used not as food but as medicine and has been part of traditional medicine as a tonic.

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 offer health-care professional and patient versions, and entries are regularly updated with the latest research findings.

The Science

Jyothirmai Gubili, MS

Polysaccharide K (PSK) and polysaccharide peptide (PSP), compounds extracted from Coriolus versicolor, are thought to be responsible for its immunomodulatory and anticancer effects.

Clinical data indicate that polysaccharide K increases the survival rates of patients with certain cancers (see below under “The Science”) without causing major adverse effects. It is commonly used in Asian countries to complement standard cancer treatments.

Versicolor polysaccharide (VPS), another extract obtained from the mushroom, is also under investigation for its potential anticancer effects.

Coriolus versicolor is available in health food stores and on the Internet in the form of capsules, extracts, or teas. Extracts, including polysaccharide peptide and versicolor polysaccharide, are sold as dietary supplements in the United States.

Coriolus versicolor acts as a biologic response modifier. When used as an adjuvant, the proteoglycan polysaccharide K improved survival rates in patients with gastric1,2 and colorectal3-5

exerted positive immunomodulatory effects.7,8 However, studies of patients with breast cancer,9 hepatocellular carcinoma,10 and leukemia11 produced mixed results.

In another study, versicolor polysaccharide, a hot water extract of ­Coriolus, was found to enhance the development of large intestinal tumors in mice.12 More research is needed to determine the anticancer potential of Coriolus extracts.

Adverse Effects

cancers. Polysaccharide peptide, used in conjunction with chemotherapy, has been shown to slow the progression of advanced non–small cell lung cancer.6 Coriolus extract by itself or in combination with other botanicals

Dark-colored stools,13 darkening of the fingernails,14 and low-grade hematologic and gastrointestinal toxicities have been reported following consumption of Coriolus along with chemotherapeutic agents.3 For additional information, visit the “About Herbs” website at https://www. mskcc.org/cancer-care/integrativemedicine/herbs/coriolus-versicolor. n Disclosure: Ms. Gubili reported no potential conflicts of interest.

Learn More About

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

http://www.mskcc.org/ cancer-care/herb/maitake

ASCOPost.com | SEPTEMBER 10, 2015

PAGE 93

Integrative Oncology References 1. Nakazato H, Koike A, Saji S, et al: Efficacy of immunochemotherapy as adjuvant treatment after curative resection of gastric cancer. Study Group of Immunochemotherapy with PSK for Gastric Cancer. Lancet 343:1122-1126, 1994.

2. Niimoto M, Hattori T, Tamada R, et al: Postoperative adjuvant immunochemotherapy with mitomycin C, futraful and PSK for gastric cancer: An analysis of data on 579 patients followed for five years. Jpn J Surg 18:681-686, 1988.

3. Ohwada S, Ikeya T, Yokomori T, et al: Adjuvant immunochemotherapy with oral Tegafur/Uracil plus PSK in patients with stage II or III colorectal cancer: A randomised controlled study. Br J Cancer 90:1003-1010, 2004.

4. Mitomi T, Tsuchiya S, Iijima N, et al: Randomized, controlled study on adjuvant immunochemotherapy with PSK in curatively resected colorectal cancer.

The Cooperative Study Group of Surgical Adjuvant Immunochemotherapy for Cancer of Colon and Rectum (Kanagawa). Dis Colon Rectum 35:123-130, 1992.

5. Torisu M, Hayashi Y, Ishimitsu T, et al: Significant prolongation of disease-free period gained by oral polysaccharide K (PSK) administration after curative surgical operation of colorectal cancer. Cancer Immunol Immunother 31:261-268, 1990.

6. Tsang KW, Lam CL, Yan C, et al: Coriolus versicolor polysaccharide peptide slows progression of advanced non-small cell lung cancer. Respir Med 97:618-624, 2003.

7. Wong CK, Tse PS, Wong EL, et al:

Immunomodulatory effects of yun zhi and danshen capsules in health subjects—A randomized, double-blind, placebo-controlled, crossover study. Int Immunopharmacol 4:201-211, 2004.

8. Wong CK, Bao YX, Wong EL, et al: Immunomodulatory activities of Yunzhi and Danshen in post-treatment breast cancer patients. Am J Chin Med 33:381-395, 2005.

9. Iino Y, Yokoe T, Maemura M, et al.

Immunochemotherapies versus chemotherapy as adjuvant treatment after curative resection of operable breast cancer.

Anticancer Res 15:2907-2911, 1995.

10. Suto T, Fukuda S, Moriya N, et al: Clinical study of biological response modifiers as maintenance therapy for hepatocellular carcinoma. Cancer Chemother

Pharmacol 33:S145-S148, 1994.

11. Ohno R, Yamada K, Masaoka T, et al: A randomized trial of chemoimmunotherapy of acute nonlymphocytic leukemia in adults using a protein-bound polysaccharide preparation. Cancer Immunol Immunother 18:149-154, 1984.

12. Toth B, Coles M, Lynch J: Effects of VPS extract of Coriolus versicolor on cancer of the large intestine using a serial sacrifice technique. In Vivo 20:341-346, 2006.

13. Shiu WCT, Leung TWT, Tao M: A clinical study of PSP on peripheral blood counts during chemotherapy. Phytotherapy Res 6:217-218, 1992.

14. Kidd PM: The use of mushroom glucans and proteoglycans in cancer treatment. Altern Med Rev 5:4-27, 2000.

To the One of the Many

By Parvez Dara, MD, FACP, MBA, Toms River, New Jersey (Using Shakespeare’s words to confront the plight of a Physician) Give me that man That is not passion’s slave Give me that blanket that comforts and soothes For in my heart There was a fighting that would not let me sleep, Our indiscretion Sometimes serves us well.

In those wakeful moments When around a surgeon’s scalpel the blood congeals And time is spent to heal.

What a piece of work is a man The quintessence of dust.

What is he Whose grief bears such emphasis Such intricate complexity Of thought and action?

How noble in reason How infinite in faculties To quell the cry of pain, How like an angel How express and admirable To drown the misery And purge the disquiet Of a thousand natural shocks That flesh is heir to

And to take arms against a sea of trouble And by opposing, end them.

Yet within the firmament of that reason I could be bounded in a nutshell And count myself a king of infinite space, Were it not that I have bad dreams.

These dreams, though this be madness There is method in’t.

The vile mechanism feeds And eyes without feeling Feeling without sight, Cannot chart the course to reason.

The spirit that I have seen, may be a devil And the devil hath power t’assume a pleasing shape Cleave the general ear with horrid speech, Make mad the guilty and appall the free.

These clever studied orphans of untruth Confound the ignorant and amaze Indeed the very faculties of eyes and ears.

They forget in their remarkable hypocrisy; This above all: to thine own self be true, And it must follow, as the night the day, Thou canst not then be false to any man.

The power that exudes such tyranny Tis dangerous when the baser nature comes between The pass and fell incensed points of mighty opposites.

They know not what they do As their power is fleeting And the unholy madness, a passing fancy A man may fish with the worm that hath eat of a king, And eat of the fish that hath fed of that worm They thus find permanence in indignity within houses that last till doomsday.

While chastising nobility, they cry and Humanity bleeds as one is lost to the many Eviscerating the noble cause of individuality The chief good and market of this time Is left wanting in art and science, Or somewhere in between.

This warlike paragon of animals Abuses me to damn me.

As villainy though it have no tongue, Will speak with most miraculous organ!

One day!

Leaving in its vile dust This beauty of the world, This noble of humans This physician.

In apprehension how like a god, I will wear him in my heart’s core, Ay, in my heart of hearts As he grunts and sweats under the weary life Bringing comfort through his discomfort To the one of the many! n

For patients with bone metastases from solid tumors

Prevent bone complications longer In a prespecified integrated analysis of 3 pivotal trials (N = 5,723),

8.2

XGEVA® was proven to delay the median time to first bone complication by

months longer vs zoledronic acid1

XGEVA® is a convenient 120 mg subcutaneous injection administered once every 4 weeks.2

Bone complications, or skeletal-related events (SREs), are defined as radiation to bone, pathologic fracture, surgery to bone, and spinal cord compression.2,3 Median Time to First Bone Complication1 27.7

months

Data from a prespecified integrated analysis of three international, phase 3, double-blind, double-dummy, active-controlled trials comparing XGEVA® with zoledronic acid for the prevention of bone complications in patients with bone metastases from solid tumors or multiple myeloma.1

XGEVA VA® 120 mg Q4W (n = 2,862) VA

19.5

months

zoledronic acid 4 mg Q4W (n = 2,861) 1 YEAR

HR* = 0.83 (95% CI: 0.76-0.90)

2 YEARS

P < 0.001

†

IMPORTANT SAFETY INFORMATION Hypocalcemia • Pre-existing hypocalcemia must be corrected prior to initiating therapy with XGEVA®. XGEVA® can cause severe symptomatic hypocalcemia, and fatal cases have been reported. Monitor calcium levels 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. 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.

Hypersensitivity • XGEVA® is contraindicated in patients with known clinically significant hypersensitivity to XGEVA®, including anaphylaxis that 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.

*Hazard ratio (HR) is defined as the increase or decrease in likelihood of an event of interest (in this case a bone complication) for one group relative to that in a comparator group.

P value for superiority.

†

Drug Products with Same Active Ingredient • Patients receiving XGEVA® should not take Prolia® (denosumab).

Osteonecrosis of the Jaw • Osteonecrosis of the jaw (ONJ) can occur 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.

• 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®.

• 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.

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.

XGEVA® is indicated for the prevention of skeletal-related events in patients with bone metastases from solid tumors.

XGEVA® is not indicated for the prevention of skeletal-related events in patients with multiple myeloma.

• RANK Ligand (RANKL) is produced by bone cells in the skeleton and is a key mediator of bone resorption4 • RANKL production is increased at sites of bone metastases, and stimulates osteoclasts to destroy bone4 • XGEVA® acts precisely to bind RANKL and inhibits osteoclast formation, function, and survival2 • Pre-existing hypocalcemia must be corrected prior to initiating therapy with XGEVA®2

Learn more at XGEVA.com

• 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.

©2014 Amgen Inc. All rights reserved. 04/14 80218-R1-V1

• Advise females of reproductive potential to use highly effective contraception during therapy, and for at least 5 months after 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®.

Adverse Reactions • The most common adverse reactions in patients receiving XGEVA® with bone metastasis from solid tumors were fatigue/asthenia, hypophosphatemia, and nausea. The most common serious adverse reaction was dyspnea. The most common adverse reactions resulting in discontinuation were osteonecrosis and hypocalcemia.

Please see brief summary of Prescribing Information on the following page.

REFERENCES: 1. Lipton A, Fizazi K, Stopeck AT, et al. Superiority of denosumab to zoledronic acid for prevention of skeletal-related events: a combined analysis of 3 pivotal, randomised, phase 3 trials.

Eur J Cancer. 2012;48:3082-3092. 2. XGEVA® (denosumab) prescribing information, Amgen. 3. Brodowicz T, O’Byrne K, Manegold C. Bone matters in lung cancer. Ann Oncol. 2012;23:2215-2222. 4. Roodman GD. Mechanisms of bone metastasis. N Engl J Med. 2004;350:1655-1664.

www.XGEVA.com

S:9.5”

Brief Summary: Consult package insert for complete Prescribing Information

DOUS14CDNY4736_XGEVA_Tabloid_BS_V10_8pt_r13.indd 1

Body System GASTROINTESTINAL Nausea Diarrhea GENERAL Fatigue/ Asthenia IN VESTIGATIONS Hypocalcemiab Hypophosphatemiab NEUROLOGICAL Headache RESPIRATORY Dyspnea Cough

Xgeva n = 2841 %

Zoledronic Acid n = 2836 %

31 20

32 19

45

46

18 32

9 20

13

14

21 15

18 15

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.

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 tested positive for binding antibodies. No patient with positive binding antibodies tested positive for neutralizing antibodies as 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. In clinical trials in patients with breast cancer metastatic to bone, Xgeva was administered in combination with standard anticancer treatment. 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.

There was no evidence that various anticancer treatments affected denosumab systemic exposure and pharmacodynamic effect. Serum denosumab concentrations at 1 and 3 months were not altered by concomitant chemotherapy and/or hormone therapy. The median reduction in uNTx/Cr from baseline to month 3 was similar between patients receiving 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. a

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 (22-621% 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. Xgeva is not recommended in pediatric patients. The safety and effectiveness of Xgeva in pediatric patients have not been established. 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.

OVERDOSAGE: There is no experience with overdosage of Xgeva.

HOW SUPPLIED/STORAGE AND HANDLING: Xgeva is supplied in a singleuse vial. Store Xgeva in a refrigerator at 2°C to 8°C (36°F to 46°F) in the original carton. Do not freeze. Once removed from the refrigerator, Xgeva must not be exposed to temperatures above 25°C/77°F or direct light and must be used within 14 days. Discard Xgeva if not used within the 14 days. Do not use Xgeva after the expiry date printed on the label. Protect Xgeva from direct light and heat. Avoid vigorous shaking of Xgeva.

PATIENT COUNSELING INFORMATION: Advise patients to contact a healthcare professional for any of the following: • Symptoms of a hypersensitivity reaction, including rash, urticaria, pruritus, lip swelling, shortness of breath, hypotension and respiratory tract edema • Symptoms of hypocalcemia, including paresthesias or muscle stiffness, twitching, spasms, or cramps • Symptoms of ONJ, including pain, numbness, swelling of or drainage from the jaw, mouth, or teeth • Persistent pain or slow healing of the mouth or jaw after dental surgery • Symptoms of atypical femoral fracture, including new or unusual thigh, hip, or groin pain • Pregnancy or nursing Advise patients of the need for: • Avoiding therapy with Xgeva if a serious allergic reaction occurred with prior Xgeva or Prolia therapy • Proper oral hygiene and routine dental care • Informing their dentist that they are receiving Xgeva • Avoiding invasive dental procedures during treatment with Xgeva • The use of highly effective contraception during and for at least 5 months after treatment with Xgeva for females of reproductive potential Advise patients that denosumab is also marketed as Prolia®. Patients should inform their healthcare provider if they are taking Prolia.

Amgen Manufacturing Limited, a subsidiary of Amgen Inc. One Amgen Center Drive Thousand Oaks, California 91320-1799 ©2010-2014 Amgen Inc. All rights reserved.

Printed in USA. 8/11/14 11:56 AM

S:13”

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.

Important Limitation of Use. Xgeva is not indicated for the prevention of skeletal-related events in patients with multiple myeloma.

DOSAGE AND ADMINISTRATION: Recommended Dosage. 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.

Preparation and Administration. Visually inspect Xgeva for particulate matter and discoloration prior to administration. Xgeva is a clear, colorless to pale yellow solution that may contain trace amounts of translucent to white proteinaceous particles. Do not use if the solution is discolored or cloudy or if the solution contains many particles or foreign particulate matter. Prior to administration, Xgeva may be removed from the refrigerator and brought to room temperature (up to 25°C/77°F) by standing in the original container. This generally takes 15 to 30 minutes. Do not warm Xgeva in any other way. Use a 27-gauge needle to withdraw and inject the entire contents of the vial. Do not re-enter the vial. Discard vial after single-use or entry.

