TAP Vol 7 Issue 1 by Harborside Press LLC

CAR-T Therapy

3, 33

| ALK in Lung Cancer

| Triple-Negative Breast Cancer

| Remembering Ellen Stovall

VOLUME 7, ISSUE 1

152

JANUARY 25, 2016

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

The 340B Drug Pricing Program: Background, Concerns, and Solutions

ASH Annual Meeting

Multiple Myeloma in 2015: A Year for the Record Books By Caroline Helwick

By Hagop Kantarjian, MD, and Robert Chapman, MD

ew malignancies have received as much attention, in the way of newly approved drugs, as multiple myeloma did in 2015. In November alone, 3 new agents were approved, bringing the total to 4 for the year as part of a record 7 approvals and to 16 regulatory approvals over the past 12 years. Speakers at myeloma sessions at the 2015 American Society of Hematology (ASH) Annual Meeting played to packed audiences. At a special session that was called “unprecedented” at the ASH meeting, U.S. Food and Drug Administration (FDA) reviewers described the rationale for the approvals while myeloma experts discussed how they will likely use the new drugs in clinical practice.1

Changing the Treatment Landscape “This is a revolutionary time in multiple myeloma. The three drugs approved in November—daratumumab (Darzalex), elotuzumab (Empliciti), and ixa-

zomib (Ninlaro)—promise to change the landscape of treatment and improve overall survival,” said S. Vincent Rajkumar, MD, Professor of Medicine at the Mayo Clinic, Rochester, Minnesota. Because of “the plethora of new drugs,” he said, more S. Vincent Rajkumar, MD than 80% of newly diagnosed patients are living more than 4 years. “Elotuzumab and daratumumab are the first available monoclonal antibodies [in this setting]. It’s been a long wait…. Ixazomib is the first oral proteasome inhibitor, and it promises to make our treatments more convenient,” Dr. Rajkumar said. The fourth drug approved in 2015 was panobinostat (Farydak), the first histone deacetylase inhibitor for myeloma. continued on page 4

News

Bevacizumab Plus Chemotherapy Fails to Prolong Survival in Early-Stage Lung Cancer By Caroline Helwick

verall survival in patients with surgically resected early-stage non–small cell lung cancer (NSCLC) did not improve with the addition of bevacizumab (Avastin) to chemotherapy, according to the findings of a study researchers have called a “top abstract” from

the 16th World Conference on Lung Cancer. Heather Wakelee, MD, Associate Professor of Medicine (Oncology) at Stanford University Medical Center, California, presented the phase III E1505 study results on behalf of the ECOG-ACRIN Cancer Research Group.1 She noted that bevacizuimab has been shown to improve With the development of other outcomes when added to platinum-based chemoactive agents in metastatic lung therapy in advanced-stage cancer, it will be important to nonsquamous NSCLC. This study evaluated the drug in investigate them fully in earlier stages early-stage patients.

and not assume the benefit seen in advanced stage will also be proven in earlier stages, though we can remain hopeful.

—Heather Wakelee, MD

Send your comments to editor@ASCOPost.com

he 340B Drug Pricing Program was created by Congress through the Veterans Health Care Act of 1992 to allow some healthcare entities—including safety-net providers with large shares of uninsured and low-income patients and other “covered entities”—to obtain drugs at discounted prices.1,2 Congress gave these providers access to drug discounts in response to escalating drug prices that made it difficult for them to handle the needs of vulnerable patients. The Health Resources continued on page 156

Dr. Kantarjian is Chairman of the Leukemia Department at The University of Texas MD Anderson Cancer Center and a Baker Institute Scholar for Health Policies at Rice University, Houston. Dr. Chapman is Medical Director of Josephine Ford Cancer Institute at the Henry Ford Health System, Detroit. Disclaimer: This commentary represents the views of the author and may not necessarily reflect the views of ASCO.

MORE IN THIS ISSUE Oncology Meetings Coverage World Lung Cancer Conference �� 1, 18, 24 ASH Annual Meeting ��3–5, 26–36 Genitourinary Cancers Symposium �� 14–17 San Antonio Breast Cancer Symposium �� 38, 45–46, 50–54 Geriatrics for the Oncologist �� 66–67 Direct From ASCO �� 81–84 Breast Cancer Roundtable �� 98, 99, 106, 107 Mantle Cell Lymphoma �� 111, 112, 117, 118 Acupuncture for Cancer Symptoms ��120 In Memoriam �� 152, 154

Study Details and Results The study involved 1,501 patients with earlystage NSCLC (stage IB to continued on page 18

A Harborside Press® Publication

The ASCO Post | JANUARY 25, 2016

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ASH Annual Meeting Immunotherapy

Could CAR-T Therapy Be Moving Into Lymphoma? By Alice Goodman

he use of T cells that are genetically engineered to express chimeric antigen receptor (CAR-T) has made headway as an approach to hematologic malignancies, with the best results achieved in leukemia. At the 2015 American Society of Hematology (ASH) Annual Meeting and Exposition, a preliminary study explored the use of CAR-T cells in lymphoma.1 Durable remissions were observed following a single infusion of CAR-T cells directed against CD19 in very sick, heavily pretreated patients with CD19-positive diffuse large B-cell lymphoma and follicular lymphoma. All patients who achieved complete remission remained in remission at a median follow-up of about 1 year. Only two patients with mantle cell lymphoma were treated, with one complete remission. “CAR-T cells targeting CD19 have achieved potent antitumor effects in relapsed/refractory acute lymphoblastic leukemia and chronic lymphocytic leukemia. It is not a stretch to hypothesize that CAR-T would be active in non-Hodgkin lymphomas that express CD19,” said lead author Stephen J. Schuster, MD, Director of the Lymphoma Program at the Abramson Cancer Center, University of Pennsylvania, Philadelphia. “We found durable responses in extensively pretreated patients with active non-Hodgkin lymphoma treated with CAR-T, with less toxicity than is reported with other therapies,” he said.

Study Eligibility Patients enrolled in the trial (n = 43 at the time of the ASH meeting) had no available curative therapies and an

expected survival of 3 months or longer. They included patients with diffuse large B-cell lymphoma, either after transplant or transplant-ineligible; patients with follicular lymphoma for whom at least two prior immunotherapy regimens had failed and who had

Of the 43 patients enrolled, 30 patients got the protocol-determined dose of CAR-T (15 diffuse large B-cell lymphoma, 13 follicular lymphoma, 2 mantle cell lymphoma); 6 patients failed to produce CAR-T sufficient for infusion.

CAR-T cells targeting CD19 have achieved potent antitumor effects in relapsed/refractory acute lymphoblastic leukemia and chronic lymphocytic leukemia. It is not a stretch to hypothesize that CAR-T would be active in non-Hodgkin lymphomas that express CD19. —Stephen J. Schuster, MD

progressive disease within 2 years of treatment; and patients with mantle cell lymphoma who had relapsed or had persistent disease after first-line rituximab (Rituxan) chemotherapy and were transplant-ineligible or relapsed after transplant. Once eligibility for the study was determined, apheresis and manufacturing of CAR-T cells were initiated. Patients were restaged by computed tomography (CT) scan and bone marrow analysis and then given lymphodepleting chemotherapy on an individualized basis according to histology, past response, and blood counts. Chemotherapy ended 1 to 4 days before the CAR-T infusion was administered.

EXPERT POINT OF VIEW

ommenting on the study presented by Schuster et al at the 2015 ASH Annual Meeting and Exposition, Marcela Maus, MD, Director of the Cellular Immunity Program at Massachusetts General Hospital in Boston, said: “These are amazing results. The study shows that [chimeric antigen receptor (CAR)-engineered] CD19directed T cells can have significant benefits in lymphoma. This opens the door for studying this Marcela Maus, MD therapy in these malignancies.” She noted, “There were a large proportion of patients with durable responses, some of them out to a year.” Dr. Maus also emphasized a notable difference between lymphomas and leukemias in the context of CAR-T therapy: “The magnitude of in vivo CART cell expansion does not correlate with response [in lymphomas].” n Disclosure: Dr. Maus reported no potential conflicts of interest.

Diffuse Large B-Cell Lymphoma Patients with diffuse large B-cell lymphoma were very sick and heavily pretreated. At the first response assessment 3 months after infusion, response rates using anatomic criteria were as follows: overall response rate of 47%, with complete response in three patients, partial response in four, and progressive disease in eight. Best response was complete remission in six, partial response in one, and progressive disease in eight. Three of the patients with a partial response at 3 months converted to complete remission by 6 months; one patient with a partial response developed progressive disease. No patients who achieved a complete remission have relapsed at a median follow-up of 14.5 months, Dr. Schuster told listeners. “Most of the disease progression [on CAR-T] occurs before 3 months. You don’t need a CT scan to show progressive disease. However, those who achieve complete remission by 6 months stay in remission. We have 1 patient in [complete remission] for 18 months,” he said. “In [diffuse large B-cell lymphoma], the peak in vivo expansion of T cells doesn’t correlate with response rates,” he added. Durable responses were observed with a single infusion of CAR-T cells, and persistence of T cells was seen on flow cytometry out to 1 year. In seven responding patients, the median overall response rate

had not been reached at 14.5 months. “These results in primary refractory [diffuse large B-cell lymphoma] are quite impressive,” Dr. Schuster said.

Follicular and Mantle Cell Lymphoma Patients with follicular lymphoma had a median age of 59 and had received a median of five prior therapies. Onethird had undergone prior stem cell transplant, 71% had increased LDH, and 29% had more than one extranodal site. In 11 evaluable follicular lymphoma patients, the 3-month overall response rate was 73%; there were 4 patients with complete remission, 4 with partial response, and 3 patients with progressive disease. Best response rate was 73%, with seven complete remissions, one partial response, and three patients with progressive disease. Three of the patients with a partial response converted to complete remission by 6 months. The majority of patients who responded have continued to maintain a response at 1 year. As in the patients with diffuse large B-cell lymphoma, the peak in vivo expansion of CAR-T cells did not correlate with remission. A median follow-up of 14.3 months showed durable responses in those who achieved partial response or complete remission, he said.

Safety Looking at overall toxicity, cytokinerelease syndrome—mostly grade 2— was reported as ≥ grade 3 in four patients. Also, reversible central nervous system toxicity was reported, including agitation and delirium. One case of encephalitis was fatal. Based on these promising results, investigators conducting a phase II trial called JULIET are planning to enroll adults with diffuse large B-cell lymphoma early in 2016. n Disclosure: Dr. Schuster has received consultant fees and/or research funding from Pharmacyclics, Novartis, Janssen, Nordic Nanovector, Celgene, Genentech, and Hoffmann-La Roche.

Reference 1. Schuster SJ, Svoboda J, Nasta SD, et al: Sustained remission following chimeric antigen receptor modified T cells directed against CD19 (CTL019) in patients with relapsed or refractory CD19+ lymphomas. 2015 ASH Annual Meeting. Abstract 183. Presented December 6, 2015.

The ASCO Post | JANUARY 25, 2016

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ASH Annual Meeting New Drugs

Multiple Myeloma in 2015 continued from page 1

The drugs all received priority review or accelerated approval, which mobilizes drug delivery to patients who have exhausted other treatment options. Newly diagnosed patients also gained a new treatment option in 2015: lenalidomide (Revlimid) plus dexamethasone, which was previously indicated only in patients who have received at least one treatment. “We have to thank the FDA for approving these drugs so rapidly,” Dr. Rajkumar commented at the special session. Sagar Lonial, MD, Professor of Medicine at Emory University School of Medicine, Atlanta, proclaimed this “a year of success,” and commented, “This ‘embarrassment of riches’ is not embarrassing at all. It’s a consequence of collaborations between patients and academic, industry, and advocacy groups. Now, the challenge is to take the pieces and put them together in a coherent fashion.”

More Drugs, More Combinations According to Dr. Lonial, more new drugs and more drug classes make for more effective combination therapy. Myeloma is not a single-clone disease; therefore, it is best attacked via multiple agents working through different mechanisms. “There is a very strong case in support of combinations. Benefits of combinations are there, for both high-risk and standard-risk patients,” he emphasized. Combination therapies targeting all coexisting subclones can achieve better depth and duration of response than sequential therapy, he added. “Here at ASH, the combination of a proteasome inhibitor and immunomod-

ulatory drug has come of age,” Dr. Lonial said, citing several studies supporting this concept. In SWOG 0777, the triplet of bortezomib (Velcade)/lenalidomide/ dexamethasone significantly reduced the risk of both progression and death by 29% over lenalidomide/dexamethasone alone.2 This study confirmed, he said, that “three-drug induction is optimal, and an [immunomodulatory drug/proteasome inhibitor] combination is best.”

This ‘embarrassment of riches’ is not embarrassing at all. It’s a consequence of collaborations between patients and academic, industry, and advocacy groups. Now, the challenge is to take the pieces and put them together in a coherent fashion. —Sagar Lonial, MD

Positioning the New Drugs While elotuzumab, daratumumab, ixazomib, and panobinostat are indicated for relapsed/refractory myeloma, these new agents will also be incorporated into the front-line setting, according to Dr. Rajkumar, who acknowledged this is an off-label use.

cannot be used. “Keep in mind, you may have a situation where you can use ixazomib in newly diagnosed patients,” he said. Phase III trials in the front-line setting are underway examining lenalidomide/ dexamethasone in combination with ixazomib, elotuzumab, and daratumumab.

This is a revolutionary time in multiple myeloma. The three drugs approved in November—daratumumab, elotuzumab, and ixazomib—promise to change the landscape of treatment and improve overall survival. —S. Vincent Rajkumar, MD

Ixazomib will be a good substitute for bortezomib (in combination with lenalidomide/dexamethasone) for standard-risk patients who are frail or elderly (≥ 75 years) and for newly diagnosed patients who need a convenient alternative to bortezomib, he suggested. “What strikes me is that this is a very simple regimen, as you take just three drugs a month, and the side-effect profile is outstanding,” Dr. Rajkumar commented. The drug would also be useful under other circumstances where bortezomib

Relapsed/Refractory Patients Paul G. Richardson, MD, the R.J. Corman Professor of Medicine at Harvard Medical School and Director of Clinical Research and Clinical Program Leader of the Jerome Lipper Multiple Myeloma Center at Dana-Farber Cancer Institute, Boston, discussed how he would position the new drugs in patients with relapsed and refractory disease. “In myeloma, you can revisit classes of drugs that you previously gave, recognizing that rational combinations of the same

drugs make sense as you seek to salvage patients with recurrent disease…. Tolerability and quality of life should be kept in mind in assuring our patients not only live longer, but live well,” Dr. Richardson emphasized. To this end, physicians should consider age, frailty, and preexisting conditions, such as peripheral neuropathy and cardiovascular as well as thromboembolic risk. Genetic profiles, which are “highly dynamic,” and the phenomenon of clonal heterogeneity are “very real” considerations in relapse, explaining why combination approaches are consistently more effective in randomized trials. “The ability to throw a wide net around the disease is a key way forward,” he commented. “The use of newer drugs, first in relapse and then, earlier in disease, is also vital…. Their recent approvals add profoundly to our armamentarium in taking on this challenge.” Focusing on the monoclonal antibodies, Dr. Richardson emphasized that their novel mechanism of action should be especially effective in treating highrisk disease. “Daratumumab and elotuzumab are paradigm-changing agents. They appear to override the impact of mutations and provide entirely non–

Don’t Miss These Important Reports in This Issue of The ASCO Post Chandrakanth Are, MBBS, MBA, FRCS, FACS, on Cancer Burden in Afghanistan see page 126

Jia Ruan, MD, PhD, on Lenalidomide Plus Rituximab as Initial Treatment in Mantle Cell Lymphoma see page 111

Lora M.A. Thompson, PhD, and Peter A.S. Johnstone, MD, FACR, on Acupuncture for Cancer Symptom Clusters see page 120

Laura J. Esserman, MD, MBA, Julie R. Gralow, MD, and Marisa C. Weiss, MD, in a Roundtable Discussion on the New Frontiers of Breast Cancer see page 98

Visit The ASCO Post online at ASCOPost.com

Martin Dreyling, MD, on Progression-Free Survival in Relpased/Refractory Mantle Cell Lymphoma: Ibrutinib vs Temsirolimus see page 117

ASCOPost.com | JANUARY 25, 2016

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ASH Annual Meeting cross-resistant strategies, which we can also add to existing drugs,” he said. All of the new agents should boost the results already being achieved with triplets that include immunomodulatory drugs, a proteasome inhibitor, and dexamethasone. To this end, regimens containing lenalidomide/dexamethasone plus bortezomib, carfilzomib (Kyprolis), panobinostat plus bortezomib or carfilzomib, ixazomib, elotuzumab, daratumumab, and the still-investigational monoclonal antibody isatuximab (SAR650984) have shown promising efficacy in clinical trials. The newer immunomodulatory drug pomalidomide (Pomalyst) is also proving to be a very promising partner with the monoclonal antibodies, he indicated, as well as being highly effective in various other combinations, including bortezomib and carfilzomib. Specifically daratumumab given with pomalidomide/ dexamethasone yielded a response rate of 71% in heavily pretreated patients.3 “This suggests that combining daratumumab with an immunomodulatory drug could be very beneficial,” he said. Dr. Rajkumar agreed. “Clearly, the 31% response rate of single-agent daratumumab—in patients who had [experienced treatment failure on] almost everything— was very impressive from a regulatory standpoint,” he said. “But when you have a triple-refractory patient in front of you who hasn’t seen daratumumab before,

most of us are probably not going to use it as a single agent, because we know that 70% will not respond.” He added, “For second and third relapse, based on data we heard at this meeting, daratumumab

Elotuzumab is approved in combination with lenalidomide/dexamethasone; however, Dr. Richardson pointed out that many patients will be on lenalidomide/ dexamethasone maintenance when relapse

The use of newer drugs, earlier in disease, is vital…. Their approvals add profoundly to the armamentarium in taking on this challenge. —Paul G. Richardson, MD

plus [pomalidomide/dexamethasone] will be one of our choices.” Elaborating on the use of ixazomib, Dr. Richardson said this drug “fits very well” in the relapsed/refractory space because of its tolerability, oral route, and convenient once-weekly dosing. He sees it as especially useful in combination with lenalidomide/dexamethasone in patients with high-risk features. Ixazomib may also be a good partner for panobinostat, as well as the monoclonal antibodies, including daratumumab. Moreover, daratumumab is an anti-CD38 agent, and panobinostat upregulates CD38, he noted, making studies incorporating histone deacetylase inhibitors and monoclonal antibodies targeting CD38 of great interest.

occurs. In this situation, he may use elotuzumab in combination with a proteasome inhibitor, with recent data supporting the activity of this combination. In relapsed patients heavily exposed to lenalidomide, he would also consider pomalidomide in combination with one of the new drugs, “recognizing that participation in a clinical trial is ideal in that s etting.” Drs. Richardson, Rajkumar, and Lonial all emphasized that it is not a question of which new drug to use, but how to sequence the drugs, and this will be further complicated (and enhanced) when next-generation agents and drugs from new classes become available. “Our patients are likely to need all these drugs,” Dr. Richardson commented.

Dr. Rajkumar ended with a plea to the pharmaceutical industry. “It’s no longer a question of doublet vs triplet. It’s which triplet is best, and which endpoint is meaningful? Those are the trials I implore pharma to support,” he said. n

Disclosure: Dr. Rajkumar reported no potential conflicts of interest. Dr. Lonial is a consultant for Millennium, Celgene, Novartis, Bristol-Myers Squibb, Onyx, and Janssen. Dr. Richardson has served on advisory committees for Celgene, Johnson & Johnson, Millennium, Takeda, Bristol Myers Squibb, and Novartis.

References 1. ASH/FDA Joint Symposium on LateBreaking Drug Approvals: Late Breaking Approvals for Myeloma Drug Products. 2015 ASH Annual Meeting. Special-Interest Session. Presented December 7, 2015. 2. Durie B, Hoering A, Rajkumar SV, et al: Bortezomib, lenalidomide and dexamethasone vs. lenalidomide and dexamethasone in patients with previously untreated multiple myeloma without an intent for immediate autologous stem cell transplant. 2015 ASH Annual Meeting. Abstract 25. Presented December 5, 2015. 3. Chari A, Lonial S, Suvannasankha A, et al: Open-label multicenter phase 1b study of daratumumab in combination with pomalidomide and dexamethasone in patients with at least 2 lines of prior therapy and relapsed or relapsed and refractory multiple myeloma. 2015 ASH Annual Meeting. Abstract 508. Presented December 7, 2015.

2016 Genitourinary Cancers Symposium Look for coverage of the 2016 Genitourinary Cancers Symposium in the next issue of The ASCO Post or visit video.ASCOPost.com now to view interviews from the meeting conducted live as part of The ASCO Post Newsreels program. The symposium, held January 7–9, 2016, at the Moscone Convention Center in San Francisco attracted more than 3,100 experts from around the world. It is sponsored by ASCO, the American Society of Radiation Oncology, and the Society of Urologic Oncology. The theme of this year’s meeting was “Patient-Centric Care: Translating Research to Results.”

Pictured here are 1. Howard I. Scher, MD, Chief, Genitourinary Oncology Service, D. Wayne Calloway Chair in Urologic Oncology, at Memorial Sloan Kettering Cancer Center; 2. William U. Shipley, MD, Professor of Radiation Oncology, Harvard Medical School and Massachusetts General Hospital; and 3. Maha Hussein, MB ChB, Professor of Medicine and Urology at the University of Michigan and the Associate Director for Clinical Research at the University of Michigan Comprehensive Cancer Center. Photos by © ASCO/Todd Buchanan 2016.

The ASCO Post | JANUARY 25, 2016

PAGE 6

San Antonio Breast Cancer Symposium Tailored Therapy

Study Suggests Luminal A Breast Cancer Patients May Not Need Chemotherapy By Alice Goodman

he ability to classify breast cancer according to biologic subtype has enabled researchers to dig deeper and determine which therapies benefit specific subgroups. Encouraging evidence from an analysis of a Danish trial presented at the 2015 San Antonio Breast Cancer Symposium suggests that patients with luminal type A breast cancer can safely forgo chemotherapy.1 “A large body of evidence suggests

We need prospective randomized trials to establish that these low-risk women do not need chemotherapy,” explained lead investigator Torsten O. Nielsen, MD, PhD, Professor in the Department of Pathology and Laboratory Medicine at the University of British Columbia, Vancouver, Canada. Dr. Nielsen and colleagues performed a test of interactions between chemotherapy benefit and breast can-

Breast Cancer Subtype and Chemotherapy Benefit ■■ Luminal A subtype breast cancer, even if associated with high-risk features, generally has an excellent prognosis. ■■ A study of premenopausal women with high-risk luminal A breast cancer found that 10-year overall survival was similar for those who received chemotherapy and those who did not. ■■ These findings suggest that women with luminal A subtype breast cancer can safely forgo chemotherapy, but randomized controlled trials are needed for confirmation.

DBCG77B Trial

This study extends the body of evidence showing that women with low-molecular-risk breast cancers do not benefit from aggressive therapy. —Torsten O. Nielsen, MD, PhD

that luminal type A breast cancer has the best prognosis of all breast cancer subtypes. It has been difficult to do randomized trials without offering women with breast cancer adjuvant chemotherapy, because we know it helps them.

cer subtypes based on women treated in a phase III randomized trial of chemotherapy vs no chemotherapy. “This is the best way to test whether intrinsic breast cancer subtype predicts the value of chemotherapy,” he said.

The investigators used tissue samples from the Danish Breast Cancer Cooperative Group 77B (DBCG77B) trial of 1,146 premenopausal women with node-positive, high-risk breast cancer with any hormone receptor or HER2 status. High-risk features included tumors of 5 cm or greater or nodepositive status; hormone receptor and HER2 status were not ascertained because in 1977, when the trial was started, this was not standard of care. In the DBCG77B study, all women received standard treatment (for 1977): mastectomy plus axillary node dissection plus radiation. They were

then randomly assigned to one of two no-chemotherapy arms (receiving levamisole [Ergamisol] or no agent), or one of two chemotherapy arms (receiving single-agent cyclophosphamide or combination therapy with CMF [cyclophosphamide, methotrexate, and fluorouracil]). Both cyclophosphamide and CMF improved 10year disease-free survival and 25-year disease-free survival.

Prospective-Retrospective Analysis For the present study, an interaction test was conducted between lucontinued on page 8

EXPERT POINT OF VIEW

“T

his study was started in 1977. In this subgroup of premenopausal women with high-risk breast cancer but luminal A subtype, data suggest that there is no benefit from chemotherapy,” said Virginia Kaklamani, MD, leader of the Breast Cancer Program at the Cancer Therapy and Research Center and Professor of Medicine at The University of Texas Health Science Center

Exciting Data “We have prospective data on genomic profiling of tumors showing that these patients have a very good prognosis. We also have data on postmenopausal node-positive patients suggesting that chemotherapy does not benefit subtype luminal A breast cancer,” she said. “These data in premenopausal women are exciting,” she continued.

There is a gray area between overtreatment and undertreatment, and it is our responsibility to conduct the right studies and get the data to help make the correct decision. —Virginia Kaklamani, MD

in San Antonio. Dr. Kaklamani moderated a press conference at the San Antonio Breast Cancer Symposium where these data were discussed.

“In our practice, we would consider not giving chemotherapy to postmenopausal women with luminal A subtype, but not in younger women.”

“Until we have randomized controlled data, these data appear to confirm that we probably don’t need chemotherapy for younger women with luminal A breast cancer. This study gives me more confidence not to give chemotherapy to my premenopausal patients,” she said.

Open Question “We deal with these questions every day in clinical practice. In node-positive women, we often give chemotherapy even if they have less aggressive cancers. In patients with hormone receptor–positive cancers, we don’t know how much we are benefitting patients with chemotherapy on top of hormone therapy. That is an open question,” said William Sikov, MD, Associate Professor of Medicine at Brown University, Providence, Rhode Island, at the press conference. “We need a large body of evidence with modern therapy. This study is a step in that direction. At some point,

William Sikov, MD

we will have to make the decision about whether we can safely withhold chemotherapy,” Dr. Kaklamani said. “We have to take into account patient preference. There is a gray area between overtreatment and undertreatment, and it is our responsibility to conduct the right studies and get the data to help make the correct decision,” she stated. “It is not good if decisions are made based on fear and lack of understanding. We need to get the data and educate women,” she added. n Disclosure: Drs. Kaklamani and Sikov reported no potential conflicts of interest.

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The ASCO Post | JANUARY 25, 2016

PAGE 8

San Antonio Breast Cancer Symposium Novel Combinations

Neoadjuvant Palbociclib Enhances Effect of Anastrozole on Complete Cell-Cycle Arrest By Caroline Helwick

he cyclin-dependent kinase (CDK) 4/6 inhibitor palbociclib (Ibrance) enhanced cell-cycle control over that achieved with anastrozole alone in a study that evaluated the drugs’ ability to induce complete cell-cycle arrest in tumor cells and to produce clinical responses, as neoadjuvant therapy for breast cancer.1 “Palbociclib enhanced cell-cycle control regardless of PIK3CA mutation status or luminal A or B status of these hormone receptor–positive, HER2-negative breast cancer patients,” said Cynthia Ma, MD, PhD, Clinical Director of the Breast Cancer

Rationale for the Study CDK4 and CDK6, together with cyclin D, promote G1-to-S phase transition by phosphorylating the retinoblastoma protein, which releases the E2F transcription factor and activates downstream target genes. CDK4/6 is particularly activated in estrogen receptor–positive breast cancer via the estrogen receptor, along with other oncogenic signaling pathways, Dr. Ma explained. Palbociclib is an oral CDK4/6 inhibitor active in the metastatic setting in combination with an aromatase inhibitor or fulvestrant (Faslodex). Adjuvant trials of the drug are underway.

EXPERT POINT OF VIEW

an E. Krop, MD, PhD, of Dana-Farber Cancer Institute, Boston, commented on the findings by Ma et al in an interview with The ASCO Post, calling the study “very elegantly designed.” “The study provides three important pieces of information. One, it sug-

It does not appear that having a PIK3CA mutation inhibits the activity of [cyclin-dependent kinase (CDK)]4/6 inhibitors, which many of us were concerned about. This is a completely new finding. —Ian E. Krop, MD, PhD

Palbociclib enhanced cell-cycle control regardless of PIK3CA mutation status or luminal A or B status of these hormone receptor–positive, HER2negative breast cancer patients. —Cynthia Ma, MD, PhD

Program at Washington University School of Medicine, St. Louis. The combination also led to an overall clinical response rate of 67%. The study was met with interest at the 2015 San Antonio Breast Cancer Symposium, where Dr. Ma presented the study findings. A number of breast cancer experts applauded the design, which looked for both biologic and clinical effects of the CDK4/6 inhibitor as a companion to endocrine therapy before surgery. (A complete list of study investigators is included in reference 1.)

Luminal A Breast Cancer continued from page 6

minal A status and chemotherapy for the trial’s primary endpoint of 10-year disease-free survival. “This was a formal prospective-retrospective study,” Dr. Nielsen noted. Tissue staining of archival samples enabled scoring and subtyping by pathologists; then intrinsic subtyping was performed by tissue microarray. Luminal A subtype was defined as in previous publications as estrogen receptor– positive, HER2-negative, progesterone receptor > 20%, and Ki67 proliferation

gests that palbociclib can add to the benefit of aromatase inhibitors in the neoadjuvant setting, which we didn’t know before,” he said. “Two, it does not appear that having a PIK3CA mutation inhibits the activity of [cyclin-dependent kinase (CDK)]4/6 inhibitors, which many of us were concerned about. This is a completely new finding,” he noted. “Lastly, there is the inadvertent finding that when they stopped the drugs to allow patients to go to surgery, Ki67 rebounded. This suggests we may need to keep patients on palbociclib longer,” Dr. Krop continued. He indicated that the adjuvant trials of palbociclib, such as the PALLAS study, are evaluating 2 years of treatment with the drug. “I think these data support that approach,” he concluded. n

Dr. Ma reported the results of a phase II study of patients with clinical stage II/ III estrogen receptor–positive, HER2negative breast cancer. The study’s hypothesis was that the addition of palbociclib to anastrozole as neoadjuvant therapy would enhance complete cell-cycle arrest, the study’s primary endpoint. Complete cell-cycle arrest was defined as a proportion of tumor cells positive for Ki67 ≤ 2.7% on cycle 1, day 15 after 2 weeks of treatment with both drugs. “This endpoint was chosen because of previous findings that increasing levels of Ki67 on neoadjuvant endocrine

therapy was associated with increased risks of relapse long-term,” she said. “The hypothesis is that palbociclib would result in at least 50% improvement in the [complete cell-cycle arrest] rate, over that achieved by the aromatase inhibitor alone.” Fifty patients were started on anastrozole alone for the first 28-day cycle. Palbociclib at 125 mg/d was added for

four additional cycles before surgery, which was performed 2 to 4 weeks after the drugs were stopped (ie, the washout period). Premenopausal patients also received goserelin (Zoladex). Serial biopsies were taken at baseline and at several points during treatment. The final 10 patients received 10 to 12 days of palbociclib therapy (ie, did not

index < 14%. Of 633 immunohistochemistry-analyzed samples, 165 were identified as luminal A subtype. The main finding was that luminal A patients had similar 10-year disease-free survival with and without chemotherapy regardless of whether they were nodepositive and not on hormonal therapy, whereas non–luminal A patients were 50% more likely to survive disease-free at 10 years if they were treated with chemotherapy. The interaction between chemotherapy and luminal A/non–luminal A subtypes was significant (P < .05). Dr. Nielsen acknowledged several

caveats about this trial. The immunohistochemistry method has limited analytic validity as a clinical test, and this was a tissue microarray study on blocks recollected for gene-profiling analysis. Moreover, this was an older trial, in which patients did not receive modern treatments such as endocrine therapy, anthracyclines, or taxanes. Nonetheless, he told The ASCO Post, “This study extends the body of evidence showing that women with low-molecular-risk breast cancers do not benefit from aggressive therapy.” That being said, larger prospective studies are needed to

change practice in this regard. n

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

continued on page 9

Disclosure: Dr. Nielsen has disclosed royalties and receipt of intellectual property rights and consulting fees from NanoString Technologies as well as ownership interest in Bioclassifer LLC.

Reference 1. Nielsen TO, Jensen MB, Gao D, et al: High-risk premenopausal luminal A breast cancer patients derive no benefit from adjuvant chemotherapy: Results from the DBCG77B randomized trial. 2015 San Antonio Breast Cancer Symposium. Abstract S1-08. Presented December 9, 2015.

ASCOPost.com | JANUARY 25, 2016

PAGE 9

San Antonio Breast Cancer Symposium Neoadjuvant Palbociclib continued from page 8

undergo washout), to assess the effect of continued treatment before surgery. “These serial specimens allowed us to assess the biologic effect of anastrozole alone and then the effect of adding palbociclib,” she said.

Primary Endpoint Solidly Met Among the 45 evaluable patients, complete cell-cycle arrest at cycle 1, day 15 was achieved in 39 (87%), which exceeded the investigators’ expectation of 66%. Complete cell-cycle arrest was seen in both patients with PIK3CA wild-type disease and those with PIK3CA-mutated disease. Ki67 analysis on serial biopsies clearly demonstrated an enhanced cell-cycle control by the addition of palbociclib to anastrozole alone.

Clinical Response and Ki67 Rebound Clinical responses were observed for 31 of the 41 patients (67%) who completed at least three cycles of treatment, including complete responses in 24%, partial responses in 43%, and stable disease in 15%. Tumors appeared to be downgraded, but no pathologic complete responses were documented. Patients tended to have a rebound in Ki67 level in the washout period; however, this increase was not observed in patients who continued palbociclib. This rebound, she said, “indicates that palbociclib, like endocrine therapy, may need to be a maintenance treatment.” The findings support the evaluation of this combination for the adjuvant treatment of estrogen receptor–positive, HER2-positive breast cancer, Dr. Ma said. The observation of complete cell-cycle arrest, vs no complete cellcycle arrest, might someday help iden-

Role of Palbociclib in Early Breast Cancer ■■ In a phase II study of 45 early breast cancer patients, palbociclib added to anastrozole enhanced complete cell-cycle arrest and yielded a 67% clinical response rate. ■■ Enhanced cell-cycle control was observed regardless of PIK3CA status and in both luminal A and luminal B tumors. ■■ When treatment was stopped 2 to 4 weeks before surgery, Ki67 rebounded, suggesting that continued treatment with palbociclib may be warranted.

tify patients who would be sufficiently treated with endocrine therapy alone, she added. Adverse events were rare—most commonly neutropenia, leukopenia, and fatigue. The most common grade 3–4 toxicity was neutropenia (56%), but no patients developed neutropenic fever. Seven patients required dose reductions. n

Disclosure: Dr. Ma has received research support from Pfizer.

Reference 1. Ma CX, Gao F, Northfelt D, Goetz M, Forero A, Naughton M, Ademuyiwa F, Suresh R, Anderson KS, Margenthaler J, Aft R, Hobday T, Moynihan T, Gillanders W, Cyr A, Eberlein TJ, Hieken T, Krontiras

H, Hoog J, Han J, Guo Z, Vij K, Mardis E, Al-Kateb H, Sanati S, Ellis MJ: A phase II trial of neoadjuvant palbociclib, a cyclindependent kinase 4/6 inhibitor, in combination with anastrozole for clinical stage 2 or 3 estrogen receptor positive HER2 negative breast cancer. 2015 San Antonio Breast Cancer Symposium. Abstract S6-05. Presented December 11, 2015.

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The ASCO Post | JANUARY 25, 2016

PAGE 10

San Antonio Breast Cancer Symposium Targeted Therapy

Plasma-Based Test Identifies Impactful Mutations in BOLERO-2 Population By Caroline Helwick

plasma-based cell-free DNA test identified mutations in the estrogen receptor 1 gene (ESR1) in 30% of patients from the BOLERO-2 trial of everolimus (Afinitor) plus exemestane, and these mutations were correlated with survival. The results, which support the use of plasma as a source of prognostic—and perhaps predictive— information, were reported at the 2015 San Antonio Breast Cancer Symposium by Sarat Chandarlapaty, MD, of Memorial Sloan Kettering Cancer Center, New York.1 “Using a simple blood test, we found that the D538G and Y537S mutations in the estrogen receptor are more common in patients with advanced, estrogen receptor–positive breast cancer than previously appreciated,” Dr. Chandarlapaty revealed. The findings were met with enthusiasm by researchers interested in correlative studies of clinical trials, including 2016 President-Elect of ASCO Daniel Hayes, MD. “These trials were started before we recognized the importance of plasma DNA, so I’m pretty certain these

samples were not handled in a way that we all believe they should be,” said Dr. Hayes, the Stuart B. Padnos Professor of Breast Cancer Research and Co-Director of the Breast Oncology Program in the University of Michigan Compre-

involved in his analyses. “We collected these plasma samples, not thinking about doing genomic analyses for estrogen receptor mutations,” he said. Aside from performing “an additional hard spin,” he added, the handling of the

Patients with the D538G mutation derived a large benefit from the addition of everolimus, whereas those with the Y537S mutation did not. —Sarat Chandarlapaty, MD

hensive Cancer Center, Ann Arbor. Dr. Hayes said during the discussion, “I am asking this, because if you did something special to the samples, the rest of the research world would like to know what it is. We are all sitting on samples that we have been told are worthless. Are we wrong?” No, said Dr. Chandarlapaty, who noted that no unusual processing was

samples was standard. “The results tell us that some of the archival samples in our freezers may be usable for analysis.”

Key Results The analysis revealed two key mutations in the estrogen receptor 1 gene (ESR1), which they observed to be associated with survival of patients in the BOLERO-2 trial. “D538G and Y537S

Visit ASCOPost.com for Interviews Filmed Live During the 2015 San Antonio Breast Cancer Symposium The ASCO Post presents these and other important discussions: ■■ ■■ ■■ ■■ ■■

Results from NSABP B-35: Patient-Reported Outcomes TH3RESA Study: Final Overall Survival Results HR-Positive Breast Cancer: Results From the ABCSG-18 Trial Results of the CREATE-X Clinical Trial on Higher-Risk Disease Mastectomy vs Lumpectomy: Complications and Costs

Visit The ASCO Post online at ASCOPost.com

mutations appear to be associated with a more aggressive disease biology, as demonstrated by shorter overall survival. Patients with these mutations don’t respond as well to currently used therapies and die sooner than patients without these mutations,” Dr. Chandarlapaty reported. The researchers conducted cell-free DNA testing on blood samples from 541 patients. Of them, 155 (28.8%) had the D538G and/or Y537S mutation; 83 (15.3%) had the D538G mutation; and 30 (5.5%) had both. In an assessment of 302 archived solid tumor samples evaluated by nextgeneration sequencing, the ESR1 mutation was identified in only 3 (1.3%) of those samples. Both D538G and Y537S mutations were associated with shorter overall survival. Median overall survival in BOLERO-2 was 32.1 months in patients without mutations, vs 20.7 months in patients with one or both mutations—a highly significant difference (P = .000037). In patients with both mutations, overall survival fell to

ASCOPost.com | JANUARY 25, 2016

PAGE 11

San Antonio Breast Cancer Symposium 15.2 months. Risk related to the Y537S mutation was more than doubled, vs no mutation. “In a multivariate analysis adjusting for sensitivity to prior hormonal therapy, visceral disease and ECOG [Eastern Cooperative Oncology Group] performance status, the effect of ESR1 mutation, compared to wild-type, on overall survival remained significant,” he added. Referring to a previous mutational analysis of tumor specimens by Hortobagyi et al, which found no association between various mutations and treatment outcomes, he said, “I think plasma will identify this particular and critically important alteration better.”

Could ESR1 Be Predictive? Further analyses, which Dr. Chandarlapaty emphasized are preliminary and hypothesis-generating only, revealed differences in how these two mutations affect response to everolimus. BOLERO-2 showed that adding

everolimus to exemestane significantly reduced the risk of disease progression by 55% in metastatic patients who progressed after treatment with an aromatase inhibitor.2 “Patients with the D538G mutation derived a large benefit from the addition of everolimus, whereas those with the Y537S mutation did not,” he reported. In the exemestane-only arm, median progression-free survival was 3.9 months in wild-type patients, 2.7 months in those with the D538G mutation, and 4.1 months in patients with the Y537S mutation. In the arm receiving exemestane plus everolimus, median survival increased to 8.5 months in wild-type patients and 5.8 months in those with the D538G mutation but remained stable at 4.2 months in those with the Y537S mutation. The addition of everolimus, therefore, seems to confer no benefit over exemestane alone in the Y537S mutation group. “These unexpected results require further validation,” he added. n

ESR1 Mutations in Hormone Receptor–Positive Breast Cancer ■■ A plasma-based cell-free DNA test evaluated 541 blood samples from patients in BOLERO-2. ■■ The test identified mutations in the estrogen receptor 1 (ESR1) gene in almost 30% of patients. ■■ Patients with the mutations had worse overall survival. ■■ The use of the technology elicited interest from other researchers, who would like to apply these methods to their own archived blood samples.

Disclosure: Dr. Chandarlapaty has consulted for Chugai, Foresite Capital, and Oncothyreon.

References 1. Chandarlapaty S, Sung P, Chen D, et al: cf DNA analysis from BOLERO-2 plasma samples identifies a high rate of ESR1 mutations: Exploratory analysis for prognostic and predictive correlation of

mutations reveals different efficacy outcomes of endocrine-therapy-based regimens. 2015 San Antonio Breast Cancer Symposium. Abstract S2-07. Presented December 9, 2015. 2. Baselga J, Campone M, Piccart M, et a: Everolimus in postmenopausal hormonereceptor-positive advanced breast cancer. N Engl J Med 366:520-529, 2012.

EXPERT POINT OF VIEW

n an interview with The ASCO Post, 2016 President-Elect of ASCO Daniel Hayes, MD, explained his interest in what he labeled “very exciting technology.” “Most of the DNA in plasma is normal, coming from white cells. Within that, there’s a small amount of tumor DNA. I have been told that you either have to draw the blood and process it right away, before the white cells start dying and swamp Daniel Hayes, MD the tumor DNA, or draw it into tubes that contain a fixative that keeps the white cells from dying,” he said. “The point is, normal DNA can swamp cancer DNA if you don’t process it correctly,” added Dr. Hayes. “The blood samples from BOLERO-2 came from all over the world, and they almost certainly sat around on desk tops before they were spun down.” “This is important because many researchers have archived samples that we are keeping, but we didn’t think we could use them. In my opinion, since this was feasible, it opens up an enormous opportunity for researchers,” he said. “We want to do this too!” Dr. Hayes emphasized that the findings have utility in the laboratory world but not yet in the clinic, as the analysis on the effect of these mutations on outcome was exploratory, with very small numbers. “This is nothing to be used clinically,” he remarked. n Disclosure: Dr. Hayes reported no potential conflicts of interest.