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 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) can occur 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 (see Adverse Reactions). 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. 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. 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.

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 (see Use in Specific Populations). 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)

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PAGE 97

In Memoriam

Breast Surgeon Carolyn Mary Kaelin, MD, MPH, FACS, Dies at 54

C

arolyn Mary Kaelin, MD, MPH, FACS, died on July 28 at the age of 54. A gifted and compassionate breast cancer surgeon, Dr. Kaelin was a surgical oncologist in the Women’s Cancers Program at Dana-Farber Cancer Center and Director of the Breast Clinic at Brigham and Women’s Hospital.

and Women’s, at that time the youngest woman to hold a position of that distinction at a major Harvard teaching hospital. She quickly established herself as one of the nation’s premier breast cancer surgeons. Also active in research, Dr. K ­ aelin focused on how doctors and patients make medical decisions and on quality-of-life issues for breast cancer survivors, particularly the role of exercise. In 2001, Newsweek featured her as 1 of 15 “Women of the New Century.”

Patient and Provider

Carolyn Mary Kaelin, MD, MPH, FACS

Dr. Kaelin graduated from Smith College and Johns Hopkins School of Medicine. She earned her master’s degree from the Harvard School of Public Health. At 34, she became the Founding Director of the Comprehensive Breast Health Center at Brigham

Dr. Kaelin rode repeatedly in the Pan-Mass Challenge, a 192-mile bicycle ride fundraiser for Dana-Farber. Shortly after a training ride in 2003, she noticed early signs of her own breast cancer.

A rare complication of breast cancer therapy prevented Dr. Kaelin from returning to clinical practice. Instead, she redoubled her patient education and survivorship efforts, with an emphasis on the underserved.

Dr. Kaelin initiated research on

the value of rowing for patients with postoperative lymphedema, with an assist from Olympian Holly Metcalf.

She coauthored two award-winning books, Living Through Breast Cancer and The Breast Cancer Survivor’s Fitness Plan, and helped create an inno-

with Barbara Berger.

In 2010, Dr. Kaelin was diagnosed with brain cancer unrelated to her previous breast cancer. She had two brain surgeries and was a trailblazer on clinical trials testing medical treatments for brain cancer.

We will miss her warmth, energy, intelligence, compassion, and humor. She was uncompromising in her pursuit of truly outstanding care for each and every patient.

—Eric Winer, MD

vative, exercise-centered breast cancer recovery program for the YMCA. She also established the Quality of Life Fund at Brigham and Women’s to support breast cancer survivorship projects and launched the successful Knowledge, Strength, and Grace conference series for breast cancer patients and their families. In Aspen, Colorado, she cofounded the Quality of Life Cancer Fund along

“We will miss her warmth, energy, intelligence, compassion, and humor,” said Eric Winer, MD, Director of the Breast Oncology Center in the Susan F. Smith Center. “She was uncompromising in her pursuit of truly outstanding care for each and every patient.”

Dr. Kaelin is survived by her husband William G. Kaelin, Jr, MD, and her children Kathryn Grace and William (Tripp). n

Chris Marshall, FRS, FMedSci, Dies at 66 of Colorectal Cancer

C

hris Marshall, FRS, FMedSci, a rigorous scientist with a lasting legacy of game-changing discoveries in cancer research and generous support for his younger colleagues, has died at 66. The cause of death was colorectal cancer.

Chris Marshall, FRS, FMedSci

Professor Marshall was the Head of the Division for Cancer Biology at the Institute of Cancer Research in London and Professor of Cell Biology, and held a Cancer Research UK Gibb Life Fellowship. He established an international reputation for his research into tumor cell signaling, with his major achievements including the discovery of the NRAS oncogene and the finding that oncogenic Ras proteins drive cancer cell proliferation through overactiva-

tion of the MAP kinase-signaling pathway. His research paved the way for four new classes of cancer drugs to enter the clinic, two of which have been approved for use in patient treatment today.

Field-Changing Discoveries Professor Marshall studied Natural Sciences at Cambridge University, followed by a DPhil in cell biology at Oxford. His graduate studies were followed by postdoctoral work at the Imperial Cancer Research Fund (now Cancer Research UK) Lincoln’s Inn Fields Laboratories, and Dana-Farber Cancer Institute.

In 1980, Professor Marshall moved to The Institute of Cancer Research and began studies to identify human cancer genes. This work, in collaboration with his colleague, the late Alan Hall, PhD, resulted in the identification of NRAS, a new human oncogene. Subsequent work from his laboratory showed that NRAS has important roles in leukemia, and others demonstrated the role of NRAS in melanoma.

Following the identification of NRAS, Dr. Marshall concentrated on studying how NRAS and the two other

RAS genes, HRAS and KRAS, act in cancer. His work in the field of cell signaling showed how RAS proteins are involved in transmitting signals from the outside of the cell to the cell nucleus. This work laid the foundation for studies that showed the importance of the BRAF cancer gene in melanoma.

ology Organisation, the Royal Society, and the Academy of Medical Sciences.

He was awarded the Sterling Medal of the University of Pennsylvania (1997), the Novartis Medal of the Biochemical Society (1999), and the Buchanan Medal of the Royal Society (2008).

Professor Marshall was a valued colleague who went out of his way to help others. This willingness to mentor, support, and nurture talent has resulted in a cadre of successful scientists working in cancer research today.

His laboratory is currently studying the cell-signaling mechanisms that allow cancer cells to disseminate in the body. These studies are revealing how RHO family GTPase signaling pathways determine different ways for tumor cells to migrate during invasion.

Innovator and Mentor Professor Marshall’s contributions to science have been recognized by election to the European Molecular Bi-

Both at the Institute of Cancer Research and in the wider scientific community, Professor Marshall was a highly valued colleague who went out of his way to help others. This willingness to mentor, support, and nurture talent has resulted in a cadre of successful scientists working in cancer research today.

His wife Lesley, his three children, and his four grandchildren survive Professor Marshall. n

The ASCO Post | SEPTEMBER 10, 2015

PAGE 98

Book Review

From Small-Town Mexico to Big Pharma, a Look at Opiates for Good and Bad

By Ronald Piana

Bookmark

Title: Dreamland: The True Tale of America’s Opiate Epidemic Author: Sam Quinones Publisher: Bloomsbury Press Publication date: April 21, 2015 Price: $28.00; hardcover, 384 pages

D

espite growing awareness within the oncology community and the emergence of the palliative care discipline, undertreatment of cancer pain in the United States remains a problematic issue. Study results have shown that pain in patients with cancer remains persistently undertreated, and the odds of undertreatment may be twice as high for minority patients. Poor communication skills between oncologists and their patients may be at the heart of the issue in assessing and treating cancer pain.

Patient misperceptions about opioids—such as confusing dependence with addiction—contribute to the problem, as does the rise in illicit drug use. For instance, over the past decade, the highly publicized rise in prescription drug overdoses has led the Drug Enforcement Administration to initiate a rescheduling of hydrocodone combination products from schedule III to schedule II; this step dramatically increased the restrictions on doctors’ prescribing and dispensing practices for these necessary pain-relieving products.

In reaction to the recent reschedul-

ing of hydrocodone, many doctors who treat cancer pain have expressed concern that sensational coverage of illicit sales of opioid analgesics will lead to even tighter restrictions on pain medications. Is our fear of illicit painkilling drugs overblown? Not according to award-winning journalist, Sam Quinones, who has just a penned a book called Dreamland: The True Tale of America’s Opiate Epidemic. With a great reporter’s narrative skill and the storytelling ability of a novelist, the author weaves together tales with hard data on pain medications, making it a compelling read for The ASCO Post audience.

A Revelatory Account Epidemic is a scary word in medicine, signifying an out-of-control spread of disease, and he boldly says that his book is a revelatory account of the corrosive threat facing America.

The title of his book, Dreamland, is taken from a public swimming pool in the blue-collar town of Portsmouth, Ohio, a watery oasis in the heartland, one that over time became an idyllic gathering place for people of all stripes and economic backgrounds.

Then, according to Mr. Quinones, the prescription painkillers arrived, and the town declined. He uses one Matt Schoonover, an all-American boy, as the victim in his allegorical warning: Your town is next. “Across America, thousands of people like Matt Schoonover were dying. Drug overdoses were killing more people every year than car accidents….

Now most of the fatal overdoses were from opiates: prescription painkillers or heroin,” writes Mr. Quinones.

However, you can’t build a nearly 400-page book on victimhood stories about good kids going wrong, falling into the trap of easy-to-access drugs, and bad guys peddling them. To that end, Mr. Quinones tries to balance the personal sagas of drug victims with enough history and facts to make his book interesting for readers looking for a deeper understanding of the drugs people use illicitly to get high and the patients with cancer who need drugs to relieve otherwise unendurable pain.

Pioneers in Pain Control For the readers of The ASCO Post, there are several specific chapters. One, aptly called “The Pain,” gives a pretty good background of the long and difficult history of pain control. He begins,

“Through most of the twentieth century, doctors treating the terminally ill faced attitudes that seemed medieval when it came to opiates.”

To drive home this arresting opening, he tends to drift into brief lapses of hyperbole and some very clunky writing. As the author moves downstream in the chapter, the waters even out, as he gives an interesting background about the nascent years of hospice and the

cacy in pain management. Then he veers into what I would call slipshod nonsense that will drive the pain community mad.

First, he never discusses the highly complex mechanisms that drive pain or the different kinds of pain, from somatic to neuropathic, nor does he talk about opioid receptors and the way these drugs actually assuage pain. Given he’s writing predominantly for a lay audience, that shortcoming may be forgiven.

Through most of the twentieth century, doctors treating the terminally ill faced attitudes that seemed medieval when it came to opiates.

—Sam Quinones

early struggles to bring much needed awareness about unnecessary suffering.

Although the chapters devoted to the emergence of pain management should be the most interesting to the readers of The ASCO Post, they also present territory where the author seems unsteady. For instance, he describes how the World Health Organization’s pioneering cancer chief, Jan Stjernswärd, MD, FRCP, changed pain management worldwide, creating the pain management ladder and finally making the declaration that freedom from pain was a universal human right.

He then segues into one of the true heroes of pain management, Kathleen Foley, MD, giving a fairly good account of her role in pain awareness and treatment. He ends his section on Dr. Foley mentioning that she argues that opiate treatment should not be confined to patients with cancer or postsurgical patients but should be for others with equally debilitating chronic pain. He seemed dangerously close to filling in the blanks for Dr. Foley, as if trying to make his point through her measured discussion on pain management.

A Closer Look at Oxycodone Since much of the brouhaha reported in the lay press about fatal opioid overdoses has centered on oxycodone, Mr. Quinones’ next chapter put Purdue Pharma in his crosshairs. To his credit, he begins by giving a well-balanced discussion of oxycodone’s history and effi-

What cannot be forgiven is his apparent ignorance on addiction. In an effort to vilify oxycodone and the people who make and sell the drug, he launches into a half-baked theory about an advertising campaign that shadily promotes oxycodone as the “Holy Grail that had eluded researchers…a new time-release method that would lead to less addiction.” He continued, “OxyContin theoretically parsed out oxycodone in a way that did not cause the intense highs and lows that cause addiction.”

The causes of psychological addiction to drugs are multifocal. Taking an opioid analgesic does not cause addiction or create an addictive personality. In effect, by vilifying an inanimate substance, the author did to oxycodone what Peter Benchley did to the great white shark.

A Good Storyteller Mr. Quinones is out of his depth when he discusses pain, but he is a very good storyteller who has traveled the country gathering information about the scourge of illicit drug use. However, there is one message that he fails to deliver. Taking drugs for a recreational high comes with risk, sometimes leading to death, but recreational drug users make a choice to take these drugs.

People with advanced cancer do not have the same choice; they need drugs to relieve their suffering. And as Russell Portenoy, MD, was quoted, “I believe in drugs. I think pharmaceuticals are a great gift to humankind.” n

ASCOPost.com | SEPTEMBER 10, 2015

PAGE 99

Announcements

ASCO and UICC Collaborate to Extend Reach of the Journal of Global Oncology

A

SCO and the Union for International Cancer Control (UICC) announced their partnership to expand the reach of the Journal of Global Oncology ( JGO), a new open-access journal that will focus on cancer care, research, and care delivery issues unique to coun-

tries and settings with limited healthcare resources.

It is estimated that today nearly two-thirds of all cancer deaths occur in low- and middle-income countries, and this is forecast to increase to 70% by 2030.1 While some journals publish

special issues and sections focused on global oncology, JGO will be the first peer-­reviewed journal dedicated solely to this area of research.

The partnership between ASCO, which boasts more than 35,000 members around the world, and UICC,

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whose membership represents more than 800 organizations in 155 countries, will extend the reach of JGO to a broad international audience. ASCO and UICC will work together to solicit high-quality original research, secure funding, and promote JGO to their respective networks.

Through this collaboration, ASCO and UICC will meet a growing need for high-quality clinical cancer research in low- and middle-income countries by providing a peer-review platform focused on the challenges faced by researchers and care providers in these countries.

TODAY!

To receive your complimentary print copy of THE ASCO POST, go to www.ascopost.com/subscribe or call the Circulation Department at (631) 935-7651 to see if you qualify.

Get up-to-date information on: n

Highly validated coverage of cancer research & policy news

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News from the National Institutes of Health, the National Cancer Institute, the US Food & Drug Administration and the US Congress

David Kerr, MD, DSc

“ASCO is committed to conquering cancer through research, education, prevention, and delivery of high quality patient care, and this aligns closely with UICC’s efforts to unite the cancer community to reduce the global cancer burden,” said David Kerr, MD, DSc, JGO’s founding Editor-in-Chief. “This partnership will amplify the impact of the Journal of Global Oncology in support of both organizations’ missions and will give a voice to those clinicians who practice cancer medicine in challenging conditions.”

JGO is funded through the Conquer Cancer Foundation of ASCO, with the support of the Doris Duke Charitable Foundation and Novartis Oncology. n Reference 1. International Agency for Research on Cancer, GLOBOCAN, 2012.

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PAGE 100

2015

2015 Oncology Meetings September

2015 Breast Cancer Symposium September 25-27 • San Francisco, CA For more information: http://breastcasym.org European Cancer Congress (ECC 2015) September 25-29 • Vienna, Austria For more information: www.esmo.org/Conferences/ European-Cancer-Congress-2015 17th Annual International Meeting of the Institute of Human Virology September 27-30 • Baltimore, Maryland For more information: http://medschool.umaryland.edu/ ihvmeeting/default.html 5th World Congress on Cancer Therapy September 28-30 • Atlanta, Georgia For more information: http://cancer. global-summit.com/americ

October

Advances in Cancer ImmunotherapyTM October 2 • Nashville, Tennessee For more information: www.sitcancer.org/sitc-meetings/ aci2015/tn Institute for Clinical ImmunoOncology (ICLIO) 1st Annual National Conference October 2 • Philadelphia, Pennsylvania For more information: http://accc-iclio.org/events/iclio-1stannual-national-conference/

5th International Breast Cancer Prevention Symposium October 2-3 • Le Gosier, Guadeloupe, French West Indies For more information: www.purdue.edu/breastcancer/ CAP ’15-The Pathologists’ MeetingTM (College of American Pathologists) October 4-7 • Nashville, Tennessee For more information: www.thepathologistsmeeting.org American College of Surgeons Clinical Congress October 4-8 • Chicago, Illinois For more information: www.facs.org/meetings_events/ future_congress/future 5th Annual Brain Tumor Symposium October 5 • Philadelphia, Pennsylvania For more information: https://cme.jefferson.edu/ content/5th-annual-brain-tumorsymposium 30th Anniversary Annual Critical Issues in Tumor Microenvironment: Angiogenesis, Metastasis, and Immunology October 5-8 • Cambridge, Massachusetts For more information: http://cmeregistration.hms.harvard. edu/events/30th-anniversaryannual-critical-issues-in-tumormicroenvironment-angiogenesismetastasis-and-immuno/ event-summary-567a0dd5664947b09 6f8a5fd33946e52.aspx 20th World Congress on Advances in Oncology and 18th International Symposium on Molecular Medicine October 8-10 • Athens, Greece For more information: www.spandidos-publications.com/ pages/conference Congress of the International Society of Pediatric Oncology October 8-11 • Cape Town, South Africa For more information: http://siop2015.kenes.com

Palliative Care in Oncology Symposium October 9-10 • Boston, MA For more information: http://pallonc.org Genetics and Genomics of Gynecologic Cancers October 15-16 • New York, New York For more information: https://www.mskcc.org/event/ genetics-and-genomics-gynecologic

National Comprehensive Cancer Network (NCCN) 10th Annual Congress: Hematologic Malignancies™ October 16-17 • San Francisco, California For more information: www.nccn.org/professionals/ meetings/hematological/default. aspx

Cutaneous Oncology Symposium 2015 October 23-24 • Fernandina Beach, Florida For more information: https:// ce.mayo.edu/hematology-andoncology/node/3306 4th Annual New Therapeutics in Oncology: The Road to Personalized Medicine October 23-25 • Los Angeles, California For more information: https:// www.regonline.com/builder/ site/?eventid=1727722 13th Annual West Coast Colorectal Cancer Symposium October 23 • Seattle, Washington http://www.swedish.org/for-healthprofessionals/cme/conferences/ colorectal-cancer-symposium 53rd Annual Meeting of the Japan Society of Clinical Oncology (JSCO) October 24-26 • Kyoto, Japan For more information: www.jsco. or.jp/english/index/page/id/73

ASTRO’s 57th Annual Meeting October 18-21 • San Antonio, Texas For more information: www.astro.org/Meetings-andEvents/2015-Annual-Meeting/Index. aspx 2015 International Cancer Education Conference October 21-23 • Tucson, Arizona For more information: http://2015.attendicec.org ACCC 32nd National Oncology Conference October 21-24 • Portland, Oregon For more information: www.accc-cancer.org/meetings/ calendar.asp Lymphoma & Myeloma 2015: An International Congress on Hematologic Malignancies October 22-24 • New York, New York For more information: http://www.imedex.com/lymphomamyeloma-conference/index.asp

ESGO 2015-International Meeting of the European Society of Gynaecological Oncology October 24-27 • Nice, France For more information: http://esgo2015.esgo.org Modern Management of Urologic Cancers: A Multidisciplinary Approach (Memorial Sloan Kettering) October 29-31 • New York, New York For more information: http://www. themerzgroup.com/mskcc/mskccurologic-conference/ Lynn Sage Breast Cancer Symposium October 29-November 1 • Chicago, Illinois For more information: www.lynnsagebreastcancer.org

continued on page 102

Learn more

The ASCO Post | SEPTEMBER 10, 2015

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2015

2015 Oncology Meetings continued from page 100

Caring for the Caregivers X October 30 • Waltham, MA For more information: http://www.massmed.org Continuing-Education-and-Events/ Event-Information/?code=CFC2015

Advanced Breast Cancer Third International Consensus Conference November 5-7 • Lisbon, Portugal For more information: www.abc-lisbon.org

November NRCI Cancer Conference November 1-4 • Liverpool, United Kingdom For more information: http://conference.ncri.org.uk 3rd International Conference on Hematology & Blood Disorders November 2-4 • Atlanta, Georgia For more information: http:// hematology.conferenceseries.com

13th Annual School of Breast Oncology November 5-7 • Atlanta, Georgia For more information: http://www.gotoper.com/ conferences/sobo/meetings/13thAnnual-School-of-Breast-Oncology AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics November 5-9 • Boston, Massachusetts For more information: http:// www.aacr.org/Meetings/Pages/ MeetingDetail

33rd Annual Chemotherapy Foundation Symposium: Innovative Cancer Therapy for Tomorrow® November 4-6 • New York, New York For more information: http://www.chemotherapyfoundationsymposium.org/CMS/ Society for Immunotherapy of Cancer 30th Anniversary Annual Meeting November 4-8 • National Harbor, Maryland For more information: www.sitcancer.org/2015 JADPRO Live at APSHO for Advanced Practitioners in ­Oncology November 5-8, 2015 • Phoenix, Arizona JW Marriott Desert Ridge For more information: jadprolive.com City of Hope Presents: Multidisciplinary Approaches to Cancer Symposium November 5-8 • Las Vegas, Nevada For mor information: https://cme. cityofhope.org/eventinfo_5980.html

14th International Kidney Cancer Symposium November 6-7 • Miami, Florida For more information: http://registeruo.niu.edu/ iebms/wbe/wbe_p1_main. aspx?oc=40&cc=WBE4014167 ESMO Summit Americas 2015– Oncology Updates: From Evidence to Practice November 6-8 • Miami, Florida For more information: www.esmo.org/Conferences/ESMOSummit-Americas-2015 10th Annual New York Lung Cancer Symposium November 7 • New York, New York For more information: http://www.gotoper.com/ conferences/nyl/meetings/10thAnnual-New-York-Lung-CancerSymposium

17th Annual Brain Tumor Update and 6th Annual International Symposium on Long-Term Control of Metastases to the Brain and Spine November 7-8 • Las Vegas, Nevada For more information: http://www. clevelandclinicmeded.com/live/ courses/2015/brainmets15/.aspx?Ev entItemID=52&DetailItemID=196#.

VSZlr_msXpU Best of ASTRO November 13-14 • San Diego, California For more information: www.astro.org/Meetings-andEvents/2015-Best-of-ASTRO/Index. aspx 2015 Oncologic Emergency Medicine Conference November 13-14 • Houston, Texas For more information: http://www.mdanderson.org/ education-and-research/educationand-training/schools-and-programs/ cme-conference-management/ conferences/d114243-2015oncologic-emergency-medicineconference.html 8th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved November 13-16 • Atlanta, Georgia For more information: http:// www.aacr.org/Meetings/ Pages/MeetingDetail. aspx?EventItemID=68#.Vba1EqTbJjq 12th International Conference of the Society for Integrative Oncology November 15-16 • Boston, MA For more information: www. integrativeonc.org/index.php/events Society for Integrative Oncology 12th International Conference November 14-16 • Boston, Massachusetts For more information: http://www.integrativeonc.org/ conference Advances in Cancer ImmunotherapyTM November 18 • San Francisco, California For more information: www.sitcancer.org/sitc-meetings/ aci2015/casf

12th International Congress of the Society for Melanoma Research November 18-21 • San Francisco, California For more information: http://www. melanomacongress.com/ 20th Annual Scientific Meeting of the Society for Neuro-Oncology November 19-22 • San Antonio, Texas For more information: www.soc-neuro-onc.org ESMO Symposium on Immuno-Oncology November 20-21 • Lausanne, Switzerland For more information: www.esmo.org/Conferences/ Immuno-Oncology-2015

December 9th European Colorectal Congress (ECC) December 1-4 • St. Gallen, Switzerland For more information: www.colorectalsurgery.eu Advances in Cancer ImmunotherapyTM December 4 • New Orleans, Louisiana For more information: www.sitcancer.org/sitc-meetings/ aci2015/la 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/

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Letters to the Editor

Unneccessary Complexity in Scientific Terminology?

I

n the highlighted quote in the article titled “Ado-Trastuzumab Emtansine Fails to Replace Standard of Care in First-Line Metastatic Breast Cancer,” which appeared in on page 3 of the July 10 issue of The ASCO Post, a most remarkable sentence was constructed:

I’ve been retired for 15 years and am astounded by the advances made since then, especially the vast array of monoclonal antibody and genetically determined treatments. Astounding complexity! But some things are made more complex than they have to be.

When treatment A demonstrates a “noninferior progression-free survival” compared to treatment B, but [at the same time] is “not found to be superior” to it, one wonders what’s going on. After three or four readings, it dawns: The new treatment is just about the same as

the old, one way or the other.

Please try to cut through the imperious pretense of erudition. “Noninferior,” for example, is a term that should be abandoned. n —Charles P. Duvall MD, MACP Hilton Head Island, South Carolina

T-DM1 and T-DM1 plus pertuzumab demonstrated a noninferior progression-free survival compared to trastuzumab/taxane, but they were not found to be superior to it.

Mayo Clinic Receives $11 Million Grant from NCI to Study NHL Survivorship

NCCN 10th Annual Congress:

Hematologic Malignancies™ October 16 – 17, 2015 | San Francisco Marriott Marquis | San Francisco, CA

M

ayo Clinic has received a 5-year, $11 million grant from the National Cancer Institute (NCI) to study survivorship in patients with non-Hodgkin lymphoma (NHL).

The Lymphoma Epidemiology of Outcomes Cohort Study will enroll 12,000 patients with NHL. The study will follow these patients for longterm prognosis and survivorship.

“With an increasing number of Americans living with NHL, we need to find new and better ways to improve the length and quality of their lives,” said the study’s principal investigator, James Cerhan, MD, PhD, Professor of Epidemiology in the Mayo Clinic College of Medicine and Chair of the Department of Health Sciences ­Research.

According to the NCI, about 70,000 cases of NHL will be diagnosed in the United States in 2015. The incidence of NHL has been increasing since 1950, although, over the past 2 decades, the rate of increase has slowed and survival rates have improved. These trends have led to an increasing number of NHL survivors—most recently estimated at 550,000.

The grant involves collaboration among multiple institutions, including lymphoma experts from Mayo Clinic, the University of Iowa, Emory University/Grady Health System, MD Anderson Cancer Center, the University of Wisconsin, Cornell University, and the University of Miami Health System/Jackson Memorial Hospital. n

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Attend 13 educational sessions featuring the latest advances in hematologic malignancies, plus 3 case-based panel discussions.

Friday, October 16, 2015

Co-Chairs:

4:30 – 6:00 pm Registration, Exhibits, and Refreshments Ranjana H. Advani, MD Stanford Cancer Institute

6:00 – 8:35 pm Educational Sessions Saturday, October 17, 2015

Andrew D. Zelenetz, MD, PhD Memorial Sloan Kettering Cancer Center

7:00 – 8:00 am Registration, Exhibits, and Breakfast 8:00 am – 5:00 pm Educational Sessions

Reserve your seat by Friday, September 11, 2015 to receive the Early Bird Registration rate.

As a benefit of membership, NCCN extends a 50% discount off the registration fee to staff employed at NCCN Member Institutions. Learn more at NCCN.org/hem.

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This activity is supported by educational grants from Actelion Pharmaceuticals US, Inc.; Astellas Scientific and Medical Affairs, Inc.; Celgene Corporation; Novartis Pharmaceuticals Corporation; Seattle Genetics; Spectrum Pharmaceuticals, Inc.; and Takeda Oncology.

Sponsorship and exhibit opportunities available! For more information, e-mail exhibits@nccn.org.

JNCCN-N-0211-0915

The ASCO Post | SEPTEMBER 10, 2015

PAGE 104

In the News Supportive Care

Increased Interest in Simple Injection to Treat Women With Postmastectomy Pain

By Charlotte Bath

A

fter presenting results of a study showing that injecting a standard analgesic combination into trigger points of pain along the inframammary fold relieved postmastectomy pain, Laura J. Esserman, MD, MBA, Director of the Carol Franc Buck Breast Care Center and Co-Leader of the Breast Oncology Program at the University of California, San Francisco, received a lot of phone calls. Some of those phone calls were from fellow physicians interested in possibly using the procedure with their own patients. Many more calls were from women who had read, heard, and/or seen media reports on the study.

“Our initial study was written up in The ASCO Post [February 15, 2014, volume 5, issue 3], and it generated an amazing response, mostly from women (or their families or friends) who were suffering and looking for a way to relieve their pain,” Dr. Esserman said in a recent interview. “We got so many calls from all over the country, from women who were feeling desperate” because of pain persisting weeks or more after their mastectomies were performed and interfering with their ability to wear a bra or to sleep.

That intense interest, along with ad-

ditional positive study results, led Dr. Esserman and colleagues at the University of California, San Francisco, to publish the study and to produce a video detailing how to determine a patient’s trigger points for neuropathic pain and to inject the analgesic. Results from 19 patients were presented at the 2013 San Antonio Breast Cancer Symposium,1 and results from 35 patients are in press (Annals of Surgical Oncology). The video has been posted at cancer.ucsf.edu/ breastcancercenter. Recent renewed interest resulted from an article in The New York Times.2

Postmastectomy Pain Is Complex Postmastectomy pain occurs in 20% to 40% of patients and “is complex,” Dr. Esserman said. The pain can be burning, shooting, or radiating. Much less commonly, patients have intense itching.

“Although patients are often “sore and uncomfortable” following a mastectomy, “usually by 2 weeks, they are quite a bit better. Beyond 2 weeks, you may hear patients say, ‘I can’t wear my bra’ or ‘I have this intense point of pain that is really too much,’” Dr. Esserman added.

“One of the causes of postmastectomy pain is irritation to the nerves that have

I am amazed at how well it has worked and how consistent that has been. The key is to know where these nerves are, and the surgeons should know where they are.

—Laura J. Esserman, MD, MBA

to be cut when you actually remove the breast,” Dr. Esserman said. These nerves “run along the chest wall going forward and backward,” she noted. “So, sometimes you can get this aching across the breast, and it may even reach into the back.”

Nerve pain, Dr. Esserman noted, “is not particularly responsive to narcotics.”

Patients may have “pain that just can’t seem to get better or is not getting better with narcotics and is just persisting.”

Such persistent pain led to the search for a more effective means of treatment.