Ado-Trastuzumab Emtansine Improved Overall Survival for Heavily Pretreated Patients With HER2-Positive Breast Cancer

mong patients with HER2-positive, metastatic breast cancer that had progressed despite treatment with two or more forms of HER2-targeted therapy (trastuzumab [Herceptin] and lapatinib [Tykerb]), median overall survival was increased for those treated with ado-trastuzumab emtansine (aka T-DM1 [Kadcyla]) compared with those who received treatment of physician’s choice, according to results from the phase III TH3RESA clinical trial presented by Hans Wildiers, MD, PhD, Professor of Medical Oncology at KU Leuven in Belgium, and colleagues at the 2015 San Antonio Breast Cancer Symposium.1

Study Background “The National Comprehensive Cancer Network guidelines, which are widely used as the standard for cancer care, were recently changed to recommend using [ado-

Hans Wildiers, MD, PhD

trastuzumab emtansine] as a preferred treatment for patients with trastuzumabexposed HER2-positive, metastatic breast cancer, meaning that it is generally used after a patient’s metastatic disease has progressed following treatment with a combination of a taxane-based chemotherapy and trastuzumab, with or without pertuzumab (Perjeta),” said Dr. Wildiers. “However, there are a lot of patients who received second- or later-line treatment before this recommendation

was put in place, and TH3RESA was designed to establish whether [adotrastuzumab emtansine] could benefit patients in later lines as well,” he added. “Previously published results from TH3RESA showed that [ado-trastuzumab emtansine] almost doubled progression-free survival,” said Dr. Wildiers. “Here we show that [the drug] actually increased overall survival for heavily pretreated patients with HER2-positive, metastatic breast cancer. This is very important because several breast cancer therapies that increase progression-free survival do not increase overall survival, and these patients urgently need new treatment options.”

Key Findings After a median follow-up of 30.5 months, the median overall survival was significantly longer among the 404 patients assigned to ado-trastuzumab em-

tansine compared with the 198 patients assigned to treatment of physician’s choice: 22.7 months compared with 15.8 months. The overall survival benefit was seen regardless of patient age, hormonereceptor status, visceral involvement, and number of prior treatment regimens. “Not only did the population of patients assigned to [ado-trastuzumab emtansine] have increased median overall survival, they also had reduced incidence of grade 3 and higher adverse events,” said Dr. Wildiers. n Disclosure: This study was supported by Roche. Dr. Wildiers has received lecture fees from Roche, Pfizer, Novartis, Teva, and Baxter Belgium and travel expenses from Roche.

Reference 1. Wildiers H, et al: 2015 San Antonio Breast Cancer SymposiumAbstract. Abstract S5-05. Presented December 11, 2015.

The ASCO Post | JANUARY 25, 2016

PAGE 12

In the Clinic Hematology

Elotuzumab in Previously Treated Multiple Myeloma By Matthew Stenger

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

n November 30, 2015, elotuzu mab (Empliciti) was approved for use in combination with lenalidomide (Revlimid) and dexamethasone for the treatment of patients with multiple myeloma who have received one to three prior therapies.1,2

Supporting Efficacy Data Approval was based on findings of improved progression-free survival and response rate in an open-label phase III trial in which 646 patients were randomized to receive elotuzumab in combination with lenalidomide and dexamethasone (n = 321) or lenalidomide plus dexamethasone alone (n = 325).2,3 Patients continued treatment until disease progression or unacceptable toxicity. Patients had a median age of 66 years (range = 37–91 years, 57% ≥ 65 years); 60% were male; 84% were white; Eastern Cooperative Oncology Group performance status was 0 or 1 in 91%; disease stage was I in 43%, II in 32%, and III in 21%; 32% had del(17p) and 9% had t(4;14); the median number of prior therapies was two; 35% had refractory disease and 65% had relapsed disease; and prior therapies included stem cell transplant (55%), bortezomib (Velcade; 70%), melphalan (65%), thalidomide (Thalomid; 48%), and lenalidomide (6%). Median progression-free survival was 19.4 months (95% confidence interval [CI] = 16.6–22.2 months) in the elotuzumab group vs 14.9 months (95% CI = 12.1–17.2 months) in the control group (hazard ratio [HR] = 0.70, P = .0004). The overall response rate was 78.5% vs 65.5% (P = .0002).

How It Works Elotuzumab is a humanized IgG1 monoclonal antibody directed against signaling lymphocyte activation molecule family 7 (SLAMF7). SLAMF7 is present on myeloma cells independent of cytogenetic abnormalities and is also expressed on natural killer cells,

plasma cells, and, at lower levels, on specific immune cell subsets of differentiated cells in the hematopoietic lineage. Elotuzumab directly activates natural killer cells through both the SLAMF7 pathway and Fc receptors. It targets SLAMF7 on myeloma cells and facilitates interaction with natural killer cells to mediate killing of myeloma cells through antibody-dependent cellular cytotoxicity. In preclinical models, the combination of elotuzumab and lenalidomide resulted in natural killer cell activation greater than that with either drug alone and increased antitumor activity in vitro and in vivo.

How It Is Used The recommended dose/schedule for elotuzumab is 10 mg/kg via intravenous (IV) infusion on days 1, 8, 15, and 22 for the first two 28-day cycles and on days 1 and 15 in every subsequent cycle until disease progression or unacceptable toxicity. Lenalidomide is given at 25 mg daily orally on

OF NOTE Elotuzumab is a humanized IgG1 monoclonal antibody directed against signaling lymphocyte activation molecule family 7, which is present on myeloma cells independent of cytogenetic abnormalities.

25–50 mg orally or IV or equivalent), an H2 blocker (ranitidine 50 mg IV or 150 mg orally or equivalent), and acetaminophen (650–1,000 mg orally). In the first dose of the first cycle, elotuzumab infusion should be started at a rate of 0.5 mL/min; if no infusion reaction is observed, the rate can be increased to 1 mL/min during minutes 30–60 and to 2 mL/min during the remainder of the infusion. During the second dose in cycle 1, infusion can be started at 1 mL/min during the first 30 minutes and increased to 2 mL/min in the absence of infusion reactions. All subsequent doses can be given at 2

Elotuzumab in Resistant Multiple Myeloma ■■ Elotuzumab (Empliciti) was approved for use in combination with lenalidomide (Revlimid) and dexamethasone for the treatment of patients with multiple myeloma who have received one to three prior therapies. ■■ The recommended dose/schedule for elotuzumab is 10 mg/kg via intravenous infusion on days 1, 8, 15, and 22 for the first two 28-day cycles and on days 1 and 15 in every subsequent cycle until disease progression or unacceptable toxicity.

days 1–21. Dexamethasone is given on days of elotuzumab infusion at 8 mg IV and 28 mg orally; on days 8 and 22 of the third and subsequent cycles, when elotuzumab is not given, dexamethasone is given at 40 mg orally. On days that elotuzumab is given, oral dexamethasone should be given at 3–24 hours before and IV dexamethasone at 45–90 minutes before elotuzumab. In addition to dexamethasone, patients should be premedicated 45–90 minutes prior to elotuzumab infusion with an H1 blocker (diphenhydramine

OF NOTE Elotuzumab carries warnings/precautions for infusion reactions, infections, second primary malignancies, hepatotoxicity, and interference with determination of complete response.

mL/min. In patients who have received four cycles, the infusion rate may be increased to a maximum of 5 mL/min. For grade ≥ 2 infusion reaction, infusion should be interrupted and appropriate medical and supportive measures instituted. With resolution to grade ≤ 1, infusion may be restarted at 0.5 mL/ min and increased at a rate of 0.5 mL/ min every 30 minutes as tolerated to the rate at which the infusion reaction occurred. The escalation regimen can be resumed if there is no recurrence. If a reaction recurs, infusion should be stopped and should not be restarted on that day. Patients who have an infusion reaction should have vital signs monitored every 30 minutes for 2 hours after the end of infusion. Severe infusion reactions may require permanent discontinuation of elotuzumab and emergency treatment. If dosing of one drug in the regimen is delayed, interrupted, or discontin-

ued, treatment with the other drugs may continue as scheduled. However, if dexamethasone is delayed or discontinued, the decision whether to administer elotuzumab should be based on clinical judgment (ie, risk of hypersensitivity). Dose delays and modifications for dexamethasone and lenalidomide should follow the prescribing information for these drugs.

Safety Profile In the phase III trial, the most common adverse events of any grade occurring with a ≥ 5% higher incidence in the elotuzumab group were fatigue (62% vs 52%), diarrhea (47% vs 36%), pyrexia (37% vs 25%), constipation (36% vs 27%), cough (34% vs 19%), and peripheral neuropathy (27% vs 21%). Grade 3 or 4 adverse events included pneumonia (14% vs 10%), fatigue (13% vs 12%), lymphopenia (9% vs 3%), and cataracts (6% vs 3%). Other important adverse reactions included infusion reactions, infections, second primary malignancies, hepatotoxicity, and interference with determination of complete response. Infections occurred in 81% vs 74% of patients, including grade 3 or 4 infections in 28% vs 24%, and fatal infections occurred in 2.5% vs 2.2%. Opportunistic infections occurred in 22% vs 13%, including fungal infections in 9.7% vs 5.4% and herpes zoster in 13.5% vs 6.9%. Second primary malignancies occurred in 9.1% vs 5.7%, including hematologic malignancies in 1.6% vs 1.6%, solid tumors in 3.5% vs 2.2%, and skin cancer in 4.4% vs 2.8%. Hepatotoxicity occurred in 2.5% vs 0.6%. The most common grade 3 or 4 lab abnormalities were lymphopenia (77% vs 49%), leukopenia (32% vs 26%), throm-

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

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In the Clinic

bocytopenia (19% vs 20%), hyperglycemia (17% vs 10%), and hypocalcemia (11% vs 5%). Vital sign abnormalities were more common with elotuzumab, including systolic pressure ≥ 160 mm Hg (33% vs 21%), diastolic pressure ≥ 100 mm Hg (17% vs 12%), systolic pressure < 90 mm Hg (29% vs 8%), and heart rate < 60 bpm (66% vs 31%). Serious adverse events occurred in 65% vs 57% of patients, with the most common in the elotuzumab group being pneumonia (15.4% vs 11%), pyrexia (6.9% vs 4.7%), respiratory tract infection (3.1% vs 1.3%), anemia (2.8% vs 1.9%), pulmonary embolism (3.1% vs 2.5%), and acute renal failure (2.5% vs 1.9%). Adverse events led to discontinuation of any component of treatment in 6.0% vs 6.3%. Elotuzumab carries warnings/precautions for infusion reactions, infections, second primary malignancies, hepatotoxicity, and interference with determination of complete response.

Elotuzumab can interfere with assays used to monitor M protein, which can affect the ability to determine complete response. Patients should have liver function monitored, and elotuzumab should be stopped if hepatotoxicity is suspected. Pregnancy risk with use of elotuzumab is unknown; lenalidomide can cause embryofetal harm and is con-

traindicated for use in pregnancy. n References 1. U.S. Food and Drug Administration: Approved drugs: Elotuzumab. Available at http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm474719. htm. Accessed January 9, 2016. 2. Empliciti (elotuzumab) for injection,

for intravenous use, prescribing information, Bristol-Myers Squibb Company, November 2015. Available at http://packageinserts.bms.com/pi/pi_empliciti.pdf. Accessed January 9, 2016. 3. Lonial S, Dimopoulos M, Palumbo A, et al: Elotuzumab therapy for relapsed or refractory multiple myeloma. N Engl J Med 373:621-631, 2015.

Contact

The ASCO Post

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

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

Editorial Office Harborside Press 94 North Woodhull Road Huntington, NY 11743 Phone: 631.692.0800 Fax: 631.692.0805 ASCOPost.com HarborsidePress.com

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Genitourinary Cancers Symposium Patient-Centric Care: Translating Research to Results

he 2016 Genitourinary Cancers Symposium was held earlier this month in San Francisco. Abstracts and presentations included data and discussion on the latest strategies in the prevention, screening, diagnosis, and treatment of prostate, kidney,

testicular, and urothelial cancers. Snapshots of data from some of the many studies presented are provided here. Further data and full coverage of the abstracts will be reported in upcoming issues of The ASCO Post. For interviews with experts

conducted live at the meeting, visit video.ascopost.com.

Metastatic Testicular Germ Cell Tumors Among patients with poor-risk metastatic testicular germ cell tumors, those

treated with first-line curative therapy who survive (and remain disease-free) for more than 2 years experience risk-of-relapse rates and survival times similar to those of favorable- or intermediate-risk patients. Such were the findings of a large multi-institutional study of patients

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Genitourinary Cancers Symposium with metastatic testicular germ cell tumors treated with first-line curative therapy from 1990 to 2012, presented by Ko et al.1 The study evaluated how initial risk changes over time for those who survived since curative treatment, a concept referred to as conditional survival. Findings from the study indicated that in patients with metastatic testicu-

lar germ cell tumors, those who survive for more than 2 years disease-free will likely remain alive in subsequent years.

Advanced Renal Cell Carcinoma New analyses from a phase III clinical trial of patients with previously treated advanced renal cell carcinoma demonstrated that patients of all risk levels

experience more benefit from cabozantinib (Cometriq), a small-molecule inhibitor of the tyrosine kinases c-MET and VEGFR2, than from the current standard of care, everolimus (Afinitor). The greater activity of cabozantinib was independent of the number of metastatic sites, number of prior treatments, and type of treatments administered.2

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Early findings from the first 375 patients showed that cabozantinib improved the median progression-free survival compared to everolimus (7.4 vs 3.8 months). The new analysis of data from all 658 patients showed that 75% of patients treated with cabozantinib experienced tumor shrinkage, continued on page 16

The ASCO Post | JANUARY 25, 2016

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Genitourinary Cancers Symposium Patient-Centric Care continued from page 15

Treatment Decision-Making in Prostate Cancer

compared to 48% of everolimus-treated patients. Researchers found that progression-free survival improvements associated with cabozantinib vs everolimus were consistent across patient subgroups such as risk category, tumor burden, and prior therapy.

An early study suggests that an experimental blood test may help aid in treatment selection for patients with prostate cancer.3 Investigators indicated that the liquid biopsy enables characterization of the heterogeneity of circulating tumor cells. Heterogeneity score was associated

with response to treatment with enzalutamide (Xtandi) or abiraterone acetate (Zytiga), both androgen receptor–directed therapies. The score was not correlated with response to taxanes.

Metastatic Urothelial Cancer In the pivotal phase II IMvigor 210 study, the investigational cancer immuno-

therapy atezolizumab produced durable and improved response rates in patients with locally advanced or metastatic urothelial carcinoma, according to data presented by Hoffman-Censits et al.4 Atezolizumab is a monoclonal antibody against programmed cell death ligand 1 (PD-L1). In the study, patients whose tumors showed high levels of PD-L1 expression

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Genitourinary Cancers Symposium had a median overall survival time of 11.4 months, while for the overall study population, median overall survival was 7.9 months. Moreover, the results showed that 84% of patients who responded to atezolizumab continued to show a benefit over almost 12 months of follow-up, regardless of their PD-L1 status. Phase III trials of atezolizumab are on-

going in metastatic urothelial cancer. n Disclosure: For full disclosures of the study authors, view the abstracts at meetinglibrary. asco.org.

References 1. Ko JJ, et al: Conditional survival of patients with metastatic testicular germ cell tumours treated with first-line curative therapy.

2016 Genitourinary Cancers Symposium. Abstract 472. Presented January 8, 2016. 2. Escudier BJ, et al: Subgroup analyses of METEOR, a randomized phase 3 trial of cabozantinib vs everolimus in patients with advanced renal cell carcinoma. 2016 Genitourinary Cancers Symposium. Abstract 499. Presented January 9, 2016. 3. Scher H, et al: Single CTC character-

ization to identify phenotypic and genomic heterogeneity as a mechanism of resistance to AR signaling directed therapies in mCRPC patients. 2016 Genitourinary Cancers Symposium. Abstract 163. Presented January 7, 2016. 4. Hoffman-Censits JH, et al: IMvigor 210, a phase II trial of atezolizumab in platinum-treated locally advanced or metastatic urothelial carcinoma. 2016 Genitourinary Cancers Symposium. Abstract 355. Presented January 8, 2016.

Even After Antiandrogen Therapy, Docetaxel Remains Useful in Prostate Cancer

study presented at the 2016 Genitourinary Cancers Symposium showed that 40% of patients with metastatic castration-resistant prostate cancer treated with docetaxel following abiraterone (Zytiga) had at least a 50% reduction in prostate-specific antigen (PSA), demonstrating the activity of this drug sequencing. These findings were presented at the by Thomas W. Flaig, MD, of the University of Colorado Cancer Center, and colleagues.1

Study Findings

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The multi-institution study followed 1,088 patients treated on the clinical trial COU-AA-302. Of the patients treated with abiraterone, 67% went on to receive further therapies, with 36% receiving two additional therapies and 17% receiving three or more. About half of all abiraterone-treated patients on the study were treated with docetaxel in the next line of therapy. Of these patients receiving docetaxel after abiraterone, 40% had PSA decline by more than half, demonstrating the effectiveness of this chemotherapy even after treatment with androgen-deprivation therapy. “Surprisingly, the next most common ‘treatment’ in this setting after docetaxel was no treatment at all,” Dr. Flaig noted. “This confirms the activity of abiraterone followed by docetaxel and represents important data on the sequencing of medical therapies under this new paradigm,” Dr. Flaig said. n Disclosure: For full disclosures of the study authors, see https://coi.asco.org/Report/ ViewAbstractCOI?id=156483.

Reference 1. Flaig TW, et al: Genitourinary Cancers Symposium. Abstract 168. Presented January 7, 2016.

The ASCO Post | JANUARY 25, 2016

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News Targeted Therapy

Bevacizumab Plus Chemotherapy continued from page 1

IIIA, squamous and nonsquamous) whose tumors were resected between 2007 and 2013. Within 6 to 12 weeks of surgery, they were randomized to receive adjuvant chemotherapy or chemotherapy plus bevacizumab. The chemotherapy regimen consisted of four cycles (every 3 weeks) of cisplatin (75 mg/m2) with vinorelbine, docetaxel, gemcitabine, or pemetrexed (Alimta) per physician’s choice. The experimental arm also received bevacizumab (15 mg/kg) every 3 weeks starting with cycle 1 of chemotherapy and continuing for 1 year. Postoperative radiation therapy was not permitted. The study results were released early, due to futility, after the interim analysis at a median follow-up of 41 months. Dr. Wakelee noted that 230 of 1,501 patients enrolled were ineligible, mostly because of inadequate nodal sampling. More than 80% completed all planned protocol treatment in the control arm, but after continued dropouts, only 37% completed the entire year of treatment in the bevacizumab arm. “The addition of bevacizumab to adjuvant chemotherapy failed to improve survival for patients with surgically resected early-stage NSCLC,” Dr. Wakelee reported. The hazard ratio for median overall survival, the primary endpoint, was 0.99 (P = .93) and was 0.98 (P = .75) for disease-free survival. “There was absolutely no difference between the arms for the overall survival and disease-free survival curves,” she added.

EXPERT POINT OF VIEW

lthough the results for E1505 were negative, “overall survival and disease-free survival are not the only things we can learn from this trial,” said Paul Bunn, Jr, MD, Distinguished Professor in the Division of Medical Oncology at the University of Colorado, Denver, who formally discussed the study. “These investigators made a tremendous effort to conduct a randomized trial with 1,500 patients. We are going to learn a lot from this story,” he said. For instance, future analyses may help to answer these questions: Was there a difference in any of the chemotherapy doublets in efficacy or toxicity when bevacizumab was present or absent? Is there a potential for a biomarker to emerge for benefit from bevacizumab? Correlative studies for E1505 will involve proteomic and microarray analysis of tissue; immunohistochemistry staining for vascular endothelial growth factor and intercellular adhesion molecule; and examination of serum, plasma, and whole blood for a number of tumor-related factors. “This study has the clinical and experimental data to answer questions. We still don’t know who to give antiangiogenic therapy to, and we hope to learn something from this negative trial in the future,” he said.

Comparing Study Designs Moving forward, Dr. Bunn asked whether large, randomized adjuvant trials are the best approach to these questions. “Is this where we should

be putting our money and effort?” The current E1505 study design was developed more than 10 years ago. “Before embarking on future such studies, we should ask whether the findings will even be relevant 10 years later,” he suggested. Regardless, he noted that many

pathologic complete responses in patients (not previously seen) and could hasten drug development, he added, noting that neoadjuvant studies of rociletinib and also the programed cell death ligand 1 (PD-L1) antibody atezolizumab are underway. “In my opinion, this is where we

We still don’t know who to give antiangiogenic therapy to, and we hope to learn something from this negative trial in the future. —Paul Bunn, Jr, MD

adjuvant trials are underway, mostly studying epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in EGFR-mutant populations. “My dime says that 5 years from now, we will have another round of negative trials,” he predicted. Instead, Dr. Bunn proposed that the lung cancer community follow the lead of the breast cancer community and conduct smaller, more short-term neoadjuvant trials. In a recent meta-analysis, neoadjuvant chemotherapy was shown to improve overall survival by an absolute 5% at 5 years (hazard ratio = 0.87, P = .007),1 which was essentially the same benefit shown in the adjuvant LACE trial.2 Neoadjuvant trials could lead to

should be going,” Dr. Bunn said. n Disclosure: Dr. Bunn has consulted for Amgen, AstraZeneca, Bayer, Biodesix, Boehringer-Ingelheim, Bristol-Myers Squibb, Celgene, Daiichi-Sankyo, Eli Lilly, GSK, Merck, Novartis, OSI/Genentech/Roche, and Sanofi-Aventis.

References 1. NSCLC Meta-analysis Collaborative Group: Preoperative chemotherapy for non-small-cell lung cancer: A systematic review and meta-analysis of individual patient data. Lancet 383:15611571, 2014. 2. Pignon JP, Tribodet H, Scagliotti GV, et al: Lung adjuvant cisplatin evaluation: A pooled analysis by the LACE Collaborative Group. J Clin Oncol 26:3552-3559, 2008.

‘Not the End of the Story’ In a press briefing, Dr. Wakelee said the failure of bevacizumab to show a benefit in early-stage disease was in keeping with what has been seen with the drug in colorectal cancer, where it also failed to show a benefit in the adjuvant setting.

Bevacizumab added no unexpected toxicities, but there was a significant increase in neutropenia and hypertension. Grades 3–5 toxicities that were significantly higher in the bevacizumab than in the control group included hypertension (30% vs 8%) and neutrope-

Bevacizumab in Early-Stage NSCLC ■■ E1505 failed to show a benefit for bevacizumab added to chemotherapy in early-stage resected non–small cell lung cancer. ■■ The hazard ratios were 0.99 for overall survival and 0.98 for disease-free survival.

nia (38% vs 33%). Overall grade 3 and higher adverse events were observed in 84% and 67%, respectively. “The study highlights the importance of randomized trials to prove—or disprove—the utility of drugs in different stages of disease,” Dr. Wakelee said. “With the development of other active agents in metastatic lung cancer, it will be important to investigate them fully in earlier stages and not assume the benefit seen in advanced stage will also be proven in earlier stages, though we can remain hopeful.” “This is not the end of the story,” she added. “We have many very impor-

tant subset analyses to be done and a significant amount of correlative work, which hopefully will be very meaningful,” she said. n Disclosure: Dr. Wakelee is an unpaid consultant for Genentech/Roche.

Reference 1. Wakelee HA, Dahlberg SE, Keller SM, et al: Randomized phase III trial of adjuvant chemotherapy with or without bevacizumab in resected non-small cell lung cancer: Results of E1505. 16th World Conference on Lung Cancer: Abstract PLEN04.03. Presented September 9, 2015.

The ASCO Post | JANUARY 25, 2016

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News Lung Cancer

ALK Rearrangements Common in Young Patients With Lung Cancer By Caroline Helwick

wo investigative groups have reported interesting observations about genomic alterations in the tumors of young patients with lung cancer. Notably, ALK rearrangement was the most common driver mutation found, in studies reported at the 16th World Conference on Lung Cancer.1,2 “To our knowledge, the Genomics of Young Lung Cancer study is the first of its kind to look prospectively at the genomic drivers of primary lung cancer in

Europe, and Australia. Comprehensive genomic profiling was done on tumor tissue by the FoundationOne assay; further genomic profiling with the FoundationOne Heme test was done on tumor samples of subjects with advanced adenocarcinoma who were wild-type for the seven anticipated oncogenes, to identify other targetable drivers. The goals of this study are to identify a “genomically enriched subtype” of lung cancer, to facilitate the delivery of

We suspected that young adults with lung cancer might be a special population enriched for driver mutations. We have far exceeded our statistical expectations, particularly when it comes to ALK rearrangements. —Barbara J. Gitlitz, MD

this population,” said Barbara J. Gitlitz, MD, Associate Professor of Clinical Medicine, Keck School of Medicine, University of Southern California, Los Angeles, presenting on behalf of the Addario Lung Cancer Medical Institute. Young patients with lung cancer may be prime candidates for personalized medicine strategies, as they tend to have more mutations that can be treated with existing targeted therapies, according to the study’s preliminary results, she added. “We wanted to draw attention to lung cancer in young adults, as far too often there is a long delay in diagnosis because lung cancer was never considered in the differential diagnosis of their symptoms. We want to end the stigma that lung cancer is only a disease of elderly smokers,” said Dr. Gitlitz.

A First in Recruitment The study is also a “first” in recruiting participants via the Internet. All subjects had developed lung cancer before age 40. “Participants can enter at a site that has IRB [institutional review board] approval, or via a website where people could remotely consent from anywhere in the world and participate in our clinical trial,” Dr. Gitlitz said at a press briefing. Because of the website (https:// www.openmednet.org/site/alcmi-goyl), 44% of patients enrolled online, primarily from all over the United States,

targeted therapy, and to lay the groundwork for further research, Dr. Gitlitz remarked.

High Proportion of Actionable Mutations Dr. Gitlitz presented data on the first 68 patients (33 men, 35 women) enrolled to date, whose median age at diagnosis was 35 years; 60 patients had adenocarcinoma, mostly stage IV; 7 had squamous cell tumors, and one patient had small cell lung cancer. Genomically, among the 50 patients with stage IV adenocarcinoma, 76% had an actionable mutation, a much

We should not miss the opportunity of EML4-ALK examination in the younger population, considering that the frequency in stage IV adenocarcinomas is nearly 60%. —Kosuke Tanaka, MD

For the other 24%, with stage IV adenocarcinoma, deeper sequencing uncovered “some very interesting genomics,” she said. These rarer mutations included an EGFR RAD51 fusion, EGFR kinase domain duplication (KDD), HER2, ATM, BRCA2, and TP53 mutations. “The EGFR RAD51 fusion is being described further as an actionable EGFR mutation,” said Dr. Gitlitz. EGFR-KDD has recently been investigated by another group.2 “EGFR-KDD was seen in a 33-yearold male with stage IV adenocarcinoma who had a 7-month partial response with afatinib [Gilotrif ], and at progression, resequencing revealed an EGFR-dependent mechanism of acquired resistance to afatinib, thereby validating EDGR-KDD as a driver alteration and therapeuic target,” she added. “Cell lines transformed to express this mutation, were also amenable to EGFR tyrosine kinase inhibition, so a new actionable mutation has been described by looking at young emergent lung cancer.” Dr. Gitlitz concluded with a plea to oncologists to perform comprehensive genomic testing on young patients. “We

Genomic Profile of Young Patients With Lung Cancer ■■ An international study and a Japanese study have elucidated the genomic profile of tumors from young (≤ age 40) patients with lung cancer. ■■ Approximately 75% of these young patients have a driver mutation. ■■ The most common mutation in both studies was ALK rearrangement.

higher proportion than the researchers expected. ALK mutations were highly prevalent (44%), whereas EGFR mutations were observed in 26% and ROS1 rearrangement was found in 6%. “We suspected that young adults with lung cancer might be a special population enriched for driver mutations. We have far exceeded our statistical expectations, particularly when it comes to ALK rearrangements,” she commented.

encourage all practitioners to obtain a panel of genomics on all of their patients, as far too often we see only one or two mutations tested for and then no further testing.” The Genomics of Young Lung Cancer trial is still accruing.

Japanese Study Results Kosuke Tanaka, MD, of the Aichi Cancer Center Research Institute in Nagoya, Japan, also reported that the

majority of young patients in his study had driver oncogenes.3 Dr. Tanaka and his colleagues retrospectively analyzed the clinical and genetic characteristics of 67 patients (40% male) with stages I–IV adenocarcinoma who were diagnosed at age 40 or younger. Median age was 36 years, 39% were never-smokers, and 68% had stage IV disease at diagnosis. Similar to Dr. Gitlitz’s study, in this study, 75% of patients had a driver oncogene, primarily ALK rearrangement (45%). EGFR mutations were observed in 27%. Rarer oncogenes included HER2 mutations, RET translocations, and KRAS. Dr. Tanaka agreed with Dr. Gitlitz: “We should not miss the opportunity of EML4-ALK examination in the younger population, considering that the frequency in stage IV adenocarcinomas is nearly 60%,” he said. “We should proceed to minor driver oncogene tests when EML4-ALK translocation and EGFR and KRAS mutations are all negative…. Comprehensive data are urgently necessary to appropriately provide tailor-made treatment with molecularly targeted therapies.” n Disclosure: Dr. Gitlitz has served on the speakers bureau for Genentech and Lilly. Dr. Tanaka reported no potential conflicts of interest.

References 1. Gitlitz BJ, Morosini D, Sable-Hunt A, et al: The genomics of Young Lung Cancer Study. 16th World Conference on Lung Cancer. Abstract ORAL22.05. Presented September 8, 2015. 2. Gallant JN, Sheehan JH, Shaver TM, et al: EGFR kinase domain duplication is a novel oncogenic driver in lung cancer that is clinically responsive to afatinib. Cancer Discov 5:1155-1163, 2015. 3. Tanaka K, Oya Y, Yoshida T, et al: Oncogenic profiling in lung adenocarcinoma emerged in the youth. 16th World Conference on Lung Cancer. Abstract ORAL22.07. Presented September 8, 2015.

The ASCO Post | JANUARY 25, 2016

PAGE 26

ASH Annual Meeting Adult Leukemia

Rituximab Adds Benefit to Chemotherapy in Adult B-Cell Precursor ALL By Caroline Helwick

he addition of rituximab (Rituxan) to the pediatric-inspired chemotherapy protocol for B-cell precursor acute lymphoblastic leukemia (ALL) significantly improved event-free sur-

vival in a large European study presented at the 2015 ASH Annual Meeting.1 The GRAALL-R 2005 phase III study is the first randomized study evaluating the role of rituximab in this population.

BRIEF SUMMARY OF PRESCRIBING INFORMATION FOR GRANIX® (tbo-filgrastim) injection, for subcutaneous use SEE PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE GRANIX is indicated to reduce the duration of severe neutropenia in patients with nonmyeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Splenic Rupture Splenic rupture, including fatal cases, can occur following administration of human granulocyte colony-stimulating factors. In patients who report upper abdominal or shoulder pain after receiving GRANIX, discontinue GRANIX and evaluate for an enlarged spleen or splenic rupture. 5.2 Acute Respiratory Distress Syndrome (ARDS) Acute respiratory distress syndrome (ARDS) can occur in patients receiving human granulocyte colony-stimulating factors. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving GRANIX, for ARDS. Discontinue GRANIX in patients with ARDS. 5.3 Allergic Reactions Serious allergic reactions including anaphylaxis can occur in patients receiving human granulocyte colony-stimulating factors. Reactions can occur on initial exposure. The administration of antihistamines‚ steroids‚ bronchodilators‚ and/or epinephrine may reduce the severity of the reactions. Permanently discontinue GRANIX in patients with serious allergic reactions. Do not administer GRANIX to patients with a history of serious allergic reactions to filgrastim or pegfilgrastim. 5.4 Use in Patients with Sickle Cell Disease Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disease receiving human granulocyte colony-stimulating factors. Consider the potential risks and benefits prior to the administration of human granulocyte colony-stimulating factors in patients with sickle cell disease. Discontinue GRANIX in patients undergoing a sickle cell crisis. 5.5 Capillary Leak Syndrome Capillary leak syndrome (CLS) can occur in patients receiving human granulocyte colonystimulating factors and is characterized by hypotension, hypoalbuminemia, edema and hemoconcentration. Episodes vary in frequency, severity and may be life-threatening if treatment is delayed. Patients who develop symptoms of capillary leak syndrome should be closely monitored and receive standard symptomatic treatment, which may include a need for intensive care. 5.6 Potential for Tumor Growth Stimulatory Effects on Malignant Cells The granulocyte colony-stimulating factor (G-CSF) receptor through which GRANIX acts has been found on tumor cell lines. The possibility that GRANIX acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which GRANIX is not approved, cannot be excluded. 6 ADVERSE REACTIONS The following potential serious adverse reactions are discussed in greater detail in other sections of the labeling: • Splenic Rupture [see Warnings and Precautions (5.1)] • Acute Respiratory Distress Syndrome [see Warnings and Precautions (5.2)] • Serious Allergic Reactions [see Warnings and Precautions (5.3)] • Use in Patients with Sickle Cell Disease [see Warnings and Precautions (5.4)] • Capillary Leak Syndrome [see Warnings and Precautions (5.5)] • Potential for Tumor Growth Stimulatory Effects on Malignant Cells [see Warnings and Precautions (5.6)] The most common treatment-emergent adverse reaction that occurred at an incidence of at least 1% or greater in patients treated with GRANIX at the recommended dose and was numerically two times more frequent than in the placebo group was bone pain. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. GRANIX clinical trials safety data are based upon the results of three randomized clinical trials in patients receiving myeloablative chemotherapy for breast cancer (N=348), lung cancer (N=240) and non-Hodgkin’s lymphoma (N=92). In the breast cancer study, 99% of patients were female, the median age was 50 years, and 86% of patients were Caucasian. In the lung cancer study, 80% of patients were male, the median age was 58 years, and 95% of patients were Caucasian. In the non-Hodgkin’s lymphoma study, 52% of patients were male, the median age was 55 years, and 88% of patients were Caucasian. In all three studies a placebo (Cycle 1 of the breast cancer study only) or a non-US-approved filgrastim product were used as controls. Both GRANIX and the non-US-approved filgrastim product were administered at 5 mcg/kg subcutaneously once daily beginning one day after chemotherapy for at least five days and continued to a maximum of 14 days or until an ANC of ≥10,000 x 106/L after nadir was reached.

“In our experience, about one-third of patients with B-cell precursor ALL have CD20-positive ALL, and in these patients, the addition of rituximab is well tolerated, significantly improves

Bone pain was the most frequent treatment-emergent adverse reaction that occurred in at least 1% or greater in patients treated with GRANIX at the recommended dose and was numerically two times more frequent than in the placebo group. The overall incidence of bone pain in Cycle 1 of treatment was 3.4% (3.4% GRANIX, 1.4% placebo, 7.5% non-USapproved filgrastim product). Leukocytosis In clinical studies, leukocytosis (WBC counts > 100,000 x 106/L) was observed in less than 1% patients with non-myeloid malignancies receiving GRANIX. No complications attributable to leukocytosis were reported in clinical studies. Additional Adverse Reactions Other adverse reactions known to occur following administration of human granulocyte colony-stimulating factors include myalgia, headache, vomiting, Sweet’s syndrome (acute febrile neutrophilic dermatosis), cutaneous vasculitis and thrombocytopenia. 6.2 Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. The incidence of antibody development in patients receiving GRANIX has not been adequately determined. 7 DRUG INTERACTIONS No formal drug interaction studies between GRANIX and other drugs have been performed. Drugs which may potentiate the release of neutrophils‚ such as lithium‚ should be used with caution. Increased hematopoietic activity of the bone marrow in response to growth factor therapy has been associated with transient positive bone imaging changes. This should be considered when interpreting bone-imaging results. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C Risk Summary There are no adequate and well-controlled studies of GRANIX in pregnant women. In animal reproduction studies, treatment of pregnant rabbits with tbo-filgrastim resulted in increased spontaneous abortion and fetal malformations at systemic exposures substantially higher than the human exposure. GRANIX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Animal Data In an embryofetal developmental study, pregnant rabbits were administered subcutaneous doses of tbo-filgrastim during the period of organogenesis at 1, 10 and 100 mcg/kg/day. Increased abortions were evident in rabbits treated with tbo-filgrastim at 100 mcg/kg/day. This dose was maternally toxic as demonstrated by reduced body weight. Other embryofetal findings at this dose level consisted of post-implantation loss‚ decrease in mean live litter size and fetal weight, and fetal malformations such as malformed hindlimbs and cleft palate. The dose of 100 mcg/kg/day corresponds to a systemic exposure (AUC) of approximately 50-90 times the exposures observed in patients treated with the clinical tbo-filgrastim dose of 5 mcg/kg/day. 8.3 Nursing Mothers It is not known whether tbo-filgrastim is secreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when GRANIX is administered to a nursing woman. Other recombinant G-CSF products are poorly secreted in breast milk and G-CSF is not orally absorbed by neonates. 8.4 Pediatric Use The safety and effectiveness of GRANIX in pediatric patients have not been established. 8.5 Geriatric Use Among 677 cancer patients enrolled in clinical trials of GRANIX, a total of 111 patients were 65 years of age and older. No overall differences in safety or effectiveness were observed between patients age 65 and older and younger patients. 8.6 Renal Impairment The safety and efficacy of GRANIX have not been studied in patients with moderate or severe renal impairment. No dose adjustment is recommended for patients with mild renal impairment. 8.7 Hepatic Impairment The safety and efficacy of GRANIX have not been studied in patients with hepatic impairment. 10 OVERDOSAGE No case of overdose has been reported. ©2014 Cephalon, Inc., a wholly-owned subsidiary of Teva Pharmaceutical Industries Ltd. All rights reserved. GRANIX is a registered trademark of Teva Pharmaceutical Industries Ltd. Manufactured by: Distributed by: Sicor Biotech UAB Teva Pharmaceuticals USA, Inc. Vilnius, Lithuania North Wales, PA 19454 U.S. License No. 1803 Product of Israel GRX-40580 January 2015 This brief summary is based on TBO-004 GRANIX full Prescribing Information.

event-free survival, and also prolongs overall survival in patients not receiving allogeneic stem cell transplant,” said Sébastien Maury, MD, of Höpital Henri-Mondor in Créteil, France, who presented the findings at the ASH Plenary Session on behalf of the Group for Research in adult ALL. The population included patients with Philadelphia chromosome (Ph)-negative, CD20-positive B-cell precursor ALL. “Adding rituximab to standard therapy should become a standard of care for these patients,” Dr. Maury suggested. The anti-CD20 monoclonal antibody rituximab has significantly improved the treatment of B-cell non-Hodgkin lymphoma and mature B-cell ALL. C20 is also expressed at diagnosis in 30%–40% of patients with B-cell precursor—and confers a worse prognosis. European researchers hypothesized that the drug may work in this malignancy as well.

Study Results The multicenter randomized GRAALL-R 2005 trial evaluated the potential benefit of adding rituximab to the pediatric-inspired GRAALL protocol.2 The study included 220 patients aged 18–59 with newly diagnosed

In our experience, about one-third of patients with B-cell precursor ALL have CD20-positive ALL, and in these patients, the addition of rituximab is well tolerated, significantly improves event-free survival, and also prolongs overall survival in patients not receiving allogeneic stem cell transplant. —Sébastien Maury, MD

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ASH Annual Meeting CD20-positive Ph-negative B-cell precursor ALL. CD20 positivity was defined as the expression of CD20 in more than 20% leukemia blasts. Rituximab (375 mg/m2) was given for a total of 16–18 infusions from induction to maintenance. Allogeneic stem cell transplantation was offered in first complete remission to patients with one or more conventional highrisk features. The primary endpoint was event-free survival.

Event-Free Survival Improved The modified intent-to-treat analysis included 209 patients (median age, 40 years). Treatment arms were well balanced for patient and disease characteristics. Within a median follow-up of 30 months, patients treated with rituximab had a significantly lower cumulative in-

cidence of relapse vs controls: 18% at 2 years, vs 30.5% (P = .029). No significant differences were observed in nonrelapse mortality, which at 2 years was 12% in each arm, Dr. Maury reported. Therefore, the study met its primary endpoint, with event-free survival rates at 2 years being 65% in the rituximab arm vs 52% in the control arm (HR = 0.66; P = .038).

Survival Benefit in Nontransplant Patients Overall survival, however, was not significantly improved with rituximab—71% at 2 years vs 64% in the control arm (HR = 0.70; P = .095)— at least in the whole population. However, when patients who received allogeneic stem cell transplant in first complete remission were censored at the time of transplant, resulting in an analysis limited to patients who did

Rituximab in B-Cell Precursor ALL ■■ Rituximab was added to a pediatric-inspired protocol for patients with CD20-positive, Ph-negative B-cell precursor acute lymphoblastic leukemia, and the study met its primary endpoint of improvement in event-free survival. ■■ At 2 years, event-free survival was 65% in the rituximab arm vs 52% in the control arm. ■■ Although overall survival was not significantly improved in the study population, survival was improved with rituximab among patients not undergoing allogeneic stem cell transplant at first complete remission.

not have transplant, overall survival was significantly prolonged with rituximab, Dr. Maury reported. With these patients censored, 2-year overall survival was 74% with rituximab plus chemotherapy and 63% with chemotherapy alone (HR = 0.55; P = .018). Event-free survival rates were 66% and 53%, respectively (HR = 0.59;

EXPERT POINT OF VIEW

obert Hromas, MD, of the University of Florida College of Medicine, Gainesville, who moderated a press briefing, commented that the finding of benefit with rituximab “resolves a long-standing controversy” with this cancer. “These results are exciting for those of us who treat leukemia,” he commented.

disease. We have not as much success in adults as we have had in treating children, so this strategy represents an advance,” he said. “We now have, for the first time, prospective evidence showing that rituximab is beneficial in this disease. One could argue that this study could be practice-changing.”

We now have, for the first time, prospective evidence showing that rituximab is beneficial in this disease. One could argue that this study could be practice-changing. —Timothy A. Graubert, MD

The ASCO Post asked Timothy A. Graubert, MD, Professor of Medicine, Harvard Medical School, and Hagler Family Chair in Oncology and Director of Hematologic Malignancies at Massachusetts General Hospital Cancer Center, Boston, for his thoughts on these findings. “Adult ALL in general is a difficult

Fewer Allergic Reactions Dr. Graubert was particularly intrigued by the occurrence of fewer hypersensitivity reactions in rituximab-treated patients. These allergic reactions may lead to discontinuation of asparaginase. “Allergic reactions were lower with rituximab, and it’s perhaps not

P = .021). A greater proportion of patients in the rituximab arm underwent allogeneic stem cell transplant (34% vs 20%; P = .029). Other factors impacting event-free survival were age, involvement of the central nervous system (CNS), and white blood cell count at diagnosis. In particular, risk was essentially doubled in patients with CNS disease and an elevated white blood cell count, even after adjustment for stem cell transplant.

Adverse Reactions

Robert Hromas, MD

surprising as to how this could happen,” he said. Rituximab depletes CD20-positive B cells but also normal B cells, which produce antibodies to mediate allergic reactions, he explained. “It’s conceivable that the positive results of the study are explained in part by this phenomenon. The open question is whether rituximab allowed these patients to receive greater cumulative exposure to asparaginase,” he added. “This needs to be analyzed and answered, but either way, the study was positive.” Disclosure: Dr. Hromas has an uncompensated and nonequity advisory position with Cloud Pharmaceuticals. Dr. Graubert reported no potential conflicts of interest.

Infection-related serious adverse events in nontransplanted patients numbered 71 in the rituximab arm and 55 in the control arm, which were not significantly different. Interestingly, fewer hypersensitivity reactions to asparaginase (a component of treatment) occurred in the rituximab arm, suggesting there could be a protective effect of rituximab via suppression of B cells producing anti-asparaginase antibodies. n Disclosure: Dr. Maury reported no potential conflicts of interest.