Step-by-Step Approach The video presents a step-by-step approach to alleviate neuropathic postmastectomy pain, caused by damage to the cutaneous branches of the T4/T5 sensory nerves. The damage likely oc-

curs when the blood vessels (branches off the intercostal vessels)—which are accompanied by nerve branches (off the intercostal nerves)—are cut as the breast is being removed from the chest wall. When vessels bleed, they are then cauterized to control the bleeding. You have to deal with the bleeding, and the nerve branches are quite tiny and very difficult to see,” Dr. Esserman said, but cautery can lead to the formation of painful neuromas.

This approach to postmastectomy pain examines the inframammary fold to identify trigger points, which correlate with the egress of the T4/ T5 cutaneous branches. Since neuropathic pain involves both inflammatory and immune mediators, which sensitize pain receptors, the trigger

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ASCOPost.com | SEPTEMBER 10, 2015

PAGE 105

In the News

points are injected with a combination of a local anesthetic and a steroid—a 2-mL mixture of equal parts 0.5% bupivacaine and 4 mg/mL of dexamethasone. The mixture is massaged in, and for most patients, that is all that is needed, although roughly 20% of the women receiving this treatment will require two injections, and 10% may require three injections.

If the patient does not experience significant reduction in pain soon after the first injection, “it is possible you are not in the right spot,” Dr. Esserman said. In such cases, Dr. Esserman would reassess the patient for a trigger point and try again. “You can try an ultrasound and look for a little neuroma,” she said. “If that doesn’t work, if someone got better, but not that much better, or got better and then a month later got worse, you go in and inject again. If you’ve done it three times and it is not working, you ought to try something different.”

Spreading the Word Dr. Esserman has used this approach with patients whose mastectomies had been performed by her or other physicians. As mentioned in the video, the technique is effective 90% to 95% of the time if trigger points can be identified.

“I am amazed at how well it has worked and how consistent that has been,” Dr. Esserman told The ASCO Post. This high success rate has led her to encourage other physicians to use

Expect Questions or Ask About Postmastectomy Pain

S

ince postmastectomy pain occurs in an estimated 20% to 40% of patients undergoing the procedure, physicians who treat these women can expect questions about the pain and how to deal with it.

However, some patients may be reluctant to ask about it.

“Sometimes, women don’t want to complain to their surgeons,” ­Laura J. Esserman, MD, MBA, said in an interview with The ASCO Post.

“These women may feel like, ‘Hey, I’m cured. I shouldn’t be complaining.’ But people legitimately have problems with pain, so I think that

the technique. “That is why I did this video,” she said.

“The key is to know where these nerves are, and the surgeons should know where they are,” Dr. Esserman said. Then by watching the video, they should be able to successfully give the injections to patients with postmastectomy pain.

“Our pain management colleagues have identified ways in which you can be very successful in alleviating pain, and in fact they aren’t that mysterious.

They are fairly easy to use, and one of the keys is to understand where the nerves are cauterized. These are things that are easy enough for us to learn and to integrate into our own day-to-day practice,” Dr. Esserman said.

Dr. Esserman has received calls about the treatment from interested physicians and sometimes initiates calls to colleagues to encourage them to try the procedure or at least to take a look at the video. “I’ve had some people email me and say that they have done it.

That’s exciting,” she added.

Dr. Esserman also has received calls from patients from other parts of the country who have heard about the procedure and are willing to travel great distances in the hope of becoming free of postmastectomy pain.

“Someone may call me up from New York and say, ‘I want to come out there,’ and I say, ‘Don’t do that. Let’s get your surgeon to take a look at this video.’” In some cases, Dr. ­E sserman refers patients to physicians in their

physicians should also ask patients about pain and make sure that they are not suffering.”

Dr. Esserman is Director of the Carol Franc Buck Breast Care Center and Co-Leader of the Breast Oncology Program at the University of California, San Francisco. She is also co-author of a study finding that injections of a combination of bupivacaine and dexamethasone into trigger points of pain identified along the inframammary fold provided a safe and effective treatment option for neuropathic postmastectomy pain (in press, Annals of Surgical Oncology).

The authors concluded, “This technique should be added to the armamentarium of all surgeons who perform breast surgery.” To help physicians learn about and practice the technique, Dr. Esserman presented a step-by-step

area who are already versed in the technique.

‘Not a Panacea’ However, Dr. Esserman stressed, “This is not a panacea for everything.”

If the pain is not neuropathic or trigger points cannot be identified, “it is not going to help,” she said, and in such cases, she would not go ahead with the treatment. “Occasionally, you have someone where that is not the cause of pain or even if it is, the technique isn’t working for some reason. I don’t have an answer for that.”

The technique has been tried a time or two in women who have pain following lumpectomies, Dr. Esserman added, but “it has not been very productive. I doubt that it is going to be the solution there, and we just have to keep looking” for other means of dealing with that type of postsurgical pain.

For some people with neuropathic pain, “the best thing to do is to try some of the medicines that block neuropathic pain, like Neurontin [gabapentin], and that can be the solution,” Dr. Esserman said. “You can use lidocaine patches.

There are a number of things that people can try, and this should just be one of the tools.”

No More Surgery Than Needed Knowing that surgery and cautery can cause postmastectomy pain “is one of the reasons I am also motivated not to do more surgery than is needed, because some people get per-

approach in a video available at cancer. ucsf.edu/breastcancercenter.

“Health-care providers should routinely screen their patients for the presence of postmastectomy pain syndrome,” the study authors added.

This screening should include asking patients whether they have pain and whether the pain hinders their ability to wear a bra or to sleep on the affected side. A focused examination should be done to ascertain whether there are trigger points of neuropathic pain caused by damage during surgery to the T4 and T5 sensory nerves as they exit the chest wall.

Listen and Look “You have to listen. You have to look. You have to work with people to keep trying to find a solution to the pain,” Dr. Esserman said. “You can try things like lidocaine patches. Pain is

sistent pain,” Dr. Esserman said. And it can be very debilitating.

Working to prevent postmastectomy pain “is part of our ongoing learning and presents an opportunity,” Dr. Esserman said. “Nobody wants to cause pain or problems afterward.

No one is doing it intentionally, but sometimes these things happen, and there is nothing we can do to stop it.

But the more we understand it, the better we understand the source of pain and how to prevent long-term problems, we can even start to think about how to prevent the problems in the first place.”

For example, Dr. Esserman noted, “We are starting to work with our anesthesia team to think about doing thoracic nerve blocks” to avoid causing injury or pain. “If you use the anesthetic first, you may reduce the chance of pain postoperatively, and patients may never experience pain,” she noted. “There are lots of opportunities to continue to improve.

That’s the great thing about medicine.” n

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

References 1. Tang CJ, Eder SE, Lee DJ, Rabow MW: A simple intervention to relieve chronic neuropathic post-mastectomy pain.

2013 San Antonio Breast Cancer Symposium. Abstract P3-10-03. Presented December 12, 2013.

2. Pfaff LG: When pain persists after breast cancer. The New York Times, June 8, 2015.

an important problem, and you have to try to pay attention to it, keep working to try to figure out what is wrong.”

If it does turn out that the pain is caused by damage to the T4 and T5 sensory nerves and trigger points of pain can be identified, an injection of a 2-mL mixture of equal parts 0.5% bupivacaine and 4 mg/mL of dexamethasone can be a safe, simple, and effective option for treating that pain.

As mentioned in the video, the technique is effective 90% to 95% of the time that trigger points can be identified. “I am amazed at how well it has worked and how consistent that has been,” Dr. Esserman stated.

“This is something new that we have figured out that has made a really big difference.” n Disclosure: Dr. Esserman reported no potential conflicts of interest.

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.

IMBRUVICA® (ibrutinib) capsules 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

PAGE 110

The ASCO Post | SEPTEMBER 10, 2015

Announcements

Joxel Garcia, MD, to Direct MD Anderson Moon Shots Program Prevention Efforts

T

he University of Texas MD Anderson Cancer Center has appointed former United States Public Health Service four-star Admiral Joxel Garcia, MD, as the inaugural Executive Director of the Cancer Prevention and Control Platform, part of MD Anderson’s Moon Shots Program. He joined MD Anderson on August 31.

sion Head of Cancer Prevention and Population Sciences and Coleader of the Cancer Prevention and Control Platform. “Cancer prevention and control, practiced at both the individual and population levels, are critical to success in our mission of ending cancer.”

“I see myself as a catalyst to bring MD Anderson’s cancer control and prevention efforts to new heights in a sustainable and ever-growing way,” said Dr. Garcia.

A High-Level, Diverse Career

Joxel Garcia, MD

“Dr. Garcia is an internationally recognized health care leader with proven experience and success in a variety of health care settings,” said Giulio Draetta, MD, PhD, Professor of Genomic Medicine and Molecular & Cellular Oncology and co-leader of the Moon Shots Program. “We’re excited to have someone of his caliber on board and know he will contribute a great deal to the platform and the program overall.”

The Cancer Prevention and Control Platform The Moon Shots Program is an effort to dramatically accelerate the pace of converting scientific discoveries into clinical and population-oriented advances that significantly reduce cancer deaths. The Cancer Prevention and Control Platform implements and disseminates evidence-based, community-focused programs to advance cancer prevention, screening, early detection, and survivorship. The platform focuses on providing policy, education and services to achieve a measurable and sustainable reduction in the cancer burden, especially in the underserved population, for whom cancer and cancer risk factors predominate. This effort focuses on what’s known about diet, exercise, sun protection, tobacco avoidance, and human papillomavirus, among other topics.

“It’s estimated that as much as 50% of the cancer burden in the American population is preventable,” said Ernest Hawk, MD, Vice President and Divi-

Dr. Garcia began his medical career as an obstetrician/gynecologist and then become the commissioner for the State of Connecticut Department of Public Health. After serving as the Deputy Director for the Pan American Health Organization/World Health Organization, he moved into the corporate sector. There, he worked as Senior Vice President and Senior Medical Officer at Maximus Federal Services Inc. President George W. Bush appointed Dr. Garcia as the 13th U.S. Assistant Secretary for Health. At the same time, he was appointed as a four-star Admiral for the United States Public Health Service, and as the U.S. Representative to the World Health Organization. During this time, and as the highest ranking medical and public health official in the U.S., Dr. Garcia led more than 6,220 U.S. Public Service Commissioned Corps officers in the U.S. and in 88 countries for the protection, promotion, and advancement of health.

Following his government service, Dr. Garcia returned to his native Puerto Rico and served as the President and Dean of Medicine for Ponce School of Medicine and Health Sciences. In 2012, he returned to serve as the Director and Chief Medical Officer for the Washington, D.C. Department of Health and as a Founding Partner with Aegis Health Security.

Dr. Garcia has served on several boards of nationally recognized health care organizations, including the U.S. Preventive Services Task Force and the National Dialogue on Cancer. He has received numerous awards and honors including the Secretary of Defense Award for Exceptional Public Service and the U.S. Public Health Service Distinguished Service Award. n

ASCOPost.com | SEPTEMBER 10, 2015

PAGE 111

Clinical Trials

Clinical Trials Actively Recruiting Patients With Thyroid Cancer Compiled by Liz Janetschek

T

he information contained in this Clinical Trials Resource Guide includes actively recruiting clinical studies for patients with thyroid cancer. The trials are investigating novel drug combinations; the effects of radioiodine; blood cell modification; biomarker-targeted therapies; and the effects of surgical intervention. All of the studies are listed on the National Institutes of Health website at ClinicalTrials.gov.

PHASE I Study Type: Phase I/Interventional/Single Group Assignment Study Title: A Phase 1 Study of Dabrafenib in Combination With Lapatinib in BRAF Mutant Thyroid Cancer Study Sponsor and Collaborators: National Cancer Institute Purpose: To study the side effects and best dose of lapatinib ditosylate when given together with dabrafenib in treating patients with thyroid cancer that cannot be removed by surgery and has not responded to previous ­treatment Primary Outcome Measures: Maximum tolerated dose of lapatinib ditosylate, in combination with the established dose of dabrafenib, defined as the highest dose at which not more than 1/6 of the patients experience dose limiting toxicity [Time Frame: First 42 days of treatment] Principal Investigator: Eric Sherman, MD, Memorial Sloan Kettering Cancer Center; 646-888-4234, shermane@mskcc.org ClinicalTrials.gov Identifier: NCT01947023 Study Type: Phase I/Interventional/Single Group Assignment Study Title: Evaluation of Thyroid Stunning From a Diagnostic Dose of I-123

Study Sponsor and Collaborators: University of Colorado, Denver Purpose: To study if the small dose of radioiodine that is used for the dosimetry study on patients with differentiated thyroid cancer may stun the cancer cells and make the thyroid cancer treatment less effective.

Primary Outcome Measures: Difference in uptake of I-123 in the thyroid remnant in the neck in the two imaging studies. [Time Frame: 11 days] Principal Investigator: Jennifer Kwak, MD, University of Colorado, Denver; contact Michelle Carr, CCRP, 720-848-6137, michelle.I2.carr@ ucdenver.edu ClinicalTrials.gov Identifier: NCT02278198

PHASE I/II Study Type: Phase I/II/Interventional/Single Group Assignment Study Title: Administering Peripheral Blood Lymphocytes Transduced With a Murine T-Cell Receptor Recognizing Human Thyroglobulin to People With Thyroglobulin Expressing Thyroid Cancer Study Sponsor and Collaborators: National Cancer Institute, National Institutes of Health Clinical Center Purpose: To study an experimental therapy for treating patient with metastatic thyroid cancer that involves taking white blood cells from the patient, growing them in the laboratory in large numbers, genetically modifying these specific cells with a type of virus (retrovirus) to attack only the tumor cells, and then giving the cells back to the patient. In this protocol, the patient’s white blood cells are being modified with a retrovirus that has the gene for antithyroglobulin incorporated.

Primary Outcome Measures: Determine a safe dose of administration and determine if this approach will result in an objective tumor regression.

[Time Frame: Approximately 4 years] Principal Investigator: James C.

Yang, MD, National Cancer Institute; 301-496-1574, jamesyang@mail.nih. gov ClinicalTrials.gov Identifier: NCT02390739

PHASE II Study Type: Phase II/Interventional/Crossover Assignment Study Title: A Randomized Phase 2 Study of Single Agent Dabrafenib (BRAFi) vs. Combination Regimen Dabrafenib (BRAFi) and Trametinib (MEKi) in Patients With BRAF Mutated Thyroid Carcinoma Study Sponsor and Collaborators: National Comprehensive Cancer Network, Ohio State University Comprehensive Cancer Center Purpose: To study how well dabrafenib works with or without trametinib in treating patients with recurrent thyroid cancer.

Primary Outcome Measures: Overall objective response rate, defined as the proportion of patients who have a minor response, partial response, or complete response assessed according to RECIST. [Time Frame: up to 24 weeks] Principal Investigator: Manisha Shah, MD, The Ohio State University Comprehensive Cancer Center; 614293-4680, manisha.shah@osumc.edu ClinicalTrials.gov Identifier: NCT01723202 Study Type: Phase II/Interventional/Parallel Assignment Study Title: Central Neck Dissection in Patients With Clinical Node Negative Thyroid Cancer Study Sponsor and Collaborators: University of Wisconsin (Madison), National Cancer Institute, National Institutes of Health Purpose: To study how well thyroid gland removal with or without central lymph node dissection works in treating patients with thyroid cancer or suspected thyroid cancer that has not

spread to the lymph nodes.

Primary Outcome Measures: Postoperative serum calcium level, postoperative PTH, total calcium consumption, average episodes of hypocalcemia (and symptom severity), and requirement for calcium/calcitriol [Time Frame: varies; see clinicaltrials.gov for more information] Principal Investigator: Rebecca Sippel, MD, University of Wisconsin Hospital and Clinics; sippel@surgery. wisc.edu ClinicalTrials.gov Identifier: NCT02138214 Study Type: Phase II/Interventional/Single Group Assignment Study Title: A Phase 2 Study of Trametinib in Combination With Radioiodine (RAI) for RAS Mutant or RAS/RAF Wild-Type, RAI-Refractory Recurrent and/or Metastatic Thyroid Cancers Study Sponsor and Collaborators: National Cancer Institute Purpose: To study how well trametinib works in increasing tumoral iodine incorporation in patients with thyroid cancer that has come back or spread to another place in the body.

Primary Outcome Measures: Iodine incorporation in thyroid cancer metastases to a predicted lesional absorbed radiation dose equal to or exceeding 2,000 cGy with the administration of =< 300 mCi RAI (Cohort B), Progression free survival (Cohort A), Proportion of patients alive following treatment with trametinib and I-124 (Cohort A) [Time Frame: At 6 months] Principal Investigator: Alan Ho, MD, Memorial Sloan Kettering Cancer Center; 646-888-4235; hoa@mskcc.org ClinicalTrials.gov Identifier: NCT02152995 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.

Visit The ASCO Post website at ASCOPost.com

In metastatic breast cancer patients whose disease is resistant to an anthracycline, a taxane, and capecitabine

Consider

IXEMPRA® (ixabepilone) monotherapy1

Indication ◗ IXEMPRA® (ixabepilone) is indicated as monotherapy for the treatment of metastatic or locally advanced breast cancer in patients whose tumors are resistant or refractory to anthracyclines, taxanes, and capecitabine

◗ Caution should be used when using IXEMPRA as monotherapy in patients with AST or ALT >5 x ULN. Use of IXEMPRA in patients with AST or ALT >10 x ULN or bilirubin >3 x ULN is not recommended

Warning: Toxicity in hepatic impairment1

◗ With monotherapy, grade 4 neutropenia, febrile neutropenia, and serious adverse reactions were more frequent in patients with hepatic impairment

◗ IXEMPRA in combination with capecitabine is contraindicated in patients with AST or ALT >2.5 x ULN or bilirubin >1 x ULN due to increased risk of toxicity and neutropenia-related death ◗ In combination with capecitabine, the overall frequency of grade 3/4 adverse reactions, febrile neutropenia, serious adverse reactions, and toxicity-related deaths was greater in patients with hepatic impairment

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

Important Safety Information Warning: Toxicity in hepatic impairment Hypersensitivity reaction ® ◗ Premedicate with an H1 and an H2 antagonist approximately ◗ IXEMPRA (ixabepilone) in combination with 1 hour before IXEMPRA (ixabepilone) infusion and observe for capecitabine is contraindicated in patients with hypersensitivity reactions (eg, flushing, rash, dyspnea, AST or ALT >2.5 x ULN or bilirubin >1 x ULN due and bronchospasm) to increased risk of toxicity and neutropenia◗ In case of severe hypersensitivity reactions, infusion of related death IXEMPRA should be stopped and aggressive supportive ◗ In combination with capecitabine, the overall frequency of treatment (eg, epinephrine, corticosteroids) started grade 3/4 adverse reactions, febrile neutropenia, serious ◗ Patients who experience a hypersensitivity reaction in one cycle adverse reactions, and toxicity-related deaths was greater in of IXEMPRA must be premedicated in subsequent cycles with patients with hepatic impairment a corticosteroid in addition to the H1 and H2 antagonists, and ◗ Caution should be used when using IXEMPRA as extension of the infusion time should be considered monotherapy in patients with AST or ALT >5 x ULN. Use of IXEMPRA in patients with AST or ALT >10 x ULN or bilirubin Pregnancy >3 x ULN is not recommended ◗ Women should be advised not to become pregnant when ◗ With monotherapy, grade 4 neutropenia, febrile neutropenia, taking IXEMPRA. If this drug is used during pregnancy and serious adverse reactions were more frequent in patients or the patient becomes pregnant, the patient should be with hepatic impairment apprised of the potential hazard to the fetus Contraindications Cardiac adverse reactions ◗ IXEMPRA is contraindicated in patients: ◗ Caution should be exercised in patients with a history of • with a known history of a severe (CTC grade 3/4) cardiac disease. Discontinuation of IXEMPRA should be hypersensitivity reaction to agents containing considered in patients who develop cardiac ischemia or Cremophor® EL or its derivatives such as impaired cardiac function due to reports of cardiovascular polyoxyethylated castor oil adverse reactions (eg, myocardial ischemia, supraventricular • who have a baseline neutrophil count <1500 cells/mm3 arrhythmia, and ventricular dysfunction). The frequency or a platelet count <100,000 cells/mm3 of cardiac adverse reactions (myocardial ischemia and Peripheral neuropathy ventricular dysfunction) was higher in the IXEMPRA in combination with capecitabine (1.9%) than in the capecitabine ◗ Peripheral neuropathy was common. Patients treated with alone (0.3%) treatment group IXEMPRA should be monitored for symptoms of neuropathy, such as burning sensation, hyperesthesia, hypoesthesia, Potential for cognitive impairment from excipients paresthesia, discomfort, or neuropathic pain ◗ IXEMPRA contains dehydrated alcohol USP. Consideration ◗ Neuropathy occurred early during treatment; ~75% of should be given to the possibility of central nervous system new onset or worsening neuropathy occurred during the and other effects of alcohol first 3 cycles. Patients experiencing new or worsening Adverse reactions peripheral neuropathy may require changes in the dose or ◗ The most common adverse reactions (≥20%) reported discontinuation of IXEMPRA by patients receiving IXEMPRA were peripheral sensory ◗ Neuropathy was the most frequent cause of treatment neuropathy, fatigue/asthenia, myalgia/arthralgia, alopecia, discontinuation due to drug toxicity. Caution should be used nausea, vomiting, stomatitis/mucositis, diarrhea, and when treating patients with diabetes mellitus or preexisting musculoskeletal pain. The following additional events peripheral neuropathy occurred in ≥20% in combination treatment: palmar-plantar Myelosuppression erythrodysesthesia (hand-foot) syndrome, anorexia, abdominal ◗ Myelosuppression is dose-dependent and primarily pain, nail disorder, and constipation. Drug-associated manifested as neutropenia. hematologic abnormalities (>40%) include neutropenia, ◗ Patients should be monitored for myelosuppression; frequent leukopenia, anemia, and thrombocytopenia peripheral blood cell counts are recommended for all patients receiving IXEMPRA Cremophor is a registered trademark of BASF AG. ◗ Patients who experience severe neutropenia or AST = aspartate aminotransferase thrombocytopenia should have their dose reduced. NeutropeniaALT = alanine aminotransferase related deaths occurred in 1.9% of 414 patients with normal ULN = upper limit of normal hepatic function or mild hepatic impairment treated with CTC = common terminology criteria IXEMPRA in combination with capecitabine. Neutropeniarelated death occurred in 0.4% of 240 patients with IXEMPRA as monotherapy Please see brief summary of Full Prescribing Information on adjacent pages.

Reference: 1. IXEMPRA (ixabepilone) Prescribing Information; 2011.

For additional information, visit www.IXEMPRA.com.

Ixempra® is a registered trademark of R-Pharm US Operating LLC, a wholly owned subsidiary of R-Pharm US LLC. © 2015, R-PHARM US. All rights reserved. IXE-00009 9/15

IXEMPRA® Kit (ixabepilone) for Injection, for intravenous infusion only Brief Summary of Prescribing Information. For complete prescribing information consult official package insert.

WARNING: TOXICITY IN HEPATIC IMPAIRMENT IXEMPRA in combination with capecitabine is contraindicated in patients with AST or ALT >2.5 x ULN or bilirubin >1 x ULN due to increased risk of toxicity and neutropenia-related death [see Contraindications and Warnings and Precautions].

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

IXEMPRA is indicated as monotherapy for the treatment of metastatic or locally advanced breast cancer in patients whose tumors are resistant or refractory to anthracyclines, taxanes, and capecitabine.

CONTRAINDICATIONS IXEMPRA is contraindicated in patients with a history of a severe (CTC grade 3/4) hypersensitivity reaction to agents containing Cremophor® EL or its derivatives (eg, polyoxyethylated castor oil) [see Warnings and Precautions].

IXEMPRA is contraindicated in patients who have a neutrophil count <1500 cells/mm3 or a platelet count <100,000 cells/mm3 [see Warnings and Precautions].

IXEMPRA in combination with capecitabine is contraindicated in patients with AST or ALT >2.5 x ULN or bilirubin >1 x ULN [see Boxed Warning and Warnings and Precautions].

WARNINGS AND PRECAUTIONS Peripheral Neuropathy Peripheral neuropathy was common (see Table 1). Patients treated with IXEMPRA should be monitored for symptoms of neuropathy, such as burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, or neuropathic pain. Neuropathy occurred early during treatment; ~75% of new onset or worsening neuropathy occurred during the first 3 cycles. Patients experiencing new or worsening symptoms may require a reduction or delay in the dose of IXEMPRA [see Dosage and Administration (2.2) in Full Prescribing Information]. In clinical studies, peripheral neuropathy was managed through dose reductions, dose delays, and treatment discontinuation. Neuropathy was the most frequent cause of treatment discontinuation due to drug toxicity. In Studies 046 and 081, 80% and 87%, respectively, of patients with peripheral neuropathy who received IXEMPRA had improvement or no worsening of their neuropathy following dose reduction. For patients with grade 3/4 neuropathy in Studies 046 and 081, 76% and 79%, respectively, had documented improvement to baseline or grade 1, twelve weeks after onset.

Table 1: Treatment-related Peripheral Neuropathy

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

IXEMPRA with capecitabine Study 046

IXEMPRA as monotherapy Study 081

67% 23% 21% 4

63% 14% 6% 4

6.0 weeks

4.6 weeks

Sensory and motor neuropathy combined.

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

A pooled analysis of 1540 cancer patients treated with IXEMPRA indicated that patients with diabetes mellitus or preexisting peripheral neuropathy may be at increased risk of severe neuropathy. Prior therapy with neurotoxic chemotherapy agents did not predict the development of neuropathy. Patients with moderate to severe neuropathy (grade 2 or greater) were excluded from studies with IXEMPRA. Caution should be used when treating patients with diabetes mellitus or preexisting peripheral neuropathy.

Myelosuppression Myelosuppression is dose-dependent and primarily manifested as neutropenia. In clinical studies, grade 4 neutropenia (<500 cells/mm3) occurred in 36% of patients treated with IXEMPRA in combination with capecitabine and 23% of patients treated with IXEMPRA monotherapy. Febrile neutropenia and infection with neutropenia were reported in 5% and 6% of patients treated with IXEMPRA in combination with capecitabine, respectively, and 3% and 5% of patients treated with IXEMPRA as monotherapy, respectively. Neutropenia-related death occurred in 1.9% of 414 patients with normal hepatic function or mild hepatic impairment treated with IXEMPRA in combination with capecitabine. The rate of neutropenia-related deaths was higher (29%, 5 out of 17) in patients with AST or ALT >2.5 x ULN or bilirubin >1.5 x ULN [see Boxed Warning, Contraindications, and Warnings and Precautions].

Neutropenia-related death occurred in 0.4% of 240 patients treated with IXEMPRA as monotherapy. No neutropenia-related deaths were reported in 24 patients with AST or ALT >2.5 x ULN or bilirubin >1.5 x ULN treated with IXEMPRA monotherapy. IXEMPRA must not be administered to patients with a neutrophil count <1500 cells/mm3. To monitor for myelosuppression, frequent peripheral blood cell counts are recommended for all patients receiving IXEMPRA. Patients who experience severe neutropenia or thrombocytopenia should have their dose reduced [see Dosage and Administration (2.2) in Full Prescribing Information].

Hepatic Impairment Patients with baseline AST or ALT >2.5 x ULN or bilirubin >1.5 x ULN experienced greater toxicity than patients with baseline AST or ALT ≤2.5 x ULN or bilirubin ≤1.5 x ULN when treated with IXEMPRA at 40 mg/m2 in combination with capecitabine or as monotherapy in breast cancer studies. In combination with capecitabine, the overall frequency of grade 3/4 adverse reactions, febrile neutropenia, serious adverse reactions, and toxicity-related deaths was greater [see Warnings and Precautions]. With monotherapy, grade 4 neutropenia, febrile neutropenia, and serious adverse reactions were more frequent. The safety and pharmacokinetics of IXEMPRA as monotherapy were evaluated in a dose escalation study in 56 patients with varying degrees of hepatic impairment. Exposure was increased in patients with elevated AST or bilirubin [see Use in Specific Populations].

IXEMPRA in combination with capecitabine is contraindicated in patients with AST or ALT >2.5 x ULN or bilirubin >1 x ULN due to increased risk of toxicity- and neutropenia-related death [see Boxed Warning, Contraindications, and Warnings and Precautions].

Patients who are treated with IXEMPRA as monotherapy should receive a reduced dose depending on the degree of hepatic impairment [see Dosage and Administration (2.2) in Full Prescribing Information]. Use in patients with AST or ALT >10 x ULN or bilirubin >3 x ULN is not recommended. Limited data are available for patients with AST or ALT >5 x ULN. Caution should be used when treating these patients [see Dosage and Administration (2.2) in Full Prescribing Information].

Hypersensitivity Reactions Patients with a history of a severe hypersensitivity reaction to agents containing Cremophor® EL or its derivatives (eg, polyoxyethylated castor oil) should not be treated with IXEMPRA. All patients should be premedicated with an H1 and an H2 antagonist approximately 1 hour before IXEMPRA infusion and be observed for hypersensitivity reactions (eg, flushing, rash, dyspnea, and bronchospasm). In case of severe hypersensitivity reactions, infusion of IXEMPRA should be stopped and aggressive supportive treatment (eg, epinephrine, corticosteroids) started. Of the 1323 patients treated with IXEMPRA in clinical studies, 9 patients (1%) had experienced severe hypersensitivity reactions (including anaphylaxis). Three of the 9 patients were able to be retreated. Patients who experience a hypersensitivity reaction in one cycle of IXEMPRA must be premedicated in subsequent cycles with a corticosteroid in addition to the H1 and H2 antagonists, and extension of the infusion time should be considered [see Dosage and Administration (2.3) in Full Prescribing Information and Contraindications].