References 1. Maury S, Chevret S, Thomas X, et al: Addition of rituximab improves the outcome of adult patients with CD20-positive, Ph-negative, B-cell precursor acute lymphoblastic leukemia: Results of the randomized Graall-R 2005 study. 2015 ASH Annual Meeting. Plenary Session. Abstract 1. Presented December 6, 2015. 2. Huguet F, Leguay T, Raffoux E, et al: Pediatric-inspired therapy in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia: The GRAALL-2003 study. J Clin Oncol 27:911-918, 2009.

Visit The ASCO Post website at ASCOPost.com

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ASH Annual Meeting Targeted Therapy

Idelalisib Improves Progression-Free Survival Over Bendamustine Plus Rituximab in Chronic Lymphocytic Leukemia By Alice Goodman

delalisib (Zydelig) combined with bendamustine (Bendeka, Treanda) plus rituximab (Rituxan) was superior to chemotherapy with bendamustine/rituximab plus placebo, reducing the risk of progressive disease and death while improving progression-free survival and overall survival in patients with relapsed/ refractory chronic lymphocytic leukemia (CLL). These results of a phase III trial were presented at a late-breaking session at the 2015 American Society of Hematology (ASH) Annual Meeting and Exposition,1 adding to other good news for CLL patients presented at this meeting. “For the first time, we may be able to talk about curative stragtegies for CLL with combinations of new therapies. Idelalisib is one of these therapies and is an important option over the current standard of care,” said A ndrew D. Zelenetz, MD, PhD, Vice Chair of Medical Informatics in the Department of Medicine at Memorial Sloan Kettering Cancer Center, New York. Idelalisib is a first-in-class PIK3 inhibitor approved in combination

with rituximab for the treatment of patients with relapsed CLL and as first-line treatment in patients with 17p deletion or TP53 mutation who are unsuitable for chemotherapy.

Study Details The study randomly assigned 416 patients with relapsed/refractory CLL in a 1:1 fashion to receive idelalisib plus bendamustine/rituximab or placebo plus bendamustine/

Role of Idelalisib in CLL ■■ Idelalisib plus bendamustine/rituximab improved survival compared with bendamustine/rituximab alone in patients with relapsed/refractory chronic lymphocytic leukemia. ■■ These results of a phase III trial provide a new treatment option for this group of patients.

age 65. High-risk features included del(17p)/TP53 mutations (39%), unmutated IGHV (83.2%), and Rai

For the first time, we may be able to talk about curative strategies for CLL with combinations of new therapies. Idelalisib is one of these therapies and is an important option over the current standard of care. —Andrew D. Zelenetz, MD, PhD

rituximab. Patients were stratified according to 17p deletion and TP53 mutation status, as well as IGHV mutation status. At baseline, 76% of patients were male, and 58% were under

stage III/IV (46%). About 30% were refractory, and patients had received a median of two prior therapies. A prespecified interim analysis found that progression-free survival

EXPERT POINT OF VIEW

“C

learly idelalisib improved overall survival when added to bendamustine (Bendetta/Treanda)/ rituximab (Rituxan). These results are similar to those from the HELIOS trial reported at last year’s ASCO meeting,” said Susan O’Brien, MD, Associate

University of California, Irvine. HELIOS had a similar design and sought to determine whether ibrutinib (Imbruvica) added benefit to bendamustine/rituximab in a similar study population, although that trial excluded patients with a 17p deletion.

Clearly idelalisib improved overall survival when added to bendamustine/rituximab. These results are similar to those from the HELIOS trial reported at last year’s ASCO meeting. —Susan O’Brien, MD

Director for Clinical Science for the Chao Family Comprehensive Cancer Center and Medical Director of the Sue and Ralph Stern Center for Cancer Clinical Trials and Research at the

“At ASCO 2015, the discussant of the HELIOS trial, Lloyd Damon, MD [Director of Blood and Marrow Transplant and Hematologic Malignancies and Chief of

the Hematology Clinic at the University of California, San Francisco, Medical Center] raised a question that also pertains to the current trial, which is whether this wellconducted, large, randomized, controlled trial with an independent review committee asked the right question. With the long-term data that we have on ibrutinib [Imbruvica] alone, the question is whether we really need chemotherapy,” Dr. O’Brien added. “I think we could ask the same question about this trial; clearly idelalisib adds chemotherapy, but are the results better than what we would have gotten with idelalisib (and rituximab) alone? It is possible that with longer follow-up, there could be more complete remissions with the addition of the chemotherapy—or this might not be the case,” she stated. n Disclosure: Dr. O’Brien reported no potential conflicts of interest.

(the primary endpoint) and overall survival (a secondary endpoint) were superior in the idelalisib arm. An independent data monitoring committee recommended unblinding the study based on “overwhelming efficacy.”

Key Outcomes Data For the primary endpoint of progression-free survival, idelalisib achieved a highly statistically significant gain: 23.1 vs 11.1 months, respectively (P < .0001), representing a 67% reduction in risk of progression or death. The progression-free survival benefit was consistent across all subgroups, regardless of mutational status. Median overall survival has not yet been reached in either arm, but at the time of the ASH meeting, it appeared that idelalisib was 45% more likely to achieve a survival benefit than bendamustine/ rituximab alone (P = .008). This benefit was also observed across all subgroups. Overall response rate was significantly higher in the idelalisib arm: 68% vs 45%. Dr. Zelenetz said that the complete response rate was low, because there weren’t enough confirmatory biopsies to determine the actual complete response rate.

Safety Profile Both arms of the study were associated with toxicity, but serious adverse events were more common in the idelalisib arm. More treatment discontinuations were reported in the idelalisib arm. The most common all-grade adverse events in the idelalisib arm were neutropenia and pyrexia: 63.3%, vs 41.5% in the placebo-plus-bendamustine/rituximab arm. The most common adverse events in the bendamustine/rituximab arm were neutropenia and nausea: 53.6%, vs 34.4% in the idelalisib arm. The most common grade 3 and higher adverse events were neutropenia (59%) and febrile neutropenia (20.3%) continued on page 30

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The ASCO Post | JANUARY 25, 2016

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ASH Annual Meeting Adverse Events

Severe Toxicities Seen in Younger Patients Receiving Front-Line Idelalisib for Chronic Lymphocytic Leukemia By Alice Goodman

ematologists and patients with chronic lymphocytic leukemia (CLL) are excited about new drugs that have dramatically improved outcomes. But all drugs have side effects, and it is important to be aware of potential consequences. Hepatotoxicity turns out to be a

Harvard Medical School, Boston. “In the span of a 2-week rotation, I had to admit three patients to the hospital with hepatotoxicity during the lead-in phase of single-agent idelalisib. We decided to assess hepatotoxicity more fully in patients enrolled on the trial who were on single-agent ideBenjamin L. Lampson, MD, PhD

The take-home message is that I would be extra cautious about using idelalisib upfront in younger, more immunocompetent, and less pretreated patients. —Jennifer R. Brown, MD, PhD

major concern in younger CLL patients treated with front-line idelalisib (Zydelig), according to a study presented at the recent American Society of Hematology (ASH) Annual Meeting and Exposition.1 (Idelalisib is not approved by the U.S. Food and Drug Administration for use in the frontline setting.)

Study Background Previous reports of idelalisib-associated hepatoxicity have ranged from 2% in phase I trials to 14% in the relapsed/refractory setting. But in an ongoing phase II trial of front-line idelalisib plus ofatumumab ( Arzerra), the rate of grade 3 and 4 toxicity was 52%. In an effort to understand why this was occurring and how to manage it, Jennifer R. Brown, MD, PhD, principal investigator for the phase II trial, and colleagues analyzed the first 24 patients to enroll on this trial. Dr. Brown is Director of the CLL Center at Dana-Farber Cancer Institute and Associate Professor of Medicine at

Idelalisib in CLL continued from page 28

in the idelalisib arm and neutropenia (45.9%) and anemia (12%) in the bendamustine/rituximab arm. Grade 3 and higher diarrhea, pneumonitis, and elevations in transaminase levels were all more frequent in the idelalisib arm.

lalisib prior to the addition of ofatumumab,” explained presenting author Benjamin L. Lampson, MD, PhD, a Clinical Fellow at Dana-Farber. “The hepatotoxicity we saw in this trial in previously untreated patients was outside the spectrum that we see in the relapse setting, in which this is readily manageable by holding drug. Our patients were rapidly worsening despite the drug being withheld. Normally that would not happen,” Dr. Brown explained. Hepatotoxicity occurred early in the course of front-line idelalisib.

Autoimmune Reaction Median time on therapy was 7.7 months for all subjects, and median follow-up was 14.7 months. The investigators found that younger patients were significantly more likely to develop hepatotoxicity compared with older patients (P = .02.). Further, they were able to characterize it as an autoimmune reaction, since liver biopsies of these patients revealed T-cell infiltrates. Approximately 73% of 11 Side effects of concern with idelalisib included elevations in liver enzymes and resultant hepatotoxicity. The rate of all grades of elevated alanine aminotransferase (ALT) was 59.9% in the idelalisib arm vs 30.6% in the bendamustine/rituximab arm; grade 3 or higher ALT elevations were 21.3% vs 2.9%, re-

subjects with matched samples had decreases in regulatory T cells over time. Twelve patients with grade 2 or higher elevated transaminases were rechallenged with idelalisib. Five were off steroids and seven were on steroids at the time of rechallenge. Of them, four (in the off-steroid group) had a recurrence of transaminase elevation within 1 to 2 days and two (in the on-steroid group) had a recurrence within 3 to 4 days. “Patients do better if they are rechallenged while on steroids, and then we taper them. If they are not on steroids they will have a rapid recurrence,” Dr. Brown noted. “Additionally, the number of prior therapies may be a risk factor. The phase I trial had patients with a median of five prior therapies and only a 2% risk of grade 3-4 transaminitis,” Dr. Lampson said. “The trial was originally designed to include all ages. Of the first 24 patients, 7 were under age 65, and it turned out that these were the most severely affected, perhaps because their immune systems were intact and more competent,” Dr. Brown explained.

Cautionary Note “Idelalisib is not approved in the front-line setting, but when using it in the relapsed/refractory setting, clinicians need to be aware of this toxicity,” she continued. spectively. Aspartate aminotransferase (AST) levels were also more elevated in the idelalisib arm: all grades, 52.2% vs 27.8%, respectively; grade 3 and higher elevated AST levels were seen in 15.5% vs 3.3%, respectively. n Disclosure: Dr. Zelenetz has received research funding from Gilead Sciences.

Dr. Brown said that they have slowed trial accrual and plan to enroll patients over age 65 as the trial goes on. “We are gearing our enrollment toward older patients with lower tumor burden,” she said. The current strategy at Dana-Farber is to perform liver function tests on all patients twice weekly from weeks 3 to 16. Grade 1 alanine aminotransferase (ALT) and aspartate aminotransferase (AST) elevations are treated with 40 mg of prednisone. Idelalisib is withheld if grade 2 elevations develop with this strategy. For higher grade 2 and grade 3 elevations, the drug is withheld, and prednisone is ramped up to 1 mg/kg, she said. “The take-home message is that I would be extra cautious about using idelalisib upfront in younger, more immunocompetent, and less pretreated patients. Lab monitoring is advised. Also, it is prudent to make sure that the patient does not have other hepatotoxins, such as [acetaminophen] or hepatitis virus infection,” she continued. At Dana-Farber, statins are currently withheld in patients treated with upfront idelalisib. “Statins are hepatotoxic, and we will withhold them until we understand all the contributing factors,” she said. n Disclosure: The study was funded by Gilead. Dr. Brown is a consultant for Gilead and Infinity. Dr. Lampson reported no potential conflicts of interest.

Reference 1. Lampson B, Matos T, Haesook T, et al: Idelalisib given front-line for the treatment of chronic lymphocytic leukemia results in frequent and severe immunemediated toxicities. 2015 ASH Annual Meeting. Abstract 497. Presented December 7, 2015.

Reference 1. Zelenetz A, Robak T, Coiffier B, et al: Idelalisib plus bendamustine and rituximab (BR) is superior to BR alone in patients with relapsed/refractory chronic lymphocytic leukemia. 2015 ASH Annual Meeting. Abstract LBA-5. Presented December 8, 2015.

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ASH Annual Meeting Leukemia

Venetoclax May Prove to Be Strong Weapon Against Poor-Prognosis Chronic Lymphocytic Leukemia By Alice Goodman

enetoclax, the latest entry into the field of treatment of chronic lymphocytic leukemia (CLL), is a powerful investigational therapy that promises to fill an important niche: treatment of highrisk relapsed/refractory patients with deletions of 17p. Nearly 80% of patients with relapsed/refractory CLL characterized by 17p deletions achieved response to venetoclax monotherapy, and responses appear to be durable, according to the results of a late-breaking phase II study presented at the 57th American Society of Hematology (ASH) Annual Meeting and Exposition.1 Deletions of 17p are associated with poor treatment outcomes. Venetoclax has received Breakthrough Designation status from the U.S. Food and Drug Administration (FDA) for patients with relapsed/refractory CLL and the 17p deletion. Venetoclax is an oral, small molecule inhibitor of Bcl-2, a protein that promotes cell survival and is overexpressed in CLL. This agent unleashes such powerful antitumor activity that tumor lysis syndrome is a major concern, which has led investigators to use a cautious dosing schedule for this new drug, starting at very low doses and ramping up to a target dose slowly. “In this pivotal multicenter phase II study of venetoclax monotherapy, we saw deep responses and acceptable toxicity in a relapsed/refractory population. We saw investigator-confirmed complete response of 7.5% and nodular partial response of 2.8%, with minimal disease negativity in greater than 20%,” said presenting author Stephan Stilgenbauer, MD, of

the University of Ulm, Germany. “In this study, venetoclax had a favorable risk-benefit profile. The

risk of tumor lysis syndrome was effectively mitigated by our careful dosing strategy, and we saw no

clinical tumor lysis syndrome,” Dr. Stilgenbauer told listeners. continued on page 32

Evasion of apoptosis may be a question of balance Increased BCL-2 expression helps cancer cells to survive1 BCL-2

Release of pro-apoptotic proteins may trigger apoptosis1

Pro-apoptotic proteins sequestered by BCL-2

Free pro-apoptotic proteins

Increased expression of BCL-2 impairs the pathway to programmed cell death Like normal cells, cancer cells will often induce expression of pro-apoptotic proteins in response to stressors like limited metabolic resources, rapid cell division, or exposure to cytotoxic agents.1 Cancer cells may increase expression of the anti-apoptotic protein, BCL-2.1 Pro-apoptotic proteins are bound and sequestered by BCL-2, helping the cancer cell to avoid programmed cell death.2 Mitochondria

Pro-apoptotic proteins—if released from BCL-2—have the potential to trigger apoptosis.1

Targeted Therapy in CLL ■■ Venetoclax, an investigational agent that targets Bcl-2, has achieved excellent and durable response rates as monotherapy in poor-prognosis patients with 17p deletion.

To learn more about the BCL-2 pathway, visit

researchBCL2.com

■■ Caution should be exercised when initiating therapy with venetoclax, as patients at high risk for tumor lysis syndrome require hospitalization when the oral drug is started.

References: 1. Letai AG. Diagnosing and exploiting cancer’s addiction to blocks in apoptosis. Nat Rev Cancer. 2008;8(2):121131. 2. Garcia-Saez AJ. The secrets of the Bcl-2 family. Cell Death Differ. 2012;19(11):1733-1740.

■■ Venetoclax is being studied in combination with other CLL drugs in relapsed/refractory disease and as upfront therapy. © 2015 Genentech USA, Inc. All rights reserved. BIO/102015/0191a Printed in USA.

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ASH Annual Meeting Venetoclax in CLL

Key Results

continued from page 31

The primary endpoint of Independent Review Committee–assessed overall response rate was 79.4%, with a com-

Study Details

The pivotal study enrolled 107 patients with relapsed/refractory CLL who had 17p deletions confirmed by a central laboratory. These patients typically have a median progression-free survival with front-line chemotherapy of less than 12 months, he said. Due to concerns about tumor lysis syndrome that emerged in preliminary studies, venetoclax was given in a stepped-up dosing schedule, starting with 20 mg/d and ramped up weekly to the target dose of 400 mg by week 4. Median age was 67; 65% were male; median number of prior therapies was two; about 50% had previous bendamustine (Treanda) at relapse. About 42% were considered to be at high risk for tumor lysis syndrome. Median time on the study was 12.1 months; 37 patients discontinued treatment with venetoclax due to disease progression, and 9 patients discontinued treatment due to adverse events. There were 18 deaths, 14 due to progressive disease.

venetoclax achieved durable responses. Median time to durability of response has not yet been reached, he noted. The 12-month estimated rate of pro-

Combination Therapy

gression-free survival is 72%, and that for overall survival is 86.7%. Median overall survival has not yet been reached.

Venetoclax is being studied in combination with other drugs in CLL. At the ASH Annual Meeting, two different phase Ib studies showed that venetoclax could be safely and effectively combined with obinutuzumab, rituximab, and bendamustine/rituximab. Another phase 1b study looked at venetoclax monotherapy in patients refractory to ibrutinib or idelalisib. The phase III MURANO trial of venetoclax in combination with rituximab vs rituximab plus bendamustine in a broader relapsed CLL population is underway.

Toxicity

Clinical Consideration

Adverse events were mostly low-grade neutropenia, anemia, and thrombocytopenia. Serious adverse events were reported in 55%. Adverse events of special interest were grades 3 and 4 neutropenia in 40%, infections in 72%, and tumor lysis syndrome (lab measurements only) in five pa-

Kanti Rai, MD, a pioneer in the staging and treatment of CLL who practices at Northwell Health System, New Hyde Park, New York, commented on Dr. Stilgenbauer’s presentation. “Although this is welcome news about venetoclax, you have not mentioned the fact that the introduction of this drug deserves a very careful entry. You did mention ramp-up dosing, but you did not mention that patients have to be admitted to the hospital for safety with this oral agent,” he stated. “Tumor lysis syndrome was effectively eliminated in this trial. Nonetheless oncologists and pharmacists who will use this drug in the future ought to know that the start requires hospitalization and frequent monitoring in the first 24 to 48 hours,” Dr. Rai said. “This is a very important point,” Dr. Stilgenbauer replied. “The initiation of venetoclax has to be handled with care. The ramp-up dosing has to be managed cautiously. Based on our management strategy, the current scheme requires hospitalization only for high-risk patients, but they need to be treated with allopurinol and have laboratory monitoring. Efficacy comes at a price, and vigilance is required.” n

In this pivotal multicenter phase II study of venetoclax monotherapy, we saw deep responses and acceptable toxicity in a relapsed/refractory population. —Stephan Stilgenbauer, MD

plete response rate of 7.5% and a nodular partial response rate of 2.8%. Minimal residual disease was negative in the peripheral blood of 18 of 45 patients. Of 87 patients with baseline lymphocytosis, the absolute lymphocyte count did not normalize in only 4 patients. Median time to normalization on the drug was 22 days. Median time to first response was 0.8 months; median time to response was 2.7 months. According to Dr. Stilgenbauer,

EXPERT POINT OF VIEW

n a separate interview, Kanti Rai, MD, of the Northwell Health System in New Hyde Park, New York, noted that venetoclax is one of several “exciting recent developments in this disease.” There is the Bruton tyrosine kinase inhibitor ibrutinib (Imbruvica), the PI3K inhibitor idelalisib (Zydelig),

cessive presence of the inhibitor protein Bcl-2. If we can successfully inhibit Bcl-2, then the leukemic cell has no protective survival advantage,” Dr Rai continued. “Venetoclax, perhaps, offers a unique opportunity to maximize the therapeutic potential of ibrutinib and idelalisib,” he added. “The potential

We have a distance to go to achieve a cure, but it is a shorter distance with these new drugs. —Kanti Rai, MD

the anti-CD20 obinutuzumab (Gazyva), “which has been shown to be more powerful than rituximab [Rituxan],” and now the Bcl-2 inhibitor venetoclax. “Venetoclax comes at the right time, when the treatment of CLL is becoming more targeted. Ibrutinib and idelalisib differ from classic chemotherapy, which indiscriminately kills normal and malignant cells. One of the key abnormalities in CLL is that CLL cells are protected from programmed cell death by the ex-

tients during the ramp-up dosing period. Only two of these patients required dose interruption on 1 day. “There was no clinical tumor lysis syndrome event,” he stated.

of adding venetoclax opens the whole field of combining this drug with other therapies to improve outcomes of this disease. Two small studies of combination therapy bear this out.”

A Potential Drawback “My reservation about venetoclax is that it is so effective in killing leukemic cells that it can cause tumor lysis syndrome. Experience with tumor lysis syndrome sobered up the company

and investigators to come up with a new dosing schedule. Patients at high risk of tumor lysis syndrome need to be admitted to the hospital, with frequent blood tests two to three times a day. This is a potential drawback that puts pressure on the patient, the public, the health-care system, and insurers. Physicians who will be using this new and effective drug should be cautioned about the need for hospitalization of patients, even if this is an orally administered agent and even if the need for hospitalization is only for 1 to 2 days,” noted Dr. Rai.

Progress but Not a Cure “People often exaggerate the benefits of new drugs. I am grateful for these new drugs that represent significant progress, but we need to recognize that they do not represent a cure. We have a distance to go to achieve a cure, but that distance has been rendered shorter because of these new drugs. We can measure our progress in inches, but we still need to go several additional feet or yards. Combining a venetoclax type of drug with an idelalisib type of drug or an ibrutinib type of drug might bring us closer to a cure by yards,” Dr. Rai concluded. n Disclosure: Dr. Rai reported no potential conflicts of interest.

Disclosure: The study was sponsored by AbbVie and Genentech. Dr. Stilgenbauer reported financial relationships with AbbVie, Amgen, BoehringerIngelheim, Celgene, Genentech, Genzyme Gilead, GlaxoSmithKline, Janssen, Mundipharma, Novartis, Pharmacyclics, and Hoffmann La Roche.

Reference 1. Stilgenbauer S, et al: Venetoclax (ABT199/GDC-0199) monotherapy induces deep remissions, including complete remission and undetectable MRD, in ultra-high risk relapsed/ refractory chronic lymphocytic leukemia with 17p deletion. ASH Annual Meeting. Abstract LBA-6. Presented December 8, 2015.

ASCOPost.com | JANUARY 25, 2016

PAGE 33

ASH Annual Meeting Immunotherapy

New Use for CAR-T Cells Post Transplantation By Alice Goodman

he approach of using genetically engineered chimeric antigen receptor (CAR)-T cells has received much attention for treating leukemias, where it has achieved spectacular longlasting complete remissions in some patients with no other treatment options. CAR-T cells are also being studied in lymphomas and other hematologic malignancies, and a new study suggests that CAR-T therapy can induce remissions in some patients who have progressed after allogeneic stem cell transplant.1 This study, presented at the 57th American Society of Hematology Annual Meeting and Exposition by James Kochenderfer, MD, of the Center for Cancer Research at the National Cancer Institute, Bethesda, Maryland, used genetically engineered CAR-T cells from a transplant donor’s T cells. This approach differs from that of other studies, which have used a patient’s own T cells to manufacture CAR-T cells. Unlike other studies of CAR-T cells, Dr. Kochenderfer’s study used a single infusion of CAR-T cells with no additional chemotherapy. “We need new therapies for progressive disease after allogeneic stem cell transplant. These patients are in a dire situation. A donor lymphocyte of unmanipulated origin has inconsistent efficacy and significantly more mortality and

graft-vs-host disease. We aimed to improve efficacy in progressive disease after transplant by using anti-CD19 CAR-T cells. We are one of the only groups to use CAR-T cells for this purpose,” explained Dr. Kochenderfer, one of the first investigators to study these cells in lymphoma. “In this small study, we used allogeneic donor T cells instead of the patient’s own T cells. We went back to the transplant donor to get more lymphocytes and genetically engineered them to make CAR-T cells,” he explained. “We used a gamma retroviral vector, and cell production took 8 days. This approach is feasible in all B-cell malignancies,” added Dr. Kochenderfer.

Study Details and Results The phase I dose-escalation study enrolled 20 patients with B-cell malignancies that progressed post allogeneic stem cell transplant. Five had acute lymphocytic leukemia (ALL), five had chronic lymphocytic leukemia (CLL), and the remaining ten had lymphoma (five diffuse large B-cell lymphoma [DLBCL] and five with mantle cell lymphoma [MCL]). Overall, 9 of 20 patients had a complete or partial response. The best responses were observed in ALL, with four of five patients achieving a complete response, although two of these patients

EXPERT POINT OF VIEW

ress briefing moderator George Daley, MD, PhD, of Boston Children’s Hospital, was enthusiastic about these results, despite the small number of patients treated in studies of CAR-T cells thus far. Most of the results have been in a positive direction, he noted. “It is remarkably exciting to see clinical proof of principle for CAR‑T therapies and other gene therapies,” Dr. Daley said. George Daley, MD, PhD At a premeeting teleconference, outgoing ASH President David Williams, MD, of Boston Children’s Hospital, singled out this study as important. “Two immunologic approaches are gaining attention in hematologic malignancies. One is to take the brakes off of the immune system [with checkpoint inhibitors]. Another is to use genetically engineered immune T cells to ‘put the pedal to the metal,’” Dr. Williams told listeners. “The study of modified T cells takes the donor’s David Williams, MD T cells and revs them up. Although this could theoretically increase graft-vs-host disease, which is not an issue with the patient’s own cells, no graft-vs-host disease occurred in this study,” he pointed out. n Disclosure: Dr. Daley disclosed financial relationships with True North Therapeutics, Raze Therapeutics, Ocata Therapeutics, MPM Capital, Solasia, Epizyme, and Verastem.

We aimed to improve efficacy in progressive disease after transplant by using anti-CD19 CAR-T cells. We are one of the only groups to use CAR-T cells for this purpose. —James Kochenderfer, MD

later relapsed. Patients with CLL also had good responses: one in five had a complete response, one had a partial response, two had stable disease, and one had progressive disease. One of five patients with MCL had an ongoing complete response, one had a partial response, and three had stable disease. In patients with DLBCL, one of five had a complete response, three had stable disease, and one had progressive disease. “This approach is most successful in ALL,” he emphasized. Responses were rapidly obtained, observed within 7 to 10 days of the single infusion of CAR-T cells. No acute graftvs-host disease was reported. One patient had worsening of preexisting graft-vs-host disease after CAR-T cell infusion, and one developed mild chronic eye graft-vs-host disease more than a year after CAR-T cell infusion, “when the CAR-T cells were no longer around,” he said. Patients with a higher disease burden developed cytokine release syndrome, which is actually a marker of activity. “In contrast to some other CAR-T cell studies, neurotoxicity was rare and mild,” Dr. Kochenderfer remarked.

peared 15 days after CAR-T cell infusion. Dr. Kochenderfer explained that patients with B cells in the blood prior to CAR-T cell infusion had a higher number of CAR-T cells after infusion, “suggesting that B cells are causing the T cells to proliferate. Patients with a low B-cell count prior to infusion tend to have lower CART cell levels after infusion,” he noted.

An Interesting Observation “Another interesting observation is that PD-1 (programmed cell death protein 1) expression [on T cells] dramatically increases during infusion and CART cell peak level. This provides a rationale for combining CAR-T cells with an anti– PD-1–blocking agent, such as nivolumab [Keytruda]. We are studying this is mice,” added Dr. Kochenderfer. “CAR-T cells can be administered without prior chemotherapy for malignancies resistant to allogeneic stem cell transplant and standard donor lymphocyte infusion. Progressive disease after allogeneic stem cell transplant regressed after a single infusion of antiCD19 CAR-T cells, with no graft-vshost disease,” he stated. n

Closer Look at Individual Patients

Disclosure: Dr. Kochenderfer has received consultation fees from Bluebird Bio.

Dr. Kochenderfer provided examples of individual patients. In one patient with ALL, disease was completely eradicated by 1 month after treatment, with no additional chemotherapy necessary. One patient with CLL has been in complete remission for 36 months, and one patient with MCL has had a complete response at 31 months. In one photo of a patient with DLBCL, large masses completely disap-

Reference 1. Brudno JN, Somerville R, Shi V, et al: Allogeneic T-cells expressing an anti-CD19 chimeric antigen receptor cause remissions of B-cell malignancies after allogeneic hematopoietic stem cell transplantation without causing graft-versus-host disease. ASH Annual Meeting. Abstract 99. Presented December 5, 2015.

CAR-T Cells in Hematologic Malignancies ■■ Genetically engineered CAR-T cells have achieved impressive results in some patients with end-stage leukemias and lymphomas who have exhausted other treatment options. ■■ A small study suggested a new application for CAR-T cells: Some patients with progressive disease following transplant gained remission using a donor’s genetically engineered CAR-T cells.

The ASCO Post | JANUARY 25, 2016

PAGE 34

ASH Annual Meeting Childhood Leukemia

Self-Reports Overestimate Mercaptopurine Intake in Childhood Acute Lymphoblastic Leukemia By Alice Goodman

ercaptopurine is critical for maintaining remission in childhood acute lymphoblastic leukemia (ALL). However, a study has shown that overreporting of intake is common, and self-reports of intake are not as reliable as electronic reporting.1 About 86% of parents and children overreported the number of days that mercaptopurine was taken, and 24% overreported by at least 5 days per month in more than 50% of study months, according to these findings, which were reported at the 57th American Society of Hematology Annual Meeting and Exposition. “Subjective overreporting of mercaptopurine intake during maintenance therapy is common for children with

toring System that records each time a bottle is opened. Self-reports and electronic monitoring were compared at the end of each of 4 study months. The study enrolled 416 patients, with a median age of 6 years. A total of 38% had high-risk disease according to National Cancer Institute criteria, and 40.4% were found to be nonadherent. Two-thirds of patients were male, and 61% were from families with paternal education less than college. Dr. Landier said they chose to include paternal education level because there was no correlation between intake and maternal level of education. The study analyzed a total of 1,344 patient-months of selfreports and Medication Event Monitoring System data.

We need a better way than selfreports to identify patients at risk of overreporting and nonadherence. The phenomenon we saw with mercaptopurine may be translatable to other cancer therapies. —Wendy Landier, PhD, RN, NP

ALL, particularly in nonadherent patients, and should be viewed with caution,” said lead study author Wendy Landier, PhD, RN, NP, of Children’s of Alabama, Birmingham, formerly of City of Hope in Duarte, California. “Durable remissions in childhood ALL require about 2 years of maintenance chemotherapy that includes daily oral mercaptopurine. Previously we have shown that adherence rates below 95% are associated with a 3.7 times higher risk of relapse. Thus, accurate assessment of mercaptopurine intake is crucial to ensure timely intervention to prevent relapse,” she told listeners.

Study Details The prospective, longitudinal Children’s Oncology Group (COG) AALL03N1 study was designed to compare self-reported mercaptopurine intake (reported by parents of children under 12 and patients aged 12 and older) vs electronic monitoring using TrackCap, a Medication Event Moni-

Patients were categorized as perfect reporters if their self-reports equaled the electronic reporting; as overreporters if their self-reported days of mercaptopurine intake exceeded their electronic report by 5 or more days for more than half of the study months.”

Nearly 25% Overreport A total of 12% of patients were perfect reporters, and 24% were overreporters by at least 5 days per month

EXPERT POINT OF VIEW

ommenting on the AALL03N1 study, press conference moderator Mark Crowther, MD, of McMaster University, Hamilton, Ontario, Canada, said: “This study is extremely important. We have many presentations on new and novel therapies that are expensive, complex, and revolutionary. But if patients don’t take their drugs as prescribed, these drugs won’t be effective.” “It’s great to have advances in therapy, but we Mark Crowther, MD need to spend some time on how to use our medications appropriately. We have to ascertain if a patient fails because he or she didn’t take [his or her] medication,” he said. n Disclosure: Dr. Crowther reported no potential conflicts of interest.

in more than half of the study months. Less than 1% of patients were underreporters, and 64% were categorized as “other.” At the end of each month, a significant difference was found between self-reports and electronic reporting (P < .0001). At all time points, the mean number of self-reported days was higher than that for the Medication Event Monitoring System.

Risk Factors A multivariate analysis identified four factors associated with overreporting: age older than 12, nonwhite race, paternal education less than college, and nonadherence. For each increasing year of age of the child, the risk of overreporting increased by 7%. Further, nonadherent patients were much more likely to be overreporters: 2% of perfect reporters were nonadherent, whereas more than 80% of overreporters were nonadherent. “We have learned that we need a

Adherence to Maintenance Therapy for Childhood ALL ■■ Maintenance therapy with mercaptopurine is necessary to keep childhood ALL in remission. ■■ Nonadherence is common and of concern, because it is associated with a 3.7 times higher likelihood of relapse. ■■ Self-reports of mercaptopurine intake by either parents of children with ALL or children themselves may not be reliable and may overestimate the intake of mercaptopurine compared with electronic reporting. ■■ Oncologists should use self-reports of mercaptopurine intake with caution when assessing adherence. Interventions are needed to improve adherence.

better way than self-reports to identify patients at risk of overreporting and nonadherence. The phenomenon we saw with mercaptopurine may be translatable to other cancer therapies,” said Dr. Landier. Future interventions will be aimed at education of parents and children about the importance of adherence. “Within the Children’s Oncology Group, we are currently testing an intervention that compares education alone with a multicomponent intervention that includes education plus a reminder system (text messaging and personalized calendars) coupled with directly supervised therapy,” Dr. Landier told The ASCO Post. n Disclosure: Dr. Landier reported no potential conflicts of interest.

References 1. Landier W, Chen Y, Hageman L, et al: 6-Mercaptopurine (6MP) intake during maintenance for childhood acute lymphoblastic leukemia (ALL): A comparison of self-report and electronic monitoring: A report from the Children’s Oncology Group (COG) Study AALL03N1. 2015 ASH Annual Meeting and Exposition. Abstract 82. Presented December 5, 2015. 2. National Institutes of Health: Assessing compliance with mercaptopurine treatment in younger patients with acute lymphoblastic leukemia in first remission (COG-ACCL1033, ClinicalTri-

als.gov identifier NCT01503632). Available at https://clinicaltrials.gov/ ct2/show/NCT01503632. Accessed December 17, 2015.

ASCOPost.com | JANUARY 25, 2016

PAGE 35

ASH Annual Meeting Stem Cell Transplant

Myeloablative Conditioning for Stem Cell Transplantation Remains Standard of Care in Patients With MDS and AML By Caroline Helwick

randomized trial from the Bone and Marrow Transplant Clinical Trials Network was halted early after concluding that allogeneic stem cell transplantation after a reduced-intensity conditioning regimen resulted in higher relapse rates compared to myeloablative conditioning. The phase III randomized study en-

compared to myeloablative conditioning regimens—findings that the BMT-CTN 0901 trial sought to further clarify. “Our hypothesis was that [reducedintensity conditioning] would be associated with lower transplant-related mortality, and that would result in improved overall survival at 18 months,” Dr. Scott said.

Novel, less toxic myeloablative conditioning regimens or more effective post-transplant maintenance regimens are needed to improve disease control in patients requiring [reduced-intensity conditioning]. —Bart L. Scott, MD

If they had been able to look at overall survival as the endpoint, the number of relapses in the [reduced-intensity conditioning] arm may have been balanced out by more toxicity in the [myeloablative conditioning] arm, but the study didn’t have time to show this. —Tsiporah Shore, MD

rolled 54 patients with myelodysplastic syndrome (MDS) and 218 with acute myeloid leukemia (AML) who had < 5% marrow myeloblasts before transplant. The primary endpoint was overall survival at 18 months after randomization. After showing a reduced risk of relapse with myeloablative conditioning though no difference in overall survival, the researchers concluded that “myeloablative conditioning remains the treatment choice over reduced-intensity conditioning for patients eligible to receive highintensity–based regimens,” said Bart L. Scott, MD, of the Fred Hutchinson Cancer Research Center and the University of Washington in Seattle. Dr. Scott presented the findings at the late-breaking abstract session of the 2015 American Society of Hematology (ASH) Annual Meeting and Exposition.1 While reduced-intensity conditioning is associated with less toxicity and less treatment-related mortality, retrospective analyses have shown higher relapse rates and similar overall survival

BMT-CTN 0901 Details The principal conditioning myeloablative conditioning regimen was 4-day busulfan (Busulfex, Myleran) with cyclophosphamide or fludarabine, whereas with reduced-intensity conditioning, it was 2-day busulfan. The reduced-intensity conditioning regimens (n = 137) included these combinations: • Fludarabine, 120–180 mg/m2, plus busulfan, ≤ 8 mg/kg orally or 6.4 mg/ kg intravenously (Flu/Bu2; n = 110)

• Fludarabine, 120–180 mg/m2, plus melphalan, ≤ 150 mg/m2 (Flu/Mel; n = 27). The myeloablative conditioning regimens (n = 135) included: • Fludarabine, 120–180 mg/m2, plus busulfan, 16 mg/kg orally or 12.8 mg/kg intravenously (Flu/Bu4; n = 87) • Busulfan, 16 mg/kg orally or 12.8 mg/kg intravenously) plus cyclophosphamide, 120 mg/kg (Bu4/Cy; n = 40) • Cyclophosphamide, 120 mg/kg, plus total-body irradiation, 1,200–1,420 cGy (Cy/TBI; n = 8). The two arms were balanced in terms of age, gender, primary diagnosis, disease duration, World Health Organization classification, and risk according to cytogenetic and mutational profiles. The planned enrollment was 356 patients. However, accrual was stopped early when the Data Safety and Monitoring Committee determined that myeloablative conditioning showed more benefit in terms of relapse reduction, Dr. Scott said.

Study Outcomes At 18 months, overall survival was 77.4% with myeloablative conditioning and 67.7% with reduced-intensity conditioning—a difference of 9.7% that did not reach statistical significance (P = .07). By disease group, survival in patients with MDS was 81.5% with myeloablative conditioning and 85.2% with reduced-intensity conditioning— again, a nonsignificant difference (P = .71). However, for patients with AML, myeloablative conditioning yielded a statistically significant difference in survival: 76.8% at 18 months vs 63.0% for reduced-intensity conditioning (P = .027), Dr. Scott reported. Relapse-free survival at 18 months,

High- vs Reduced-Intensity Conditioning Regimens ■■ The BMT-CTN 0901 trial concluded that reduced-intensity conditioning regimens allow for a higher risk of relapse, compared to myeloablative conditioning. ■■ In a study of patients with myelodysplastic syndrome and acute myeloid leukemia (AML), relapses were observed in 22% more patients on the reduced-intensity regimen. ■■ At 18 months, overall survival was not significantly different, although in the AML subgroup, the myeloablative regimen did confer a survival benefit. ■■ More graft-vs-host disease was observed with the stronger regimen.

a secondary endpoint, was superior for myeloablative conditioning at 68.8%, vs 47.3% for reduced-intensity conditioning (P < .01). This held true for both disease subcategories. Relapses occurred in 50% of AML patients receiving reduced-intensity conditioning, vs 16.5% receiving myeloablative conditioning. Among MDS patients, relapses occurred in 37% and 3.7%, respectively. Dr. Scott acknowledged, however, that the small number of patients, especially in the MDS subgroup, limited the study’s power to make conclusions about differences within subsets. Transplant-related mortality at 18 months was significantly higher with myeloablative conditioning: 15.8% vs 4.4% (P = .02). The primary causes of death were graft-vs-host disease for myeloablative conditioning–treated patients and relapse for patients receiving reduced-intensity conditioning. Reduced-intensity conditioning recipients had a longer time to neutrophil engraftment, a median of 19 days vs 15 days with myeloablative conditioning (P = .002) but a shorter time to platelet engraftment, 13 days vs 16 days (P = .065). Acute graft-vs-host disease, grades 2 to 4, was more common among myeloablative conditioning recipients, who had a cumulative incidence of 44.7% at 100 days, compared to 31.6% in the reduced-intensity conditioning group (P = .024). Chronic graft-vs-host disease was also more common with myeloablative conditioning, 64% vs 47.6% at 18 months (P = .019). “Novel, less toxic myeloablative conditioning regimens or more effective post-transplant maintenance regimens are needed to improve disease control in patients requiring [reduced-intensity conditioning],” Dr. Scott suggested.

Were Regimens Appropriately Categorized? Tsiporah Shore, MD, of New York Presbyterian–Weill Cornell Medical Center, New York, felt that the categorization of the different regimens as myeloablative conditioning vs reduced-intensity conditioning was somewhat flawed, and this may have affected the findings. “I am concerned that the range of regimens is too broad, when Flu/Mel is grouped together with the lower-level continued on page 36

The ASCO Post | JANUARY 25, 2016

PAGE 36

ASH Annual Meeting Conditioning Regimens continued from page 35

Flu/Bu2 regimen in the [reduced-intensity conditioning] arm, and the Flu/ Bu4 regimen is put in the [myeloablative conditioning] arm,” she said during the discussion. She noted that studies recently found improved outcomes with Flu/Mel, compared to Flu/Bu. Dr. Scott responded, “That’s an appropriate criticism. We can’t definitely state anything about Flu/Mel. The study was not powered to answer questions about the choice of the individual regimen.” In an interview with The ASCO Post, Dr. Shore elaborated on her concerns. “The [myeloablative conditioning] arm contained very traditional, strong regimens as well as Flu/Bu4 (which delivered 4 days of busulfan). It’s somewhat myeloablative but perhaps not as strong as the other two. On the [reduced-intensity conditioning] arm we had Flu/Bu2 (which delivered 2 days of busulfan), and we had Flu/ Mel. I consider Flu/Mel to be more like Flu/Bu4, but they listed it on the [reduced-intensity conditioning] side,” she noted. “My center uses a lot of Flu/Mel, and we consider it to be pretty close to [myeloablative conditioning], with less toxicity. I think Flu/Mel got a bad rap by being in the [reduced-intensity conditioning] group, when they made a broad generalization that [reducedintensity conditioning] is not strong enough to kill leukemia,” she said. She added that multiple options needed to be offered, “to provide some level of comfort to clinicians,” who often have their preferences, “but I think it left the study open to some uncertainty.” In response to Dr. Shore’s remarks, Dr. Scott told The ASCO Post: “Some centers may look at this study and state that there were very few patients who received melphalan, and maybe a melphalan-containing regimen would perform better. This is an appropriate question, but this study was not designed to answer that.… Previous publications from several centers have classified melphalan-based regimens as reduced intensity and not myeloablative. This was a multicenter study, and since many centers use melphalan as their reduced-intensity regimen, it was important to include this regimen in order to meet accrual goals.” Dr. Shore was also disappointed that the study was terminated early, before all patients could be accrued. “If they had been able to look at overall

survival as the endpoint, the number of relapses in the [reduced-intensity conditioning] arm may have been balanced out by more toxicity in the [myeloablative conditioning] arm, but the study didn’t have time to show this,” she added. “The Data Safety and Monitoring Board had to do what they thought

was appropriate, and I won’t question that, but it’s unfortunate that it left us not able to look at the endpoint we really wanted,” she said. n Disclosure: Drs. Scott and Shore reported no potential conflicts of interest.

Reference 1. Scott BL, Pasquini MC, Logan B,

et al: Results of a phase III randomized, multicenter study of allogeneic stem cell transplantation after high versus reduced intensity conditioning in patients with myelodysplastic syndrome or acute myeloid leukemia: Blood and Marrow Transplant Clinical Trials Network 0901. 2015 ASH Annual Meeting. Abstract LBA-8. Presented December 8, 2015.