Pregnancy Pregnancy Category D. IXEMPRA may cause fetal harm when administered to pregnant women. There are no adequate and well-controlled studies with IXEMPRA in pregnant women. Women should be advised not to become pregnant when taking IXEMPRA. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

Ixabepilone was studied for effects on embryo-fetal development in pregnant rats and rabbits given IV doses of 0.02, 0.08, and 0.3 mg/kg/day and 0.01, 0.03, 0.11, and 0.3 mg/kg/day, respectively. There were no teratogenic effects. In rats, an increase in resorptions and post-implantation loss and a decrease in the number of live fetuses and fetal weight was observed at the maternally

toxic dose of 0.3 mg/kg/day (approximately one-tenth the human clinical exposure based on AUC). Abnormalities included a reduced ossification of caudal vertebrae, sternebrae, and metacarpals. In rabbits, ixabepilone caused maternal toxicity (death) and embryo-fetal toxicity (resorptions) at 0.3 mg/kg/day (approximately one-tenth the human clinical dose based on body surface area). No fetuses were available at this dose for evaluation.

Cardiac Adverse Reactions The frequency of cardiac adverse reactions (myocardial ischemia and ventricular dysfunction) was higher in the IXEMPRA (ixabepilone) in combination with capecitabine (1.9%) than in the capecitabine alone (0.3%) treatment group. Supraventricular arrhythmias were observed in the combination arm (0.5%) and not in the capecitabine alone arm. Caution should be exercised in patients with a history of cardiac disease. Discontinuation of IXEMPRA should be considered in patients who develop cardiac ischemia or impaired cardiac function.

Potential for Cognitive Impairment from Excipients Since IXEMPRA contains dehydrated alcohol USP, consideration should be given to the possibility of central nervous system and other effects of alcohol [see Description (11) in Full Prescribing Information].

ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections.

• Peripheral neuropathy [see Warnings and Precautions] • Myelosuppression [see Warnings and Precautions] • Hypersensitivity reactions [see Warnings and Precautions] Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in clinical practice.

Unless otherwise specified, assessment of adverse reactions is based on one randomized study (Study 046) and one single-arm study (Study 081). In Study 046, 369 patients with metastatic breast cancer were treated with IXEMPRA 40 mg/m2 administered intravenously over 3 hours every 21 days, combined with capecitabine 1000 mg/m2 twice daily for 2 weeks followed by a 1-week rest period. Patients treated with capecitabine as monotherapy (n=368) in this study received 1250 mg/m2 twice daily for 2 weeks every 21 days. In Study 081, 126 patients with metastatic or locally advanced breast cancer were treated with IXEMPRA 40 mg/m2 administered intravenously over 3 hours every 3 weeks.

The most common adverse reactions (≥20%) reported by patients receiving IXEMPRA were peripheral sensory neuropathy, fatigue/asthenia, myalgia/arthralgia, alopecia, nausea, vomiting, stomatitis/mucositis, diarrhea, and musculoskeletal pain. The following additional reactions occurred in ≥20% in combination treatment: palmar-plantar erythrodysesthesia (hand-foot) syndrome, anorexia, abdominal pain, nail disorder, and constipation. The most common hematologic abnormalities (>40%) include neutropenia, leukopenia, anemia, and thrombocytopenia.

Table 2 presents nonhematologic adverse reactions reported in 5% or more of patients. Hematologic abnormalities are presented separately in Table 3.

Table 2:

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

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

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

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

4

0

3

0

6

0

5

4c

1

1d

3

3d

2

1d

0

0

5

1d

34 5

3d 2

15 2

1d <1d

19 2

2d 1d

9

<1d

2

0

5

0

65 16 8 12 8

21 5d <1d 0 1d

16 <1 3 4 5

0 0 0 0 1d

62 10 11 6 7

14 1d 0 0 0

5

0

4

<1d

4

0

5

0

2

0

6

0

7 6

1 0

4 2

1 0

9 2

1d 0

53 39 31 44 22 24 7

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

40 24 20 39 6 14 8

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

42 29 29 22 16 13 6

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

31 17 24 64

0 1d 2d 18d

3 7 10 63

0 0 <1d 17d

48 9 9 8

0 2d 0 2d

5 5 11

0 <1d 0

2 3 14

0 0 0

6 2 2

1d 0 0

39 23

8d 2d

5 5

<1d 0

49 20

8d 3d

60 8 10 9 4

16 0 1d 1d 1d

29 5 4 2 <1

4 <1d 0 0 0

56 9 8 8 5

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

Table 2: (Continued)

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

System Organ Classa/ Preferred Term

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

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

a

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

Table 3:

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

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

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

36 16 2 3

9 5 4 2

2 1 1 2

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

23 13 2 2

a

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

The following serious adverse reactions were also reported in 1323 patients treated with IXEMPRA as monotherapy or in combination with other therapies in Phase 2 and 3 studies.

Infections and Infestations: sepsis, pneumonia, infection, neutropenic infection, urinary tract infection, bacterial infection, enterocolitis, laryngitis, lower respiratory tract infection Blood and Lymphatic System Disorders: coagulopathy, lymphopenia Metabolism and Nutrition Disorders: hyponatremia, metabolic acidosis, hypokalemia, hypovolemia Nervous System Disorders: cognitive disorder, syncope, cerebral hemorrhage, abnormal coordination, lethargy Cardiac Disorders: myocardial infarction, supraventricular arrhythmia, left ventricular dysfunction, angina pectoris, atrial flutter, cardiomyopathy, myocardial ischemia Vascular Disorders: hypotension, thrombosis, embolism, hemorrhage, hypovolemic shock, vasculitis Respiratory, Thoracic, and Mediastinal Disorders: pneumonitis, hypoxia, respiratory failure, acute pulmonary edema, dysphonia, pharyngolaryngeal pain Gastrointestinal Disorders: ileus, colitis, impaired gastric emptying, esophagitis, dysphagia, gastritis, gastrointestinal hemorrhage Hepatobiliary Disorders: acute hepatic failure, jaundice Skin and Subcutaneous Tissue Disorders: erythema multiforme Musculoskeletal, Connective Tissue, and Bone Disorders: muscular weakness, muscle spasms, trismus Renal and Urinary Disorders: nephrolithiasis, renal failure General Disorders and Administration Site Conditions: chills Investigations: increased transaminases, increased blood alkaline phosphatase, increased gamma-glutamyltransferase Postmarketing Experience Radiation recall has been reported during postmarketing use of IXEMPRA. Because this reaction was reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure.

DRUG INTERACTIONS Effect of Other Drugs on Ixabepilone Drugs That May Increase Ixabepilone Plasma Concentrations CYP3A4 Inhibitors: Coadministration of ixabepilone with ketoconazole, a potent CYP3A4 inhibitor, increased ixabepilone AUC by 79% compared to ixabepilone treatment alone. If alternative treatment cannot be administered, a dose adjustment should be considered.

The effect of mild or moderate inhibitors (eg, erythromycin, fluconazole, or verapamil) on exposure to ixabepilone has not been studied.

Therefore, caution should be used when administering mild or moderate CYP3A4 inhibitors during treatment with IXEMPRA, and alternative therapeutic agents that do not inhibit CYP3A4 should be considered. Patients receiving CYP3A4 inhibitors during treatment with IXEMPRA should be monitored closely for acute toxicities (eg, frequent monitoring of peripheral blood counts between cycles of IXEMPRA) [see Dosage and Administration (2.2) in Full Prescribing Information].

Drugs That May Decrease Ixabepilone Plasma Concentrations CYP3A4 Inducers: IXEMPRA is a CYP3A4 substrate. Coadministration of IXEMPRA with rifampin, a potent CYP3A4 inducer, decreased ixabepilone AUC by 43% compared to IXEMPRA treatment alone. Other strong CYP3A4 inducers (eg, dexamethasone, phenytoin, carbamazepine, rifabutin, and phenobarbital) may also decrease ixabepilone concentrations leading to subtherapeutic levels. Therefore, therapeutic agents with low enzyme induction potential should be considered for coadministration with IXEMPRA. St. John’s Wort may decrease ixabepilone plasma concentrations unpredictably and should be avoided. If patients must be coadministrated a strong CYP3A4 inducer, a gradual dose adjustment may be considered [see Dosage and Administration (2.2) in Full Prescribing Information].

Effect of Ixabepilone on Other Drugs Ixabepilone does not inhibit CYP enzymes at relevant clinical concentrations and is not expected to alter the plasma concentrations of other drugs [see Clinical Pharmacology (12.3) in Full Prescribing Information].

Capecitabine In patients with cancer who received ixabepilone (40 mg/m2) in combination with capecitabine (1000 mg/m2), ixabepilone Cmax decreased by 19%, capecitabine Cmax decreased by 27%, and 5-fluorouracil AUC increased by 14%, as compared to ixabepilone or capecitabine administered separately. The interaction is not clinically significant given that the combination treatment is supported by efficacy data.

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category D [see Warnings and Precautions].

Nursing Mothers It is not known whether ixabepilone is excreted into human milk. Following intravenous administration of radiolabeled ixabepilone to rats on days 7 to 9 postpartum, concentrations of radioactivity in milk were comparable with those in plasma and declined in parallel with the plasma concentrations. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from ixabepilone, a decision must be made whether to discontinue nursing or to discontinue IXEMPRA taking into account the importance of the drug to the mother.

Pediatric Use The effectiveness of IXEMPRA (ixabepilone) in pediatric patients has not been established. IXEMPRA was evaluated in one Phase 1 and one Phase 2 trial. The pediatric patients had a safety profile consistent with that seen in adults, and no new safety signals were identified.

In the Phase 1 open-label, dose-finding trial, the safety of IXEMPRA was evaluated in 19 pediatric patients with advanced or refractory solid tumors and 2 with acute leukemias. IXEMPRA was administered as a one-hour IV infusion daily for the first five days of a 21-day cycle at one of 5 dose levels, ranging from 3 to 10 mg/m2. Among the 21 patients, 12 ranged in age from 2 to 12 years and 9 ranged from 13 to 18 years. The maximum tolerated dose was 8 mg/m2 IV daily for 5 days every 21 days. No significant activity was observed. The pharmacokinetics of ixabepilone were characterized by population pharmacokinetic analysis of data for 16 patients from this trial, who were aged 2 to 18 years (median 12 years). The pharmacokinetic parameters of ixabepilone in these pediatric patients were compared to the corresponding parameters of 130 adult patients enrolled in clinical trials using the same dosing schedule. The median BSA normalized clearance of ixabepilone in pediatric patients (17 L/h/m2) was similar to that in adult patients (20 L/h/m2).

In the Phase 2 trial of 59 patients with advanced or refractory solid tumors, 28 ranged in age from 3 to 12 years and 19 ranged in age from 13 to 18 years. Twelve additional patients over the age of 18 were treated in this trial. IXEMPRA was administered at a dose of 8 mg/m2 IV daily for 5 days every 21 days. This trial was terminated early due to lack of efficacy.

Geriatric Use Clinical studies of IXEMPRA did not include sufficient numbers of subjects aged sixty-five and over to determine whether they respond differently from younger subjects.

Forty-five of 431 patients treated with IXEMPRA in combination with capecitabine were ≥65 years of age and 3 patients were ≥75. Overall, the incidence of grade 3/4 adverse reactions was higher in patients ≥65 years of age versus those <65 years of age (82% versus 68%) including grade 3/4 stomatitis (9% versus 1%), diarrhea (9% versus 6%), palmar-plantar erythrodysesthesia syndrome (27% versus 20%), peripheral neuropathy (24% versus 22%), febrile neutropenia (9% versus 3%), fatigue (16% versus 12%), and asthenia (11% versus 6%). Toxicity-related deaths occurred in 2 (4.7%) of 43 patients ≥65 years with normal baseline hepatic function or mild impairment.

Thirty-two of 240 breast cancer patients treated with IXEMPRA as monotherapy were ≥65 years of age and 6 patients were ≥75. No overall differences in safety were observed in these patients compared to those <65 years of age.

Hepatic Impairment IXEMPRA was evaluated in 56 patients with mild to severe hepatic impairment defined by bilirubin levels and AST levels. Compared to patients with normal hepatic function (n=17), the area under the curve (AUC0-infinity) of ixabepilone increased by: • 22% in patients with a) bilirubin >1 – 1.5 x ULN or b) AST >ULN but bilirubin <1.5 x ULN; • 30% in patients with bilirubin >1.5 – 3 x ULN and any AST level; and • 81% in patients with bilirubin >3 x ULN and any AST level.

Doses of 10 and 20 mg/m2 as monotherapy were tolerated in 17 patients with severe hepatic impairment (bilirubin >3 x ULN).

IXEMPRA in combination with capecitabine must not be given to patients with AST or ALT >2.5 x ULN or bilirubin >1 x ULN [see Boxed Warning, Contraindications, and Warnings and Precautions]. Dose reduction is recommended when administering IXEMPRA as monotherapy to patients with hepatic impairment [see Dosage and Administration (2.3) in Full Prescribing Information]. Because there is a need for dosage adjustment based upon hepatic function, assessment of hepatic function is recommended before initiation of IXEMPRA and periodically thereafter.

Renal Impairment Ixabepilone is minimally excreted via the kidney. No controlled pharmacokinetic studies were conducted with IXEMPRA in patients with renal impairment. IXEMPRA in combination with capecitabine has not been evaluated in patients with calculated creatinine clearance of <50 mL/min. IXEMPRA as monotherapy has not been evaluated in patients with creatinine >1.5 times ULN. In a population pharmacokinetic analysis of IXEMPRA as monotherapy, there was no meaningful effect of mild and moderate renal insufficiency (CrCL >30 mL/min) on the pharmacokinetics of ixabepilone.

OVERDOSAGE Experience with overdose of IXEMPRA is limited to isolated cases. The adverse reactions reported in these cases included peripheral neuropathy, fatigue, musculoskeletal pain/myalgia, and gastrointestinal symptoms (nausea, anorexia, diarrhea, abdominal pain, stomatitis). The highest dose mistakenly received was 100 mg/m2 (total dose 185 mg).

There is no known antidote for overdosage of IXEMPRA. In case of overdosage, the patient should be closely monitored and supportive treatment should be administered. Management of overdose should include supportive medical interventions to treat the presenting clinical manifestations.

NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies with ixabepilone have not been conducted. Ixabepilone did not induce mutations in the microbial mutagenesis (Ames) assay and was not clastogenic in an in vitro cytogenetic assay using primary human lymphocytes. Ixabepilone was clastogenic (induction of micronuclei) in the in vivo rat micronucleus assay at doses ≥0.625 mg/kg/day.

There were no effects on male or female rat mating or fertility at doses up to 0.2 mg/kg/day in both males and females (approximately one-fifteenth the expected human clinical exposure based on AUC). The effect of ixabepilone on human fertility is unknown. However, when rats were given an IV infusion of ixabepilone during breeding and through the first 7 days of gestation, a significant increase in resorptions and pre- and post-implantation loss and a decrease in the number of corpora lutea was observed at 0.2 mg/kg/day.