Scanning electron micrograph of T-cell lymphocytes attacking a cancer cell

ASCOPost.com | JANUARY 25, 2016

PAGE 37

Journal Spotlight

Study Finds Colorectal Cancer More Likely to Affect Minorities at Younger Age

esearchers at the University of Missouri School of Medicine reported that minority and ethnic groups are being diagnosed with colorectal cancer at younger ages and more advanced stages than non-Hispanic whites. The study was recently published in Cancer Medicine.1

“While we know the risk of developing colorectal cancer increases with age, little is known about its prevalence within various minority and ethnic groups,” said Jamal Ibdah, MD, PhD, Professor of Medicine and R aymond E. and Vaona H. Peck Chair

in Cancer Research at the University of Missouri School of Medicine. Dr. Ibdah’s research team used the Surveillance, Epidemiology, and End Results (SEER) and the North American Association of Central Cancer Registries (NAACCR) databases analyze the TRIM: 15.15” Xto 10.575” Jamal Ibdah, MD, PhD

prevalence, stage, and survival rates for colorectal cancer diagnoses in the United States based on race and ethnicity from 1973 to 2009.

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“We found that minorities under the age of 50 were twice as likely to be diagnosed with colorectal cancer compared to non-Hispanic whites,” said Dr. Ibdah, who also serves as Director of the Division of Gastroenterology and Hepatology at the University of Missouri School of Medicine. “On average, minorities were diagnosed between the ages of 64 and 68, while non-Hispanic whites were typically diagnosed at age 72. When diagnosed, minority groups also had more advanced stages of cancer.” There are several issues that could influence the development of colorectal cancer at a younger age, such as hereditary and environmental factors, diet, and lifestyle. Dr. Ibdah said that possible reasons for advanced-stage diagnosis among minorities may include lower screening rates, lower income levels, and reduced access to education and health care. “Regular screening for colorectal cancer is essential for prevention and early diagnosis,” Dr. Ibdah said. Further studies are needed to examine current guidelines for all minority groups in the United States and the development of possible new interventional strategies. “Hispanic, Asian, Pacific Islander, American Indian, Alaska Native, and African American populations are the fastest-growing racial and ethnic minority groups in the United States. Having the most accurate statistical data is critical to providing cancer prevention and control programs for these groups,” Dr. Ibdah said. n Reference 1. Rahman R, Schmaltz C, Jackson CS, et al: Increased risk for colorectal cancer under age 50 in racial and ethnic minorities living in the United States. Cancer Med. October 16, 2015 (early release online).

The ASCO Post | JANUARY 25, 2016

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San Antonio Breast Cancer Symposium Targeted Therapy

PI3K Inhibitor Buparlisib Extends Progression-Free Survival in Advanced Breast Cancer By Caroline Helwick

ddition of the oral investigational pan-PI3K inhibitor buparlisib to the endocrine agent fulvestrant (Faslodex) improved progression-free survival among postmenopausal women with advanced hormone receptor–positive/ HER2-negative advanced breast cancer. “We are happy to announce that the phase III BELLE-2 trial met its primary endpoint, demonstrating a modest pro-

BELLE-2 Details The BELLE-2 trial is the first randomized phase III study to assess the safety and efficacy of a pan-PI3K inhibitor combined with fulvestrant in hormone receptor–positive and HER2-negative advanced breast cancer.1 Included in this trial were 1,147 patients who had progressed on or after treatment with an aromatase inhibitor; patients could have

We are happy to announce that the phase III BELLE-2 trial met its primary endpoint, demonstrating a modest progression-free survival improvement for combined buparlisib and fulvestrant. The primary outcome was quite dramatic in patients whose tumors had mutant PIK3CA. —Jose Baselga, MD, PhD

gression-free survival improvement for combined buparlisib and fulvestrant,” announced Jose Baselga, MD, PhD, Physician-in-Chief and Chief Medical Officer at Memorial Sloan Kettering Cancer Center, New York, at the 2015 San Antonio Breast Cancer Symposium. “The primary outcome was quite dramatic in patients whose tumors had mutant PIK3CA,” he noted. Buparlisib is designed to target all isoforms of mutated PIK3CA. Activation of the PI3K pathway is a hallmark of hormone receptor–positive breast cancer cells resistant to endocrine therapy, and approximately 35% of hormone receptor–positive patients have PIK3CA mutations. Preclinical and early clinical data have suggested that combining buparlisib with endocrine therapy may provide clinical benefit in this setting, Dr. Baselga explained.

received no more than one prior chemotherapy for metastatic disease. All patients received 500 mg of fulvestrant for 14 days and then were randomly assigned also to receive buparlisib at 100 mg/d or placebo. All patients continued on 500 mg of fulvestrant. Baseline characteristics were well balanced. The statistical assessment was by onesided alpha, which determined the P values for statistical significance would be .014 for the full population analysis and .01 for the PI3K-activated group. Randomization was stratified by PI3K pathway status, as measured in archival tumor tissue (PIK3CA mutation or PTEN loss; activated, nonactivated, unknown). Baseline PIK3CA mutation status in circulating tumor DNA was assessed at trial entry in a subset 587 patients. The key endpoints were locally as-

Buparlisib and Fulvestrant in Endocrine-Resistant Breast Cancer ■■ The combination of the pan-PI3K inhibitor buparlisib and fulvestrant improved progression-free survival, to a median of 6.9 months, vs 5.0 months with fulvestrant alone, in hormone receptor–resistant patients. ■■ No significant benefit was observed in patients with PI3K pathway–activated tumors from the whole-population analysis, based on archival tumor samples. ■■ However, in a subset of the PIK3CA-mutated patients, the combination treatment significantly prolonged progression-free survival by 3.8 months, according to circulating tumor DNA assessment.

sessed progression-free survival in the full population and in the PI3K pathway–activated group.

Study Results and Toxicity BELLE-2 found that median progression-free survival in the full population (n = 1147) was significantly improved with the combination of buparlisib plus fulvestrant. Median progression-free survival was 6.9 months with the combination vs 5.0 months with fulvestrant alone (hazard ratio [HR] = 0.78; P < .001). The data for overall survival are immature, Dr. Baselga noted. In the subset of 372 patients with

PI3K-activated tumors assessed in archival samples at baseline, median progression-free survival was 6.8 months with the combination and 4.0 months with endocrine therapy alone—a 24% reduction in risk that was not statistically significant (HR = 0.76; P = .014; median progression-free survival in the PI3Kactivated group was tested at a one-sided alpha of 0.01 level of significance). Grade 3–4 adverse events were greater in the combination arm, 77.3% vs 32.0%. The most common toxicities with the combination were transaminitis, hyperglycemia, rash, and mood continued on page 45

EXPERT POINT OF VIEW

arlos L. Arteaga, MD, the Donna S. Hall Chair in Breast Cancer Research and Director of the Center for Cancer Targeted Therapies at Vanderbilt University School of Medicine, Nashville, commented on the BELLE-2 trial for The ASCO Post. “We have learned that there is a subgroup of patients, who are identifiable with a blood test, that may benefit from this class of drugs, several of which are in development. The pan-PI3K inhibitor buparlisib inhibits all PI3K molecules—alpha, beta, gamma, delta. Of these, the main offender in breast cancer is the alpha type, which is frequently mutated and, as a result, is overactivated,” he explained.

We believe that PI3K-alpha inhibitors may be even better than pan-PI3K inhibitors. —Carlos L. Arteaga, MD

“Because of this, we believe that PI3K-alpha inhibitors may be even better than pan-PI3K inhibitors,” he added. Since these would not inhibit all PI3K molecules, they may be less toxic and better tolerated. This is very important with long-term therapy. Whether response rates would be higher with PI3K alpha-specific more specific inhibitors is not yet clear, said Dr. Arteaga. “But what we are seeing so far is encouraging,” he commented. He added, however, that the pan-PI3K inhibitors may have most value against tumors where other PI3K molecules are cancer drivers.

More on Circulating Tumor DNA Dr. Arteaga further commented on using circulating tumor DNA to detect mutations, which he said would be particularly useful for clinical trial enrollment, particularly in patients where a tumor biopsy is not doable and/or safe. “Beware, though,” he added, “that the blood test does not detect the whole universe of alterations that could still be detected in a tissue biopsy.” n Disclosure: Dr. Arteaga reported no potential conflicts of interest.

ASCOPost.com | JANUARY 25, 2016

PAGE 45

San Antonio Breast Cancer Symposium Surgical Oncology

Surgical Margin Width Not Related to Breast Cancer Recurrence By Alice Goodman

he width of the surgical margin doesn’t matter, as long as the margin is negative, according to a large study of breast-conserving surgery in patients with invasive breast cancer. The risk of ipsilateral breast tumor recurrence was similar for wide negative margins (2–4 mm) or narrow negative margins (0 to < 1 mm) in a large study of 11,900 Danish women who underwent breast-con-

serving surgery or reexcision, the study found. A final positive margin of any width was associated with a 2.5-fold increased risk of ipsilateral breast tumor recurrence. The study was presented at the 2015 San Antonio Breast Cancer Symposium.1 “We found that the risk of [ipsilateral breast tumor recurrence] was associated with a final positive margin, and local control was not improved with negative margins greater than

1 mm. Residual disease at reexcision increased the risk of [ipsilateral breast tumor recurrence], and overall survival was not affected by repeat surgery,” said presenting author Anne Bodilsen, MD, PhD, of Aarhus University Hospital, Aarhus, Denmark.

Study Details The study was based on data from 11,900 women aged 18 to 75 years who underwent breast-conserving surgery

for unilateral invasive breast cancer and no prior cancer. The women were also treated with radiation therapy and could elect to receive systemic adjuvant treatment. Median follow-up was 4.9 years. The overall risk of ipsilateral breast tumor recurrence was 2.4% at 5 years and 5.9% at 9 years. For narrower margins (ie, 0–1 mm), no decreased risk for ipsilateral breast continued on page 46

EXPERT POINT OF VIEW

“T

his study confirms that what is important is a negative margin, not the margin size,” said Kevin S. Hughes, MD, a breast surgeon who is

consensus guidelines issued by the Society of Surgical Oncology and American Society for Radiation Oncology.1 ‘Ink on tumor’ means increased rate

The assumption that bigger margins were better led to repeat operations that we now know are unnecessary and cosmetically deforming. Now the standard of care for invasive breast cancer is no ink on tumor.

Buparlisib in Breast Cancer continued from page 38

disorders. There was one grade 4 treatment-related depression in the buparlisib arm; the patient recovered after treatment discontinuation. “Frequent discontinuations due to adverse events reduced treatment duration in the buparlisib arm, potentially limiting the efficacy of combination therapy,” noted Dr. Baselga. Treatmentrelated discontinuation occurred in 13.2% of the combination arm, compared with 1.8% of the fulvestrant arm.

PIK3CA Mutation by Circulating Tumor DNA “In clinical trials, archival tumor biopsy samples typically represent the primary tumor at the time of initial diagnosis. Recent evidence suggests that tumor mutation status can change due to disease progression or exposure to

Greater Awareness Needed

of ipsilateral breast tumor recurrence, and ‘no ink on tumor’ means the margin is adequate,” he explained. “In the past, larger margins were

“The assumption that bigger margins were better led to repeat operations that we now know are unnecessary and cosmetically deforming. Now the standard of care for invasive breast cancer is no ink on tumor. The jury is still out on [ductal carcinoma in situ], but the standard will likely be the same,” he said. “Some surgeons will still opt for

prior treatments,” Dr. Baselga said. To this end, circulating tumor DNA obtained from blood samples has emerged as a sensitive, reliable, and minimally invasive way to measure the PIK3CA mutation status at the time of treatment. Among the 587 patients for whom these “liquid biopsies” were available, 200 had PIK3CA mutations. In this mutated subset, “clinically meaningful” improvements in progression-free survival were observed with buparlisib plus fulvestrant treatment, said Dr. Baselga. Median progression-free survival was 7.0 months with the combination, vs 3.2 months with fulvestrant alone— a statistically significant 46% reduction in risk (P < .001). The 3.8-month improvement was supported by higher response rates (18.4% vs 3.5%) in this patient population. To the contrary, among patients with wild-type PIK3CA, no benefit ac-

crued from the addition of the PI3K inhibitor. In this subset of 387 patients, median progression-free survival was 6.8 months in either arm. “Patients with tumors harboring PIK3CA mutations detected in circulating tumor DNA performed poorly on fulvestrant monotherapy but achieved a clinically meaningful progression-free survival improvement with buparlisib plus fulvestrant,” he said. Dr. Baselga pointed to a 21% discrepancy in frequency of mutations detected in the tumors by Sanger sequencing, vs those detected via circulating tumor DNA. He believes the difference reflects “temporal and technical issues.” He added that mutations detected by circulating tumor DNA were “hot spot mutations that we know are activating” and are therefore most relevant. “Bloodbased sampling is probably more predictive,” he added.

—Kevin S. Hughes, MD

Co-Director of the Avon Comprehensive Breast Evaluation Center at Massachusetts General Hospital, Boston. “This is a confirmatory study of the

thought to decrease the risk of recurrence. These authors did not find that. The consensus guidelines state that there is little difference between 1-mm, 2-mm, and 5-mm margins in reducing the risk of local recurrence. Positive margins herald local recurrence. What we aim for is no ink on tumor, no matter what the margin width is,” Dr. Hughes continued.

bigger margins. It takes time for the new guidelines to filter down. We need to promote greater awareness about the new guidelines and have more widespread adoption. No ink on tumor is a reasonable approach to lumpectomy with the best cosmetic outcome,” Dr. Hughes said. n Disclosure: Dr. Hughes reported no potential conflicts of interest.

Reference 1. Moran MS, Schnitt SJ, Giuliano AE, et al: Society of Surgical Oncology– American Society for Radiation Oncology consensus guideline on margins for breast-conserving surgery with wholebreast irradiation in stages I and II invasive breast cancer. Int J Radiat Oncol Biol Phys 88:553-564, 2014.

“The BELLE-2 study suggests that assessment of PIK3CA mutations in circulating tumor DNA may help select patients who benefit from adding a PI3K inhibitor to endocrine therapy,” Dr. Baselga concluded. Phase III studies with PI3K alpha–selective inhibitors are underway to confirm the predictive value of PIK3CA mutations detected in circulating tumor DNA and tumor tissue. n Disclosure: Dr. Baselga reported no potential conflicts of interest.

Reference 1. Baselga J, Im S-A, Iwata H, et al: PIK3CA status in circulating tumor DNA predicts efficacy of buparlisib plus fulvestrant in postmenopausal women with endocrineresistant HER+/HER2- advanced breast cancer: First results from the randomized, phase III BELLE-2 trial. 2015 San Antonio Breast Cancer Symposium. Abstract S6-01. Presented December 11, 2015.

The ASCO Post | JANUARY 25, 2016

PAGE 46

San Antonio Breast Cancer Symposium Surgical Margin Width continued from page 45

tumor recurrence was observed; the same was true for wider margins (ie, 2–4 mm). A final positive margin increased the risk for ipsilateral breast tumor recurrence 2.5-fold.

Seventeen percent of patients had repeat surgery: 11% reexcision and 6% mastectomy. Among these patients, 20% had residual disease in the surgical sample: 23% with invasive carcinoma, 63% with ductal carcinoma in situ, and 14% with both. The presence of residual disease following reexcision increased the risk of

ipsilateral breast tumor recurrence between 2.5- and 3-fold. Although reexcision increased the risk for ipsilateral breast tumor recurrence, Dr. Bodilsen pointed out that this was because negative margins were not obtained at reexcision. n Disclosure: Dr. Bodilsen reported no potential conflicts of interest.

Reference 1. Bodilsen A, Bjerre K, Offersen BV, et al: Importance of margin width and reexcision in breast conserving treatment of early breast cancer: A Danish Breast Cancer Cooperative Group study of 11,900 women. 2015 San Antonio Breast Cancer Symposium. Abstract S2-01. Presented December 9, 2015.

When multiple myeloma relapses

We found that the risk of [ipsilateral breast tumor recurrence] was associated with a final positive margin, and local control was not improved with negative margins greater than 1 mm. —Anne Bodilsen, MD, PhD

Factors associated with increased risk of ipsilateral breast tumor recurrence included younger age (3 times higher risk), more than 4 positive lymph nodes (1.8 times higher) and reexcision (1.5 times higher). The risk of ipsilateral breast tumor recurrence was reduced by chemotherapy (P < .001), and estrogen receptor–positive disease treated with hormonal therapy (P < .001).

Surgical Margins and Breast Cancer Recurrence ■■ With breast-conserving surgery for invasive breast cancer, margin width is not related to recurrence. ■■ The presence of residual disease in the margin increases the risk of recurrence 2.5 times. ■■ These findings of a large Danish Cooperative Group study confirm consensus guidelines for breastconserving surgery in invasive breast cancer.

INDICATION Kyprolis® (carfilzomib) for Injection is a proteasome inhibitor that is indicated in combination with lenalidomide and dexamethasone for the treatment of patients with relapsed multiple myeloma who have received one to three prior lines of therapy.

IMPORTANT SAFETY INFORMATION Cardiac Toxicities: New onset or worsening of pre-existing cardiac until resolved or returned to baseline and consider whether to restart

failure (e.g., congestive heart failure, pulmonary edema, decreased ejection fraction), restrictive cardiomyopathy, myocardial ischemia, and myocardial infarction including fatalities have occurred following administration of Kyprolis. Death due to cardiac arrest has occurred within a day of Kyprolis administration. • Withhold Kyprolis for Grade 3 or 4 cardiac adverse events until recovery, and consider whether to restart Kyprolis based on a benefit/risk assessment. • Adequate hydration is required prior to each dose in Cycle 1. Monitor all patients for evidence of volume overload, especially patients at risk for cardiac failure. Adjust total fluid intake as clinically appropriate in patients with baseline cardiac failure or who are at risk for cardiac failure. • Patients ≥ 75 years, the risk of cardiac failure is increased. Patients with New York Heart Association Class III and IV heart failure, recent myocardial infarction, and conduction abnormalities may be at greater risk for cardiac complications.

Kyprolis based on a benefit/risk assessment.

Dyspnea: Dyspnea was reported in patients treated with Kyprolis. Evaluate dyspnea to exclude cardiopulmonary conditions including cardiac failure and pulmonary syndromes. Stop Kyprolis for Grade 3 or 4 dyspnea until resolved or returned to baseline. Consider whether to restart Kyprolis based on a benefit/risk assessment. Hypertension: Hypertension, including hypertensive crisis and

hypertensive emergency, has been observed with Kyprolis. Some of these events have been fatal. Monitor blood pressure regularly in all patients. If hypertension cannot be adequately controlled, withhold Kyprolis and evaluate. Consider whether to restart Kyprolis based on a benefit/risk assessment.

Venous Thrombosis: Venous thromboembolic events (including

deep venous thrombosis and pulmonary embolism) have been observed with Kyprolis. Thromboprophylaxis is recommended and should be based on an assessment of the patient’s underlying risks, treatment regimen, and clinical status.

Acute Renal Failure: Cases of acute renal failure and renal insufficiency adverse events (renal impairment, acute renal failure, renal failure) have occurred in patients receiving Kyprolis. Acute renal failure was reported more frequently in patients with advanced relapsed and refractory multiple myeloma who received Kyprolis monotherapy. This risk was greater in patients with a baseline reduced estimated creatinine clearance. Monitor renal function with regular measurement of the serum creatinine and/or estimated creatinine clearance. Reduce or withhold dose as appropriate.

Infusion Reactions: Infusion reactions, including life-threatening reactions, have occurred in patients receiving Kyprolis. Symptoms include fever, chills, arthralgia, myalgia, facial flushing, facial edema, vomiting, weakness, shortness of breath, hypotension, syncope, chest tightness, or angina. These reactions can occur immediately following or up to 24 hours after administration of Kyprolis. Premedicate with dexamethasone to reduce the incidence and severity of infusion reactions. Inform patients of the risk and of symptoms of an infusion reaction and to contact a physician immediately if they occur.

Tumor Lysis Syndrome: Cases of Tumor Lysis Syndrome (TLS), including fatal outcomes, have occurred in patients receiving Kyprolis. Patients with multiple myeloma and a high tumor burden should be considered at greater risk for TLS. Adequate hydration is required prior to each dose in Cycle 1, and in subsequent cycles as needed. Consider uric acid lowering drugs in patients at risk for TLS. Monitor for evidence of TLS during treatment and manage promptly. Withhold Kyprolis until TLS is resolved.

Thrombocytopenia: Kyprolis causes thrombocytopenia with

recovery to baseline platelet count usually by the start of the next cycle. Thrombocytopenia was reported in patients receiving Kyprolis. Monitor platelet counts frequently during treatment with Kyprolis. Reduce or withhold dose as appropriate.

Hepatic Toxicity and Hepatic Failure: Cases of hepatic failure, including fatal cases, have been reported during treatment with Kyprolis. Kyprolis can cause increased serum transaminases. Monitor liver enzymes regularly. Reduce or withhold dose as appropriate.

Pulmonary Toxicity: Acute Respiratory Distress Syndrome (ARDS), acute respiratory failure, and acute diffuse infiltrative pulmonary disease such as pneumonitis and interstitial lung disease have Thrombotic Thrombocytopenic Purpura/Hemolytic Uremic occurred in patients receiving Kyprolis. Some events have been fatal. Syndrome (TTP/HUS): Cases of TTP/HUS including fatal outcome In the event of drug-induced pulmonary toxicity, discontinue Kyprolis. have occurred in patients receiving Kyprolis. Monitor for signs and symptoms of TTP/HUS. Discontinue Kyprolis if diagnosis is suspected. Pulmonary Hypertension: Pulmonary arterial hypertension (PAH) If the diagnosis of TTP/HUS is excluded, Kyprolis may be restarted. The was reported in patients treated with Kyprolis. Evaluate with cardiac safety of reinitiating Kyprolis therapy in patients previously experiencing imaging and/or other tests as indicated. Withhold Kyprolis for PAH TTP/HUS is not known.

Onyx, Onyx Pharmaceuticals, Onyx Pharmaceuticals logo, KYPROLIS, and KYPROLIS logo are all trademarks of Onyx Pharmaceuticals, Inc. ©2015 Onyx Pharmaceuticals, Inc., an Amgen Inc. subsidiary, Thousand Oaks, CA USA-KYPR-118486 November 2015 Printed in USA

ASCOPost.com | JANUARY 25, 2016

PAGE 47

Announcements

Karmanos Cancer Institute Announces New Leadership Roles for Elisabeth Heath, MD, FACP, and Ulka Vaishampayan, MD

he Barbara Ann Karmanos Cancer Institute recently announced the promotion of two physician scientists: Elisabeth Heath, MD, FACP, and Ulka Vaishampayan, MD.

Elisabeth Heath, MD, FACP Dr. Heath will lead the Genitourinary Oncology Multidisciplinary Team at Karmanos Cancer Institute. She will also continue to serve

as Medical Director of the Infusion Center and Leader of the Prostate Cancer Research Team at Karmanos. She has been an active clinical and scientific member of Karmanos since

RESPOND

with the power of significantly improved progression-free survival (PFS)

Posterior Reversible Encephalopathy Syndrome (PRES):

The KYPROLIS® regimen significantly improved PFS in patients with relapsed multiple myeloma

• Females of reproductive potential should be advised to avoid becoming pregnant while being treated with Kyprolis and the potential hazard to the fetus if Kyprolis is used during pregnancy.

26.3 months median progression-free

Cases of PRES have occurred in patients receiving Kyprolis. PRES was formerly known as Reversible Posterior Leukoencephalopathy Syndrome. Consider a neuro-radiological imaging (MRI) for onset of visual or neurological symptoms. Discontinue Kyprolis if PRES is 1 suspected and evaluate. The safety of reinitiating Kyprolis therapy in patients previously experiencing PRES is not known. In the ASPIRE study of KYPROLIS + lenalidomide + low-dose Embryo-fetal Toxicity: Kyprolis can cause fetal harm when dexamethasone (KRd) vs lenalidomide + low-dose dexamethasone delivered improved efficacy with a safety administered to a pregnant woman based on its mechanism of action (Rd), the KYPROLIS regimen profile comparable to Rd.1,2* and findings in animals.

ADVERSE REACTIONS The most common adverse events occurring in at least 20% of patients treated with Kyprolis in the combination therapy trial: decreased lymphocytes, decreased absolute neutrophil count, decreased phosphorus, anemia, neutropenia, decreased total white blood cell count, decreased platelets, diarrhea, fatigue, thrombocytopenia, pyrexia, muscle spasm, cough, upper respiratory tract infection, decreased hemoglobin, hypokalemia. You are encouraged to report negative side effects of prescription drugs to the FDA. Visit MedWatch or call 1-800-FDA-1088. References: 1. KYPROLIS [prescribing information]. Thousand Oaks, CA: Onyx Pharmaceuticals, Inc., an Amgen Inc. subsidiary; 2015. 2. Stewart AK, Rajkumar SV, Dimopoulos MA, et al; for the ASPIRE Investigators. Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. N Engl J Med. 2015;372(2):142-152.

Please see Brief Summary of full Prescribing Information on adjacent pages.

survival with the KYPROLIS regimen vs 17.6 months with Rd, a 49% improvement over Rd (P value [two-sided] 0.0001)1

Find out more at www.kyprolis.com/hcp *ASPIRE was a global, multicenter, open-label, randomized phase 3 pivotal trial that evaluated KYPROLIS in combination with lenalidomide and low-dose dexamethasone (KRd) vs lenalidomide and low-dose dexamethasone (Rd) in patients with relapsed multiple myeloma who had received 1 to 3 prior lines of therapy. 792 patients were randomized in a 1:1 ratio (396 patients to KRd, 396 to Rd). Patients received their randomized study treatment in 28-day cycles until disease progression or unacceptable toxicity.1,2 KYPROLIS was discontinued after Cycle 18. The primary endpoint was progression-free survival. Secondary endpoints included overall survival, overall response rate (partial response or better), duration of response, and safety. 2

2003 and is Professor of Oncology at Wayne State University School of Medicine. Dr. Heath has a distinguished career continued on page 48

The ASCO Post | JANUARY 25, 2016

PAGE 48

Announcements Karmanos Cancer Institute

Department of Defense grant in the nationally recognized Prostate Clinical Trials Cancer Consortium.

continued from page 47

as a prostate cancer researcher, serving as the Patricia C. and E. Jan Hartmann Endowed Chair for Prostate Cancer Research. She is also involved with the Developmental Therapeutics-Molecular Therapeutics Committee of ASCO and is the principal investigator for a

Ulka Vaishampayan, MD

Elisabeth Heath, MD, FACP

Dr. Vaishampayan is now Director of the Phase 1 Clinical Trials Program at Karmanos Cancer Institute’s Eisenberg Center for Translational Therapeutics

after serving as Interim Director for nearly 2 years. She will also serve as the new Division Chief for Solid Tumor Oncology within the Department of Oncology at Wayne State University School of Medicine. Dr. Vaishampayan has led the Karmanos Cancer Institute’s Genitourinary Multidisciplinary Team since 2005 and