Testicular atrophy or degeneration was observed in 6-month rat and 9-month dog studies when ixabepilone was given every 21 days at intravenous doses of 6.7 mg/kg (40 mg/m2) in rats (approximately 2.1 times the expected clinical exposure based on AUC) and 0.5 and 0.75 mg/kg (10 and 15 mg/m2) in dogs (approximately 0.2 and 0.4 times the expected clinical exposure based on AUC).

Animal Toxicology Overdose In rats, single intravenous doses of ixabepilone from 60 to 180 mg/m2 (mean AUC values ≥8156 ng•h/mL) were associated with mortality occurring between 5 and 14 days after dosing, and toxicity was principally manifested in the gastrointestinal, hematopoietic (bone-marrow), lymphatic, peripheral-nervous, and male-reproductive systems. In dogs, a single intravenous dose of 100 mg/m2 (mean AUC value of 6925 ng•h/mL) was markedly toxic, inducing severe gastrointestinal toxicity and death 3 days after dosing.

PATIENT COUNSELING INFORMATION [see FDA-Approved Patient Labeling in Full Prescribing Information] Peripheral Neuropathy Patients should be advised to report to their physician any numbness and tingling of the hands or feet [see Warnings and Precautions].

Fever/Neutropenia Patients should be instructed to call their physician if a fever of 100.5° F or greater or other evidence of potential infection such as chills, cough, or burning or pain on urination develops [see Warnings and Precautions].

Hypersensitivity Reactions Patients should be advised to call their physician if they experience urticaria, pruritus, rash, flushing, swelling, dyspnea, chest tightness or other hypersensitivity-related symptoms following an infusion of IXEMPRA [see Warnings and Precautions].

Pregnancy Patients should be advised to use effective contraceptive measures to prevent pregnancy and to avoid nursing during treatment with IXEMPRA [see Warnings and Precautions and Use in Specific Populations].

Cardiac Adverse Reactions Patients should be advised to report to their physician chest pain, difficulty breathing, palpitations or unusual weight gain [see Warnings and Precautions].

IXEMPRA® (ixabepilone) for injection Manufactured by: Baxter Oncology GmbH, 33790 Halle/Westfalen, Germany DILUENT for IXEMPRA Manufactured by: Baxter Oncology GmbH, 33790 Halle/Westfalen, Germany Distributed by Bristol-Myers Squibb Company, Princeton, NJ 08543 USA

1236925A7

5645-0006

Rev October 2011 RPH-00001

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In the Literature

Emerging Clinical Data on Cancer Management COLORECTAL CANCER Long-Term Use of Thyroid Hormone Replacement Linked to Decreased Risk of Colorectal Cancer Long-term thyroid hormone replacement was associated with a decreased risk of colorectal cancer, but hyperthyroidism and untreated hypothyroidism were associated with a modestly elevated risk, according to a study using a large population-based medical records database from the United Kingdom.

A total of 20,990 colorectal cancer patients and 82,054 control patients, exclusive of those with familial colorectal cancer syndromes or inflammatory bowel disease, were identified for this nested case-control study. Every colorectal cancer case patient was matched with four eligible control patients on age, sex, practice site, and duration of follow-up.

“As expected, case patients were more likely to have a medical history of diabetes mellitus and more likely to be former or current smokers and alcohol users,” the investigators noted.

Significant Results The results were reported in the Journal of the National Cancer Institute. Yu-Xiao Yang, MD, of the Perelman School of Medicine, University of Pennsylvania, Philadelphia, served as the corresponding author of this article.

Patients with clinical or subclinical hypothyroidism (thyroid-stimulating hormone [TSH] levels > 4 mg/dL) who were treated with thyroid hormone replacement “had lower risk of colorectal cancer, with an adjusted odds ratio of 0.92 (95% CI = 0.86–0.98, P = .009),” the researchers reported. In further analysis, thyroid hormone replacement for more than 1 year was associated with a lower colorectal cancer risk, and this protective association was stronger with increasing time.

The adjusted odds ratios for colorectal cancer associated with thyroid hormone replacement were 0.88 (95% CI = 0.79–0.99, P = .03) for treatment initiated 5 to 10 years before the index date and 0.68 (95% CI = 0.55–0.83, P < .001) for treatment initiated more than 10 years before. The protective effect of thyroid hormone replacement was also higher for patients who underwent colectomy and was more evident among women.

Among patients who did not receive thyroid hormone replacement, those

with clinical or subclinical hypothyroidism had a modestly higher risk for colorectal cancer than those without documented thyroid dysfunction, with an adjusted odds ratio of 1.16 (95% CI = 1.08–1.24, P < .001). Patients with hyperthyroidism (TSH < 4 mg/dL) also had an increased risk of colorectal cancer, with an adjusted odds ratio of 1.21 (95% CI = 1.08–1.36, P = .001).

Potential Impact “If confirmed, results from this study may help health care providers decide between early vs late treatment with thyroid hormone replacement in asymptomatic subclinical hypothyroidism or alternatively increased colonic screening in those individuals,” the investigators concluded. “Further research evaluating the chemopreventive potential of thyroid hormone replacement and the exact biological mechanism for this effect might enable more specific chemopreventive drugs in the future.”

This study was supported by the National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health.

Boursi B, et al: J Natl Cancer Inst 107:djv084, 2015.

HODGKIN LYMPHOMA Increased Lifetime Risk of Cardiovascular Disease for Patients Treated for Hodgkin Lymphoma Survivors of Hodgkin lymphoma treated as adolescents or adults are at increased risk of cardiovascular diseases throughout their lives, according to results of a retrospective cohort study of 2,524 Dutch patients followed for a median of 20 years. “Treating physicians and patients should be aware of the persistently increased risk of cardiovascular diseases throughout life, and the results of our study may direct guidelines for follow-up of patients with Hodgkin lymphoma,” Frederika A. van ­Nimwegen, MSc, of the Netherlands Cancer Institute, Amsterdam, advised in JAMA Internal Medicine.

All patients were diagnosed with Hodgkin lymphoma when younger than 52 years (median age, 27.3 years), had been treated from 1965 through 1995, and had survived for 5 years since their diagnosis. Among the 2,524 patients, 2,052 individuals (81.3%) had

received mediastinal radiation, and 773 patients (30.6%) had received anthracycline-containing chemotherapy.

At a median follow-up of 20.3 years (range, 5–47 years), the researchers identified 1,713 cardiovascular events in 797 patients, with 410 patients having two or more events. The most frequently occurring cardiovascular disease was coronary heart disease, with 401 patients developing it as their first event, followed by valvular heart disease (374 events) and heart failure (140 events). The median intervals between Hodgkin lymphoma treatment and first cardiovascular disease events were 18 years for coronary heart disease, 24 years for valvular heart disease, and 19 years for heart failure.

Cumulative Risks The cumulative risk of any type of cardiovascular disease was 50% at 40 years after diagnosis, and 51% of patients with a cardiovascular disease had multiple events. For patients treated before age 25, the cumulative risk at 60 years of age or older was 20% for coronary heart disease, 31% for valvular heart disease, and 11% for heart failure as first events.

“Compared with the general population, four- to sevenfold increased risks of coronary heart disease or heart failure are observed 35 years or more after Hodgkin lymphoma treatment, resulting in 857 excess cardiovascular events per 10,000 person-years,” the researchers reported. Although patients treated before 25 years of age had the highest relative risks, “substantial absolute excess risks were also observed for patients treated at older ages,” the authors added.

“Adjusted for year of Hodgkin lymphoma diagnosis, sex, and ever smoking, mediastinal radiotherapy and anthracycline-containing chemotherapy were associated with an increased risk of any cardiovascular disease,” the investigators noted. Mediastinal radiotherapy increased the risk of coronary heart disease, valvular heart disease, and heart failure, whereas anthracycline-containing chemotherapy increased the risks of valvular heart disease and heart failure as first events compared with patients who did not receive those cancer treatments. “Radiation below the diaphragm or vincristine-containing chemotherapy did not influence the risks of any cardiovascular disease,” the researchers stated.

“No interactions on a multiplicative scale were found between mediastinal radiotherapy and anthracycline dose or

mediastinal radiotherapy and smoking; the joint effects of these outcomes appeared to be additive rather than multiplicative,” the authors wrote.

Accompanying Commentary “This work by van Nimwegen et al can specifically help physicians identify their highest-risk patients: those with a history of Hodgkin lymphoma who were treated at a younger age and those who are the longest from treatment,” Emily Tonorezos, MD, MPH, of the Weill Cornell Medical College, New York, and Linda Overholser, MD, of the University of Colorado Denver School of Medicine, Aurora, wrote in a related commentary.

“For most encounters, starting by asking a few key cancer history questions will help identify these patients: (1) What kind of cancer did you have? (2) How old were you when your lymphoma was diagnosed? (3) Did you receive chest radiotherapy? (4) Did you receive doxorubicin (many patients know it by the brand name Adriamycin [the red medicine])? Our clinical experience has been that patients typically know the answers to these basic questions, and these responses will go a long way toward identifying at-risk patients. Nonetheless, the future of good care for cancer survivors will require establishment of the evidence-based best practices for this population,” the commentary concluded.

van Nimwegen FA, et al: JAMA Intern Med 175:1007-1017, 2015.

Tonorezos E, Overholser L: JAMA Intern Med 175:1017-1018, 2015.

HIV INFECTION Determining Why Patients With HIV Infection and Non–AIDS-Defining Cancers Are Less Likely to Receive Cancer Treatment A survey sent to medical and radiation oncologists to identify factors contributing to observed disparities in cancer treatment between patients infected with HIV and those not infected “found that a substantial proportion of physicians (21%) would alter their treatment recommendations based on HIV status,” Gita Suneja, MD, of the University of Salt Lake City, Utah, and colleagues reported in the Journal of Oncology Practice. “The likelihood of offering standard treatment was associcontinued on page 118

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In the Literature Emerging Clinical Data continued from page 116

ated with concerns about toxicity, efficacy, and comfort level with discussing cancer treatment adverse effects and prognosis,” the investigators stated.

Before the advent of highly active antiretroviral therapy improved survival in HIV-infected individuals, “cancers in HIVinfected individuals were largely AIDSdefining cancers related to severe immunosuppression, such as Kaposi sarcoma,” the researchers wrote. With improved survival in HIV-infected individuals, cancers considered non–AIDS-defining cancers, “such as lung, colorectal, and anal cancers, have become an increasingly important cause of mortality in the HIV-infected population. Despite improvements in the management of HIV, HIV-infected patients with cancer have worse survival compared with uninfected counterparts,” the authors stated. This lower survival, they noted, could be due in part to a disparity in receiving cancer treatment, as seen in recent population-based studies.

The survey was mailed to 500 medical and radiation oncologists randomly selected from the American Medical Association Physician Masterfile, with greater sampling in areas of highest HIV prevalence. Recipients had the option of responding by mail or online.

Among 273 physicians who responded, 79% indicated they would provide standard cancer treatment to HIV-infected patients, but 69% disagreed with the statement, “Sufficient guidelines are available to aid in treatment decision-making for HIV-infected patients with non–AIDSdefining malignancies.” In addition, 45% never or rarely discussed their cancer management plan with an HIV specialist; 20% were not comfortable discussing cancer

treatment adverse effects with their HIVinfected patients with cancer, and 15% were uncomfortable discussing prognosis.

Multivariable Analysis “In multivariable analysis, physicians comfortable discussing adverse effects and prognosis were more likely to provide standard cancer treatment (adjusted odds ratio, 1.52; 95% CI, 1.12–2.07). Physicians with concerns about toxicity and efficacy of treatment were significantly less likely to provide standard cancer treatment (adjusted odds ratio, 0.67; 95% CI, 0.53–0.85),” the investigators stated.

Among medical oncologists, 77% scored as providing standard therapy to HIV-infected patients. This was assessed by responses to three specialtyspecific management questions, with 18% indicating they would not use standard chemotherapy agents, 48% indicating that they would use lower doses and fewer cycles, and 51% indicating that they would discontinue therapy if adverse effects occurred when treating HIV-infected patients with cancer.

Among radiation oncologists, 80% scored as providing standard therapy to HIV-infected patients. Responses to three specialty-specific management questions showed that 20% would use lower radiation doses, 27% would treat with smaller fields, and 31% would discontinue therapy if adverse effects occurred when treating HIV-infected patients with cancer.

The authors noted that concerns cited regarding safety and efficacy of cancer treatment in HIV-infected patients “are not surprising, given the dearth of high-quality data and resulting lack of evidence-based guidelines specific to

HIV-infected patients with non–AIDSdefining cancers. Clinical trial data are available to inform the management of HIV-infected patients with non-Hodgkin lymphoma and anal cancer but not most other non–AIDS-defining cancers. This is because HIV-infected patients have historically been excluded from clinical trials, so randomized trial data regarding treatment outcomes are largely unavailable.” The authors added that the National Cancer Institute and other organizations have initiated steps to address this issue.

“Inclusion of HIV-infected patients in cancer clinical trials, development of cancer treatment guidelines specific to HIV-infected patients, and enhanced care coordination between oncologists and HIV specialists may reduce cancer treatment disparities for HIV-infected patients with cancer,” the investigators concluded.

Suneja G, et al: J Oncol Pract 11:e380e387, 2015.

HEPATOCELLULAR CARCINOMA More Than One-Third of Those Diagnosed With Hepatocellular Carcinoma as Outpatients Have Diagnostic Delays of 3 or More Months Nearly 20% of patients with hepatocellular carcinoma “wait more than 3 months from presentation to diagnosis, which can contribute to interval tumor growth,” Nishant Patel, MD, and colleagues concluded in the Journal of the National Comprehensive Cancer Network. They based their conclusions on a review of records of consecutive patients with cirrhosis and hepatocellular carcinoma at Parkland Memorial Health and Hospital System, a large urban safety net hospital in Dallas, between January 2005 and July 2012.

“Diagnostic delays are particularly common among outpatients, occurring in more than one-third,” the researchers found. “These delays may be related to several potential issues, including providers failing to recognize positive surveillance tests, patients missing radiology appointments, and insensitive diagnostic tests. Although we did not find any difference in receipt of hepatocellular carcinoma–directed treatment, diagnostic delays were associated with potential interval tumor growth in nearly one-fifth of patients.”

Study Details

© George Booth/The New Yorker Collection/www.cartoonbank.com

Among 457 patients with cirrhosis and hepatocellular carcinoma, 231 were inpatients, and 226 (49.5%) were diagnosed as outpatients. Although the time from presentation to diagnosis was

less than 1 week for more than 90% of inpatients, the median time to diagnosis was 2.2 months for outpatients, with 87 patients (38.5%) experiencing a diagnostic delay, defined as a time to diagnosis exceeding 3 months.

Higher rates of diagnostic delays were observed among those diagnosed as outpatients who had hepatic encephalopathy (56% vs 35%). “Among 49 patients with mass-forming hepatocellular carcinoma and diagnostic delay, 18% had interval tumor growth of 2 cm or greater,” the investigators stated.