® ® ® for®injection, 5.10 Thrombocytopenia KYPROLIS (carfilzomib) for injection, forinjection, intravenous use use use 5.10 Thrombocytopenia 5.10 Thrombocytopenia KYPROLIS (carfilzomib) forinjection, intravenous use KYPROLIS (carfilzomib) for for intravenous 5.10 Thrombocytopenia KYPROLIS (carfilzomib) for for intravenous Gene Brief Summary ofSummary Prescribing Information. Brief Summary Prescribing Information. Brief of Prescribing Information. BriefofSummary of Prescribing Information. Kyprolis causes thrombocytopenia with platelet nadirs observed between 8 and Kyprolis causes thrombocytopenia with platelet nadirs observed between Day 8 Day andbetween Kyprolis causes thrombocytopenia with platelet nadirs observed Kyprolis causes thrombocytopenia with platelet nadirs observed between Day 8 Day and 8 and Fat see the KYPROLIS package insert for full prescribing information. PleasePlease see the KYPROLIS package insert for full prescribing information. Please see the KYPROLIS package insert for full prescribing information. Please see the KYPROLIS package insert for full prescribing information. Day 15Day 15Day of28-day each cyclerecovery with to baseline platelet countplatelet usually by theusually start of each cycle with to baseline platelet count usually by theusually start 15 of28-day each 28-day cycle with recovery to baseline count the 15Day of28-day each cyclerecovery with recovery to baseline platelet count by the by start of the next cycle. Thrombocytopenia was reported in approximately 40% of patients of the next cycle. Thrombocytopenia was reported in approximately 40% of patients of the next cycle. Thrombocytopenia was reported in approximately 40% of patients of the next cycle. Thrombocytopenia was reported in approximately 40% of patients Pyr 1. INDICATIONS AND USAGE 1. INDICATIONS AND USAGE 1. INDICATIONS AND USAGE 1. INDICATIONS AND USAGE in clinical trials with Monitor platelet counts frequently during treatment with in clinical trials with Monitor platelet counts frequently during treatment with inKyprolis. clinical trials with Kyprolis. Monitor platelet counts frequently during treatment in clinical trialsKyprolis. with Kyprolis. Monitor platelet counts frequently during treatment with wit Kyprolis in combination with lenalidomide and dexamethasone is indicated thefor the Kyprolis in combination withinlenalidomide and is indicated for thefor Kyprolis combination withdexamethasone lenalidomide and dexamethasone is indicated for the Kyprolis in combination with lenalidomide and dexamethasone is indicated Ede Kyprolis. Reduce or withhold dose asdose appropriate. Kyprolis. Reduce orKyprolis. withhold dose as Reduce orappropriate. withhold dose as appropriate. Kyprolis. Reduce or withhold as appropriate. treatment of treatment patients with relapsed multiple myeloma whomyeloma have onereceived to one toone to treatment of treatment patients with relapsed multiple myeloma who have received onereceived to of patients with relapsed multiple who have of patients with relapsed multiple myeloma whoreceived have 5.11 Hepatic Toxicity andToxicity Hepatic Failure 5.11 Hepatic Toxicity and Hepatic Failure 5.11 Hepatic and Hepatic 5.11 Hepatic Toxicity and Hepatic FailureFailure Ast threelines prior oflines therapy. three prior oflines therapy. three prior of therapy. three prior oflines therapy. of hepatic failure, including fatalincluding cases, have been (<1%) during treatment Cases Cases of hepatic failure, including fatal cases, have (<1%) during treatment Cases of hepatic failure, fatalreported cases, have been reported (<1%) during trea Cases of hepatic failure, including fatal been cases, havereported been reported (<1%) during treatment Infec 5. WARNINGS AND PRECAUTIONS 5. WARNINGS 5.PRECAUTIONS WARNINGS AND PRECAUTIONS 5. AND WARNINGS AND PRECAUTIONS with Kyprolis. Kyprolis can cause increased serum transaminases. Monitor liver Monitor enzymes with Kyprolis. Kyprolis can cause increased serum transaminases. Monitor liver Monitor enzymes with Kyprolis. Kyprolis can cause increased serum transaminases. liver enzy with Kyprolis. Kyprolis can cause increased serum transaminases. liver enzymes Upp regularly. Reduce or withhold dose asdose appropriate. regularly. Reduce orregularly. withhold dose as Reduce orappropriate. withhold dose as appropriate. regularly. Reduce or withhold as appropriate. 5.1 Cardiac Toxicities 5.1 Cardiac Toxicities 5.1 Cardiac Toxicities 5.1 Cardiac Toxicities 5.12 Thrombotic Purpura/Hemolytic Syndrome (TTP/HUS) 5.12failure, Thrombotic Purpura/Hemolytic UremicUremic Syndrome (TTP/HUS) 5.12 Thrombocytopenic Thrombotic Thrombocytopenic Purpura/Hemolytic Uremic Syndrome (TTP/ 5.12 Thrombocytopenic Thrombotic Thrombocytopenic Purpura/Hemolytic Uremic Syndrome (TTP/HUS) New or onset or worsening pre-existing failure (e.g., congestive heart failure, New onset worsening ofworsening pre-existing failurecardiac (e.g.,cardiac congestive Nas New onset orofworsening of cardiac pre-existing failure (e.g.,failure, congestive heart New onset or of cardiac pre-existing failure (e.g.,heart congestive heart failure, pulmonary edema, decreased ejection fraction), restrictive cardiomyopathy, myocardial pulmonary edema, decreased ejection fraction), restrictive cardiomyopathy, myocardial pulmonary edema, decreased ejection fraction), restrictive cardiomyopathy, myocardial pulmonary edema, decreased ejection fraction), restrictive cardiomyopathy, myocardial Cases of TTP/HUS including fatalincluding outcome haveoutcome been in patients who received Cases of TTP/HUS including fatalincluding outcome haveoutcome been reported in patients who received Cases of TTP/HUS fatal have been reported in patients who recei Cases of TTP/HUS fatal havereported been reported in patients who received Bro ischemia, andischemia, myocardial including fatalities havefatalities occurred following ischemia, andischemia, myocardial including fatalities have occurred following andinfarction myocardial infarction including have occurred following andinfarction myocardial infarction including fatalities have occurred following Kyprolis. Monitor for and signs and symptoms TTP/HUS. Ifofthe diagnosis is suspected, Kyprolis. Monitor forKyprolis. signs symptoms ofsymptoms TTP/HUS. Ifofthe diagnosis is suspected, Monitor for signs andofsymptoms TTP/HUS. If the diagnosis isstop suspected, Kyprolis. Monitor for signs and TTP/HUS. If the diagnosis isstop suspected, stop administration of Kyprolis. Inofclinical studies with Kyprolis, these events typically occurred administration of Kyprolis. Inofclinical studies with Kyprolis, these events typically occurred administration Kyprolis. In clinical studies with Kyprolis, these events typically occurred administration Kyprolis. In clinical studies with Kyprolis, these events typically occurred Pne Kyprolis and Kyprolis evaluate. If the diagnosis of TTP/HUS is excluded, Kyprolis may be restarted. Kyprolis and Kyprolis evaluate. If the diagnosis of TTP/HUS is excluded, Kyprolis may be restarted. and evaluate. If the diagnosis of TTP/HUS is excluded, Kyprolis may be resta and evaluate. If the diagnosis of TTP/HUS is excluded, Kyprolis may be restarted. the course ofthe Kyprolis therapy (<5 cycles). Death due toDeath cardiac arrest has early inearly the in course Kyprolis therapy (<5Kyprolis cycles). Death due cardiac arrest hasto cardiac early in course of therapy (<5 to cycles). has early inof the course of Kyprolis therapy (<5 cycles). Death due todue cardiac arrest arrest has The safety of reinitiating therapy in patients previously experiencing TTP/HUS is TTP/HU The safety ofThe reinitiating therapy in patients previously experiencing TTP/HUS is TTP/HUS The safety ofKyprolis reinitiating Kyprolis therapy in patients previously experiencing safety ofKyprolis reinitiating Kyprolis therapy in patients previously experiencing is Meta occurred within a day of Kyprolis administration. occurred within a day of Kyprolis administration. occurred within a day of Kyprolis administration. occurred within a day of Kyprolis administration. not known. not known. not known. not known. Hyp Withhold Kyprolis for Grade 3cardiac orfor4 Grade adverse events until recovery, andrecovery, consider Withhold Kyprolis for Grade 3Kyprolis orfor4 Grade adverse untiladverse recovery, andrecovery, consider Withhold orevents 4 cardiac events until and Withhold Kyprolis 3cardiac or 4 3cardiac adverse events until and consider 5.13 Posterior Reversible Encephalopathy Syndrome (PRES) 5.13consider Posterior Reversible Encephalopathy Syndrome (PRES) 5.13 Posterior Reversible Encephalopathy Syndrome 5.13 Posterior Reversible Encephalopathy Syndrome (PRES)(PRES) whether to restart Kyprolis at 1level dose based on a benefit/risk whether to restart Kyprolis atto1restart dose based onreduction a benefit/risk whether Kyprolis at reduction 1level dose level based on aassessment. benefit/risk assessment. whether to restart Kyprolis at reduction 1level dose reduction based on aassessment. benefit/risk assessment. Cases of have PRES have been in patients receiving Kyprolis. Posterior Cases of PRES in patients receiving Posterior Cases ofreported PRESreported have been reported inKyprolis. patients receiving Kyprolis. Posterior Hyp Cases ofbeen PRES have been reported in patients receiving Kyprolis. Posterior While adequate hydration is required toprior eachtoinprior dose Cycle 1, allinpatients While adequate hydration is required prior toprior each dose Cycle 1, allindose patients should While adequate hydration is required toindose each Cycle 1,should all patients should While adequate hydration is required each Cycle 1, all patients should reversible encephalopathy syndrome (PRES), formerly termed Reversible Posterior reversible encephalopathy syndrome (PRES), formerly termed Reversible Posterior reversible encephalopathy syndrome (PRES), formerly termed Reversible Posterior reversible encephalopathy syndrome (PRES), formerly termed Reversible Posterior Hyp bealso monitored evidence of volume overload, especially patients atforrisk forrisk cardiac also bealso monitored evidence of volume overload, patients at risk cardiac also beformonitored for evidence ofespecially volume overload, especially patients atforrisk forLeukoencephalopathy cardiac befor monitored for evidence of volume overload, especially patients at cardiac Syndrome (RPLS), is a neurological which can present Leukoencephalopathy Syndrome (RPLS), isSyndrome a neurological which can disorder present Leukoencephalopathy (RPLS), is a disorder neurological which can prese Leukoencephalopathy Syndrome (RPLS), is a disorder neurological disorder which can present Adjust totalintake fluid asfluid clinically appropriate inappropriate patients with baseline cardiac failure.failure. Adjustfailure. total failure. fluid asfluid clinically appropriate inappropriate patients with baseline cardiac Adjust total intake as clinically in patients with baseline cardiac Adjust totalintake intake as clinically in patients with baseline cardiac with seizure, headache, lethargy, confusion, blindness, altered consciousness, and other with seizure, headache, lethargy, confusion, blindness, altered consciousness, and other with seizure, headache, lethargy, confusion, blindness, altered consciousness, and o with seizure, headache, lethargy, confusion, blindness, altered consciousness, and other Musc orare who atfor forare cardiac failure. failurefailure or whofailure atfailure risk cardiac failure. orrisk who atforrisk for cardiac orare who are at risk cardiac failure.failure. and neurological alonghypertension, with and theand diagnosis is diagnosis visual visual and neurological alongdisturbances, with and diagnosis isand visual and disturbances, neurological alonghypertension, withthe hypertension, the is visual and disturbances, neurological disturbances, alonghypertension, with the diagnosis is Mu byconfirmed neuro-radiological imaging (MRI). Discontinue Kyprolis if is PRES suspected byconfirmed neuro-radiological (MRI). Discontinue if PRES suspected by imaging neuro-radiological imaging (MRI). Discontinue Kyprolis if is PRES is suspe by neuro-radiological imaging (MRI).Kyprolis Discontinue Kyprolis if isPRES suspected In patients ≥75 years age, the of risk cardiac failure is increased. withPatients New In patients ≥75 years of age,ofyears the risk of risk cardiac failure is ofincreased. withPatients New In patients ≥75 years ofthe age, theof risk cardiac failure isPatients increased. withconfirmed New In patients ≥75 of age, cardiac failure isPatients increased. withconfirmed New and Theevaluate. safety of reinitiating therapy in patients previously experiencing and Theevaluate. safety ofThe reinitiating therapy in patients previously experiencing and The safety ofKyprolis reinitiating Kyprolis therapy in patients previously experie and safety ofKyprolis reinitiating Kyprolis therapy in patients previously experiencing York Association Heart and IV heartIIIIVfailure, recent myocardial infarction, andinfarction, York Heart and IIIIV heartIII failure, recent myocardial infarction, andinfarction, Nerv YorkClass HeartIIIClass Association Class and IV failure, heart failure, recent myocardial andevaluate. YorkAssociation Heart Association Class and heart recent myocardial andevaluate. PRES isPRES not known. PRES is not known. PRES is not known. is not known. conduction abnormalities uncontrolled by medications were not eligible for clinical conduction abnormalities uncontrolled by medications eligible fornot theeligible clinical conduction abnormalities uncontrolled bynot medications were nottheeligible the clinical conduction abnormalities uncontrolled by were medications were for thefor clinical Per trials. These patients bemay at greater risk cardiac complications. trials. These patients mayThese bemay at patients greater risk cardiac complications. trials. may be atfor greater for cardiac complications. 5.14 Embryo-fetal trials. These patients be atfor greater risk forrisk cardiac complications. 5.14 Embryo-fetal Toxicity Toxicity 5.14 Embryo-fetal Toxicity 5.14 Embryo-fetal Toxicity 5.2 Acute Renal FailureRenal 5.2 Acute Renal Failure 5.2 Acute 5.2 Acute Renal FailureFailure Kyprolis can cause fetal harm when to a pregnant basedwoman Kyprolis can cause fetal to a pregnant Kyprolis canwhen cause fetaladministered harm administered when administered towoman abased pregnant Kyprolis canharm cause fetaladministered harm when towoman a pregnant woman based based Psyc on its mechanism action andoffindings in animals. There noThere adequate andadequate on its mechanism andoffindings in animals. There are noare adequate and onaction its ofmechanism action and findings in animals. are no on its ofmechanism action and findings in animals. There are no adequate and and Ins of renal acute renal have in patients receiving Kyprolis. Renal Cases Cases of acute have in patients receiving Renal Cases offailure acuteoccurred renaloccurred failure have occurred inKyprolis. patients receiving Kyprolis. Cases offailure acute renal failure have occurred in patients receiving Kyprolis. Renal Renal well-controlled studies in pregnant women usingwomen Kyprolis. Carfilzomib caused well-controlled studies in pregnant women Kyprolis. Carfilzomib caused well-controlled studies inusing pregnant using Kyprolis. Carfilzomib well-controlled studies in pregnant women using Kyprolis. Carfilzomib causedcaused insufficiency adverse events (renal impairment, acute renal failure) occurred insufficiency adverse events (renal impairment, renal failure, failure) occurred insufficiency adverse events (renal impairment, acutefailure, renal failure, renal failure) occurred insufficiency adverse events (renal acute impairment, acutefailure, renal renal failure) occurred Resp toxicity in pregnant rabbits at doses that were lower inthan patients toxicityembryo-fetal in pregnant rabbits doses thatrabbits lower inthan patients toxicity inat pregnant at doses that were lower in patients toxicity in pregnant rabbits atwere doses thatthan were lower inthan patients in approximately 8% patients in randomized trial. Acute renal was in approximately 8%in patients in randomized trial. Acute renal was approximately 8%a patients in a controlled randomized controlled trial. failure Acute renalembryo-fetal failure was embryo-fetal in approximately 8%a patients in a controlled randomized controlled trial. failure Acute renal failure was embryo-fetal receiving thereceiving recommended dose. dose. dose. receiving thereceiving recommended dose. the recommended the recommended reported morereported frequently in frequently patients with advanced relapsed andrelapsed refractory multiple reported morereported frequently in frequently patients with advanced relapsed andrelapsed refractory multiple more in patients with advanced and refractory multiple more in patients with advanced and refractory multiple Cou myeloma whomyeloma received Kyprolis monotherapy. Thiswas risk was greater inwas patients a with myeloma whomyeloma received Kyprolis monotherapy. This monotherapy. risk greater inwas patients with a with who received Kyprolis This risk greater in patients who received Kyprolis monotherapy. This risk greater in patients a with Females of reproductive potential should be advised tobe avoid pregnant while Females ofareproductive potential should be potential advised to becoming pregnant while Females of reproductive should advised to becoming avoid becoming pregnant Females of reproductive potential should beavoid advised tobecoming avoid pregnant while wh baseline reduced estimated creatinine clearance (calculated using Cockcroft andCockcroft Gault baseline reduced estimated creatinine clearance (calculated using Cockcroft andCockcroft Gault baseline reduced estimated creatinine clearance (calculated using andtreated Gaulttreated baseline reduced estimated creatinine clearance (calculated using andbeing Gault being with Kyprolis. If this used during pregnancy, if theorpatient with Kyprolis. If this drug isdrug pregnancy, if theorpregnancy, patient being treated with Kyprolis. Ifduring thisisdrug used or during if the patient Dys being treated with Kyprolis. Ifused thisisdrug usedisduring pregnancy, if theorpatient equation). Monitor renalMonitor function withfunction regular measurement of the serum creatinine and/ equation). Monitor renalMonitor function withfunction regular measurement of themeasurement serum equation). renal with regular theand/ serum creatinine and/ equation). renal with regular measurement ofcreatinine the of serum creatinine and/ becomes pregnant while taking this drug, the patient should be apprised of potential becomes pregnant while taking this the patient should be of potential becomes pregnant while taking this drug, theapprised patient should bethe apprised the Skin pote becomes pregnant whiledrug, taking this drug, the patient should bethe apprised of the of potential or estimated creatinine clearance. Reduce or withhold Kyprolis dose asdose appropriate. or estimated creatinine clearance. Reduce or withhold Kyprolis as appropriate. or estimated creatinine clearance. Reduce ordose withhold Kyprolis dose as appropriate. or estimated creatinine clearance. Reduce or withhold Kyprolis as appropriate. to thehazard fetus. hazardhazard to thehazard fetus. the fetus. Disor to the to fetus. 5.3 Tumor Lysis Syndrome 5.3 Tumor Lysis Syndrome 5.3 Tumor Lysis(TLS) Syndrome 5.3 Tumor Lysis(TLS) Syndrome (TLS) (TLS) 6. ADVERSE REACTIONS 6. ADVERSE REACTIONS 6. ADVERSE REACTIONS 6. ADVERSE REACTIONS Ras ofincluding TLS,Cases fatalincluding outcomes, have been in patients who received Cases Cases of TLS,Cases fatal outcomes, been reported in patients who received ofincluding TLS, fatal outcomes, have been reported in patients who ofincluding TLS, fatalhave outcomes, havereported been reported in patients who received The following adverse reactions have been above andbecan becan found the Thereceived following adverse reactions have been discussed above and can found the The following adverse reactions have been discussed above andbecan be found The following adverse reactions havediscussed been discussed above and found the the Vasc Kyprolis. Patients withPatients multiple myeloma atumor high should be considered Kyprolis. Patients with multiple myeloma and a and highmyeloma burden should be considered Kyprolis. with multiple and high tumor burden should be considered Kyprolis. Patients with multiple myeloma and atumor highaburden tumor burden should be considered Warning and Warning Precautions of thesection prescribing They include Cardiac Warning and Warning Precautions of thesection prescribing They include Cardiac and section Precautions of theinformation. prescribing information. They include and section Precautions of theinformation. prescribing information. They include CardiacCardi be attogreater risk TLS.forrisk Ensure patients arehydrated well before administration to be atto greater riskattofor TLS. Ensure patients areEnsure well before administration be atfor greater forEnsure TLS. patients arehydrated well hydrated before administration be greater risk TLS. patients arehydrated well before administration Toxicities, Acute Renal TLS, Failure, Pulmonary Pulmonary Hypertension, Dyspnea, Toxicities, Acute Renal Failure, TLS, Renal Pulmonary Pulmonary Hypertension, Dyspnea, Toxicities, Acute TLS,Toxicity, Pulmonary Toxicity, Pulmonary Hypertension, Dy Toxicities, Acute Failure, Renal Failure, TLS,Toxicity, Pulmonary Toxicity, Pulmonary Hypertension, Dyspnea, Em of Kyprolis inof Cycle in and subsequent as needed. Consider uriclowering acid of Kyprolis inofCycle 1, and inand subsequent cycles as needed. Consider acid Kyprolis in 1, Cycle 1,inand incycles subsequent cycles asuric needed. Consider uriclowering acid lowering Kyprolis in 1, Cycle subsequent cycles as needed. Consider uriclowering acid Hypertension, Venous Thrombosis, Infusion Reactions, Thrombocytopenia, Hypertension, Venous Thrombosis, Infusion Reactions, Thrombocytopenia, HepaticHepaticHepaticHepaticVen Hypertension, Venous Thrombosis, Infusion Reactions, Thrombocytopenia, Hypertension, Venous Thrombosis, Infusion Reactions, Thrombocytopenia, in patients atforinrisk forrisk TLS. Monitor for evidence ofduring TLS during treatment andtreatment drugs drugs in patients atdrugs TLS. Monitor forforevidence of TLS treatment patients atforrisk TLS. Monitor for evidence TLSand during and drugs inrisk patients at TLS. Monitor for evidence of TLSofduring treatment and Toxicity and Hepatic Failure, TTP/HUS and PRES. Toxicity and Hepatic Failure, TTP/HUS and PRES.TTP/HUS and Hepatic Failure, and PRES. ToxicityToxicity and Hepatic Failure, TTP/HUS and PRES. Hyp manage promptly including interruption ofinterruption Kyprolis until TLS is TLS resolved. manage promptly including interruption ofinterruption Kyprolis until TLS resolved. manage promptly including ofisKyprolis untilis TLS is resolved. 6.1 Clinical manage promptly including of Kyprolis until resolved. 6.1 Clinical Trials Safety Experience Trials Safety Experience 6.1 Clinical Trials Safety Experience 6.1 Clinical Trials Safety Experience 5.4 Pulmonary 5.4 Pulmonary KRd 5.4Toxicity Pulmonary Toxicity 5.4Toxicity Pulmonary Toxicity Because clinical trials are conducted widely varying conditions, adverse reaction Because clinical trials are conducted under widely varying conditions, adverse reaction Because clinical trials areunder conducted under widely varying conditions, adverse react= Because clinical trials are conducted under widely varying conditions, adverse reaction Acute Respiratory Syndrome (ARDS), acute(ARDS), respiratory and diffuse acute Acute Respiratory Syndrome (ARDS), acute respiratory and acute AcuteDistress Respiratory Distress Syndrome acutefailure, respiratory failure, and diffuse acute diffuse AcuteDistress Respiratory Distress Syndrome (ARDS), acutefailure, respiratory failure, anddiffuse acute rates observed in the clinical oftrials acannot drug be directly compared with the low-do rates observed in the clinical oftrials a drug be compared rates inrates the inrates rates observed the clinical ofdirectly acannot drug cannot be with directly compared with rates observed intrials the in clinical oftrials acannot drug be directly compared with inrates the a infiltrative pulmonary disease assuch pneumonitis and interstitial lunginterstitial disease have disease infiltrative pulmonary disease such assuch pneumonitis and interstitial lunginterstitial disease have disease Pne infiltrative pulmonary disease as pneumonitis and lung have infiltrative pulmonary disease assuch pneumonitis and lung have clinical oftrials another drug, and may not reflect thenot rates in medical practice. clinical trials clinical oftrials another drug, and not reflect thenot rates observed in medical practice. clinical ofmay another drug, and may reflect the rates observed in medical prac oftrials another drug, and may reflect theobserved rates observed in medical practice. b occurred inthan less than of patients receiving Kyprolis. Some events havefatal. been Infatal. occurred in less 1% of 1% patients receiving Some events have been Infatal. occurred inthan less than ofKyprolis. patients receiving Kyprolis. Some events have been occurred in less 1% of 1% patients receiving Kyprolis. Some events have been Perw TheInsafety of Kyprolis inofcombination with lenalidomide and dexamethasone (KRd) was TheInfatal. safety ofThe Kyprolis insafety withinlenalidomide and (KRd) was The Kyprolis combination withdexamethasone lenalidomide and dexamethasone (KRd) safety ofcombination Kyprolis in combination with lenalidomide and dexamethasone (KRd) was the of event drug-induced pulmonary toxicity, discontinue Kyprolis. the event drug-induced pulmonary toxicity, discontinue Kyprolis. the of event of drug-induced pulmonary toxicity, discontinue Kyprolis. theofevent drug-induced pulmonary toxicity, discontinue Kyprolis. neu evaluated in an open-label study instudy patients with relapsed multiple myeloma. evaluated in an open-label study in patients with relapsed multiple myeloma. evaluated in anrandomized open-label randomized study in patients with relapsed multiple mye evaluated in anrandomized open-label randomized in patients with relapsed multiple myeloma. 5.5 Pulmonary (PAH) (PAH) (PAH) 5.5 Pulmonary (PAH) 5.5 Hypertension Pulmonary Hypertension 5.5 Hypertension Pulmonary Hypertension The median number of cycles initiated 22was cycles for thearm KRdthe arm and 14and cycles for 14 ccycles The median number of cycles initiated was 22was cycles for22 the KRd and 14the cycles for The median number of cycles initiated was 22 cycles for KRd arm14and The median number of cycles initiated cycles for KRd arm cycles forDys Rdthe Rdthe Rd arm. arm. d PAHreported was in approximately 1% of patients treated with Kyprolis andGrade was 3 was PAH was inPAH approximately 1%inofapproximately patients with Kyprolis and was 3 was was reported of patients treated with Kyprolis andthe Grade 3arm.Rdthe PAHreported was reported in approximately 1%treated of 1% patients treated with Kyprolis andGrade Grade 3arm. Em or greater inthan lessgreater of patients. Evaluate withEvaluate cardiac imaging and/or other and/or or greater in or lessgreater 1% of 1% patients. Evaluate cardiac imaging and/or other or inthan less than of with patients. with cardiac imaging other inthan less 1% of 1% patients. Evaluate with cardiac imaging and/or other Deaths due toDeaths adverse events within 30 the last oftherapy any therapy in thetherapy KRd Deaths due toDeaths adverse events within 30 days ofdays the last dose ofdose any inany theoftherapy KRd to adverse events within 30 of lastof dose any the due todue adverse events within 30of days ofdays the lastthe dose in the in KRd narK tests astests indicated. Kyprolis foruntil PAH until resolved or returned toorbaseline and tests as indicated. Withhold Kyprolis for PAH resolved or returned toorbaseline and tests asWithhold indicated. Withhold Kyprolis PAH until resolved returned to arm baseline and as indicated. Withhold Kyprolis for PAHfor until resolved returned to baseline and vs. Rdwas arm (7%)27/392 patients vs. 27/389 (7%) patients in Rd arm.in The vs.arm Rd arm 27/392 (7%) patients vs. 27/389 (7%) patients in thepatients Rdthe arm. The arm vs. Rdwas arm27/392 was (7%) patients vs. 27/389 (7%) patients RdeThe arm. arm vs. Rdwas arm27/392 (7%) patients vs. 27/389 (7%) in the Rdthe arm. Hyp consider whether to restart Kyprolis based on a benefit/risk consider whether toconsider restart Kyprolis based on aKyprolis benefit/risk whether to restart based on aassessment. benefit/risk assessment. most common consider whether to restart Kyprolis based on aassessment. benefit/risk assessment. most common cause of deaths occurring in patients (%) 10 (3%) vs. 710(2%), cause of deaths occurring patients (%) 10 vs. 710(2%), most common cause ofindeaths occurring in cardiac patients (%) cardiac (3%) vs. 7 (2%) most common cause of deaths occurring in cardiac patients (%)(3%) cardiac (3%) vs. 7 (2%), hyp infection 9 (2%) vs. 10 (3%), renal 0 (0%) vs. 1 (<1%), and other adverse events 9 (2%) infection 9 (2%) vs. 10 (3%), renal 0 (0%) vs. 1 (<1%), and other adverse events 9 (2%) infection 9 (2%) vs. 10 (3%), renal 0 (0%) vs. 1 (<1%), and other adverse events 9( infection 9 (2%) vs. 10 (3%), renal 0 (0%) vs. 1 (<1%), and other adverse events 9 (2%) 5.6 Dyspnea 5.6 Dyspnea 5.6 Dyspnea 5.6 Dyspnea There vs. 10 (3%). Serious adverse events were reported in 60% vs. 54% of patients in the vs. 10 (3%). Serious adverse events were reported in 60% vs. 54% of patients in the vs. 10 (3%). Serious adverse events were reported in 60% vs. 54% of patients in th vs. 10 (3%). Serious adverse events were reported in 60% vs. 54% of patients in the Dyspnea wasDyspnea reported inof28% patients treated with Kyprolis andGrade was 3 was or Grade Dyspnea wasDyspnea reported in 28% patients treated with Kyprolis and Kyprolis was 3 was orandGrade was reported inof28% of patients treated with Kyprolis was reported inof28% patients treated with andGrade 3 or 3 or There KRdvs.arm Rd arm. The most common serious adverse events reported in the KRd KRd arm Rd arm. most common serious adverse events reported in the KRd arm KRdThe arm vs. Rd arm. The most common serious adverse events reported in the KRd KRdvs. arm vs. Rd arm. The most common serious adverse events reported in thearm KRd arm in of patients. Evaluate dyspnea to exclude cardiopulmonary conditions greatergreater in 4%greater of 4% patients. Evaluate toEvaluate exclude cardiopulmonary conditions greater in ofdyspnea patients. dyspnea to exclude cardiopulmonary conditions in 4% of 4% patients. Evaluate dyspnea to exclude cardiopulmonary conditions Grade verses the armRd were pneumonia (14% vs. 11%), respiratory tract infection (4%infection vs.(4% vs. armRdwere pneumonia 11%), respiratory infection (4%infection vs. verses the arm(14% werevs. pneumonia (14% vs.tract 11%), respiratory tract (4% v the armRd were pneumonia (14% vs. 11%), respiratory tract including cardiac failure and pulmonary Stop Kyprolis for Grade 3 orfor4 Grade including cardiac failure and cardiac pulmonary Stop Kyprolis for Grade 3Kyprolis orfor4 Grade including failure andsyndromes. pulmonary syndromes. Stop 4 Rdverses including cardiac failure andsyndromes. pulmonary syndromes. Stop Kyprolis 3 orverses 4 3 or the substa 1.5%), pyrexia (4% vs. 2%), and pulmonary embolism (3% vs. 2%). Discontinuation due 1.5%), pyrexia (4% vs. 2%), and pulmonary embolism (3% vs. 2%). Discontinuation due 1.5%), pyrexia (4% vs. 2%), and pulmonary embolism (3% vs. 2%). Discontinuation 1.5%), pyrexia (4% vs. 2%), and pulmonary embolism (3% vs. 2%). Discontinuation due dyspnea until resolved or returned to baseline. Consider whether to restart Kyprolis based dyspnea untildyspnea resolved or returned toorbaseline. Consider toConsider restart Kyprolis based dyspnea until resolved or returned to whether baseline. whether to restart Kyprolis until resolved returned to baseline. Consider whether to restart Kyprolis based based any to adverse event occurred inin26% thearm vs.arm in the arm.in Adverse to any toadverse event occurred in 26% theinin KRd vs.arm 25% in25% the Rd arm. Adverse any adverse event occurred inKRd in the KRd vs.Rd Rd Adverse arm.hypok Adve any toadverse event occurred 26% in26% the KRd vs.arm 25% in25% the Rdthe arm. on a benefit/risk on a benefit/risk on aassessment. benefit/risk assessment. on aassessment. benefit/risk assessment. leading to discontinuation of Kyprolis occurred inof12% patients theand most eventsevents leading to discontinuation oftoKyprolis occurred 12% patients and theand most events leading discontinuation ofinKyprolis occurred inof12% of patients the mo events leading to discontinuation of Kyprolis occurred inof12% patients theand most Labor 5.7 Hypertension 5.7 Hypertension 5.7 Hypertension 5.7 Hypertension common events included pneumonia (1%), myocardial (0.8%), and upper common events included pneumonia (1%), myocardial (0.8%), and upper common events included pneumonia (1%),infarction myocardial infarction (0.8%), and upper common events included pneumonia (1%),infarction myocardial infarction (0.8%), and upper Hypertension, including hypertensive crisishypertensive and hypertensive emergency, has been Hypertension, including hypertensive crisis and emergency, has been Hypertension, including hypertensive crisishypertensive and hypertensive emergency, has been respiratory tract infection (0.8%). Hypertension, including hypertensive crisis and emergency, has been respiratory tract infection (0.8%). respiratory tract infection respiratory tract infection (0.8%).(0.8%). observed withobserved Kyprolis. Some of these havefatal. been fatal. bloodMonitor pressure observed withobserved Kyprolis. Some of these events have bloodMonitor pressure with Kyprolis. Some of been these events haveMonitor been fatal. blood pressure with Kyprolis. Some of events these events haveMonitor been fatal. blood pressure Common Adverse Events (≥in10% the KRd Arm) inOccurring Cycles 1–12 Common Adverse Events (≥Adverse 10% the KRd Cycles 1–12 Common Events (≥Arm) 10% in theOccurring KRdinOccurring Arm) in Cycles Common Adverse Events (≥in 10% in theOccurring KRd Arm) in Cycles 1–12 1–1 regularly in allregularly patients. cannot be adequately withhold Kyprolis regularly in allregularly patients. cannot be adequately withhold Kyprolis inIfallhypertension patients. If hypertension cannot becontrolled, adequately controlled, withhold Kyprolis inIfallhypertension patients. If hypertension cannot becontrolled, adequately controlled, withhold Kyprolis (Combination Therapy) (Combination Therapy) (Combination Therapy) (Combination Therapy) and evaluate. Consider whether to restart Kyprolis based on a benefit/risk and evaluate. Consider whether toConsider restart Kyprolis based on aKyprolis benefit/risk and evaluate. whether to restart based on aassessment. benefit/risk assessment. and evaluate. Consider whether to restart Kyprolis based on aassessment. benefit/risk assessment. KRd Arm 5.8 Venous Thrombosis KRd Arm Rd ArmRd ArmRd ArmRd Arm KRd Arm 5.8 Venous Thrombosis 5.8 Venous Thrombosis KRd Arm 5.8 Venous Thrombosis Decre Organ Class (N = 392) (N = 389) OrganSystem Class System (N = 389) (N = 392) (N = 389) Organ Organ Class Class(N = 392) (N = 392) (N = 389) thromboembolic events (including deep venous thrombosis and pulmonary VenousVenous thromboembolic events (including deep venous thrombosis and pulmonary Venous thromboembolic events (including deep venous thrombosis and pulmonary SystemSystem Venous thromboembolic events (including deep venous thrombosis and pulmonary embolism) have been withobserved Kyprolis. In theKyprolis. combination study, the incidence of incidence embolism) have been observed withobserved Kyprolis. In theKyprolis. combination incidence of incidence embolism) have been with In the the combination study, the of Preferred embolism) haveobserved been with In the study, combination study, the of Preferred TermPreferred Any Grade ≥Any Any Grade ≥Any TermPreferred ≥Any Grade 3Grade Any Grade ≥Any Grade 3Grade TermGrade Grade ≥ 3Grade 3 Grade Grade Term Any Grade ≥ 3Grade ≥ 3Grade≥Decre 3Gra thromboembolic events in the12events first 12first was12 in13% the venousvenous thromboembolic events in the events first was in13% the combination venous thromboembolic incycles the1213% first cycles wasKyprolis incombination the Kyprolis combination venous thromboembolic incycles the cycles wasKyprolis in13% the Kyprolis combination Decre Blood and Lymphatic System Disorders Blood and Lymphatic System Disorders Blood and Lymphatic Disorders Blood and Lymphatic SystemSystem Disorders arm versus 6% in versus the With monotherapy, the incidence of venous arm versus 6% the control monotherapy, the incidence of venous arm 6% inarm. theKyprolis control arm.Kyprolis With Kyprolis monotherapy, the incidence of venous armin versus 6%control inarm. theWith control arm.Kyprolis With monotherapy, the incidence of venous thromboembolic events wasThromboprophylaxis 2%. Thromboprophylaxis is recommended and should beand based thromboembolic events was 2%. is recommended and beand based thromboembolic events wasThromboprophylaxis 2%. Thromboprophylaxis is should recommended should beAnemia basedAnemiaAnemia thromboembolic events was 2%. is recommended should beAnemia based Decre 138 (35%) 53 (14%) 127 (33%) 47 (12%) 138 (35%) 53 (14%) 127 (33%) 47 (12%) 138 (35%) 53 (14%) 127 (33%) 47 (1 138 (35%) 53 (14%) 127 (33%) 47 (12%) on an assessment ofassessment the patient’s risks, treatment regimen, andregimen, clinical status. on an assessment risks, treatment regimen, andregimen, clinical status. onthe anpatient’s of underlying the patient’s underlying risks, treatment and clinical on anofassessment of underlying the patient’s underlying risks, treatment and clinical status.status. Decre Neutropenia 124 (32%) 104 (27%) 115 (30%) 89 (23%) Neutropenia 124 (32%) 104 (27%) 115 (30%) 89 (23%) Neutropenia 124 (32%) 104 (27%) 115 (30%) 89 (2 Neutropenia 124 (32%) 104 (27%) 115 (30%) 89 (23%) 5.9 Infusion Reactions 5.9 Infusion Reactions 5.9 Infusion Reactions 5.9 Infusion Reactions Decre Thrombocytopenia 100 (26%) 58 (15%) 75 39 Thrombocytopenia 58 (15%) 75 39 Thrombocytopenia 100 (26%) 100 (26%) 58 (19%) (15%) 75 (10%) (19%) 39 (1 Thrombocytopenia 100 (26%) 58 (19%) (15%) 75 (10%) (19%) 39 (10%) Infusion reactions, including life-threatening reactions, have occurred in patients Infusion reactions, including life-threatening reactions, have occurred in patients Infusion reactions, including life-threatening reactions, have occurred in patients Infusion reactions, including life-threatening reactions, have occurred in patients receiving Kyprolis. Symptoms include fever,include chills, myalgia, facialmyalgia, flushing, receiving Kyprolis. Symptoms include fever,include chills, arthralgia, myalgia, facialmyalgia, flushing, receiving Kyprolis. Symptoms fever, chills, arthralgia, facial Gastrointestinal flushing, receiving Kyprolis. Symptoms fever, arthralgia, chills, arthralgia, facial flushing, Decre Gastrointestinal Disorders Disorders Gastrointestinal Disorders Gastrointestinal Disorders facial edema, vomiting, weakness, shortness of shortness breath, hypotension, syncope, chest facial edema, vomiting, weakness, shortness of shortness breath, hypotension, syncope, chest facial edema, vomiting, weakness, of breath, hypotension, syncope, facial edema, vomiting, weakness, of breath, hypotension, syncope, chest chest KRd DiarrheaDiarrheaDiarrhea 115 (29%) 7 (2%) 105 (27%) 12 (3%) 115 (29%) 7 (2%) 105 (27%) 12 (3%) 115 (29%) 7 (2%) 105 (27%) 12 = (3 115 (29%) 7 (2%) 105 (27%) 12 (3%) tightness, or tightness, angina. These reactions canreactions occur or 24 up toor24 tightness, or tightness, angina. These reactions canThese occur immediately or up to hours or angina. can following occur following immediately following or 24 up hours toDiarrhea 24 hours or angina. These reactions can immediately occur immediately following uphours to low-do after administration of Kyprolis. Administer dexamethasone toprior Kyprolis totoreduce thetoConstipation after administration of Kyprolis. Administer dexamethasone prior toprior Kyprolis totoreduce the after administration of Kyprolis. Administer dexamethasone prior Kyprolis reduce the Constipation after administration of Kyprolis. Administer dexamethasone Kyprolis to reduce the Constipation 68 (17%) 0 53 (14%) 1 (0%) 68 (17%) 0 68 (17%) 1 (0%) Constipation 0 53 53 (14%)1 (0%) 1 (0 68 (17%) 0 53 (14%) (14%) incidence andincidence severity of reactions. Inform patients of risk and of symptoms incidence andincidence severity of reactions. patients of the riskthe and symptoms andinfusion severity of Inform infusion reactions. Inform patients of theand riskofand of symptoms andinfusion severity of infusion reactions. Inform patients of of the risk symptoms 60 (15%) 1 (0%) 3 (1%) NauseaNauseaNauseaNausea 60 (15%) 1 (0%) 391 (10%) 3 (1%) 60 (15%) (0%)39 39 (10%)3 (1%) 3 (1 to and contact a physician immediately ifimmediately symptoms an infusion occur. 60 (15%) (0%)391 (10%) (10%) and toand contact a physician immediately ifimmediately symptoms an infusion to contact a physician ifofsymptoms ofreaction anoccur. infusion reaction toand contact a physician ifofsymptoms ofreaction an infusion reaction occur. occur.

ASCOPost.com | JANUARY 25, 2016

PAGE 49

Announcements

Ulka Vaishampayan, MD

has extensive clinical research expertise. She serves as the Charles Martin Endowed Chair for Cancer Research and is Professor of Oncology at Wayne State University. She has held a number of national committee appointments, including Chair of the GU Group of the National Cancer Institute Phase II Clinical Trial

Consortium and Co-Chair of the California Consortium GU Clinical Trials. She is a member of the Education Committee of ASCO. “We are extremely grateful to have Dr. Heath and Dr. Vaishampayan as part of our team of experts at Karmanos,” said Gerald Bepler, MD, PhD, President and CEO of Karmanos.

6.2 Post-marketing Experience 6.2 Post-marketing 6.2Experience Post-marketing Experience 6.2 Post-marketing Experience The following adverse reactions were reported in the post-marketing experience with The following adverse reactions were reported in the post-marketing experience with The following adverse reactions were reported the post-marketing experience The following adverse reactions were reported in the in post-marketing experience with with 109 (28%) 21 (5%) 104 20 (5%) 109 (28%) 21 (5%) 104 20 (5%) 109 (28%) 21 (27%) (5%) 104 (27%) (5%) 109 (28%) 21 (27%) (5%) 104 (27%) 20 (5%)20 Kyprolis. Because these reactions arereactions reported voluntarily afrom population uncertain Kyprolis. Because these reactions arereactions reported voluntarily from afrom population uncertain Kyprolis. Because these are reported voluntarily aofpopulation of uncertain Kyprolis. Because these are reported voluntarily aoffrom population of uncertain is notitsize, always to reliably estimate theirestimate frequency or frequency establish aorcausal notit size, always to reliably estimate their frequency or frequency establish aorcausal ispossible not always possible to reliably their establish a causal ispossible notit always possible to reliably estimate their establish a causal 93 (24%) 5 (1%) 1 (0%) 93 (24%) 5 (1%) 645 (17%) 1 (0%) 93 (24%) (1%)64 64 (17%)size, 1is(0%) 93 (24%) (1%)645 (17%) (17%) 1 (0%)itsize, relationship drugtoexposure: dehydration, TTP/HUS, TLSTTP/HUS, including fatalincluding outcomes, relationship torelationship drugtorelationship exposure: dehydration, TTP/HUS, TLSTTP/HUS, including fatalincluding outcomes, toexposure: drug exposure: dehydration, TLS fatal outcomes, drug dehydration, TLS fatal outcomes, Peripheral 63 (16%) 2 (1%) 2 (1%) ema Edema Peripheral 2 (1%) 572 (15%) 2 (1%) Edema Peripheral 63 (16%) 63 (16%) (1%)57 57 (15%)and 2 (1%) Edema Peripheral 63 (16%) (1%)572 (15%) (15%) 2 (1%) and PRES. PRES. and PRES. and PRES.

Disorders andDisorders Administration Site Conditions eralGeneral Disorders and Administration Site General andConditions Administration Site Conditions General Disorders and Administration Site Conditions

d tigue startFatigue FatigueFatigue srexiaPyrexia PyrexiaPyrexia th

AstheniaAsthenia thenia Asthenia

53 (14%) 11 (14%) (3%) 46 7 (2%) 53 (14%) 11 (14%) (3%)53 46 7 (2%) 11(12%) (3%) 46 (12%)7. 7 (2%) 53 11(12%) (3%) 46 (12%) 7 (2%) 7. DRUG INTERACTIONS DRUG INTERACTIONS

7. DRUG INTERACTIONS 7. DRUG INTERACTIONS Kyprolis is primarily metabolized via peptidase andpeptidase epoxide hydrolase activities, asand asand as Kyprolis is primarily metabolized via peptidase andpeptidase epoxide hydrolase andactivities, asandactivities, Kyprolis is primarily metabolized via and activities, epoxide hydrolase Kyprolis is primarily metabolized via and epoxide hydrolase ymes a result, the pharmacokinetic profile of Kyprolis is unlikely to be affected by concomitant a result, the pharmacokinetic profile of Kyprolis is unlikely to be affected by concomitant a result, the pharmacokinetic profile of Kyprolis is unlikely to be affected by concomitant a result, the pharmacokinetic profile of Kyprolis is unlikely to be affected by concomitant Upper Respiratory Tract Infection 85 (22%) 7 (2%) 52 (13%) 3 (1%) per Respiratory Tract Infection 85Infection (22%) 7 (2%) 527 (13%) 3 (1%) Upper Respiratory Tract 85 (22%) 52 (13%)3 (1%) 3 (1%) Upper Respiratory Tract Infection 85 (22%) (2%) 7 (2%)52 (13%) administration of cytochrome P450 inhibitors andinhibitors inducers. Kyprolis is notKyprolis expected to expected administration of cytochrome andinhibitors inducers. Kyprolis is notKyprolis expected to expected administration of inhibitors cytochrome P450 and inducers. is not administration of P450 cytochrome P450 and inducers. is not to to /HUS) Nasopharyngitis 63 (16%) 0 43 (11%) 0 influence sopharyngitis 63 (16%) 0 63 (16%) 0 43 (11%) Nasopharyngitis 0 43 (11%) 0exposure exposure of drugs. other Nasopharyngitis 63 (16%) 0 43 (11%) 0 influence of other influence exposure of drugs. other drugs. influence exposure ofdrugs. other ivedBronchitis 54 (14%) 5 (1%) 2 (1%) onchitis 54 (14%) 5 (1%) 395 (10%) 2 (1%) Bronchitis 54 (14%) (1%)39 39 (10%)8. 2IN (1%) Bronchitis 54 (14%) (1%)395 (10%) (10%) 2 (1%) USE SPECIFIC POPULATIONS USE8. SPECIFIC POPULATIONS 8.IN USE IN SPECIFIC POPULATIONS 8.INUSE SPECIFIC POPULATIONS , stop a a a a 8.1(7%) Pregnancy 8.1(7%) Pregnancy 8.1 Pregnancy 54 (14%) 35 (14%) (9%) 43 27 (11%) (7%)27 Pneumonia 8.1 Pregnancy 54 (14%) 35 (14%) (9%)54 43 27 (11%) (7%)43 eumonia 35(11%) (9%) 27 Pneumonia 54 35(11%) (9%) 43 Pneumonia arted. US is and Nutrition Kyprolis may Kyprolis cause fetal There are noThere adequate andadequate well-controlled studies in studies Kyprolis may Kyprolis cause fetal There are adequate and well-controlled studies in studies mayharm. cause fetalnoharm. are no and well-controlled in mayharm. cause fetal harm. There are no adequate and well-controlled in Metabolism and Nutrition Disorders abolism Disorders Metabolism and Nutrition Disorders Metabolism and Nutrition Disorders pregnant women usingwomen Kyprolis. pregnant women using Kyprolis. pregnant using Kyprolis. pregnant women using Kyprolis. Hypokalemia 78 (20%) 22 (20%) (6%)35 pokalemia 78 (20%) 22 (20%) (6%)78 Hypokalemia 22 (9%) (6%)12 35 (3%) (9%)12 (3%) Hypokalemia 78 22 (9%) (6%)35 35 (3%) (9%)12 (3%)12 Females of reproductive potential should be advised tobe avoid pregnant while Females of reproductive potential should be potential advised to becoming pregnant while Females of reproductive should advised to becoming avoid becoming pregnant Females of reproductive potential should beavoid advised tobecoming avoid pregnant while while being with Kyprolis. Consider the Consider benefits and risks Kyprolis and possible riskspossible with Kyprolis. Consider the Consider benefits and risks Kyprolis and possible riskspossible being treated with Kyprolis. theofbenefits and of Kyprolis and being treated with Kyprolis. the benefits andofrisks ofrisks Kyprolis and risks risks Hypocalcemia 55 (14%) 10 (14%) (3%) 39 5 (1%) pocalcemia 55 (14%) 10 (14%) (3%)55 39 5 (1%) Hypocalcemia 10(10%) (3%) 39 (10%)being 5 (1%)treated Hypocalcemia 55 10(10%) (3%) 39 (10%) 5 (1%)treated thewhen fetus when to a Kyprolis pregnant If Kyprolis isduring used to the to fetus to a Kyprolis pregnant Kyprolis is used to theprescribing fetusKyprolis whenKyprolis prescribing towoman. a Ifpregnant woman. If Kyprolis used during to theprescribing fetus when prescribing towoman. a pregnant woman. If Kyprolis isduring usedisduring Hyperglycemia 43 (11%) 18 (11%) (5%)33 33 15 perglycemia 43 (11%) 18 (11%) (5%)43 (9%) (4%) Hyperglycemia 18 (9%) (5%)15 33 (4%) (9%)15 15 (4%) Hyperglycemia 43 18 (5%) 33 (9%) (4%) pregnancy, if theorpatient pregnant while taking Kyprolis, advise the patient ofthe patient pregnancy, orpregnancy, if theorpregnancy, patient while taking Kyprolis, advise theKyprolis, patient ofadvise ifbecomes thepregnant patient becomes pregnant while taking of ifbecomes theorpatient becomes pregnant while taking Kyprolis, advise the patient of ent the potential hazard to thehazard fetus. the potential hazard to potential thehazard fetus. the the fetus. the potential to the to fetus. other Musculoskeletal and Connective Tissue Disorders culoskeletal andMusculoskeletal Connective Tissue Disorders and Connective Tissue Disorders Musculoskeletal and Connective Tissue Disorders 8.2 Lactation 8.2 Lactation 8.2 Lactation 8.2 Lactation SpasmsMuscle 88 (22%) 3 (1%) 3 (1%) uscleMuscle SpasmsMuscle 88 (22%) 3 (1%) 733 (19%) 3 (1%) 88 (22%) (1%)73 73 (19%)3 (1%) 3 (1%) SpasmsSpasms 88 (22%) (1%)733 (19%) (19%) pected isThere no information theregarding presence of Kyprolis inofhuman milk, the effects onthe effects There There is no information theregarding presence of Kyprolis inofhuman milk, the effects onthe There is noregarding information the presence Kyprolis in human milk, is noregarding information the presence Kyprolis in human milk, effects on on encing Nervous System Disorders vous System Disorders Nervous System Disorders Nervous System Disorders the breastfed infant, or the infant, effects onthe milk The developmental and health the breastfed infant, or breastfed the infant, effects milk production. developmental and developmental health the or effects milk production. The and health the breastfed oronthe effects onproduction. milkonThe production. The developmental and health of breastfeeding should be considered along with thewith mother’s clinical need clinical for of breastfeeding should be considered the mother’s clinical need for b NECb benefits of breastfeeding should bewith considered along with the mother’s need for b benefits of breastfeeding should bealong considered along the mother’s clinical need for b NEC 43 (11%) 7 (2%) 4 (1%) Peripheral Neuropathies (11%) 7 (2%) 377 (10%) 4 (1%) ripheral Neuropathies NEC 43 (11%) (2%)37 37 (10%)benefits 4 (1%) Peripheral Neuropathies 43 (11%) (2%)377 (10%) (10%) 4 (1%)benefits Peripheral Neuropathies NEC43 Kyprolis andpotential anyand potential adverse effects on theeffects breastfed infant from or from Kyprolis and Kyprolis any adverse effects on the breastfed infant from Kyprolis or from Kyprolis andpotential any potential adverse on the breastfed infant from Kyprolis any adverse effects on the breastfed infantKyprolis from Kyprolis or fromor from Psychiatric Disorders chiatric Disorders Psychiatric Disorders Psychiatric Disorders the underlying condition. the underlying condition. thematernal underlying maternal condition. thematernal underlying maternal condition. 8.3 Contraception Contraception 8.3 Contraception Insomnia 63 (16%) 6 (2%) 8 (2%) 8.3 Contraception somnia 63 (16%) 6 (2%) 506 (13%) 8 (2%) Insomnia 63 (16%) (2%)50 50 (13%)8.3 8 (2%) Insomnia 63 (16%) (2%)506 (13%) (13%) 8 (2%) Kyprolis can cause fetal harm when to pregnant women. Advise females Kyprolis can cause fetal to pregnant women. females Kyprolis canwhen cause fetaladministered harm administered when administered toAdvise pregnant women. Advise females Kyprolis canharm cause fetaladministered harm when to pregnant women. Advise females Respiratory, Thoracic, and Thoracic, Mediastinal piratory, Thoracic, and Thoracic, Mediastinal Respiratory, andDisorders Mediastinal Disorders Respiratory, andDisorders Mediastinal Disorders of reproductive potential toeffective use effective contraception measures to measures prevent pregnancy of reproductive potential to use contraception measures to measures prevent pregnancy of reproductive potential toeffective use effective contraception to prevent pregnancy of reproductive potential to use contraception to prevent pregnancy 85 (22%) 1 (0%) 0 during ugh Cough Cough Cough 85 (22%) 1 (0%) 461 (12%) 0 46 (12%) 85 (22%) (0%)46 (12%) 0 during treatment with Kyprolis and forand at2least weeks following completion ofcompletion therapy. 85 (22%) (0%)461 (12%) 0 during treatment with Kyprolis and Kyprolis forwith at least weeks following completion ofcompletion therapy. during treatment Kyprolis and for at2least 2 weeks following of therapy. treatment with for at2least weeks following of therapy. hile c c c 8.4 Pediatric Use c 8.4 Pediatric Use 8.4 Pediatric Use 8.4 Pediatric Use 70 (18%) 9 (2%) 58 (15%) 6 (2%) Dyspnea 70 (18%) 9 (2%) 589 (15%) 6 (2%) spnea 70 (18%) 58 (15%)6 (2%) 6 (2%) Dyspnea 70 (18%) (2%) 9 (2%)58 (15%) Dyspnea The safety and of Kyprolis inofpediatric patients have not been established. The safety and ofand Kyprolis inofpediatric patients not been established. Theeffectiveness safety effectiveness Kyprolis inhave pediatric patients have notestablished. been established. Theeffectiveness safety and effectiveness Kyprolis in pediatric patients have not been ential Skin and Subcutaneous Tissue Tissue Tissue and Subcutaneous Tissue Skin and Subcutaneous Skin and Subcutaneous 8.5 Geriatric UseGeriatric 8.5 Geriatric UseGeriatric 8.5 8.5 Use Use Disorders rders Disorders Disorders 392 patients treated with Kyprolis in combination with lenalidomide and Of 392Ofpatients treated withpatients Kyprolis in combination withinlenalidomide and Of 392 treated with Kyprolis combination with lenalidomide and 45 (12%) 5 (1%) 5 (1%) sh Rash Rash Rash 45 (12%) 5 (1%) 535 (14%) 5 (1%) 45 (12%) (1%)53 53 (14%)5 (1%) 5 (1%) Of 392 patients treated with Kyprolis in combination with lenalidomide and 45 (12%) (1%)535 (14%) (14%) dexamethasone, 185 patients (47%) wereyears ≥65 years age43of and 43ofand patients (11%) were dexamethasone, 185 patients (47%) werepatients ≥65 age and patients (11%) were dexamethasone, 185 (47%) wereofyears ≥65 years age 43 patients dexamethasone, 185 patients (47%) wereof ≥65 age 43and patients (11%) (11%) were were Disorders cular Disorders ≥75 of years age. No overall differences indifferences effectiveness were observed between these Vascular Disorders ≥75 years age.ofyears No overall differences effectiveness were observed between these Vascular Disorders ≥75 years ofNo age. No in overall in effectiveness were observed between ≥75 of age. overall differences in effectiveness were observed between these these iacVascular and younger patients. Thepatients. incidence of serious adverse events wasin50% patients and younger patients. The incidence of serious adverse events wasadverse 50% patients and younger The incidence of serious events wasin50% in patients and younger patients. The incidence of serious adverse events wasin50% patients yspnea, , Embolic 49 (13%) 16 (13%) (4%)22 9 (2%) and Thrombotic Events, 49 Events, (13%) 16 (13%) (4%)49 9 (2%) mbolic and Thrombotic Events, 16 (6%) (4%)22 (6%)9 (2%) 9 (2%) Embolic and Thrombotic 49 16 (6%) (4%)22 (6%)22 Embolic and Thrombotic Events, ≤65 years of age, 70% in patients 65 to 74 years of age, and 74% in patients ≥75 years ≤65 years of age, 70% in patients 65 to 74 years of age, and 74% in patients ≥75 years ≤65 years of age, 70% in patients 65 to 74 years of age, and 74% in patients ≥75 years ≤65 years of age, 70% in patients 65 to 74 years of age, and 74% in patients ≥75 years d d d d Venous nous VenousVenous of age.of age.of age.of age. e e e e 41 (11%) 12 (11%) (3%)15 4 (1%) Hypertension 41 (11%) 12 (11%) (3%)41 4 (1%) pertension 12 (4%) (3%)15 (4%)8.6 4 (1%) Hypertension 41 12 (4%) (3%)15 (4%)15 4 (1%) Hypertension 8.6 Renal Impairment Renal Impairment 8.6 Renal Impairment 8.6 Renal Impairment KRd = KRd Kyprolis, lenalidomide, and low-dose dexamethasone; Rd = lenalidomide and No No dose adjustment isadjustment required inispatients with baseline mild,baseline moderate, =tion Kyprolis, lenalidomide, and low-dose dexamethasone; Rddexamethasone; = lenalidomide and dose adjustment required inispatients with baseline mild,baseline moderate, = Kyprolis, lenalidomide, and low-dose Rd = lenalidomide andstarting No starting dose required in patients with mild, moderate, =KRd Kyprolis, lenalidomide, and low-dose dexamethasone; Rd = lenalidomide andstarting No starting doseisadjustment required in patients with mild, moderate, low-dose dexamethasone or severe renal impairment orimpairment patients onorchronic dialysis based on a phase 2on a phase dexamethasone or severe renal impairment patients onorchronic dialysis based on adialysis phase 2based low-dose dexamethasone or severe renal patients on chronic 2 low-dose dexamethasone or severe renalorimpairment patients on chronic dialysis based on a phase 2 in the esose a a includes preferred terms of pneumonia, bronchopneumonia pharmacokinetic and safety Kyprolis. The pharmacokinetics of Kyprolis was notwas not a includes and safety trial Kyprolis. The pharmacokinetics Kyprolis was not pharmacokinetic andofsafety of Kyprolis. Theofpharmacokinetics of Kyprolis was not pharmacokinetic andoftrial safety trial oftrial Kyprolis. The pharmacokinetics of Kyprolis Pneumonia eumonia preferred terms of pneumonia, Pneumonia includes preferred of pneumonia, bronchopneumoniapharmacokinetic Pneumonia includes preferred terms terms of bronchopneumonia pneumonia, bronchopneumonia ctice. influenced the by degree ofthe baseline renal impairment, when patients werepatients influenced byinfluenced the by degree ofthe baseline renal impairment, including when patients werepatients influenced by degree of baseline renal including impairment, including when were degree of baseline renal impairment, including when were b bneuropathies NEC includes preferred terms under HLT peripheral b Peripheral ripheral neuropathies NEC includes preferred under HLT peripheral Peripheral neuropathies NEC terms includes preferred terms HLT peripheral receiving dialysis. Administer KYPROLIS after the dialysis procedure. Peripheral neuropathies NEC includes preferred terms under under HLT peripheral was receiving dialysis. Administer KYPROLIS after theKYPROLIS dialysis receiving dialysis. Administer after the dialysis procedure. receiving dialysis. Administer KYPROLIS afterprocedure. the dialysis procedure. neuropathies NEC NEC NEC uropathies NEC neuropathies neuropathies eloma. 8.7 Hepatic Impairment 8.7 Hepatic Impairment 8.7 Hepatic Impairment 8.7 Hepatic Impairment c c sc forDyspnea includes preferred terms of dyspnea, dyspnea exertional spnea includes preferred terms of dyspnea, dyspnea Dyspnea includes preferred terms of exertional dyspnea, dyspnea exertional Dyspnea includes preferred terms of dyspnea, dyspnea exertional The safety, efficacy and pharmacokinetics of Kyprolis have not been evaluated in patients The safety, efficacy and pharmacokinetics Kyprolis have not evaluated in patients The safety, efficacy andofpharmacokinetics ofbeen Kyprolis have not been evaluated in patients The safety, efficacy and pharmacokinetics of Kyprolis have not been evaluated in patients d d d Embolic and Embolic thrombotic venous include preferred terms in MedDRA SMQ mbolic and Embolic thrombotic venous include preferred terms in MedDRA SMQ andevents, thrombotic events, venous include preferred terms in MedDRA SMQ andevents, thrombotic events, venous include preferred terms in MedDRA SMQ with baseline hepatic impairment. Patients with thewith following laboratory values were values with baseline hepatic impairment. Patients withPatients the following laboratory values were with baseline hepatic impairment. Patients with the following laboratory with baseline hepatic impairment. the following laboratory values were were KRd scope search of embolic and thrombotic venous. rrownarrow scopenarrow search of embolic and thrombotic venous. narrow scope search of embolic andevents, thrombotic events, venous. scope search of embolic andevents, thrombotic events, venous. excluded from the Kyprolis clinical trials:clinical ALT/AST ≥3 × upper normal (ULN) and excluded fromexcluded the Kyprolis clinical trials: ALT/AST ≥3 × upper limit normal (ULN) and excluded from the Kyprolis trials: ALT/AST ≥3 ×ofupper of normal (ULN) and from the Kyprolis clinical trials: ALT/AST ≥3 ×oflimit upper limit oflimit normal (ULN) and eThe e e Hypertension includes preferred terms of hypertension, hypertensive crisis, crisis, crisis, pertension includes preferred terms of hypertension, hypertensive crisis,hypertensive Hypertension includes preferred terms of hypertension, Hypertension includes preferred terms of hypertension, hypertensive bilirubin ≥2 ×bilirubin ULN. bilirubin ≥2 ×bilirubin ULN. ≥2 × ULN. ≥2 × ULN. ),pertensive hypertensive emergency emergency hypertensive emergency hypertensive emergency 8.8 Cardiac Impairment 8.8 Cardiac Impairment 8.8 Cardiac Impairment 8.8 Cardiac Impairment (2%) were 274 patients in thepatients KRd arm who received treatment beyond Cyclebeyond 12. were 274 (70%) patients in the KRd arm who received treatment beyond Cycle 12. There were(70%) 274 (70%) in the KRd armreceived who received treatment Cycle 12. There were(70%) 274 patients in the KRd arm who treatment beyond Cycle 12. heThere Safety of patients with New York Heart Association and IV heartIIIIVfailure or recent Safety of patients with New York Heart Association and IIIIV heartIII failure or recent Safety of patients with New YorkClass HeartIIIClass Association Class and IV failure heart failure or recent Safety of patients with New York Heart Association Class and heart or recent were newno clinically relevant AEsemerged that emerged in the later cycles. were newno clinically relevant AEs that inAEs the later treatment cycles. There were noclinically new clinically relevant that emerged in the later treatment cycles. There were new relevant AEs that emerged in thetreatment later treatment cycles. dThere arm no myocardial infarction (within 3months) to 6(within nothas been evaluated. myocardial infarction (within 3 infarction to 6(within not been evaluated. myocardial tohas 6 months) notevaluated. been evaluated. myocardial infarction 3months) tohas 6 3months) nothas been Grade 3higher and Grade higher adverse reactions that occurred during Cycles 1-12 with a evs. 3 and Grade adverse reactions that occurred during Cycles 1-12 with a 3 and higher adverse reactions that occurred during Cycles 1-12 with a 3 and higher adverse reactions that occurred during Cycles 1-12 with a 10. OVERDOSAGE 10. OVERDOSAGE 10. OVERDOSAGE substantial difference (≥2%) between twothe arms were thrombocytopenia, 10. OVERDOSAGE (≥2%) between the(≥2%) twothearms were neutropenia, thrombocytopenia, substantial difference between twoneutropenia, armsneutropenia, were neutropenia, thrombocytopenia, substantial difference (≥2%) between twothe arms were thrombocytopenia, nantial due difference hypokalemia, and hypophosphatemia. kalemia, and hypophosphatemia. hypokalemia, and hypophosphatemia. hypokalemia, and hypophosphatemia. erse onset of chills, hypotension, renal insufficiency, thrombocytopenia and lymphopenia Acute Acute onset of chills, hypotension, renal insufficiency, thrombocytopenia and lymphopenia Acute onset of chills, hypotension, renal insufficiency, thrombocytopenia and lymphopenia Acute onset of chills, hypotension, renal insufficiency, thrombocytopenia and lymphopenia ost hasreported been following aofdose 200 ofofKyprolis administered in error.in error.in error. has been following areported dose 200aofmg ofaofmg Kyprolis administered in error. hasreported been following dose 200 of Kyprolis administered hasreported been following dose 200 mg of mg Kyprolis administered Laboratory Abnormalities ratory Abnormalities Laboratory Abnormalities Laboratory Abnormalities isThere no specific for Kyprolis overdosage. In the of event overdose, the patient There There is no specific forspecific Kyprolis overdosage. In theoverdosage. event patient There isantidote no antidote for Kyprolis the the event of overdose, the patient isantidote no specific antidote for Kyprolis overdosage. In overdose, the ofIn event of overdose, the patient 3–4 Laboratory ( ≥10%) in Cycles 1-12 GradeGrade 3–4 Laboratory ( ≥10%) in Cycles Grade 3–4Abnormalities Laboratory Abnormalities (1-12 ≥10%) in Cycles Grade 3–4Abnormalities Laboratory Abnormalities ( ≥10%) in Cycles 1-12 1-12 be monitored, thefor adverse reactions in the adverse reaction section. shouldshould be monitored, forspecifically thefor adverse reactions the adverse should bespecifically monitored, specifically theinadverse reactions thesection. adverse reaction section. should bespecifically monitored, thefor adverse reactions in reaction the in adverse reaction section. (Combination Therapy) (Combination Therapy) (Combination Therapy) (Combination Therapy) 12 2. DOSAGE AND ADMINISTRATION 2. DOSAGE AND ADMINISTRATION 2. DOSAGE AND ADMINISTRATION 2. DOSAGE AND ADMINISTRATION KRd KRd KRd KRd Rd Rd Rd Rd Adequate hydration is required toprior dosing in 1,Cycle especially in atinhigh Adequate hydration is required prior toprior dosing in Cycle patients atinhigh Adequate hydration is required toespecially dosing in in 1, patients especially patients Adequate hydration is required toprior dosing in1,Cycle 1,Cycle especially patients at highat high Laboratory Abnormality (N = 392) (N = 389) Laboratory Abnormality (N = 392) (N = 389) Laboratory Abnormality (N = 392) (N = 389) Laboratory Abnormality (N = 392) (N = 389) TLS orrisk renal and following the following administration of Kyprolis with both oral and risk of risk TLSoforrisk renal toxicity andorfollowing the following administration oftheKyprolis with both and ofortoxicity TLS renal toxicity and administration oforal Kyprolis with bothand oral and of TLS renal toxicity and the administration of Kyprolis with both oral Decreased Lymphocytes 182 (46%) 119 (31%) eased Lymphocytes 182 (46%) 119 (31%) Decreased Lymphocytes 182 (46%) 119 (31%) Decreased Lymphocytes 182 (46%) 119 (31%) intravenous (IV) fluids, needed. Premedicate with dexamethasone toprior administering intravenous (IV) fluids, if needed. with dexamethasone prior toprior administering intravenous (IV)Premedicate fluids, if needed. Premedicate with dexamethasone to administering intravenous (IV) iffluids, if needed. Premedicate with dexamethasone toprior administering Kyprolis for monotherapy. Calculate theCalculate Kyprolis dose using the patient’s actual body actual Kyprolis for monotherapy. Calculate theCalculate Kyprolis dose using the patient’s actual body Kyprolis for monotherapy. the Kyprolis dose using the patient’s Kyprolis for monotherapy. the Kyprolis dose using the patient’s actual body body Decreased Absolute Neutrophil Count 152 (39%) 140 (36%) eased Neutrophil Count 152 (39%) 140 (36%) Decreased Absolute Neutrophil 152 (39%) 140 (36%) Decreased Absolute Neutrophil Count Count 152 (39%) 140 (36%) ade 3 Absolute atarea baseline. Administer Kyprolis a over 10-minute infusion. notDo notDo not surfacesurface area surface atarea baseline. Administer Kyprolis over Kyprolis a over 10-minute infusion. Do notDo surface at baseline. Administer Kyprolis aIV10-minute IV infusion. atarea baseline. Administer aIVover 10-minute IV infusion. Decreased Phosphorus 122 (31%) 106 (27%) eased Phosphorus 122 (31%) 106 (27%) Decreased Phosphorus 122 (31%) 106 (27%) Decreased Phosphorus 122 (31%) 106 (27%) administer asadminister a bolus. Flush the IVwith line with saline or 5% saline dextrose injection administer asadminister a bolus. Flush the line normal saline or 5%normal dextrose injection as IV a bolus. Flush the IVwith linenormal with or 5% dextrose injection as a bolus. Flush the IV linenormal saline or 5% dextrose injection immediately before andKyprolis after administration. mixnot Kyprolis orwith orwith or immediately before and after administration. Do administration. notDo mixnotKyprolis with orwith immediately before andKyprolis after Kyprolis Do mix Kyprolis immediately before andKyprolis after administration. Do mixnotKyprolis Decreased Platelets 101 (26%) 59 (15%) eased Platelets 101 (26%) 59 (15%) Decreased 101 (26%) 59 (15%) Decreased PlateletsPlatelets 101 (26%) 59 (15%) 12%) administer asadminister an infusion with other is recommend administer asadminister an infusion other is recommend as an medicines. infusion withThromboprophylaxis otherThromboprophylaxis medicines. Thromboprophylaxis is for recommend aswith an infusion withmedicines. other medicines. Thromboprophylaxis is for recommend for for Decreased TotalDecreased White Blood Cell Count 97 (25%) 71 (18%) eased TotalDecreased White Blood Cell Count (25%) 71 (18%) Total White Blood Cell97 Count 97 (25%) 71 (18%) Total White Blood Cell Count 97 (25%) 71 (18%) 23%) patients beingpatients treated with the combination of Kyprolis, lenalidomide and dexamethasone. patients beingpatients treated with the combination of the Kyprolis, lenalidomide and dexamethasone. being treated with combination of Kyprolis, lenalidomide and dexamethasone. being treated with the combination of Kyprolis, lenalidomide and dexamethasone. Consider antiviral prophylaxis inprophylaxis patients being treated with Kyprolis. Consider antiviral prophylaxis inprophylaxis patients being treated with Kyprolis. Consider antiviral in patients being treated with Kyprolis. Consider antiviral in patients being treated with Kyprolis. Decreased Hemoglobin 58 (15%) 68 (18%) eased Hemoglobin 58 (15%) 68 (18%) Decreased Hemoglobin 58 (15%) 68 (18%) Decreased Hemoglobin 58 (15%) 68 (18%) 10%) Theinformation risk provided iscomprehensive. not is comprehensive. The FDA-approved The risk provided here ishere not FDA-approved Theinformation risk information provided here not The comprehensive. The FDA-approved Theinformation risk provided here not iscomprehensive. The FDA-approved Decreased Potassium 41 (11%) eased Potassium 41 (11%) 23 (6%)23 (6%)23 (6%)product Decreased Potassium 41 (11%) 23 (6%)product Decreased Potassium 41 (11%) labeling becan found at be www.kyprolis.com or contact Amgen Medical labeling can becan found at be www.kyprolis.com or contact Amgen product labeling can found at www.kyprolis.com orMedical contact Amgen Medical product labeling found at www.kyprolis.com or contact Amgen Medical at 1-800-772-6436. at 1-800-772-6436. Information at 1-800-772-6436. at 1-800-772-6436. KRd = KRd KYPROLIS, and low-dose dexamethasone; Rd = lenalidomide andInformation =3%) KYPROLIS, and low-dose dexamethasone; Rddexamethasone; = lenalidomide and KRd =lenalidomide, KYPROLIS, lenalidomide, and low-dose Rd = lenalidomide andInformation =lenalidomide, KYPROLIS, lenalidomide, and low-dose dexamethasone; Rd = lenalidomide andInformation low-dose dexamethasone ose dexamethasone low-dose dexamethasone ThisSummary Brief is Summary based on the Kyprolis Prescribing Information v9, 07/15. low-dose dexamethasone This Brief is Summary based on the Kyprolis Prescribing Information v9, 07/15. This Brief is based the Kyprolis Prescribing Information v9, 07/15. ThisSummary Brief is based on theon Kyprolis Prescribing Information v9, 07/15. 0%) U.S. Patent Numbers: http://pat.amgen.com/kyprolis U.S. Patent Numbers: U.S.http://pat.amgen.com/kyprolis Patent Numbers: http://pat.amgen.com/kyprolis U.S. Patent Numbers: http://pat.amgen.com/kyprolis

atment t Infections andInfections Infestations ctions andInfections Infestations and Infestations and Infestations

1%)

“The commitment of these two nationally recognized medical oncologists is demonstrated each day by the compassionate care they provide to our patients. Their outstanding work is helping to advance and discover new lifesaving cancer therapies that will lead to the next standard of cancer care.” n

Sally Vernon, PhD, Appointed to National Cancer Institute Board

ally Vernon, PhD, Chair of the Department of Health Promotion and Behavioral Sciences at The University of Texas Health Science Center at

Sally Vernon, PhD

Houston (UTHealth) School of Public Health, has been appointed to the Board of Scientific Counselors for Clinical Sciences and Epidemiology at the National Cancer Institute (NCI). She will hold a 5-year appointment with the Board, which meets several times a year. As part of her duties, Dr. Vernon will evaluate and review research projects of cancer scientists and clinicians in the NCI’s Center for Cancer Research (CCR) and Division of Cancer Epidemiology and Genetics (DCEG). This will involve evaluation of the performance and productivity of senior scientists and senior clinicians through periodic site visits to NCI laboratories. The board members will provide advice to the Director and Deputy Director of the NCI about matters concerning scientific program policy and progress and future direction of the research programs carried out by CCR and DCEG. “It’s an honor and an important responsibility to evaluate the research programs the NCI is carrying out,” said Dr. Vernon, who holds the Blair Justice Professorship in Mind-Body Medicine and Public Health at UTHealth. Dr. Vernon’s research has focused on the promotion of evidence-based cancer screening tests for breast, cervical, and colon cancers. n

The ASCO Post | JANUARY 25, 2016

PAGE 50

San Antonio Breast Cancer Symposium Cardiotoxicity

Prophylactic Beta-Blocker Preserves Left-Ventricular Function in Patients Receiving Trastuzumab By Alice Goodman

he beta-blocker bisoprolol was able to prevent trastuzumab (Herceptin)-associated declines in left-ventricular ejection fraction, whereas the effect of the angiotensinconverting–enzyme (ACE) inhibitor perindopril was less robust. Use of bisoprolol reduced dose interruptions for trastuzumab due to left-ventricu-

left-ventricular dysfunction, and about 1%–5% develop heart failure.

Study Details and Results The MANTICORE study was a three-arm 1:1:1 randomization, placebo-controlled, double-blind, multicenter trial that included 99 patients taking trastuzumab. At baseline, all

Routine use of standard heart failure pharmacotherapy protects against trastuzumab-associated declines in left ventricular ejection fraction and appears safe in HER2-overexpressing early breast cancer.

EXPERT POINT OF VIEW

“F

or the most part, the cardiotoxicity with trastuzumab appears to be largely reversible, unlike anthracyclines, which cause permanent cardiac damage,” said Lisa Carey, MD, Distinguished Professor at the UNC Lineberger Breast Center, Chapel Hill, North Carolina. “In this small study, they saw no congestive heart failure, but the drug had to be withheld in eight patients in the placebo group and one patient each in the bisoprolol and perindopril groups. In clinical practice, we routinely image the heart for patients on trastuzumab, and if we have to hold the drug, we refer the patient to a cardiologist,” she continued.

This study is a nice addition to an emerging literature in cardiooncology. We need to partner with cardiologists to determine when and how to intervene when using cardiotoxic drugs.

—Edith Pituskin, RN, PhD

lar dysfunction and was safe. Despite the positive findings for bisoprolol, neither drug was able to prevent leftventricular remodeling (as measured by left-ventricular end-diastolic volume) associated with trastuzumab therapy. The MANTICORE (Multidisciplinary Approach to Novel Therapies in Cardiology Oncology Research) trial was designed to determine whether prophylactic use of a beta-blocker or an ACE inhibitor (two drugs used to treat established cardiovascular disease) could reduce trastuzumab-associated cardiotoxicity in patients with HER2-positive early breast. These results were presented at the 2015 San Antonio Breast Cancer Symposium.1 “To date, there have been no effective prevention strategies for trastuzumabassociated cardiotoxicity. Routine use of standard heart failure pharmacotherapy protects against trastuzumab-associated declines in left-ventricular ejection fraction and appears safe in HER2-overexpressing early breast cancer,” stated lead author Edith Pituskin, RN, PhD, of the University of Alberta in Edmonton. HER2 is overexpressed in about 20% of all women with breast cancer, and trastuzumab reduces mortality by about one-third in women with HER2-positive breast cancer. All drugs come with risks and benefits, and cardiotoxicity is a concern with trastuzumab. About 20% of patients treated with trastuzumab experience

patients had a left-ventricular ejection fraction ≥ 50%. Patients were randomized to receive bisoprolol, perindopril, or placebo during trastuzumab-based chemotherapy for 24 months. Cardiac magnetic resonance imaging parameters were assessed at baseline, at 3 months, at 12 months, and at 24 months. Accrual for the study was stopped after the first 99 patients were enrolled due to the low likelihood that additional participants would change the primary outcome. Mean age at baseline was about 50 years. Anthracyclines, known to be cardiotoxic, were given (along with trastuzumab) to 23% of the placebo group, 33% of the perindopril group, and 12% of the bisoprolol group. Bisoprolol significantly prevented reduction in left-ventricular ejection fraction from baseline vs placebo (P = .001) and also prevented trastuzumab interruptions due to drop in left-ventricular ejection fraction (P = .002). Post-treatment left-ventricular ejection fraction declined from 61% to 56% for placebo,

—Lisa Carey, MD

Support for Prophylaxis “These data support prophylactic use of a beta-blocker more strongly than an ACE inhibitor. However, there were baseline imbalances; in particular, more patients were taking anthracyclines in the placebo and ACE inhibitor arms than in the beta-blocker arm, so while this suggests that you may prevent asymptomatic ejection fraction declines by prophylactic therapy, this trial cannot be considered definitive.” Dr. Carey noted. “The truth is we not infrequently have to hold trastuzumab for cardiac issues. Giving cardioprotective drugs may minimize time off trastuzumab, but I wouldn’t change practice based on this small study,” she said. “This study is a nice addition to the literature. We need cardiologists with an interest in oncology to weigh in, and that is a whole new field that is emerging. I am encouraged that a group of cardiologists are interested in cancer patients. We need to collaborate with cardiologists to define when to intervene and what are expectations are,” concluded Dr. Carey. n Disclosure: Dr. Carey reported no potential conflicts of interest.

from 62% to 59% for perindopril, and from 62% to 61% for bisoprolol. A multivariate analysis showed that baseline left-ventricular ejection fraction

Cardioprotection for Patients Receiving Trastuzumab ■■ Cardiotoxicity is a concern with trastuzumab. ■■ A phase III study suggested that prophylactic use of a beta-blocker may prevent declines in left ventricular ejection fraction. ■■ Neither a beta-blocker nor an ACE inhibitor was able to prevent cardiac remodeling in this study. ■■ More research is needed on optimal cardioprotection for patients receiving trastuzumab.

and bisoprolol and perindopril were the only factors that affected left-ventricular ejection fraction during the study. n Disclosure: Dr. Pituskin reported no potential conflicts of interest.

Reference 1. Pituskin E, Mackey JR, Koshman S, et al: Prophylactic beta blockade preserves left ventricular ejection fraction in HER2-overexpressing breast cancer patients receiving trastuzumab: Primary results of the MANTICORE randomized, controlled trial. 2015 San Antonio Breast Cancer Symposium. Abstract S1-05. Presented December 9, 2015.

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The ASCO Post | JANUARY 25, 2016

PAGE 52

San Antonio Breast Cancer Symposium Novel Therapies

Immunotherapy for Breast Cancer: Early Lackluster Study Results yet Promise Remains By Alice Goodman

mmunotherapy is at the forefront of exciting new approaches to cancer, with excellent and long-lasting responses in metastatic melanoma and non–small cell lung cancer (NSCLC) and several immunotherapy agents now approved for those malignancies by the U.S. Food and Drug Administration (FDA). The hope is that other tumors will follow suit. However, at the 2015 San Antonio Breast Cancer Symposium (SABCS), two separate preliminary studies of immunotherapy presented lackluster results, but it is still early in the days of immunotherapy for breast cancer.

Avelumab The JAVELIN trial explored the use of the investigational IgG1 anti–PD-L1 (anti–programmed cell death ligand 1) antibody avelumab in patients with lo-

ab is ongoing,” said presenting author Luc Dirix, MD, of Sint Augustinus– University of Antwerp, Belgium. The study enrolled 168 patients unselected for PD-L1 expression. A total of 58 had triple-negative breast cancer, 72 had estrogen receptor–positive/ HER2-negative or progesterone receptor–positive disease, and 26 had HER2positive disease (another 12 patients had disease of an unknown molecular subtype). Avelumab was given at 10 mg/kg intravenously every 2 weeks until disease progression. Response to avelumab appeared to be related to PD-L1 expression on immune cells within the tumor: 33% for those with positive PD-L1 expression vs 2.4% for tumors that were PD-L1– negative. Of the five triple-negative breast cancer responders, four had PDL1–positive immune cells.

Despite the modest overall response rate in unselected metastatic breast cancer patients, there were signs of greater clinical activity...among patients with triple-negative breast cancer and patients expressing PD-L1. Further analysis of PD-L1 expression and clinical activity of avelumab is ongoing. —Luc Dirix, MD

cally advanced or metastatic breast cancer and showed a low overall response rate of 4.8%.1 However, there was an early signal for hope in triple-negative breast cancer; of the eight patients who responded in this trial, five had triplenegative breast cancer. Tumor shrinkage of 30% or more was observed in 16 patients (9.5%) in the overall study population. “Despite the modest overall response rate in unselected metastatic breast cancer patients, there were signs of greater clinical activity among patients with triple-negative breast cancer and patients expressing PD-L1 [PD-1 ligand]. Further analysis of PD-L1 expression and clinical activity of avelum-

The safety profile of avelumab was acceptable. Grade 3 or higher treatment-related adverse events were reported in 13.7%. Immune-related side effects were reported in 17 patients (ie, hypothyroidism, thrombocytopenia, and/or autoimmune hepatitis). Eight patients discontinued treatment with avelumab (4.8%). Treatment-related deaths were reported in two patients (1.2%). At the time of data cutoff, nine patients remained on avelumab.

Pembrolizumab Pembrolizumab (Keytruda), an FDA-approved anti–PD-1 antibody for melanoma and NSCLC, was studied in a “basket” trial that included

Based on these data, we believe that further investigation of immune therapies in HER2-positive, estrogen receptor–negative breast cancer is warranted, particularly if combination therapies can expand the T-cell compartment. —Hope Rugo, MD

several types of advanced cancers that express PD-L1.2 Among 25 evaluable patients (from a cohort of 261 breast cancer patients) with estrogen receptor–positive/ HER2-negative breast cancers that express PD-L1, the overall response rate was 12% (comprising only 3 partial responders), with another 4 patients (16%) having stable disease. Five patients (60%) progressed on pembrolizumab, and three (22%) were not evaluable at the time of presentation. The clinical benefit rate (response rate plus stable disease) was 20%. Responses were durable in this group, ranging from 8.7 weeks to more than 44 weeks. Despite these results, lead author Hope Rugo, MD, of the University of California San Francisco, was encouraged. “Based on these data, we believe that further investigation of immune therapies in HER2-positive, estrogen receptor–negative breast cancer is warranted, particularly if combination therapies can expand the T-cell compartment,” she told listeners. At the 2015 SABCS, Dr. Rugo presented preliminary efficacy results of 25 evaluable patients with estrogen receptor–positive/HER2-negative breast cancer in KEYNOTE-028. The total breast cancer cohort included 261 patients who were screened for PD-L1 expression; 48 had PD-L1–positive tumors, according to the assay used in this trial (which is different from the assay used in the JAVELIN and other trials of anti–PD-1 and anti– PD-L1 therapies). At the time of data cutoff, all three partial responders remained on therapy with pembrolizumab. Dr. Rugo and other investigators in

this field believe that standardization of PD-L1 assays is critical. Despite the lack of such standardization, some studies show responses in PD-L1–negative tumors, so the jury is out as to whether PD-L1 expression will select all patients who will respond to these therapies. As in the JAVELIN trial, patients enrolled in the KEYNOTE-028 trial were heavily pretreated with advanced disease. No new safety signals related to treatment with checkpoint inhibitors were raised. Grade 3 or 4 adverse events were reported in 4 of 25 patients; 4 immune-related grade 3 events occurred, and there was 1 grade 4 event. No treatment-related deaths were reported at a median follow-up of 7.3 months. Disclosure: The JAVELIN study was sponsored by Merck and Serono, and the KEYNOTE-028 study was funded by Merck. Dr. Dirix reported no potential conflicts of interest. Dr. Rugo disclosed research funding from Merck and Genentech to the University of California San Francisco.

References 1. Dirix LY, Takacs I, Nikolinakos P, et al: Avelumab (MSB0010718C), an anti– PD-L1 antibody, in patients with locally advanced or metastatic breast cancer: A phase Ib JAVELIN solid tumor trial. 2015 San Antonio Breast Cancer Symposium. Abstract S1-04. Presented December 9, 2015. 2. Rugo HS, Delord J-P, Im S-A, et al: Preliminary efficacy and safety of pembrolizumab (MK-3475) in patients with PDL1–positive estrogen receptor–positive/ HER2-negative advanced breast cancer enrolled in KEYNOTE-028. 2015 San Antonio Breast Cancer Symposium. Abstract S5-07. Presented December 11, 2015.

ASCOPost.com | JANUARY 25, 2016

PAGE 53

San Antonio Breast Cancer Symposium Neoadjuvant Chemotherapy

Role of Carboplatin in Triple-Negative Breast Cancer Still Unclear By Caroline Helwick

tudies presented at the 2015 San Antonio Breast Cancer Symposium built upon an increasing body of data in support of the neoadjuvant use of carboplatin in patients with triple-negative breast cancer. Overall, however, the studies fell short of establishing carboplatin’s role in this malignancy and left oncologists still uncertain as to when and how to incorporate the drug. The studies were the phase II CALGB/Alliance 40603 trial, which showed improvements in pathologic

The current analysis evaluated the association between pathologic complete response and event-free and overall survival among 443 patients followed for a median of 39 months. The study population had a 3-year event-free survival rate of 74% and a 3-year overall survival rate of 83%. William Sikov, MD, Associate Professor of Medicine at Brown University, Providence, Rhode Island, reported that pathologic complete response was achieved in the breast by 52% and in

Despite significantly higher [pathologic complete response] rates seen in CALGB 40603, neither carboplatin nor bevacizumab has yet been shown to improve relapse-free survival or overall survival when administered as part of neoadjuvant therapy in stage II to III triple-negative breast cancer. —William Sikov, MD

GeparSixto supports the use of carboplatin as part of neoadjuvant treatment in all patients with triplenegative breast cancer. —Gunter von Minckwitz, MD

complete response rates with carboplatin,1 and the phase II German GeparSixto trial, which showed improved pathologic complete response rates and demonstrated a benefit for carboplatin in event-free survival.2

CALGB 40603 Details This study evaluated carboplatin administered every 3 weeks at an area under the curve [AUC] of 6 and bevacizumab (Avastin) at 10 mg/kg as a component of neoadjuvant chemotherapy for triple-negative breast cancer. A previous analysis showed that the addition of these agents to weekly paclitaxel followed by dose-dense doxorubicin and cyclophosphamide significantly improved pathologic complete response rates in the breast, and carboplatin also improved pathologic complete responses in the breast and axilla.3

the breast/axilla by 47%. Achievement of pathologic complete response or residual cancer burden class 1 was observed in 60%. The achievement of pathologic complete response was associated with risk reductions of approximately 70% for event-free survival and up to 80% for overall survival. These results are consistent with the meta-analysis by Cortazar et al showing a 76% reduction in events and 84% reduction in mortality when patients with triple-negative disease achieve a pathologic complete response,4 Dr. Sikov pointed out. The 3-year event-free survival rate was 86% for patients achieving pathologic complete response in the breast/ axilla, vs 62% for those who did not (P < .0001). The 3-year overall survival rate was 93% and 73%, respectively (P < .0001). These improved outcomes,

Carboplatin for Neoadjuvant Treatment of Triple-Negative Breast Cancer ■■ CALGB 40603 and GeparSixto evaluated the benefit of adding carboplatin to neoadjuvant chemotherapy in triple-negative breast cancer patients. ■■ CALGB 40603 showed that pathologic complete response rates were increased with the addition of carboplatin; there was no association between carboplatin use and improved event-free or overall survival, but the study was underpowered to demonstrate such a benefit. ■■ GeparSixto, on the other hand, found that carboplatin improved pathologic complete response rates and also increased disease-free survival rates by approximately 10%. ■■ Experts maintain that the benefit of carboplatin in these patients remains unclear, and larger studies are needed.

however, could not be specifically tied to treatment with carboplatin or bevacizumab, Dr. Sikov reported. “Despite significantly higher [pathologic complete response] rates seen in CALGB 40603, neither carboplatin nor bevacizumab has yet been shown to improve relapse-free survival or overall survival when administered as part of neoadjuvant therapy in stage II to III triple-negative breast cancer,” he said. He acknowledged, however, that the study was underpowered to make this determination. “Our results support the value of [pathologic complete response] as a good surrogate for long-term outcomes on a patient level,” he said, but evidence remains lacking that pathologic complete response can be used as a surrogate for event-free or overall survival “on a trial level.”

GeparSixto Details “GeparSixto supports the use of carboplatin as part of neoadjuvant treatment in all patients with triple-negative breast cancer,” according to Gunter von Minckwitz, MD, Chair of the German Breast Group in Neu-Isenburg and Professor of Gynecology at the University Women’s Hospital in Frankfurt, Germany. GeparSixto involved 595 patients with triple-negative or HER2-positive breast cancer, randomly assigned to neoadjuvant therapy with weekly paclitaxel and liposomal doxorubicin, with or without weekly carboplatin (AUC 2, later reduced to AUC 1.5). The triplenegative subset also received concurrent bevacizumab, while those with HER2positive tumors received trastuzumab (Herceptin) and lapatinib (Tykerb). The primary endpoint, pathologic complete response in all patients, was

not improved by the addition of carboplatin: 43.7% with carboplatin vs 36.9% without (P = .107). However, the benefit was clear in the triple-negative subgroup, whose pathologic complete response rates improved from 37% to 53% with carboplatin (P = .005), Dr. von Minckwitz reported. “Carboplatin improved disease-free survival substantially in patients with triple-negative breast cancer,” he noted. In this subgroup, disease-free survival was 85.8% with carboplatin and 76.1% without (hazard ratio = 0.56, P = .0350). The drug showed no effect in patients with HER2-positive breast cancer. “The disease-free survival effect of carboplatin was correctly predicted by its extensive effect on [pathologic complete response], supporting the surrogacy of [pathologic complete response],” he added. GeparSixto also demonstrated a strongly positive effect for carboplatin on pathologic complete response and disease-free survival in patients with wild-type BRCA1/2, 50.8% of whom achieved a pathologic complete response with carboplatin, compared to 33.1% who did not (P = .005). “BRCA wild-type patients who did not get carboplatin had worse diseasefree survival. The effect of carboplatin was mostly seen in wild-type patients, and this was a surprise,” he said. There were only 50 patients with BRCA mutations, which may have diminished the power to show an effect in this group, he acknowledged. “Favorable prognosis after [pathologic complete response] was confirmed and was independent of germline BRCA status,” he concluded. n Disclosure: Dr. Sikov is on the speakers continued on page 54

The ASCO Post | JANUARY 25, 2016

PAGE 54

San Antonio Breast Cancer Symposium Triple-Negative Breast Cancer continued from page 53 bureau for Eisai and is on advisory boards for Celgene and AbbVie. Dr. von Minckwitz disclosed relationships with Roche, Teva, and GlaxoSmithKline.

References 1. Sikov WM, Berry DA, Perou CM, et al: Event-free and overall survival fol-

lowing neoadjuvant weekly paclitaxel and dose-dense AC +/- carboplatin and/ or bevacizumab in triple-negative breast cancer: Outcomes from CALGB 40603 (Alliance). 2015 San Antonio Breast Cancer Symposium. Abstract S2-05. Presented December 9, 2015. 2. von Minckwitz G, Loibl S, Schneeweiss A, et al: Early survival analysis of the randomized phase II trial investigating the

addition of carboplatin to neoadjuvant therapy for triple-negative and HER2positive early breast cancer (GeparSixto). 2015 San Antonio Breast Cancer Symposium. Abstract S2-04. Presented December 9, 2015. 3. Sikov WM, Berry DA, Perou CM, et al: Impact of the addition of carboplatin and/or bevacizumab to neoadjuvant onceper-week paclitaxel followed by dose-

dense doxorubicin and cyclophosphamide on pathologic complete response rates in stage II to III triple-negative breast cancer: CALGB 40603 (Alliance). J Clin Oncol 33:13-21, 2015. 4. Cortazar P, Zhang L, Untch M, et al: Pathological complete response and long-term clinical benefit in breast cancer: The CTNeoBC pooled analysis. Lancet 384:164-172, 2014.

EXPERT POINT OF VIEW

he formal discussant for the CALGB 40603 and GeparSixto studies at the San Antonio Breast Cancer Symposium was Angela DeMichele, MD, Professor of Medicine and Miller Chair in Breast Cancer Excellence at the Perelman School of Medicine, University of Pennyslvania. “The key questions raised by these

breast cancer remains “an individualized decision,” she added. “The hazard ratios suggest benefit, but currently there are not enough data to be conclusive.” Regarding the use of pathologic complete response as a surrogate for outcomes in early triple-negative disease, she noted, “The hazard ratios are in the right direction despite the small

The hazard ratios suggest benefit, but currently there are not enough data to be conclusive. —Angela DeMichele, MD

At the end of the day, we need a bigger study. —Melinda L. Telli, MD

trials,” she said, “are whether they provide sufficient data to warrant routine use of carboplatin in early triplenegative breast cancer and whether [pathologic complete response] is a valid surrogate for outcomes.” Dr. DeMichele noted that GeparSixto yielded better overall prognosis and a larger, incremental carboplatin effect (Table 1) and suggested this may be due to a more effective dosing schedule. The chemotherapy backbone and carboplatin dose and schedule may be critical to its optimal efficacy, she said. Whether the data warrant routine use of carboplatin in triple-negative

sample sizes and variability in eventfree survival estimates.” She gave this question “a qualified yes.” The data at least contribute to the development of models to better understand this relationship, “but to draw definitive conclusions about event-free survival, we need to power neoadjuvant studies for these endpoints, Dr. DeMichele concluded. Meanwhile, Dr. DeMichele advised that carboplatin can be considered outside of clinical trials in patients who need rapid control of locoregional disease (to increase operability and reduce morbidity) or have the highest risk of relapse

(stage III, very young). Benefit to BRCA mutation carriers is still under investigation, she added, and she emphasized the need to carefully select patients for carboplatin, since it may contribute to shortterm and possibly long-term toxicity.

‘Incredibly Important Question’ Also weighing in was Melinda L. Telli, MD, Assistant Professor of Medicine at Stanford University School of Medicine, Palo Alto, who has spearheaded research in the area of triple-negative disease. In an interview with The ASCO Post, Dr. Telli agreed with many of Dr. DeMichele’s points, including the suggestion that the improvement seen in GeparSixto may be due to its more intensive chemotherapy regimen. “The German study looked at a somewhat unconventional, very doseintensive regimen of 18 weeks of a taxane/anthracycline with bevacizumab [Avastin], with and without carboplatin. It showed an elevation in [pathologic complete response] rate and a 3-year disease-free survival difference of about 10% that appeared to clearly favor the carboplatin-treated patients,” she said. The CALGB study, however, used an anthracycline/cyclophosphamide/ taxane backbone, with or without carboplatin, which is more familiar to U.S. clinicians. This resulted in increased patho-

logic complete response rates but no improvement in long-term outcomes. Dr. Telli said it is possible that the “carboplatin made up ground” for the lack of an alkylating agent in GeparSixto. “Cyclophosphamide wasn’t included, so potentially the platinum filled that role. The point was also raised that the intensive weekly regimen given for 18 cycles led to higher cumulative doses of the different drugs,” she noted. “At the end of the day, we need a bigger study,” she said. To this end, carboplatin is being evaluated in adjuvant, postadjuvant, and neoadjuvant trials of triple-negative breast cancer, including the neoadjuvant Brightness trial of standard taxane followed by doxorubicin/cyclophosphamide chemotherapy with and without carboplatin and with and without veliparib. “It’s a big study that is better powered for long-term outcomes. Maybe that study will give us better answers,” Dr. Telli said. The value of adding carboplatin is “an incredibly important question,” she concluded. “Certainly if there’s a drug that is inexpensive and that can improve disease-free survival by 10% in this high-risk group of patients, that would be great. But I’m not going to change my practice yet.” n Disclosure: Drs. DeMichele and Telli reported no potential conflicts of interest.

Table 1: CALGB 40603 vs GeparSixto Outcome

CALGB 40603

GeparSixto

3-year event-free or disease-free survival in control arm

71.6%

76.1%

3-year event-free or disease-free survival in carboplatin arm

76.5%

85.8%

Carboplatin event-free or disease-free survival benefit

4.9%

9.7%

Event-free or disease-free survival hazard ratio, with vs without carboplatin

0.84 (0.58–1.22)

0.56 (0.33–0.96)

Atezolizumab (MPDL3280A): an investigational, engineered anti-PDL1 antibody

CURRENTLY ENROLLING Clinical trials in various tumor types for atezolizumab (MPDL3280A)* Trials for atezolizumab (MPDL3280A), an investigational anti-PDL1 antibody, are currently recruiting patients in various tumor types †: • Bladder

• Kidney

— NCT02589717 (Ph IV) — NCT02450331 (Ph III) IMvigor 010 — NCT02302807 (Ph III) IMvigor 211

• Breast — NCT02425891 (Ph III) IMpassion 130 — NCT02605915

• Colorectal — NCT02291289

• Hematologic malignancies — NCT02431208 — NCT02220842 — NCT02508870

— NCT02420821 (Ph III) IMmotion 151

• Lung

• Melanoma — NCT01656642

• Solid tumors

— NCT02486718 (Ph III) — NCT02409355 (Ph III) IMpower 111 — NCT02409342 (Ph III) IMpower 110 — NCT02367794 (Ph III) IMpower 131 — NCT02367781 (Ph III) IMpower 130 — NCT02366143 (Ph III) IMpower 150 — NCT02013219

— NCT02458638 — NCT02471846 — NCT02350673 — NCT02323191 — NCT02304393 — NCT01633970 — NCT02410512 — NCT02174172 — NCT01375842

For more information about the atezolizumab (MPDL3280A) clinical trial program Visit: Find.AntiPDL1trials.com or ClinicalTrials.gov Call: Genentech Trial Information Support Line: 1-888-662-6728 (US only) Email: global.rochegenentechtrials@roche.com *Product under investigation has not been approved for use outside of the clinical trial setting. This information is presented only for the purpose of providing an overview of the clinical trials and should not be construed as a recommendation for use of any product for unapproved purposes. † All trials consistent with information on ClinicalTrials.gov as of November 17, 2015.

The ASCO Post | JANUARY 25, 2016

PAGE 56

In the Clinic Supportive Care

Uridine Triacetate Granules for Fluorouracil or Capecitabine Overdose or Early Severe Toxicity By Matthew Stenger

n December 11, 2015, uridine triacetate (Vistogard) was approved for emergency treatment of adult and pediatric patients following fluorouracil (5FU) or capecitabine overdose regardless of the presence of symptoms or patients who exhibit early-onset severe or lifethreatening cardiac or central nervous system (CNS) toxicity or early-onset unusually severe adverse reactions (eg, gastrointestinal toxicity or neutropenia) within 96 hours following the end of 5-FU or capecitabine administration.1,2 Uridine triacetate is not recommended for the nonemergent treatment of adverse reactions associated with 5-FU or capecitabine, since it may diminish the efficacy of these drugs. The safety and efficacy of uridine triacetate started > 96 hours after the end of 5-FU or capecitabine administration have not been established.

ric patients. The severe or life-threatening toxicities involved the CNS (eg, encephalopathy, acute mental status change), cardiovascular system, gastrointestinal system (eg, mucositis), and bone marrow. Of the 112 patients with 5-FU overdose, 105 (94%) were overdosed by infusion rate only (range = 1.3–720 times planned infusion rate), 4 (4%) were overdosed by dose only, and 3 (3%) were overdosed by both dose and rate. Four patients initiated uridine triacetate at > 96 hours after the end of 5-FU or capecitabine administration. The major efficacy outcome was survival at 30 days or the resumption of chemotherapy if prior to 30 days.

OF NOTE Uridine triacetate carries warnings/precautions and contraindications.

no no

Uridine competitively inhibits cell damage and cell death caused by the cytotoxic antimetabolite 5-FU. A cytotoxic intermediate of 5-FU (FdUMP) inhibits thymidylate synthase and blocks thymidine synthesis. Thymidine is required for DNA replication and repair; uridine is not found in DNA. 5-FU also exerts a cytotoxic effect through incorporation of the metabolite 5-fluoridine triphosphate (FUTP) into

Emergency Treatment for Fluorouracil or Capecitabine Overdose ■■ Uridine triacetate (Vistogard) was approved for emergency treatment of adult and pediatric patients following fluorouracil (5-FU) or capecitabine overdose or patients who exhibit early-onset severe or life-threatening cardiac or central nervous system toxicity or early-onset unusually severe adverse reactions within 96 hours following the end of 5-FU or capecitabine administration. ■■ In adults, uridine triacetate should be given at 10 g (1 packet) orally every 6 hours for 20 doses without regard to meals. In pediatric patients, it should be given at 6.2 g/m2, not to exceed 10 g per dose, orally every 6 hours for 20 doses without regard to meals.