The median age of the patients was 56 years, and more than 75% were men.

“Our population was racially diverse, with 36% African Americans, 30% Hispanic Caucasians, and 26% non-Hispanic Caucasians,” the researchers noted.

Lower rates of diagnostic delays were observed in patients diagnosed as outpatients who presented after implementation of a comprehensive electronic medical record system, 26% vs 60% for those presenting before electronic medical records. The authors noted, “diagnostic delays may be more common in hospital systems without an electronic medical record, because of higher rates of unrecognized positive surveillance tests.”

Patients presenting with an abnormal ultrasound, with or without an elevated alpha-fetoprotein level, also had lower rates of diagnostic delay, 27% vs 50%.

Outcome Disparities The investigators noted that the incidence of hepatocellular carcinoma is increasing because of a growing number of cases of nonalcoholic fatty liver disease and hepatitis C virus. Curative options are “only available for those diagnosed at an early stage. Patients with early hepatocellular carcinoma achieve 5-year survival rates near 70% with resection or liver transplantation, whereas those with advanced hepatocellular carcinoma have a median survival of less than 1 year,” the authors added.

“Despite the availability of efficacious surveillance tests, only 40% of hepatocellular carcinoma cases are diagnosed at an early stage nationally,” the researchers wrote. “Tumor stage at diagnosis can be impacted by several factors in clinical practice, including low surveillance rates and delays in follow-up of abnormal screening tests. These issues may be particularly prevalent among racial minorities and socioeconomically disadvantaged patients, potentially contributing to racial and socioeconomic disparities in cancer outcomes.”

Patel N, Yopp AC, Singal AG: J Natl ­Compr Canc Netw 13:543-549, 2015.

ASCOPost.com | SEPTEMBER 10, 2015

PAGE 119

In the Literature

COMORBIDITIES Cancer Diagnosis Among Patients With Diabetes Reduced Adherence to Evidence-Based Medications “A cancer diagnosis among patients with diabetes reduced adherence with evidence-based medications, particularly if patients’ life expectancy was short,” according to a study among Medicare beneficiaries reported in the Journal of Oncology Practice. “These findings emphasize the vulnerability of individuals faced with a new cancer diagnosis and the difficulty in maintaining ongoing therapy for comorbid conditions, which may have potentially important consequences for longer-term survivorship,” concluded Bruce C. Stuart, PhD, of the University of Maryland School of Pharmacy, Baltimore, and colleagues.

The study compared 4,348 patients with newly diagnosed cancer between January and December 2007 with 28,507 cancer-free controls “assigned a pseudo­ diagnosis date,” the researchers explained, so that the distribution of index months was the same for the patients with cancer and the controls. All patients were selected from a 5% random sample of Medicare beneficiaries with diabetes enrolled in Medicare Part D in 2007 and 2008.

The patients with cancer were older, had higher rates of comorbid conditions, and were less likely to receive Medicare Part D low-income subsidies.

Key Findings Adherence was determined by tracking for 6 months before and 6 months after the diagnosis (or pseudodiagnosis) date the proportion of days covered with oral hypoglycemic agents, renin-angiotensin-aldosterone system inhibitors, and statins. Overall, the patients with cancer had “relatively larger declines in medication adherence” of between 3% and 5% (P < .001) than did the controls, the researchers reported. Patients with cancer who had sharper declines of between 8% and 11% (P < .001) had a short life expectancy, defined by the investigators as death occurring 7 to 12 months after the index date.

For longer-term survivors, the researchers noted, “the declines in proportion of days covered values were relatively small but still appear larger for patients with cancer than for controls.”

The largest declines in adherence to evidence-based medications recommended in diabetes treatment guidelines “were observed for patients who died in the 6 months after our observa-

tion period, suggesting that poor cancer prognosis was at least partly responsible.

The declines in treatment associated with a cancer diagnosis persisted even when limited to persons with longerterm survival, suggesting that not all of the decline can be attributed to short life expectancy,” the investigators observed.

“We did not find a differential effect

on diabetes medication adherence associated with Part D low-income subsidy enrollment, suggesting that new financial burdens associated with cancer treatment were not associated with the observed declines in adherence to these drug classes after a cancer diagnosis,” the researchers reported. “Many of the medications recommended for individu-

TUMOR BOARD SERIES

als with diabetes during this period were generic, and copayments for generic drugs, which were already low, decreased further during the study period. Recent evidence indicates that the financial burden associated with adherence to typical diabetes drug regimens is not large.” n Stuart BC, Davidoff AJ, Erten MZ: J Oncol Pract. June 23, 2015 (early release online).

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The ASCO Post | SEPTEMBER 10, 2015

PAGE 120

Announcements

James Welsh, MD, FACRO, Elected President of the American College of Radiation Oncology

L

oyola University Medical Center radiation oncologist James Welsh, MD, FACRO, was recently elected president of the American College of Radiation Oncology (ACRO).

Dr. Welsh, installed as president during ACRO’s Annual Meeting in Washington, DC, will serve a 2-year term as President. In 2017, Dr. Welsh will transition to Chairman of the Board for ACRO. ACRO is the essential professional society for success in the day-to-day practice of radiation oncology. It focuses on ensuring the highest quality of care for radiation therapy patients and promoting success in the practice of radiation oncology through education, responsible socioeconomic advocacy, and integration of science and technology into clinical practice.

In addition to ACRO, Dr. Welsh has actively and extensively served in other professional organizations.

Dr. Welsh recently concluded an

8-year term as Advisor to the Nuclear Regulatory Commission’s Advisory Committee on the Medical Uses of Isotopes. He formerly served as Chair of the Radiological Society of North America’s Radiation Oncology Scientific Program Subcommittee and as an Alternate Councilor in the American College of Radiology. Dr. Welsh held or holds several leadership positions within the American Society for Radiation Oncology.

Dr. Welsh is Professor, Medical Director, and Director of Clinical and Translational Research in the Department of Radiation Oncology of Loyola University Chicago Stritch School of Medicine. He also is Chief of Radiation Oncology at Edward Hines Jr VA Hospital. Dr. Welsh is a fellow of the American College of Radiation Oncology.

Dr. Welsh earned his medical degree from the State University of New York at Stony Brook and a master’s degree in molecular biophysics and biochem-

istry from Yale University. Dr. Welsh completed a residency in radiation oncology at Johns Hopkins Hospital and

completed a fellowship in helical tomotherapy while at the University of Wisconsin-Madison. n

Arno Mundt, MD, outgoing President of the American College of Radiation ­Oncology, passes the gavel to incoming President James Welsh, MD, FACRO. Photo courtesy of Loyola University of Chicago Stritch School of Medicine and the American College of Radiation Oncology.

Chief Executive Officer The American Society of Clinical Oncology (ASCO) is seeking an accomplished leader in clinical oncology to serve as their next Chief Executive Officer (CEO). ASCO is a professional society committed to conquering cancer through research, education, prevention, and delivery of high quality patient care.

Founded in 1964, ASCO today counts more than 36,000 members worldwide and has an annual budget of $100M. The CEO works with a distinguished Board of Directors, a talented professional staff of more than 350 individuals, and hundreds of dedicated volunteers to envision and implement a strategic plan that engages and serves all physicians as they work to fight cancer. The CEO provides leadership and vision on the execution of strategic plans and oversees the fiscal health of the organization while building and supporting a highly committed and capable management team. The CEO must ensure that ASCO’s current major initiatives are successful and also guide a conversation about new opportunities for ASCO to support the field in a dynamic healthcare environment. All of these efforts will be sustained by responsible management of internal resources and diligent philanthropic efforts.

The successful candidate for this prestigious position will have experience as a leader in clinical oncology with a deep passion for, commitment to, and track record of accomplishments in cancer clinical medicine. The candidate should have working knowledge of and some experience in the many areas in which ASCO plays an important role in improving cancer care, including clinical and translational research, physician and public education and communication, cancer care delivery, governmental affairs and policy, and global health. A prior leadership role with ASCO in a volunteer or board capacity is strongly desired as is an in-depth understanding of the current trends and issues affecting oncology clinical practice and clinical research today.

A medical degree is required. The ideal candidate must have a demonstrated track record of managing and leading a large and complex organization with a comparably sized budget and a highly educated, high intellect professionals. The CEO also serves as CEO of the affiliated Conquer Cancer Foundation, and experience with philanthropy is beneficial.

This position is based at ASCO headquarters in Alexandria, Virginia. Candidates from all oncology disciplines and sub-specialties, domestic and international, are encouraged to apply. ASCO is proud to be an Equal Opportunity Employer (EOE).

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

ASCOPost.com | SEPTEMBER 10, 2015

PAGE 121

Perspective Julie M. Vose, MD, MBA, FASCO continued from page 1

Mr. Collender is so right. All new cancer drugs must go through the rigors of clinical trial investigations to ensure their safety and efficacy, but unless we can significantly improve the current paltry rate of just 3% adult participation in clinical studies—participation is even lower among minority patients and patients aged 65 and older—we will not be able to advance cancer care for all patients in the future. In fact, a study of genitourinary cancer clinical trials found that 1 in 10 adult clinical trials ends prematurely due to poor accrual,2 which can unnecessarily doom a potentially effective drug from ever making it to the marketplace.

Barriers to Trial Participation The barriers to patient participation in clinical trials are many. Patients may fear a reduced quality of life, have concerns about not receiving the experimental drug, worry about potential treatment side effects and loss of control over treatment decisions, and have anxiety about the inconvenience a trial might cause.

Physicians hamper the process, too, by not encouraging patients to join studies or not referring them to appropriate trials. Excessive administrative and regulatory burdens and decreased federal funding for clinical trials are big contributing factors as well.

Federally funded research through the National Institutes of Health (NIH) has played a critical role in every major advance in cancer treatment over the past 50 years. But this funding has remained flat for more than a decade, leaving NIH federal research funds with a 23% loss when adjusted for biomedical inflation. Promising research is now going unfunded, and new studies are being scaled back, leaving fewer patients with the opportunity to participate in clinical trials.

Recently, the U.S. House of Representatives passed the 21st Century Cures Act, which includes more than $9 billion in additional funding for the NIH and the U.S. Food and Drug Administration (FDA). The increased funding will strengthen both agencies and the medical community as a whole.

I applaud this effort and urge the Senate to pass the bill.

All of these challenges are occurring at a pivotal point in cancer research, and ASCO is taking steps to help mitigate the problem of low patient participation in clinical studies. In July, ASCO published a position statement, “Im-

proving the Evidence Base for Treating Older Adults With Cancer,” which calls for federal agencies to broaden clinical trials to include older patients,3 and members of ASCO’s Cancer Research Committee published “Modernizing Eligibility Criteria for Molecularly Driven Trials,” which examines the need to redefine eligibility criteria for

participation in clinical studies investigating molecularly targeted agents.4

Including Older Patients Although more than 60% of cancers in the United States occur in people aged 65 and older—a population that is expected to double by midcentury5— the evidence base for treating these pa-

tients is lacking because older adults are underrepresented in clinical trials, and trials designed specifically for this age group are rare. The result is that we have less evidence on how to treat this population of patients and less knowledge regarding the risk of toxicity and key endpoints of importance than we do for continued on page 122

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The ASCO Post | SEPTEMBER 10, 2015

PAGE 122

Perspective Julie M. Vose, MD, MBA, FASCO continued from page 121

younger adult and pediatric patients.

To make clinical trials more inclusive and expand the number of older patients in clinical trials, ASCO is proposing five recommendations: 1. Use clinical trials to improve the evidence base for treating older adults.

2. Leverage research designs and infrastructure to improve the evidence base for treating older adults.

3. Increase FDA authority to incentivize and require research on older adults with cancer.

4. Increase clinicians’ recruitment of older adults with cancer into clinical trials.

5. Utilize journal policies to incentivize researchers to consistently report on the age distribution and health-risk profiles of research participants.

In the paper, ASCO also outlines 16 specific action items to facilitate implementation of its recommendations.

These measures include asking regulatory agencies, research funders, and researchers to consider whether evidence exists to support eligibility criteria based on the three primary reasons older adults are excluded from clinical studies: age, performance status, and comorbid health conditions.

Molecularly Driven Trials In ASCO’s second position paper, members of ASCO’s Cancer Research Committee propose the organization

of a public workshop, with input from regulatory bodies and key stakeholders, to develop a streamlined algorithmic approach to determining eligibility criteria for study protocols in this era of molecularly driven therapy.

ASCO is working with collaborators, including the FDA and Friends of Cancer Research, toward a meeting in spring 2016.

of investigational targeted therapies based on the molecular characteristics of cancer.

Advancing Cures In addition to the steps ASCO is taking on a national level to boost clinical trial participation, there are also approaches on the community level that can improve patient recruitment and

Unless we can significantly improve the current paltry rate of just 3% adult participation in clinical studies … we will not be able to advance cancer care for all patients in the future.

—Julie M. Vose, MD, MBA, FASCO

This is an important first step as trials of molecularly targeted cancer therapies increase in number and our understanding of the molecular drivers of cancer advances. “Although eligibility criteria are necessary to define the population under study and conduct trials safely, excessive requirements may severely restrict the population available for study,” wrote the paper’s authors.

Hopefully, fewer eligibility restrictions will enable more patients to participate in clinical trials and speed our understanding of the risks and benefits

retention. For example, you can budget time during an office visit to provide all eligible patients with clear information about appropriate clinical studies at your institution or refer them to a study at another cancer center. At this time, you can answer any questions patients may have regarding potential risks and benefits, time involved, and any costs associated with the trial.

I commend Mr. Collender for his courage in speaking out about the need for all of us— clinicians, scientists, and public officials—to step up our efforts to encourage more patients to join

clinical trials. Our patients are the true heroes of cancer research, and without their participation in clinical studies, we will not make the progress necessary to find cures for cancer.

We owe it to Mr. Collender and to the millions of other patients with cancer to advance scientific discovery into more effective therapies and improved outcomes for all patients. n

Disclosure: Dr. Vose reported no potential conflicts of interest

References 1. Collender S: Clinical trials need cancer patients. The New York Times. June 19, 2015.

Available at www.nytimes.com/2015/06/19/ opinion/clinical-trials-need-cancer-patients. html. Accessed July 28, 2015.

2. Stensland KD, McBride R, Wisnivesky JP, et al: Premature termination of genitourinary cancer clinical trials. 2014 ASCO Annual Meeting. Abstract 288.

3. Hurria A, Levit LA, Dale W, et al: Improving the evidence base for treating older adults with cancer: American Society of Clinical Oncology statement. J Clin Oncol.

July 20, 2015 (early release online).

4. Kim ES, Bernstein D, Hilsenbeck SG, et al: Modernizing eligibility criteria for molecularly driven trials. J Clin Oncol. July 20, 2015 (early release online).

5. West LA, Cole S, Goodkind D, et al: 65+ in the United States: 2010. U.S. Census Bureau. June 2014. Available at www. census.gov/content/dam/Census/library/ publications/2014/demo/p23-212.pdf.

Accessed July 28, 2015.

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.

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