Supporting Efficacy Data Approval was based on two singlearm open-label expanded access studies in 135 patients who had either 5-FU (n = 112) or capecitabine (n = 5) overdose or presented with severe or life-threatening toxicities within 96 hours after

OF NOTE Uridine triacetate is an acetylated prodrug of uridine, which competitively inhibits cell damage and cell death caused by the cytotoxic antimetabolite 5-FU.

the end of receiving 5-FU (n = 18).2 Patients had a median age of 59 years (range = 1–83 years), 56% were male, 72% were white, 9% were black, 6% were Hispanic, 4% were Asian, and 95% had a cancer diagnosis; 6 were pediat-

Of the 135 patients in the two studies, 130 (96%) survived and 5 (4%) died. Of the five patients who died, two were treated at > 96 hours following the end of 5-FU administration. Retrospective historical data from 25 patients who were overdosed with 5-FU (by rate, range = 1.9–64 times planned rate) and received supportive care only indicate that 84% had died. Among the 117 patients with overdose, 114 (97%) were alive at 30 days. Of the 18 patients with severe toxicity, 16 (89%) were alive at 30 days. Overall, 45 patients (33%) resumed chemotherapy within 30 days.

How It Works Uridine triacetate is an acetylated prodrug of uridine. Following oral administration, uridine triacetate is deacetylated by nonspecific esterases throughout the body, yielding uridine in the circulation.

RNA, with incorporation being proportional to systemic 5-FU exposure. Excess circulating uridine derived from uridine triacetate is converted into uridine triphosphate, which competes with FUTP for incorporation into RNA.

How It Is Used In adults, uridine triacetate should be given at 10 g (1 packet) orally every 6 hours for 20 doses without regard to meals. In pediatric patients, it should be given at 6.2 g/m2, not to exceed 10 g per dose, orally every 6 hours for 20 doses without regard to meals. Any unused portion of granules should be discarded. Treatment should begin as soon as possible after overdose or early-onset toxicity within 96 hours following the end of 5-FU or capecitabine administration. Each dose should be mixed with 3 to 4 ounces of soft foods (eg, apple-

sauce, pudding, or yogurt) and ingested within 30 minutes; granules should not be chewed. The patient should drink at least 4 ounces of water after the dose. If a patient vomits within 2 hours of a dose, another complete dose should be given as soon as possible after the vomiting episode, and the next dose should be given at the regularly scheduled time. Treatment can be given via nasogastric tube or gastrostomy tube when necessary.

Safety Profile In the two single-arm trials (N = 135), the most common adverse events of any grade were vomiting (10%), nausea (5%), and diarrhea (3%). One patient experienced serious adverse events of grade 3 nausea and vomiting. Treatment was discontinued due to adverse events in two patients (1.4%). Five patients died within 30 days of the last dose of uridine triacetate, with none of the deaths being considered attributable to treatment. Uridine triacetate carries no warnings/ precautions and no contraindications. n References 1. U.S. Food and Drug Administration: Uridine triacetate. Available at http://www. fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm476930.htm. Accessed January 9, 2016. 2. Vistogard (uridine triacetate) oral granules prescribing information, Wellstat Therapeutics Corporation, December 2015. https://www.vistogard.com/Vistogard/ media/Vistogard/Files/final-labeling-textvistogard.pdf. Accessed January 9, 2016.

ASCOPost.com | JANUARY 25, 2016

PAGE 57

News

Pancreas Cancer Liquid Biopsy: Proof-of-Principle Study

ancreatic cancer tumors are ripe for analysis with a liquid biopsy, according to researchers at The University of Texas MD Anderson Cancer Center. In a proof-of-principle study published recently in Annals of Oncology,1 the investigators reported on research in which they conducted whole-genome, wholeexome, and gene-expression analysis of tumors in three patients with pancreatic cancer using DNA and RNA found inside exosomes circulating in their blood or other liquid biospecimens. “Analysis of exosomal DNA and RNA

to access, even using needle or core biopsies, so getting enough tissue to enable a full next-generation sequencing is difficult.” Other liquid biopsies under development rely mainly on cell-free DNA found circulating in the blood. Unprotected DNA in the blood is “chopped up” by enzymes, so cell-free DNA allows some genomic analysis, Dr. Maitra said, but not whole-genome or wholeexome sequencing. Cell-free RNA is even more easily destroyed in the blood. Exosomes are membrane balls that protect the DNA and the RNA cargo inside from destruction, preserving high-quality samples.

Analyzing Gene Expression

Anirban Maitra, MBBS

allows us to do everything you can do off a direct biopsy of tumor tissue,” said senior author Anirban Maitra, MBBS, Professor of Pathology and Director of MD Anderson’s Sheikh Ahmed Bin Zayed Al Nahyan Center for Pancreatic Cancer Research. The research was conducted under MD Anderson’s Moon Shots Program to accelerate development of clinical and prevention advances from scientific knowledge. Dr. Maitra is Co-Leader of the Pancreatic Cancer Moon Shot, one of 12 in the program. The proof-of-principle study opens the door to validation studies in multiple tumor types of a liquid biopsy that could be used to determine prognosis, guide targeted therapy, and monitor treatment.

Meeting Pancreatic Biopsy Challenge Maitra and colleagues detected a variety of cancer-derived biomarkers, including genetic mutations, insertions, deletions, copy number profiles, and gene fusions that can act as neoantigens—new targets for the immune system. Potentially treatable mutations, including BRCA2 and NOTCH1, were identified. “A comprehensive liquid biopsy would meet one of the major challenges of characterizing pancreatic cancer and other cancers deep in the body,” Dr. Maitra said. “These tumors are hard

“Full RNA sequencing is important because genome sequencing tells you what genes are altered, while analysis of RNA tells you what abnormal genes are actually being expressed,” he said. “Shed exosomes allow us to do matched DNA and RNA simultaneously in liquid biopsies at a resolution that is not amenable with cell-free approaches.” Common clinical practice now calls for only a pretreatment biopsy in deeply located tumors at presentation. Conducting biopsies during treatment would more closely monitor therapy success or failure and help researchers better understand how the cancer genome evolves in response to treatment. “Tumors continuously evolve during therapy. New changes, new pathways, new mutations show up,” Dr. Maitra said. Payers don’t usually cover multiple biopsies. “Now you can bypass the need for tissue and get the full genome, exome, and transcriptome from a vial of blood,” Dr. Maitra said. Exosomes may actually paint a more complete picture of a tumor’s genomic diversity because all genetic mutations present in primary and metastatic tumors would flow into a liquid biopsy via the exosomes, the researchers noted. Sampling part of a tumor might only capture mutations in that area and not reflect its overall genomic diversity. Exosomes were isolated from blood samples in two patients and also from pleural fluid in a patient who had lung metastases. Whole genome sequencing covered up to 91% of the human genome, whereas exome sequencing of only the protein-coding genes covered 95% to 99%. continued on page 61

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The ASCO Post | JANUARY 25, 2016

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San Antonio Breast Cancer Symposium Biomarkers

Homologous Recombination Deficiency Score Correlated With Response to Platinum in Breast Cancer By Caroline Helwick

he homologous recombination deficiency (HRD) score may be a predictive biomarker of response to neoadjuvant platinum-based therapy in patients with triple-negative breast cancer, according to studies presented at the 2015 San Antonio Breast Cancer Symposium. “We found, in our adjusted analysis, that patients with [homologous recombination]–deficient tumors were 4.6 times more likely to achieve a pathologic complete response,” said Melinda L. Telli, MD, of Stanford University School of Medicine, Palo Alto, California. Dr. Telli presented findings from a pooled analysis of six phase II trials in which patients with triple-negative breast cancer received a platinum agent.1 Homologous recombination deficiency status was significantly associated with an improved odds of achieving a pathologic complete response (ypT0/

is ypN0), regardless of BRCA1/2 mutation status.

We found, in our adjusted analysis, that patients with a high score on HRD assay were 4.6 times more likely to achieve a pathologic complete response in response to platinum agents.

HRD Assay Homologous recombination–deficient tumors have lost the ability to repair double-stranded DNA breaks, resulting in increased susceptibility to DNA-damaging drugs such as platinum agents and PARP (poly ADP-ribose polymerase) inhibitors. Genomic instability and a high frequency of BRCA1 and BRCA2 germline mutations are commonly associated with triple-negative breast cancer. Myriad Genetics has developed an HRD assay that generates an HRD score and assesses BRCA1 and BRCA2 in the tumor. The test, which may become available this year for ovarian cancer, is a next-generation sequencing assay that uses DNA extracted from formalin-fixed paraffin-embedded or frozen tumor tis-

EXPERT POINT OF VIEW

eorge Sledge, MD, Professor, and Chief, Division of Oncology, Stanford University Medical Center, told The ASCO Post that he found the data from the pooled analysis “very exciting.” “One of the big questions in triple-negative breast cancer is how to select which drugs work best for which patients. We know that platinum agents are active, but not for all patients. We know that BRCA mutations are potentially

We saw a striking relationship between HRD score and pathologic complete response. —George Sledge, MD

good markers for who will benefit from DNA-damaging agents, but most patients don’t have BRCA mutations,” he noted. “Finding a signal that would allow us to select patients for treatment would obviously be very useful.”

A Word of Caution He said the strength of this study is that it “brought together researchers who have been doing this work across the world but with smaller numbers of patients.” In the pooled analysis, all patients had a platinum backbone, all were evaluated for HRD status, and all had long-term follow-up, he pointed out. “We saw a striking relationship between HRD score and pathologic complete response,” Dr. Sledge said, but offered a word of caution: “This is a compilation of patients.” What is needed next, he suggested, is a larger, prospective, and “definitive” trial to prove that homologous recombination deficiency is a biomarker for response to platinum. “This will give us a clean-kill answer.” n Disclosure: Dr. Sledge reported no potential conflicts of interest.

—Melinda L. Telli, MD

sue. The test labels a tumor homologous recombination–deficient or –nondeficient by combining the HRD score that it generates and the BRCA1/2 mutation status of the tumor. In short, this deficiency corresponds to an HRD score ≥ 42 and/or a mutation in BRCA1/2. “What this test gives you is a readout of how genetically unstable the genome is,” Dr. Telli told The ASCO Post. The goal is to have an assay that can identify patients without BRCA mutations who might have a good chance of responding to DNA-damaging therapies, such as platinum, she explained.

Details of Pooled Analysis A total of 267 patients with triple-negative breast cancer and known HRD status were analyzed from the following clinical trials: GeparSixto (n =101), PrECOG 0105 (N = 72), NCT00580333 (N = 32), NCT01372579 (N = 26), NCT00148694 (N = 18), and TBCRC 008 (N = 18). Neoadjuvant chemotherapy regimens in the respective trials included (1) paclitaxel, nonpegylated liposomal doxorubicin, carboplatin, and bevacizumab (Avastin); (2) carboplatin, gemcitabine, and iniparib; (3) cisplatin and bevacizumab; (4) cisplatin; (5) carboplatin plus eribulin (Halaven); and (6) and carboplatin and nanoparticle albumin-bound (nab) paclitaxel (Abraxane), with or without vorinostat (Zolinza). The primary endpoint was correlation of pathologic complete response and homologous recombination deficiency status. Secondary analyses correlated pathologic complete response and a binary HRD score (< 42 [low] vs ≥ 42 [high]) as well as pathologic complete response and homologous recombination deficiency in the BRCA1/2-negative subgroup.

Response Rates In the pooled analysis, 178 (67%) patients had homologous recombina-

tion–deficient tumors, 89 (33%) had homologous recombination–nondeficient tumors, and 106 (39.7%) had tumors that had a high HRD score but were BRCA-negative. A pathologic complete response was achieved in 41% of all patients. Patients with triple-negative breast cancer with homologous recombination–deficient tumors were significantly more likely to achieve a pathologic complete response than those with homologous recombination–nondeficient tumors: 53% vs 18% (adjusted odds ratio = 4.64; P < .0001), Dr. Telli reported. In patients who were BRCA-negative but had a high HRD score, 50% achieved a pathologic complete response. This group had 4.5 times greater odds of achieving pathologic complete response than BRCA-negative patients who were homologous recombination– nondeficient (P < .0001). Associations between response and stage, age, and planned duration of therapy were not statistically significant.

Findings From TBCRC 008 Although HRD has been investigated in triple-negative breast cancer and BRCA-associated breast cancers, it has not been studied in hormone receptor–positive breast cancer. Researchers from the TBCRC 008 trial reported the results of an exploratory biomarker study correlating baseline HRD status with pathologic complete response in patients with HER2-negative breast cancer treated with neoadjuvant therapy including a platinum, regardless of estrogen receptor status.3 HRD status and pathologic complete response data were available for 48 of the 62 patients from the study, including 30 who were hormone receptor–positive and 18 with triple-negative breast cancer. Of these continued on page 60

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The ASCO Post | JANUARY 25, 2016

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San Antonio Breast Cancer Symposium Novel Agents

Exploratory Analysis of ExteNET Trial Shows Consistency of Benefit With Neratinib By Caroline Helwick

n exploratory analysis of the ExteNET study of neratinib in early HER2-positive breast cancer after treatment with trastuzumab (Herceptin) upheld the findings previously reported for the 2-year analysis, according to the study’s principal investigator Arlene Chan, MD, of the Breast Cancer Research Centre, Western Australia, and Curtin University in Perth.1 “The purpose of presenting results at this meeting is to demonstrate to the oncology community that with ongoing follow-up, we are seeing a consistent benefit for neratinib,” Dr. Chan said at the 2015 San Antonio Breast Cancer Symposium. “We see the most benefit in three populations: patients with centrally confirmed HER2-positive disease, those with hormone receptor–positive disease, and those who commence neratinib shortly after completing 1 year of adjuvant trastuzumab,” she reported. Neratinib is an oral tyrosine kinase inhibitor of HER1, HER2, and HER4 that has shown activity in preclinical models, in patients previously treated with trastuzumab, and in those naive to trastuzumab therapy. It is believed that

Predictive Biomarker continued from page 58

patients, 46% were homologous recombination–deficient, including 33% of the hormone receptor–positive tumors and 67% of the triple-negative breast cancer tumors. “This is the first study to look at a hormone receptor–positive cohort treated with a platinum,” declared Roisin M. Connolly, MB, BCh, of

Roisin M. Connolly, MB, BCh

Johns Hopkins School of Medicine, Baltimore, who presented the poster at the 2015 San Antonio Breast Cancer Symposium. The results of the exploratory analysis support prior observations that HRD

We see the most benefit in three populations: patients with centrally confirmed HER2-positive disease, those with hormone receptor–positive disease, and those who commence neratinib shortly after completing 1 year of adjuvant trastuzumab. —Arlene Chan, MD

neratinib might help prevent relapse after stopping trastuzumab, which is observed in about one-quarter of patients with HER2-positive early breast cancer.

ExteNET Details ExteNET enrolled 2,840 HER2positive patients after chemotherapy and 1 year of trastuzumab treatment. Patients were node-positive or had residual disease after neoadjuvant therapy and thus were considered at high risk for relapse. Half received 12 months of neratinib (140 mg/d) and half, placebo. In the primary analysis of ExteNET, HER2-positive breast cancer patients status is a promising potential predictive biomarker of response to platinum agents in triple-negative breast cancer, Dr. Connolly added. “We observed a significantly higher pathologic complete response rate in patients with homologous recombination deficiency, vs no deficiency (50% vs 7.7%; P = .002). In the hormone receptor–positive and triple-negative breast cancer subgroups, we did see an increase in pathologic complete response with homologous recombination deficiency, but these values were not statistically significant; they were trends,” she said. Within the subset without BRCA mutations, a significantly higher pathologic complete response rate was observed in those with high vs low HRD scores (64.3% vs 7.7%; P < .001). “Further evaluations are warranted in both triple-negative breast cancer and estrogen receptor–positive breast cancer to help determine if the predictive effect is restricted to platinum-based chemotherapy,” Dr. Connolly said. n

who received neratinib for 1 year following adjuvant chemotherapy plus trastuzumab had a 2.3% absolute improvement in invasive disease–free survival at 2 years (P = .009), she reported at the 2015 ASCO Annual Meeting.2 The differences were statistically significant in the hormone receptor–positive subset (hazard ratio [HR] = 0.51, P = .001), though the hormone receptor– negative subset saw no benefit.

Rationale for Exploratory Analysis “Due to the change in the trial’s sponsor in 2011, the study stopped recruitment after 2,840 patients, and follow-up was Disclosure: Dr. Telli reported no potential conflicts of interest. Dr. Connolly has received research funding for clinical trials from Genentech, Clovis, Novartis, Merrimack, Puma Biotechnology.

References 1. Telli ML, et al: Homologous recombination deficiency (HRD) as a predictive biomarker of response to neoadjuvant platinum-based therapy in patients with triple negative breast cancer. 2015 San Antonio Breast Cancer Symposium. Abstract P3-07-12. Presented December 10, 2015.

truncated at 2 years. Subsequently, the current sponsor reopened the design of the study, thus allowing us to “re-consent” patients and gather further information that is the basis of the current presentation and subsequent analyses,” Dr. Chan explained. The current unplanned, exploratory 3-year analysis of invasive disease–free survival included 1,778 patients, which accounts for 85% of the patients at risk. The arms were well balanced except for slightly more node-negative patients in the placebo arm. The hazard ratios are based on 3-year data, the P values are unadjusted for multiplicity and shown for descriptive purposes only, and Kaplan-Meier curves are drawn to 4 years, she said. Patients were recruited based on local HER2 testing. Central HER2 testing was performed on 2,041 patients, of whom 84% were confirmed to be HER2-positive and 16% were HER2-negative.

Consistent Benefit at 3 Years “In the 3-year invasive disease–free analysis, we see again a consistent benefit in those patients receiving neratinib, extended up to 4 years,” Dr. Chan reported. “We thought this analysis was 2. Connolly R, et al: Homologous recombination deficiency as a predictive biomarker of response to preoperative systemic therapy in TBCRC 008 comprising a platinum in HER2-negative primary operable breast cancer. 2015 San Antonio Breast Cancer Symposium. Abstract P3-07-13. Presented December 10, 2015. 3. Connolly RM, et al: TBCRC 008: Early change in 18F-FDG uptake on PET predicts response to preoperative systemic therapy in human epidermal growth factor receptor 2-negative primary operable breast cancer. J Nucl Med 56:31-37, 2015.

Predictive Assay in Breast Cancer ■■ A pooled analysis of six phase II trials of patients with triple-negative breast cancer receiving a platinum agent as neoadjuvant chemotherapy found that homologous recombination deficiency was strongly associated with response. ■■ Patients with tumors deemed to be homologous recombination–deficient (by high HRD score or positive BRCA1/2 mutation status) had a 4.6 times higher rate of pathologic complete response. ■■ The TBCRC 008 study also found that pathologic complete response rates were 50% for homologous recombination–deficient tumors vs 7.7% for homologous recombination–nondeficient tumors.

ASCOPost.com | JANUARY 25, 2016

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San Antonio Breast Cancer Symposium important to show. It demonstrates a consistent benefit from neratinib beyond the 2-year analysis.” At 3 years, invasive disease–free survival rates were 90.5% in the neratinib arm and 88.6% in the placebo arm (HR = 0.74, P = .023). In the predefined subgroups, again, significant benefit after longer follow-up was observed among patients whose trastuzumab therapy was completed within 1 year from study entry (HR = 0.72, P = .020), those with centrally confirmed HER2-positive disease (HR = 0.70, P = .037), and those with hormone receptor– positive disease (HR = 0.57, P = .003). Patients with hormone receptor–negative disease did not benefit from neratinib. Substantial benefit was observed among the patients who both en-

rolled within 1 year of trastuzumab therapy and who were hormone receptor–positive; their invasive disease– free survival at 3 years was 92.0%, vs 86.9% without neratinib (HR = 0.57, P = .004). Similarly, patients who were hormone receptor–positive and centrally confirmed to be HER2-positive had a 3-year invasive disease–free survival of 94.3%, vs 86.8% without the drug (HR = 0.40, P < .001). “This illustrates the clinical scenarios where delayed adjuvant neratinib would be of benefit,” Dr. Chan commented.

Dealing With Diarrhea The main adverse event was diarrhea, which was grade 3 in 39.9% of patients. Median duration of diarrhea was 5 days, and most occurred within the first month of treatment. Qualityof-life worsening (as measured by

ExteNET Exploratory Analysis ■■ An unplanned exploratory analysis of 3-year invasive disease–free survival was conducted on the ExteNET population of HER2-positive patients who received neratinib after chemotherapy and 1 year of treatment with trastuzumab. ■■ The addition of neratinib improved invasive disease–free survival by 2.1%, compared to placebo. ■■ Diarrhea (grade 3) occurred in about 40% of patients, but this was before a prophylactic regimen was instituted.

Pancreatic Liquid Biopsy continued from page 57

Validation in Larger Sample, More Cancers Coauthor Ignacio Wistuba, MD, Chair of Translational Molecular Pathology, is working with Dr. Maitra and other investigators at MD Anderson to develop an assay to capture exosomes and validate the approach across other “visceral” (deeply located) cancers. Drs. Maitra and Wistuba plan to work with other cancer moon shots initially, with the ultimate goal of developing a clinical-quality liquid biopsy for use institution-wide. “We’ll validate in a larger population cohort and correlate our findings with patient outcomes,” Dr. Wistuba said. “There’s no clinical application yet, we’re early in development, but it’s very exciting.”

Dr. Maitra holds the Sheikh Khalifa Bin Zayed Al Nahyan Distinguished University Chair. The Annals of Oncology is the official publication of the European Society for Medical Oncology.

Ignacio Wistuba, MD

Co-authors with Drs. Maitra and Wistuba are co–first authors Francis San Lucas, PhD, of Translational Molecular Pathology; Kelvin Allenson, MD, of Surgical Oncology; and Vincent Bernard, of Pathology, who is also a graduate student

EXPERT POINT OF VIEW

ame Abraham, MD, FACP, Director of the Breast Oncology Program at the Taussig Cancer Institute of the Cleveland Clinic in Ohio, said he believes neratinib is “an extremely active drug, once we learn how best to give it.” Dr. Abraham has been involved in some of the studies of neratinib. “In this exploratory analysis, we are seeing a signal. The analysis showed that even after giving trastuzumab [Herceptin] for 1 year, patients Jame Abraham, MD, FACP can still derive some benefit. The question will be where this drug will fit into our armamentarium,” Dr. Abraham said. n Disclosure: Dr. Abraham reported no potential conflicts of interest.

FACT‑B questionnaire) was observed at month 1, but these differences abated thereafter, she noted. At the time of the study design, there was no protocol-mandated antidiarrheal prophylaxis in place, but it is now known that an intensive loperamide prophylactic regimen can reduce the rates of grade 3 diarrhea to 17% or lower. Better patient education may lower this rate even more, she suggested. A prospective phase II trial is evaluating the efficacy of diarrhea prophylaxis in patients receiving neoadjuvant neratinib. n Disclosure: Dr. Chan has had a consulting or advisory role with Pfizer, Amgen, and Eisai.

in The University of Texas Graduate School of Biomedical Sciences, jointly operated by MD Anderson and The University of Texas Health Science Center at Houston; and Hector Alvarez, MD, PhD, who is Scientific Manager of the Liquid Biopsy platform in the pancreatic cancer research center and co–senior author of the publication. Other coauthors include Jonathan Castillo, PhD, Dong Kim, MD, and Kristen Ellis of Pathology; Donghui Li, PhD, Robert Wolff, MD, and Gauri Varadhachary, MD, MBBS, of Gastrointestinal Medical Oncology; Matthew Katz, MD, of Surgical Oncology, and Eric Ehli, PhD, Gareth Davies, PhD, and Jason Petersen, PhD, of Avera Institute for Human Genetics, Sioux Falls, South Dakota. This research was funded by MD An-

References 1. Chan A, Delaloge S, Holmes FA, et al: Neratinib after trastuzumab-based adjuvant therapy in early-stage HER2+ breast cancer: 3-year analysis from a phase 3 randomized, placebo-controlled, double-blind trial (ExteNET). 2015 San Antonio Breast Cancer Symposium. Abstract S5-02. Presented December 11, 2015. 2. Chan A, Delaloge S, Holmes F, et al: Neratinib after adjuvant chemotherapy and trastuzumab in HER2-positive early breast cancer: Primary analysis at 2 years of a phase 3, randomized, placebo-controlled trial (ExteNET). 2015 ASCO Annual Meeting. Abstract 508. Presented June 1, 2015.

derson’s Pancreatic Cancer Moon Shot, the Sheikh Ahmed Pancreatic Cancer Research Center, grants from the National Cancer Institute of the National Institutes of Health (5T32CA009599-27, R01CA113669, U01CA196403, U01DK108328, P30CA016672), MD Anderson’s NCI Cancer Center Support Grant (CA16672) for the High Resolution Electron Microscopy Facility, the Translational Molecular Pathology Fellowship at MD Anderson; and the Cancer Prevention and Research Institute of Texas. n Reference 1. San Lucas FA, Allenson K, Bernard V, et al: Minimally invasive genomic and transcriptomic profiling of visceral cancers by next-generation sequencing of circulating exosomes. Ann Oncol. December 17, 2015 (early release online).

Visit The ASCO Post website at ASCOPost.com

NEW PERMANENT J-CODE FOR CYRAMZA: J9308, injection, ramucirumab, 5 mg Effective January 1, 2016

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. This information is presented for informational purposes only and is not intended to provide reimbursement or legal advice. Providers are encouraged to contact third-party payers for specific information on their coverage, coding, and payment policies. Please consult with your legal counsel or reimbursement specialist for any reimbursement or billing questions. For more information please call the Lilly PatientOne Program at 1-866-472-8663.

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. Discontinue CYRAMZA therapy in patients with impaired 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.

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

TIME FROM RANDOMIZATION (MONTHS) Number at Risk

CYRAMZA 330 + paclitaxel Placebo 335 + paclitaxel

308

267

228

185

148

116

294

241

180

143

109

• 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 Embryofetal Toxicity • Based on its mechanism of action, CYRAMZA can cause fetal harm when administered to pregnant women. Animal models link angiogenesis, VEGF, and VEGF Receptor 2 (VEGFR2) to critical aspects of female reproduction, embryofetal development, and postnatal development. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with CYRAMZA and for at least 3 months after the last dose of CYRAMZA.

Most Common Adverse Reactions—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 CYRAMZA-treated 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 infusion-related 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 infusion-related 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-G HCP ISI 17SEP2015 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. PP-RB-US-0359 11/2015 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

12 2

44 14

6 1

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

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The ASCO Post | JANUARY 25, 2016

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Geriatrics for the Oncologist

Deconditioning in Older Adults With Cancer: A Cascade to Dependency By Lorraine K. McEvoy, DNP, MSN, RN, OCN

t is estimated that nearly half of adults over age 80 living in the community are frail despite apparent functional well-being.1 Frailty is recognized as a clinical syndrome in which three or more of the following criteria are present: unintentional weight loss, self-reported exhaustion, weakness, slow walking speed, and low physical activity.2 Deconditioning is a syndrome in which an acute stressor event in a frail older adult causes the physiologic reserve capacity threshold to be surpassed, resulting in the simultaneous deterioration of physical, physiologic, and psychological processes. The subtle onset of deconditioning manifests as a constellation of health issues: weakness, fatigue, altered cognition, inactivity, decreased food intake, weight loss, and depression that can begin within hours of an acute event and rapidly become profound during hospitalization.3 Deconditioning in the setting of an urgent clinical scenario may go unrecognized by the health-care team focused on the patients’ immediate needs. The result is a cascade of decline leading to dependency.

Impact on Care In addition to increasing the risk for complications and reducing the quality of life for the older adult, deconditioning is associated with a several-fold increase in the risk of dying.4 During the past decade, oncologists, geriatricians, nurses, and allied health professionals have begun to work together to integrate the principles of geriatrics into oncology care.5 Early detection and prevention of deconditioning are acknowledged as a benchmark of good practice,4 yet deconditioning is often unrecognized and undertreated in older adults. Interventions to ameliorate deconditioning are often missed opportunities to enhance outcomes when older adults undertake cancer treatment.4,6 It is important for all oncology clinicians to recognize that reconditioning can take twice as long as deconditioning7 and requires diligent work on the part of the patient, caregivers, and the multidisciplinary team to reconstitute prior levels of functional status.

Comprehensive Approach to Reconditioning Changes in U.S. cancer care delivery have distanced the specialties of cancer treatment, survivorship, and rehabilita-

tion,8 presenting significant challenges to coordination of care. Nevertheless, care delivery that focuses on effective disease management, preservation of pretreatment levels of functioning and independence, prevention of decline, and aggressive reconditioning in older adults with cancer has demonstrated effectiveness.9 The integration of a multidisciplinary team of providers to optimize the patient’s physical, psychological, occupational, and social functioning is required to simultaneously take action to enhance capacity and reduce task demands.10 Close coordination of the timing and types of interventions is required to optimize reconditioning outcomes.11 Depending on the specific treatment, older cancer patients face numerous adverse sequelae. These consequences include fatigue, depression, anxiety, fear of recurrence, cognitive dysfunction, pain syndromes, peripheral neuropathy, sexual dysfunction, bal-

Promoting Health Outcomes Available data clearly indicate that social relationships have the potential for health promotion in older adults and that there are biologically plausible pathways for these effects.16 The complex physical, physiologic, and psychological interplay of adaptive capacity and functional reserve suggests that aspects of the social environment play an important role in reconditioning interventions following cancer treatment.17 Both the quantity and quality of social relationships have been reliably related to morbidity and mortality.16 In a large survey of community-dwelling older adults, risk for debilitated activities of daily living and mobility disability was related to psychosocial alterations. Less physical activity and fewer social contacts among older adults increased disability over time. Seeman et al studied the relationship of social ties and support to patterns of

It is important for all oncology clinicians to recognize that reconditioning can take twice as long as deconditioning and requires diligent work on the part of the patient, caregivers, and the multidisciplinary team to reconstitute prior levels of functional status. —Lorraine K. McEvoy, DNP, MSN, RN, OCN

ance and gait problems, mobility issues, lymphedema, bladder and bowel problems, stoma care, dysphagia, communication difficulty, and depression—any of which can lead to profound deconditioning in the older adult.12,13 In a comprehensive care approach, the team evaluates the totality of problems that the patient faces and coordinates treatment to address specific issues.14 Assessment of the patient-caregiver support system, intensive patientcaregiver education, behavior modification, nutritional support, physical activity, weight stabilization, and psychosocial support can be strategies that promote management of symptoms.12 Comprehensive care management begins with cancer treatment and integrates the multidisciplinary team to preserve the ability to remain independent, functionally active, and maximize health and longevity.15

cognitive aging and demonstrated that participants receiving more emotional support had better baseline performance and better cognitive function at 7.5-year follow-up.16 The findings support the need for ongoing interactions among patients, their caregivers, and their health-care professionals to provide assessment, monitoring, and reassurance. Furthermore, evidence suggests that the degree to which older people are engaged in their social environment is associated with a clear survival benefit, whether this engagement is defined by specific social or productive activities or by the nature and quality of their social relationships.18

Implications for Practice Oncology physicians, nurses, and allied health professionals can readily leverage their access to the settings in which patients are accessing care and

GUEST EDITOR

Stuart M. Lichtman, MD

eriatrics for the Oncologist is guest edited by Stuart M. Lichtman, MD, and developed in collaboration with the International Society of Geriatric Oncology (SIOG). Dr. Lichtman is an Attending Physician at Memorial Sloan Kettering Cancer Center, Commack, New York, and Professor of Medicine, Weill Cornell Medical College, New York. He is also President Elect of the International Society of Geriatric Oncology (www.siog.org).

assess an individual’s risk for deconditioning. Greater efforts are needed to screen for and recognize deconditioning as well as to intervene early on in the treatment planning process in order to prevent the downward spiral in terms of functional decline, loss of independence, and impaired health-related quality of life. Resources for reconditioning should be assessed and interventions initiated concurrently so that opportunities to enhance outcomes when older adults undertake cancer treatment are incorporated into current practice. Oncology clinicians should recognize the potential benefits of routine assessment of deconditioning risk and providing patient/caregiver education for maintaining current levels of performance. The goal of reducing the burden of deconditioning during cancer treatment can best be achieved through an ongoing multidisciplinary, multimodal, collaborative approach that integrates the patient, family, caregivers, and their supportive network with the clinical team.7 In order for this approach to be successful, it must be initiated when cancer treatment is undertaken and be conscientiously maintained throughout the disease course and during transitions in care. Additionally, gerontol-

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Geriatrics for the Oncologist

ogy education programs for health-care providers should incorporate deconditioning assessment, recognition, and prevention as core components of the instruction curriculum.3 n Disclosure: Dr.. McEvoy reported no potential conflicts of interest.

References 1. Palacios-Ceña D, Alvarez-López C, Cachón-Pérez M, et al: Early detection of functional and cognitive decline after hospital discharge: The role of community nursing and multidisciplinary teams. J Gerontol Nurs 35(9):13-17, 2009. 2. Bond SM, Davis ME, McEvoy L: Physiology of aging and its impact on the older adult, in McEvoy L, Cope D (eds): Caring for the Older Adult With Cancer in the Ambulatory Setting, pp 9-31. Pittsburgh, Oncology Nursing Society, 2012. 3. Cheruiyot J, Reinhard J, Laoingco C, et al: Knowledge of staff nurses on management of deconditioning in older adults: A

cross-sectional study. J Nat Sci Res 3:82-91, 2013. 4. Gillis A, McDonald B: Nurses’ knowledge, attitudes, and confidence regarding preventing and treating deconditioning in older adults. J Contin Educ Nurs 39:547554, 2008. 5. Extermann M, Hurria A: Comprehensive geriatric assessment for older patients with cancer. J Clin Oncol 25:18241831, 2007. 6. Luctkar-Flude MF, Groll DL, Tranmer JE, et al: Fatigue and physical activity in older adults with cancer: A systematic review of the literature. Cancer Nursing 30(5):E35-E45, 2007. 7. Hardy SE, Dubin JA, Holford TR, et al: Transitions between states of disability and independence among older persons. Am J Epidemiol 161:575-584, 2005. 8. Barr TR, Towle EL: National oncology practice benchmark: An annual assessment of financial and operational parameters—2010 report on 2009 data. J Oncol

Pract 7S(suppl):2s-15s, 2011. 9. Alfano CM, Ganz PA, Rowland JH, et al: Cancer survivorship and cancer rehabilitation: Revitalizing the link. J Clin Oncol 30:904-906, 2012. 10. Boyd CM, Landefeld CS, Counsell SR, et al: Recovery of activities of daily living in older adults after hospitalization for acute medical illness. J Am Geriatr Soc 56:2171-2179, 2008. 11. King BD: Functional decline in hospitalized elders. Medsurg Nursing 15:265272, 2006. 12. Stubblefield M, O’Dell M: Cancer Rehabilitation: Principles and Practice, pp 1-1093. New York, Demos Medical Publishing, 2009. 13. Bowman KF, Rose JH, Deimling GT: Families of long-term cancer survivors: Health maintenance advocacy and practice. Psychooncology 14:1008-1017, 2005. 14. Hewitt M, Greenfield S, Stovall E (eds): From Cancer Patient to Cancer Survivor: Lost in Transition, pp 1–506.

Washington, DC, National Academies Press, 2006. 15. Davis ME, Derby SA, McEvoy L: Symptom management, in McEvoy L, Cope D (eds): Caring for the Older Adult With Cancer in the Ambulatory Setting, pp 57-111. Pittsburgh, Oncology Nursing Society, 2012. 16. Seeman TE, Lusignolo TM, Albert M, et al: Social relationships, social support, and patterns of cognitive aging in healthy, high-functioning older adults: MacArthur studies of successful aging. Health Psychol 20:243-255, 2001. 17. Seeman TE: Health promoting effects of friends and family on health outcomes in older adults. Am J Health Promot 14:362-370, 2000. 18. Wang HX, Karp A, Winblad B, et al: Late-life engagement in social and leisure activities is associated with a decreased risk of dementia: A longitudinal study from the Kungsholmen project. Am J Epidmiol 155:1081-1087, 2002.

News

Computerized Cognitive Training Promising for Reducing Cognitive Late Effects in Childhood Cancer Survivors

n a study reported in the Journal of Clinical Oncology, Heather M. Conklin, PhD, of St. Jude Children’s Research Hospital, and colleagues found that computerized cognitive training showed promise in reducing cognitive late effects in survivors of childhood cancer.1

Study Details In the study, conducted at St. Jude Children’s Research Hospital, 68 survivors of childhood acute lymphoblastic leukemia or brain tumor with identified cognitive deficits were randomly assigned to a computerized cognitive intervention (n = 34, 18 male; mean age = 12.2 years) or wait list (n = 34, 18 male; mean age = 11.8 years). The intervention group was to complete 25 training sessions (30- to 45-minutes each) at home over 5 to 9 weeks, with weekly telephone-based coaching. Sessions consisted of v isual-spatial and verbal working memory exercises presented as games; exercise difficulty was ad-

justed based on performance. Cognitive assessments and functional magnetic resonance imaging (MRI) scans (in the intervention group) were performed before and after intervention; immediate change in Wechsler Intelligence Scale for Children–4th edition (WISC-IV) spatial span backward was the primary outcome measure.

Improved Function Compared with controls, the 30 survivors who completed the intervention showed significantly greater

Cognitive Training in Cancer Survivors ■■ The cognitive training group showed improvements in working memory, attention, processing speed, and executive function. ■■ Functional MRI showed reduction in activation of left lateral prefrontal and bilateral medial frontal areas.

processing speed (eg, P = .02, effect size = 0.61, for Conners’ Continuous Performance Test hit reaction time), as well as a greater reduction in reported executive dysfunction (eg, P =

Study findings show computerized cognitive training is feasible and efficacious for childhood cancer survivors, with evidence for training-related neuroplasticity. —Heather M. Conklin, PhD, and colleagues

improvement in working memory (eg, P = .002, effect size = 0.84, for WISC-IV spatial span backward), attention (eg, P = .01, effect size = 0.65, for WISC-IV spatial span forward, and

.002, effect size = 0.84, for Conners’ Parent Rating Scale III). Functional MRI showed a significant reduction in activation of left lateral prefrontal and bilateral medial frontal areas.

The investigators concluded: “Study findings show computerized cognitive training is feasible and efficacious for childhood cancer survivors, with evidence for training-related neuroplasticity.” n Disclosure: The study was supported by the National Cancer Institute, American Cancer Society, and American Lebanese Syrian Associated Charities. For full disclosures of the study authors, visit jco.ascopubs.org.

Reference 1. Conklin HM, Ogg RJ, Ashford JM, et al: Computerized cognitive training for amelioration of cognitive late effects among childhood cancer survivors: A randomized controlled trial. J Clin Oncol 33:38943902, 2015.

Visit The ASCO Post website at ASCOPost.com

OVERALL SURVIVAL AT 5 YEARS IN DLBCL IS

60%

1 Could a better understanding of this disease be within our grasp?

DLBCL is an aggressive disease2 Remarkably, more than half of patients are able to survive diffuse large B-cell lymphoma (DLBCL) for 5 years or longer.1,3

Although strides have been made in the science of DLBCL, weâ&#x20AC;&#x2122;re casting an even wider net to further our knowledge of this aggressive disease

To learn more, visit BCellResearch.com

References: 1. Howlader N, Noone AM, Krapcho M, et al, eds. SEER Cancer Statistics Review, 1975-2012. National Cancer Institute website. http://seer.cancer.gov/csr/1975_2012/results_single/sect_19_table.29_2pgs.pdf. Updated April 23, 2015. Accessed June 15, 2015. 2. Jaffe ES, Harris NL, Stein H, Campo E, Pileri SA, Swerdlow SH. Introduction and overview of the classification of the lymphoid neoplasms. In: Swerdlow SH, Campo E, Harris NL, et al, eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. Lyon, France: International Agency for Research on Cancer; 2008:158-166. 3. Larouche J-F, Berger F, Chassagne-ClĂŠment C, et al. Lymphoma recurrence 5 years or later following diffuse large B-cell lymphoma: clinical characteristics and outcome. J Clin Oncol. 2010;28(12):2094-2100.

The ASCO Post | JANUARY 25, 2016

PAGE 70

Patient’s Corner

I Am Not Afraid of Cancer

A family history of cancer and my own bout with anal cancer have left me fearless about the future. By Carol Veio, as told to Jo Cavallo

t age 73, I’m no shrinking violet and I don’t run to the doctor at the first sign of a problem. I practice naturopathy and can usually ward off potential health issues by maintaining a healthy diet and lifestyle. When I began experiencing some mild discomfort in my rectum 2½ years ago, I was convinced that it was caused by hemorrhoids and took sitz baths to relieve the pain. When that failed to remedy the problem, I saw my primary care physi-

my rectum had increased so much, I went to the emergency room of my local hospital to seek relief. Once again, I wasn’t examined and was instead prescribed pain medication. It took two more trips to the emergency room before a doctor finally examined my rectum and made an appointment for me to see a surgeon. Still convinced that the problem I was having was caused by nothing more serious than hemorrhoids, I was sur-

Oncologists give patients a nutsand-bolts textbook assessment of their cancer. Survivors can give patients their hearts and souls. Patients need the mind, body, and the soul to survive this disease. —Carol Veio

cian, who, without even examining me, suggested that I see a surgeon to have the hemorrhoids removed. Since I hadn’t been examined and wasn’t sure what the problem was, I decided to wait before seeking other medical advice. Within a month, the pain in

prised when I awoke from the surgery to find my bed surrounded by a group of nurses who blurted out that I had anal cancer. Fortunately, the cancer was caught relatively early; it was stage II and localized to my anus, so my longterm prognosis is good.

I was prescribed 30 sessions of intensity-modulated radiation therapy and 2 weeks of fluorouracil chemotherapy, and today my cancer is in remission.

Cancer Is No Stranger to Me Cancer has taken the lives of many family members, including my father, brother, and two aunts. My older sister was diagnosed with anal cancer several years ago and also survived, but she is now facing a diagnosis of breast cancer, and an older brother has recurrent skin cancer. Despite the toll cancer has taken on my family and me, I am not afraid of the disease. I actually have more of a fascination with cancer than fear. Perhaps if I were younger and just starting out in a career or relationship, the specter of death would have more impact, but at my age, death is not a frightening prospect. Don’t get me wrong. I’m not anxious to die, nor am I giving up. I still live my life to the fullest every day. I’m just saying that I am not afraid of whatever the future may hold.

Surviving Cancer Cancer and its treatments have left their mark on my life. I still experience

some rectal discomfort and have to contend with frequent bowel movements that curtail my activities and keep me close to home. Still, I’ve made a lot of progress over the past few months, and I’m grateful to my oncologist and medical team for the care they have given me and continue to give me. I see my oncologist every 6 months for follow-up care assessment and monitoring, and, so far, all is well. The one aspect of my early care that I wish I could change is that I wasn’t introduced to a survivorship forum for patients with anal cancer. As wonderful as my oncologist is, I think that talking with other survivors of the same type of cancer I have would have been hugely beneficial to me. I was never given a recommended list of online cancer forums, and I was too sick to find a local cancer support group network on my own to seek comfort and information. Oncologists give patients a nutsand-bolts textbook assessment of their cancer. Survivors can give patients their hearts and souls. Patients need the mind, body, and the soul to survive this disease. n Carol Veio lives in Clearlake, California.

The ASCO Post

Patient Guides Available Through ASCO University Bookstore • ASCO Answers: Managing the Cost of Cancer Care explains the various costs associated with cancer treatment, including health-care coverage through the Affordable Care Act. It also provides a list of financial resources available to help offset expenses related to care and tips for organizing financial paperwork. Learn more at www.cancer.net/managingcostofcare. • ASCO Answers: Survivorship helps patients transition into life after active treatment has finished. In addition to information on the challenges survivors may face and the importance of follow-up care, it includes a blank treatment summary and survivorship care form that patients can fill out with the help of their health-care team. Learn more at www.cancer.net/survivorship.

Wants to Hear From You

We encourage readers to share their opinions and thoughts on issues of interest to the oncology community.

Copies of these booklets can be purchased through the ASCO University Bookstore at www.cancer.net/estore. All booklets ship for free, and ASCO members receive a 20% discount. n

Write to The ASCO Post at editor@ASCOPost.com

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ASCOPost.com | JANUARY 25, 2016

PAGE 71

ASH Annual Meeting Treatment Advances

Study Confirms Benefit of Triplet vs Doublet in Newly Diagnosed Multiple Myeloma By Caroline Helwick

riplets should be the standard of care in most newly diagnosed multiple myeloma patients, according to a study that validated a practice that has become common in the United States, though not necessarily elsewhere. The use of three drugs led to significant reductions in disease progression and death—by about 29%—in the phase III SWOG S0777 trial, as reported at the 2015 American Society of Hematology (ASH) Annual Meeting and Exposition by Brian G.M. Durie, MD, Chairman of the International Myeloma Foundation and an attending physician at Cedars-Sinai Comprehensive Cancer Center, Los Angeles.1 It was the first and only randomized trial comparing initial treatment with a doublet vs a triplet in this setting. The triplet of bortezomib (Velcade), lenalidomide (Revlimid), and low-dose dexamethasone, with continuous lenalido-

mide/dexamethasone maintenance, significantly improved progression-free and overall survival, compared with lenalidomide/dexamethasone plus maintenance, Dr. Durie reported. “[Bortezomib/lenalidomide/lowdose dexamethasone] induction followed by continuous [lenalidomide/ dexamethasone] is a potential new standard of care,” he said. The findings might spur the use of triplets outside of the United States, some experts indicated, where the use of two drugs is still common.

Outcomes Improved With Triplet The study randomly assigned 525 patients (n = 471 analyzable) to the triplet, which included bortezomib at 1.3 mg/m2 intravenously plus lenalidomide at 25 mg/d plus dexamethasone at 20 mg/d for 8 cycles of 21 days each, or the doublet of lenalidomide at 25

[Bortezomib/lenalidomide/lowdose dexamethasone] induction followed by continuous [lenalidomide/ dexamethasone] is a potential new standard of care. —Brian G.M. Durie, MD

mg/d plus dexamethasone at 40 mg/d for 6 cycles of 28 days each. Both arms were offered maintenance with lenalidomide at 25 mg plus dexamethasone at 40 mg; a total of 135 in the triplet group and 143 in the doublet group started maintenance and had a median time on maintenance of 385 days. Overall, 46% of patients went off maintenance without having progressive disease,

and 14% of eligible patients were still on maintenance at the time of the analysis. The overall response rates were 81.5% with the triplet and 71.5% with the doublet; complete responses were observed in 15.7% and 8.4%, respectively, and very good partial responses or better occurred in 27.8% and 23.4%, respectively, Dr. Durie reported. continued on page 72

EXPERT POINT OF VIEW

esponding to the assertion that bortezomib (Velcade)/lenalidomide (Revlimid)/low-dose dexamethasone induction followed by continuous lenalidomide/dexamethasone is potentially a new standard of care in newly diagnosed multiple myeloma, Sagar Lonial, MD, Chief Medical Officer of Winship Cancer Institute of Emory University and Professor of Hematology and Medical Oncology at Emory University School of Medicine, Atlanta, agreed, suggesting that the triple regimen of a proteasome inhibitor, immunomodulatory drug, and steroid has “come of age” as the best initial treatment. “In my view, the take-home message from ASH 2015 is that threedrug induction is optimal, and the [immunomodulatory drug]/proteasome inhibitor combination is likely the best regimen to use in newly diagnosed patients,” he said. Dr. Lonial commented that with the results of SWOG S0777, “We have now established in the induction therapy setting that three drugs are better than two, for most patients across the board.” Essentially the only persons who might be exceptions to this new standard are frail patients, he added.

In contrast to some earlier studies of different drugs, triplets of novel agents have now been shown in a large randomized trial to significantly improve response rates, progression-free survival, and overall survival, he said.

Synergistic Combinations “In the era of novel agents, we now have the ability to give non–cross-re-

the time of diagnosis, the average myeloma patient has approximately 60 different mutations, and this number only increases as the disease worsens. Resistant clones may thrive under the weaker power of sequential therapy, but they can be squelched with combinations that work through different mechanisms of action, he said. In addition to the existence of mu-

In my view, the take-home message from ASH 2015 is that three-drug induction is optimal [for multiple myeloma], and the [immunomodulatory drug]/ proteasome inhibitor combination is likely the best regimen to use in newly diagnosed patients. —Sagar Lonial, MD

sistant drugs in synergistic combinations,” he said. Combinations of immunomodulatory drugs and proteasome inhibitors lead to deeper and more durable responses and also add benefit by potentially suppressing resistant clones. At

tations at diagnosis, genomic instability and the existence of subclones are at play from the start. With subsequent lines of treatment, this genomic instability and the number of subclones grow— and this is true not only for patients with high-risk cytogenetics but also for

some standard-risk patients. High-risk patients, however, do especially benefit from triplets, which appear to overcome negative adverse features, such as the t(4;14) translocation, he pointed out. “This pushes the idea of using combination therapy to attack the genomically unstable, clonally heterogeneous disease at the time of initial presentation,” he concluded. “The best shot of eliminating or suppressing the disease is at the very beginning.… It’s the best way to embark on curative or suppressive therapy.”

Cautionary Notes While Dr. Lonial said that he might combine three to five drugs, he does not use novel agents in combination with chemotherapy. “This does not enhance efficacy; it only enhances toxicity,” he cautioned. He also emphasized that the triplet he advocates involves an immunomodulatory drug, proteasome inhibitor, and dexamethasone. While the combination regimen of cyclophosphamide, bortezomib, and dexamethasone may be less expensive, he acknowledged, it is not the optimal triplet. n Disclosure: Dr. Lonial is a consultant for Millennium, Celgene, Novartis, Bristol-Myers Squibb, Onyx, and Janssen.

The ASCO Post | JANUARY 25, 2016

PAGE 72

ASH Annual Meeting Triplet vs Doublet Therapy continued from page 71

Median progression-free survival was 43 months with the triplet, vs 31 months with the doublet (hazard ratio [HR] = 0.712, one-sided P = .0018). Median overall survival was 75 months vs 64 months, respectively (HR = 0.709, two-sided P = .0250). In the multivariate age-adjusted analysis, the one factor that positively affected progression-free and overall survival were treatment with bortezomib/lenalidomide/low-dose dexamethasone, whereas factors negatively associated with outcomes included stage III disease (HR = 1.58 and 2.16,

icity (23% vs 3%), and gastrointestinal side effects (22% vs 8%), “but bortezomib was administered intravenously twice a week, as was the practice in 2008,” he noted. Subcutaneous administration or less frequent dosing, as is typically done now, might have ameliorated some of these side effects, he suggested.

At a median follow-up of 55 months, secondary primary malignancies were reported in only 4% of each study arm. n

Disclosure: Dr. Durie has been a consultant for Johnson & Johnson, Takeda, Onyx, and Celgene.

Reference 1. Durie B, Hoering A, Rajkumar

SV, et al: Bortezomib, lenalidomide and dexamethasone vs. lenalidomide and dexamethasone in patients with previously untreated multiple myeloma without an intent for immediate autologous stem cell transplant: Results of the randomized phase III trial SWOG S0777. 2015 ASH Annual Meeting. Abstract 25. Presented December 5, 2015.

Triplet vs Doublet in Myeloma ■■ In newly diagnosed multiple myeloma patients, initial treatment with three drugs has previously not been formally compared to treatment with two drugs. ■■ SWOG S0777 randomized patients to receive bortezomib, lenalidomide, and dexamethasone or to lenalidomide plus dexamethasone; both arms received maintenance lenalidomide/dexamethasone. ■■ The triplet significantly reduced both disease progression and deaths by 29%.

respectively) and age ≥ 65 (HR = 1.32 and 1.88, respectively). Dr. Durie noted that mutation data had not been fully analyzed. “Both regimens are safe but with significantly greater grade 3 neuropathic and gastrointestinal adverse events with [the triplet],” Dr. Durie reported. Adverse events ≥ grade 3 possibly related to treatment were significantly more common in the bortezomib/ lenalidomide/dexamethasone arm, including neurologic events (33% vs 11%), pain (12% vs 4%), sensory tox-

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ASCOPost.com | JANUARY 25, 2016

PAGE 73

ASH Annual Meeting Biomarkers

Blood Test Can Predict High-Risk Cancers in Patients Treated With CAR-T By Alice Goodman

ramatic advances have been made in using genetically engineered chimeric antigen receptor–modified T cells (CAR-T) with anti-CD19 specificity to treat highly

refractory hematologic malignancies. The highest complete remission rates have been achieved in patients with relapsed or refractory acute lymphoblastic leukemia (ALL). However, pa-

tients treated with CAR-T infusions, especially those who respond, can develop cytokine-release syndrome, which can be fatal if not treated. Although cytokine-release syndrome

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is treatable with the interleukin-6 inhibitor tocilizumab (Actemra), ideally, predictive biomarkers could identify which patients are at risk for continued on page 74

The ASCO Post | JANUARY 25, 2016

PAGE 74

ASH Annual Meeting Predicting High-Risk Cancers continued from page 73

this serious adverse event, enabling early intervention and resolution of cytokine-release syndrome.

Assay in Development Researchers at the University of Pennsylvania—one of the hotbeds of CAR-T

testing—are developing a rapid assay that can identify patients at risk of developing severe cytokine-release syndrome. Although other centers are working on the problem, these investigators appear to be the furthest along in their research. At the 2015 American Society of Hematology (ASH) Annual Meeting and Exposition, David T. Teachey,

Predicting Cytokine-Release Syndrome ■■ A blood test for two cytokines is specific and sensitive for predicting the onset of severe cytokine-release syndrome in patients receiving CAR-T therapy. ■■ If correlative studies support this test, it will be clinically useful.

MD, Assistant Professor of Pediatrics at the University of Pennsylvania and

Children’s Hospital of Philadelphia, presented a study that identified two

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ASCOPost.com | JANUARY 25, 2016

PAGE 75

ASH Annual Meeting predictive biomarkers for cytokine-release syndrome after CAR-T therapy in patients with ALL.1 “If we check certain cytokines in the blood in the first 48 hours after infusion of CAR-T before patients develop fullblown [cytokine-release syndrome]— but they may have fever—we have a high likelihood of predicting who will

become critically ill and who won’t,” Dr. Teachey said. “We can tell early who may need intervention. We could treat with tocilizumab or a different cytokine blocker if the patient is likely to become critically ill—before he or she becomes critically ill. If the patient is not likely to become critically ill with cytokine-

release syndrome, you would not necessarily need to monitor him or her as closely and would not need to use empiric cytokine blockade,” he explained.

Study Details The investigators studied clinical, laboratory, and biomarker data for 39 children and 12 adults with re-

lapsed/refractory ALL treated with anti-CD19 CAR-T at the University of Pennsylvania. They serially measured 43 cytokines using a multiplex bead array assay. Other biomarkers were tested in a Clinical Laboratory Improvement Amendments/College of American Pathologists (CLIA/ CAP)–certified lab. Of the 51 patients, 48 developed grade 1–5 cytokine-release syndrome. Most cases were mild (grade 1–2) or continued on page 76

EXPERT POINT OF VIEW

“I

nvestigators are looking at biomarkers to predict the probability of cytokine-release syndrome [in patients receiving

Marcela V. Maus, MD, PhD

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chimeric antigen receptor–modified T-cell (CAR-T) therapy] so that they can intervene early. This study [from the University of Pennsylvania] identified two biomarkers that appear to predict for severe [cytokine-release syndrome], but these are still early data and we need correlative studies before this test is deemed useful in clinical practice,” stated Marcela V. Maus, MD, PhD, Director of the Cellular Immunotherapy Program at Massachusetts General Hospital, Boston. “For now, people in the field are using clinical markers such as fever, hypotension, and organ failure to identify [cytokine-release syndrome]. We need a clinically actionable assay, but this is not yet ready for prime time,” she added. Dr. Maus trained under two pioneers in the development of CAR-T therapy: Michel Sadelain, MD, at Memorial Sloan Kettering Cancer Center in New York, and Carl June, MD, at the University of Pennsylvania, Philadelphia. n Disclosure: Dr. Maus reported no potential conflicts of interest.

The ASCO Post | JANUARY 25, 2016

PAGE 76

Journal Spotlight Thoracic Cancer

Global and North American Phase II Studies Show Alectinib Is Highly Active in Crizotinib-Resistant/Refractory ALK-Rearranged NSCLC By Matt Stenger

n two phase II trials, reported in the Journal of Clinical Oncology and The Lancet Oncology, the ALK inhibitor alectinib (Alecensa), which is active against acquired crizotinib resistance mutations and exhibits high central nervous system (CNS) penetration, was associated with considerable activity in crizotinib (Xalkori)-resistant/ refractory ALK-positive non–small cell lung cancer (NSCLC), including CNS metastases.1,2 Sai-Hong Ignatius Ou, MD, PhD, of the University of California School of Medicine, is the corresponding author of the Journal of Clinical Oncology article, and Alice T. Shaw, MD, PhD, of Massachusetts General Hospital, is the corresponding author of The Lancet Oncology article.

Global Phase II Study Details In the study reported by Ou et al,1 138 patients from 56 sites in 16 countries were treated with oral alectinib at 600 mg twice daily until disease progression, unacceptable toxicity, or withdrawal of consent. Treatment could continue beyond disease progression if considered to be of benefit by the treating physician. The primary endpoint was objective response rate by central independent review committee assessment. A total of 16 patients did not have Response Evaluation Criteria I Solid Tumors (RECIST)-measurable target lesions when assessed by the independent review committee, with 122 thus being considered evaluable for response. These patients had a median age of

Predicting High-Risk Cancers continued from page 75

moderate (grade 3). Fourteen patients developed severe cytokine-release syndrome (grade 4–5). Twenty-one patients were treated with tocilizumab,

52 years, 56% were female, and 66% were white. Among all patients, 61% had CNS metastases, 42% had measurable CNS metastases, and 73% had received prior brain radiation (64% of these at > 6 months before starting alectinib). Best response to prior crizotinib was a partial response in 54%.

Responses At the time of primary analysis, at a median follow-up of 30 weeks, the objective response rate was 49% (95% confidence interval [CI] = 40%–58%). At updated analysis at a median follow-

13.0 months (95% CI = 5.5 months to not reached) among 28 chemotherapynaive patients.

CNS Response Among 84 patients with baseline CNS metastases, 23 (27%) had a CNS complete response, and the overall CNS disease control rate was 83% (95% CI = 74%–91%); CNS duration of response was 10.3 months (95% CI = 7.6–11.2 months). The CNS response rate in 35 patients with measurable CNS lesions was 57% (95% CI = 39%–74%; 7 with a complete response). Of 23 patients

Alectinib is highly active and well tolerated in patients with advanced, crizotinib-refractory ALK-positive NSCLC, including those with CNS metastases. —Sai-Hong Ignatius Ou, MD, PhD, and colleagues

up of 47 weeks, the response rate was 50% (95% CI = 41%–59%). The disease control rate was 79% (95% CI = 70%– 86%), and median duration of response was 11.2 months (95% CI = 9.6 months to not reached). Among 96 patients (79%) who had received prior chemotherapy, the objective response rate was 45% (95% CI = 35%–55%), and the disease control rate was 77% (95% CI = 67%–85%). Median progression-free survival was 8.9 months (95% CI = 5.6– 11.3 months) among all patients and and most had rapid marked clinical improvement, quick resolution of fever, and weaning of vasoactive medications. They found that peak levels of two cytokines measured during the first 3 days after CAR-T infusion—

If we check certain cytokines in the blood in the first 48 hours after infusion of CAR-T before patients develop full-blown [cytokine-release syndrome] … we have a high likelihood of predicting who will become critically ill and who won’t. —David T. Teachey, MD

with measurable or nonmeasurable CNS metastases and no prior radiation, 10 (43%) had a complete CNS response. At 12 months, the cumulative CNS progression rate was 24.8%, and the cumulative non-CNS progression rate was 33.2% for all patients.

Adverse Events Median duration of treatment was 27.1 weeks (range = 2.4–53.0 weeks) at data cutoff. The most common adverse events of any grade were constipation interferon-gamma and sgp130—were significant predictors of developing severe cytokine-release syndrome (P < .001). Overall, using regression modeling, they identified a threecytokine signature that had a positive predictive value of 92%, negative predictive value of 100%, sensitivity of 100%, and specificity of 96%) in children treated with CTL019. “No test is perfect,” Dr. Teachey remarked. He and his colleagues at the University of Pennsylvania, in collaboration with Novartis, are applying for a patent for this rapid blood assay. “We believe we are the furthest ahead in developing a rapid clinically usable assay. The plan is to develop

(33%, all grade 1 or 2), fatigue (26%, 1% grade 3), and peripheral edema (25%, 1% grade 3). The most common grade 3 or 4 adverse event was dyspnea (3%, grade 3). The most common adverse events considered related to study treatment were myalgia (17%), constipation (15%), fatigue (14%), and asthenia (11%). Adverse events led to dose reduction/interruption in 21% of patients and to treatment discontinuation in 8%. Four patients (3%) died due to adverse events (intestinal perforation, dyspnea, pulmonary embolism, and hemorrhage), with a death due to intestinal perforation considered possibly related to study treatment. The investigators concluded: “Alectinib is highly active and well tolerated in patients with advanced, crizotinib-refractory ALK-positive NSCLC, including those with CNS metastases.”

North American Phase II Study Details In the study reported by Shaw et al, 87 patients with stage IIIB to IV ALK-positive NSCLC who had progressed after crizotinib from 27 sites in the United States and Canada were enrolled between September 2013 and August 2014 and treated with oral alectinib at 600 mg twice daily until disease progression, death, or withdrawal. Treatment could continue beyond disease progression if it was considered to be of benefit by the treating physician. The primary endpoint was the pro2

continued on page 77

a rapid testing kit that would need regulatory approval to be used in the clinic,” he said. Researchers at Juno Therapeutics and Fred Hutchinson Cancer Center are also working on a predictive blood assay for cytokine-release syndrome. n

Disclosure: Dr. Teachey has received research funding from Novartis.

Reference 1. Teachey DT, Lacey SF, Shaw PA, et al: Biomarkers accurately predict cytokine release syndrome after chimeric antigen receptor (CAR) T cell therapy for acute lymphoblastic leukemia. 2015 ASH Annual Meeting. Abstract 1334. Presented December 5, 2015.

ASCOPost.com | JANUARY 25, 2016

PAGE 77

Journal Spotlight Alectinib in NSCLC continued from page 76

portion of patients achieving objective response on independent review committee assessment using RECIST criteria; response endpoints were assessed in the response-evaluable population (ie, patients with measurable disease at baseline who received at least one dose of study drug), and efficacy and safety analyses were performed in the intent-to-treat population. The study is ongoing, and patients are still receiving treatment. Patients had a median age of 54 years, 55% were women, 84% were white, 90% had an Eastern Cooperative Oncology Group performance status of 0 or 1, 62% were never-smokers, 99% had stage IV disease, 94% had adenocarcinoma, 60% had CNS metastases, and 74% had received prior chemotherapy. Of 34 patients (39%) who had received prior brain radiotherapy, treatment had occurred > 6 months before starting alectinib in 16 (47%).

Response Rates At the time of primary analysis, at median follow-up of 4.8 months, 33 of 69 patients with measurable disease had a confirmed partial response, yielding a response rate of 48% (95% CI = 36%– 60%); an additional 22 patients (32%) had stable disease. At updated analysis at a median follow-up of 9.9 months, 35

(52%, 95% CI = 40%–65%) of 67 patients with measurable disease had independent review committee–assessed objective response. Among the 35 patients with an objective response, median duration of response was 13.5 months (95% CI = 6.7 months to not estimable), with data from 21 of these patients censored at the time of data cutoff. Estimated median progression-free survival among all 87 patients was 8.1 months (95% CI = 6.2–12.6 months), with data from 38 patients censored at the time of data cutoff. Estimated overall survival at 12 months was 71% (95% CI = 61%–81%).

CNS Response Among 16 patients with measurable CNS disease at baseline, 4 (25%) achieved complete CNS response and 8 (50%) had a partial response, for an overall response rate of 75% (95% CI = 48%–93%); median duration of CNS response was 11.1 months (95% CI = 5.8–11.1 months). All 16 patients had disease control in the CNS. Among 52 patients with measurable or nonmeasurable CNS disease, 21 (40%, 95% CI 27%–55%) had an objective response, including 13 (25%) with a complete response; 33 (63%) with a noncomplete response or stable disease. Median duration of response was 11.1 months (95% CI = 10.8 months to not estimable). Disease control was achieved in 46 patients

Alectinib in ALK-Positive NSCLC ■■ Objective response to alectinib was observed in approximately 50% of patients with resistant/refractory ALK-positive NSCLC, according to the results of two phase II studies. ■■ The CNS disease control rate was > 80%.

(89%, 95% CI = 77%–96%). Among 18 of the 52 patients who had not received previous brain radiation therapy, an objective response occurred in 12 (67%), including a complete response in 10; 5 patients had stable disease.

Adverse Events The most common adverse events of any grade were constipation (36%), fatigue (33%), myalgia (24%), and peripheral edema (23%). The most common grade 3 or 4 adverse events were changes in laboratory values, including increased levels of blood creatine phosphokinase (8%), alanine transaminase (6%), and aspartate transaminase (5%) as well as dyspnea (3%). Serious adverse events occurred in 15% of patients. Dose interruption occurred in 36%, and dose reduction occurred in 16%. Death due to adverse events occurred in two patients and was considered possibly related to study treatment in one patient (due to hemorrhage in a patient on anticoagulant therapy). The investigators concluded: “Alec-

tinib showed clinical activity and was well tolerated in patients with ALKpositive NSCLC who had progressed on crizotinib. Therefore, alectinib could be a suitable treatment for patients with ALK-positive disease who have progressed on crizotinib.” n Disclosure: Both studies were funded by F. Hoffmann-La Roche. For full disclosures of the study authors, visit www.jco.ascopubs.org and www.thelancet.com.

References 1. Ou SI, Ahn JS, De Petris L, et al: Alectinib in crizotinib-refractory ALKrearranged non-small-cell lung cancer: A phase II global study. J Clin Oncol. November 23, 2015 (early online release). 2. Shaw AT, Gandhi L, Gadgeel S, et al: Alectinib in ALK-positive, crizotinibresistant, non-small-cell lung cancer: A single-group, multicentre, phase 2 trial. Lancet Oncol. December 18, 2015 (early release online). See commentary by Alice T. Shaw, MD, PhD, on page 86.

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APPROVED IN THE FIRST LINE FOR PATIENTS WITH WT KRAS* mCRC

VECTIBIX

FOLFOX In an exploratory analysis of the PRIME† study, Vectibix® improves median OS in the first line by 4.4 months vs FOLFOX alone in WT KRAS mCRC1

+4.4 MONTHS MEDIAN OS1

• Phase

3, open-label, randomized, multicenter study of 1,183 previously untreated patients with mCRC

• Vectibix®

+ FOLFOX extended the prespecified major efficacy measure of PFS vs FOLFOX alone (9.6 months vs 8.0 months, respectively)

• In

an exploratory analysis of OS, median OS in Vectibix® -treated patients was 23.8 months vs 19.4 months with FOLFOX alone

• No

benefits in OS or PFS were observed in patients with mutant RAS mCRC

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

Important Safety Information WARNING: DERMATOLOGIC TOXICITY Dermatologic Toxicity: Dermatologic toxicities occurred in 90% of patients and were severe (NCI-CTC grade 3 and higher) in 15% of patients receiving Vectibix® monotherapy [see Dosage and Administration (2.3), Warnings and Precautions (5.1), and Adverse Reactions (6.1)]. • In Study 1, dermatologic toxicities occurred in 90% of patients and

were severe (NCI-CTC grade 3 and higher) in 15% of patients with mCRC receiving Vectibix®. The clinical manifestations included, but were not limited to, acneiform dermatitis, pruritus, erythema, rash, skin exfoliation, paronychia, dry skin, and skin fissures. • Monitor patients who develop dermatologic or soft tissue toxicities while receiving Vectibix® for the development of inflammatory or infectious sequelae. Life-threatening and fatal infectious complications including necrotizing fasciitis, abscesses, and sepsis have been observed in patients treated with Vectibix®. Life-threatening and fatal bullous mucocutaneous disease with blisters, erosions, and skin sloughing has also been observed in patients treated with Vectibix®. It could not be determined whether these mucocutaneous adverse reactions were directly related to EGFR inhibition or to idiosyncratic immune-related effects (eg, Stevens-Johnson syndrome or toxic epidermal necrolysis).

Withhold or discontinue Vectibix® for dermatologic or soft tissue toxicity associated with severe or life-threatening inflammatory or infectious complications. Dose modifications for Vectibix® concerning dermatologic toxicity are provided in the product labeling. • Vectibix® is not indicated for the treatment of patients with colorectal

cancer that harbor somatic mutations in exon 2 (codons 12 and 13), exon 3 (codons 59 and 61), and exon 4 (codons 117 and 146) of either KRAS or NRAS and hereafter is referred to as“RAS”.

• Retrospective subset analyses across several randomized clinical trials

were conducted to investigate the role of RAS mutations on the clinical effects of anti-EGFR-directed monoclonal antibodies (panitumumab or cetuximab). Anti-EGFR antibodies in patients with tumors containing RAS mutations resulted in exposing those patients to anti-EGFR related adverse reactions without clinical benefit from these agents.

Important Safety Information • Additionally, in Study 3, 272 patients with RAS-mutant mCRC tumors

received Vectibix® in combination with FOLFOX and 276 patients received FOLFOX alone. In an exploratory subgroup analysis, OS was shorter (HR = 1.21, 95% CI: 1.01–1.45) in patients with RAS-mutant mCRC who received Vectibix® and FOLFOX versus FOLFOX alone.

• Progressively

decreasing serum magnesium levels leading to severe (grade 3–4) hypomagnesemia occurred in up to 7% of patients in Study 2. Monitor patients for hypomagnesemia and hypocalcemia prior to initiating Vectibix® treatment, periodically during Vectibix® treatment, and for up to 8 weeks after the completion of treatment. Other electrolyte disturbances, including hypokalemia, have also been observed. Replete magnesium and other electrolytes as appropriate.

• In Study 1, 4% of patients experienced infusion reactions and 1% of

patients experienced severe infusion reactions (NCI-CTC grades 3–4). Infusion reactions, manifesting as fever, chills, dyspnea, bronchospasm, and hypotension, can occur following Vectibix® administration. Fatal infusion reactions occurred in postmarketing experience. Terminate the infusion for severe infusion reactions.

• Severe

diarrhea and dehydration, leading to acute renal failure and other complications, have been observed in patients treated with Vectibix® in combination with chemotherapy.

• Fatal

and non-fatal cases of interstitial lung disease (ILD) (1%) and pulmonary fibrosis have been observed in patients treated with Vectibix®. Pulmonary fibrosis occurred in less than 1% (2/1467) of patients enrolled in clinical studies of Vectibix®. In the event of acute onset or worsening of pulmonary symptoms, interrupt Vectibix® therapy. Discontinue Vectibix® therapy if ILD is confirmed.

• In

patients with a history of interstitial pneumonitis or pulmonary fibrosis, or evidence of interstitial pneumonitis or pulmonary fibrosis, the benefits of therapy with Vectibix® versus the risk of pulmonary complications must be carefully considered.

• Exposure

to sunlight can exacerbate dermatologic toxicity. Advise patients to wear sunscreen and hats and limit sun exposure while receiving Vectibix®.

• Keratitis

and ulcerative keratitis, known risk factors for corneal perforation, have been reported with Vectibix® use. Monitor for evidence of keratitis or ulcerative keratitis. Interrupt or discontinue Vectibix® for acute or worsening keratitis.

• NCI-CTC grade 3–5 pulmonary embolism occurred at a higher rate

in Vectibix®-treated patients (7% vs 3%) and included fatal events in three (< 1%) Vectibix®-treated patients.

• As

a result of the toxicities experienced, patients randomized to Vectibix®, bevacizumab, and chemotherapy received a lower mean relative dose intensity of each chemotherapeutic agent (oxaliplatin, irinotecan, bolus 5-FU, and/or infusional 5-FU) over the first 24 weeks on study, compared with those randomized to bevacizumab and chemotherapy.

• Advise patients of the need for adequate contraception in both males

and females while receiving Vectibix® and for 6 months after the last dose of Vectibix® therapy. Vectibix® may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women.

• Because

many drugs are excreted into human milk and because of the potential for serious adverse reactions in nursing infants from Vectibix®, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. If nursing is interrupted, it should not be resumed earlier than 2 months following the last dose of Vectibix®.

• Women

who become pregnant during Vectibix® treatment are encouraged to enroll in Amgen’s Pregnancy Surveillance Program. Women who are nursing during Vectibix® treatment are encouraged to enroll in Amgen’s Lactation Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll.

• In Study 1, the most common adverse reactions (≥ 20%) with Vectibix®

were skin rash with variable presentations, paronychia, fatigue, nausea, and diarrhea. The most common (> 5%) serious adverse reactions in the Vectibix® arm were general physical health deterioration and intestinal obstruction.

• In

Study 3, the most commonly reported adverse reactions (≥ 20%) in patients with wild-type KRAS mCRC receiving Vectibix® (6 mg/kg every 2 weeks) and FOLFOX therapy (N = 322) were diarrhea, stomatitis, mucosal inflammation, asthenia, paronychia, anorexia, hypomagnesemia, hypokalemia, rash, acneiform dermatitis, pruritus, and dry skin. Serious adverse reactions (≥ 2% difference between treatment arms) in Vectibix® -treated patients with wild-type KRAS mCRC were diarrhea and dehydration.

• In an interim analysis of an open-label, multicenter, randomized clinical

trial in the first-line setting in patients with mCRC, the addition of Vectibix® to the combination of bevacizumab and chemotherapy resulted in decreased OS and increased incidence of NCI-CTC grade 3–5 (87% vs 72%) adverse reactions. NCI-CTC grade 3–4 adverse reactions occurring at a higher rate in Vectibix®-treated patients included rash/acneiform dermatitis (26% vs 1%), diarrhea (23% vs 12%), dehydration (16% vs 5%; primarily occurring in patients with diarrhea), hypokalemia (10% vs 4%), stomatitis/mucositis (4% vs < 1%), and hypomagnesemia (4% vs 0).

Visit VectibixData.com to learn more

mCRC = metastatic colorectal cancer; OS = overall survival; PFS = progression-free survival; WT = wild type. *Exon 2 on codons 12 or 13. † PRIME = The Panitumumab Randomized Trial In Combination With Chemotherapy for Metastatic Colorectal Cancer to Determine Efficacy. Reference: 1. Vectibix® (panitumumab) prescribing information, Amgen. Please see Brief Summary of full Prescribing Information on adjacent pages.

KING SIZE (6 pt condensed type) S:9.25”

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

VECT15CDLA0437_B_Vectibix_BS_9.25x13_v23_Mar2015_r11_MBS.indd 1

Study 1

SYSTEM ORGAN CLASS Preferred Term

Vectibix® Plus Best Supportive Care (N = 229)

Best Supportive Care (N = 234)

Any Grade n (%)

Grade 3-4 n (%)

Any Grade n (%)

Grade 3-4 n (%)

1 (< 1)

EYE DISORDERS Growth of eyelashes

13 (6)

GASTROINTESTINAL DISORDERS Nausea

52 (23)

2 (< 1)

37 (16)

Diarrhea

49 (21)

4 (2)

26 (11)

Vomiting

43 (19)

6 (3)

28 (12)

Stomatitis

15 (7)

2 (< 1)

GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS Fatigue

60 (26)

10 (4)

34 (15)

Mucosal inflammation

15 (7)

1 (< 1)

2 (< 1)

57 (25)

4 (2)

7 (3)

INFECTIONS AND INFESTATIONS Paronychia RESPIRATORY, THORACIC, AND MEDIASTINAL DISORDERS Dyspnea

41 (18)

12 (5)

30 (13)

Cough

34 (15)

1 (< 1)

17 (7)

Erythema

150 (66)

13 (6)

2 (< 1)

Pruritus

132 (58)

6 (3)

4 (2)

Acneiform dermatitis

131 (57)

17 (7)

2 (< 1)

Rash

51 (22)

3 (1)

2 (< 1)

Skin fissures

45 (20)

3 (1)

1 (< 1)

Exfoliative rash

41 (18)

4 (2)

Acne

31 (14)

3 (1)

Dry skin

23 (10)

Nail disorder

22 (10)

Skin exfoliation

21 (9)

2 (< 1)

Skin ulcer

13 (6)

1 (< 1)

8 (3)

SKIN AND SUBCUTANEOUS TISSUE DISORDERS

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

FOLFOX Alone (n = 327)

Any Grade n (%)

Grade 3-4 n (%)

Any Grade n (%)

Grade 3-4 n (%)

58 (18)

5 (2)

10 (3)

Diarrhea

201 (62)

59 (18)

169 (52)

29 (9)

Stomatitis

87 (27)

15 (5)

42 (13)

1 (< 1)

EYE DISORDERS Conjunctivitis GASTROINTESTINAL DISORDERS

GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS Mucosal inflammation

82 (25)

14 (4)

53 (16)

1 (< 1)

Asthenia

79 (25)

16 (5)

62 (19)

11 (3)

68 (21)

11 (3)

58 (18)

3 (< 1)

22 (7)

Anorexia

116 (36)

14 (4)

85 (26)

6 (2)

INFECTIONS AND INFESTATIONS Paronychia

Vectibix® Plus FOLFOX (n = 322) SYSTEM ORGAN CLASS Preferred Term

FOLFOX Alone (n = 327)

Any Grade n (%)

Grade 3-4 n (%)

Any Grade n (%)

Grade 3-4 n (%)

179 (56) 104 (32) 75 (23) 68 (21) 50 (16) 50 (16) 47 (15) 44 (14) 32 (10)

55 (17) 33 (10) 3 (< 1) 5 (2) 7 (2) 1 (< 1)

24 (7)

1 (< 1)

10 (3) 4 (1)

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

30 (9)

4 (1)

9 (3)

SKIN AND SUBCUTANEOUS TISSUE DISORDERS Rash Acneiform dermatitis Pruritus Dry skin Erythema Skin fissures Alopecia Acne Nail disorder Palmar-plantar erythrodysesthesia syndrome

2 (< 1)

Adverse reactions that did not meet the threshold criteria for inclusion in Table 2 were abdominal pain (28% vs 23%), localized infection (3.7% vs < 1%), cellulitis (2.5% vs 0%), hypocalcemia (5.6% vs 2.1%), and deep vein thrombosis (5.3% vs 3.1%). Infusion Reactions Infusional toxicity manifesting as fever, chills, dyspnea, bronchospasm or hypotension was assessed within 24 hours of an infusion during the clinical study. Vital signs and temperature were measured within 30 minutes prior to initiation and upon completion of the Vectibix ® infusion. The use of premedication was not standardized in the clinical trials. Thus, the utility of premedication in preventing the first or subsequent episodes of infusional toxicity is unknown. Across clinical trials of Vectibix® monotherapy, 3% (24/725) experienced infusion reactions of which < 1% (3/725) were severe (NCI-CTC grade 3-4). In one patient, Vectibix® was permanently discontinued for a serious infusion reaction [see Dosage and Administration (2.2, 2.3)]. Immunogenicity As with all therapeutic proteins, there is potential for immunogenicity. The immunogenicity of Vectibix® has been evaluated using two different screening immunoassays for the detection of binding anti-panitumumab antibodies: an acid dissociation bridging enzyme-linked immunosorbent assay (ELISA) detecting high-affinity antibodies and a Biacore ® biosensor immunoassay detecting both high- and low-affinity antibodies. For patients whose sera tested positive in screening immunoassays, an in vitro biological assay was performed to detect neutralizing antibodies. Monotherapy: The incidence of binding anti-panitumumab antibodies (excluding preexisting and transient positive patients) was 0.4% (5/1123) as detected by the acid dissociation ELISA and 3.2% (36/1123) as detected by the Biacore® assay. The incidence of neutralizing anti-panitumumab antibodies (excluding preexisting and transient positive patients) was 0.8% (9/1123). There was no evidence of altered pharmacokinetic or safety profiles in patients who developed antibodies to Vectibix®. In combination with chemotherapy: The incidence of binding anti-panitumumab antibodies (excluding preexisting positive patients) was 0.9% (12/1297) as detected by the acid dissociation ELISA and 0.7% (9/1296) as detected by the Biacore® assay. The incidence of neutralizing antipanitumumab antibodies (excluding preexisting positive patients) was 0.2% (2/1297). No evidence of an altered safety profile was found in patients who developed antibodies to Vectibix®. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to panitumumab with the incidence of antibodies to other products may be misleading. Postmarketing Experience The following adverse reactions have been identified during post-approval use of Vectibix ®. Because these reactions are reported in a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. • Skin and subcutaneous tissue disorders: Skin necrosis, angioedema, life-threatening and fatal bullous mucocutaneous disease [see Boxed Warning, Dosage and Administration (2.3), and Warnings and Precautions (5.1)] • Immune system disorders: Infusion reaction [see Dosage and Administration (2.3) and Warnings and Precautions (5.4)] • Eye disorders: Keratitis/ulcerative keratitis [see Warnings and Precautions (5.8)] DRUG INTERACTIONS No formal drug-drug interaction studies have been conducted between Vectibix® and oxaliplatin or fluoropyrimidine. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C There are no studies of Vectibix® in pregnant women. Reproduction studies in cynomolgus monkeys treated with 1.25 to 5 times the recommended human dose of panitumumab resulted in significant embryolethality and abortions; however, no other evidence of teratogenesis was noted in offspring [see Nonclinical Toxicology (13.3)]. Vectibix® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Based on animal models, EGFR is involved in prenatal development and may be essential for normal organogenesis, proliferation, and differentiation in the developing embryo. Human IgG is known to cross the placental barrier; therefore, panitumumab may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women. Women who become pregnant during Vectibix® treatment are encouraged to enroll in Amgen’s Pregnancy Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll. Nursing Mothers It is not known whether panitumumab is excreted into human milk; however, human IgG is excreted into human milk. Published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are excreted into human milk and because of the potential for serious adverse reactions in nursing infants from Vectibix®, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. If nursing is interrupted, based on the mean half-life of panitumumab, nursing should not be resumed earlier than 2 months following the last dose of Vectibix® [see Clinical Pharmacology (12.3)]. Women who are nursing during Vectibix® treatment are encouraged to enroll in Amgen’s Lactation Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll. Pediatric Use The safety and effectiveness of Vectibix® have not been established in pediatric patients. The pharmacokinetic profile of Vectibix® has not been studied in pediatric patients. Geriatric Use Of the 737 patients who received Vectibix® monotherapy in Study 1 and 2, 36% were 65 and over while 8% were 75 and over. No overall differences in safety or efficacy were observed in elderly patients (≥ 65 years of age) treated with Vectibix® monotherapy. Of the 322 patients in Study 3 who received Vectibix® plus FOLFOX, 128 (40%) were 65 and over while 8% were 75 and over. Patients older than 65 years of age experienced an increased incidence of serious adverse events (52% vs 36%) and an increased incidence of serious diarrhea (15% vs 5%) as compared to younger patients. OVERDOSAGE Doses up to approximately twice the recommended therapeutic dose (12 mg/kg) resulted in adverse reactions of skin toxicity, diarrhea, dehydration, and fatigue. Patient Counseling Information Advise patients to contact a healthcare professional for any of the following: • Skin and ocular/visual changes [see Boxed Warning, Dosage and Administration (2.3), Warnings and Precautions (5.1, 5.8), and Adverse Reactions (6.1, 6.3)] • Signs and symptoms of infusion reactions, including fever, chills, or breathing problems [see Dosage and Administration (2.3), Warnings and Precautions (5.4), and Adverse Reactions (6.1, 6.3)] • Diarrhea and dehydration [see Warnings and Precautions (5.5)] • Persistent or recurrent coughing, wheezing, dyspnea, or new-onset facial swelling [see Warnings and Precautions (5.6) and Adverse Reactions (6.1)] • Pregnancy or nursing [see Use in Specific Populations (8.1, 8.3)] Advise patients of the need for: • Periodic monitoring of electrolytes [see Warnings and Precautions (5.3)] • Limitation of sun exposure (use of sunscreen, wear hats) while receiving Vectibix® and for 2 months after the last dose of Vectibix® therapy [see Warnings and Precautions (5.7)] • Adequate contraception in both males and females while receiving Vectibix ® and for 6 months after the last dose of Vectibix® therapy [see Use in Specific Populations (8.1, 8.3)]

INVESTIGATIONS Weight decreased METABOLISM AND NUTRITION DISORDERS Hypomagnesemia

96 (30)

21 (7)

26 (8)

1 (< 1)

Hypokalemia

68 (21)

32 (10)

42 (13)

15 (5)

Dehydration

26 (8)

8 (2)

10 (3)

5 (2)

RESPIRATORY, THORACIC, AND MEDIASTINAL DISORDERS Epistaxis

46 (14)

30 (9)

This brief summary is based on the Vectibix ® Prescribing Information v23, 03/15. Vectibix® (panitumumab) Manufactured by: Amgen Inc. One Amgen Center Drive Thousand Oaks, CA 91320-1799 USA Patent: http://pat.amgen.com/vectibix/ © 2006-2015 Amgen Inc. All rights reserved. v23 03/15

4/27/15 6:12 PM

S:13”

INDICATIONS AND USAGE Metastatic Colorectal Cancer Vectibix® is indicated for the treatment of patients with wild-type KRAS (exon 2 in codons 12 or 13) metastatic colorectal cancer (mCRC) as determined by an FDA-approved test for this use: • As first-line therapy in combination with FOLFOX [see Clinical Studies (14.2)]. • As monotherapy following disease progression after prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy [see Clinical Studies (14.1)]. Limitation of Use Vectibix® is not indicated for the treatment of patients with RAS-mutant mCRC or for whom RAS mutation status is unknown [see Dosage and Administration (2.1), Warnings and Precautions (5.2), and Clinical Pharmacology (12.1)]. DOSAGE AND ADMINISTRATION Patient Selection Prior to initiation of treatment with Vectibix®, assess RAS mutational status in colorectal tumors and confirm the absence of a RAS mutation. Information on FDA-approved tests for the detection of KRAS mutations in patients with metastatic colorectal cancer is available at: http://www.fda.gov/CompanionDiagnostics. Recommended Dose The recommended dose of Vectibix® is 6 mg/kg, administered as an intravenous infusion over 60 minutes, every 14 days. If the first infusion is tolerated, administer subsequent infusions over 30 to 60 minutes. Administer doses higher than 1000 mg over 90 minutes [see Dosage and Administration (2.4)]. Appropriate medical resources for the treatment of severe infusion reactions should be available during Vectibix® infusions [see Warnings and Precautions (5.4)]. Dose Modifications Dose Modifications for Infusion Reactions [see Warnings and Precautions (5.4) and Adverse Reactions (6.1, 6.3)] • Reduce infusion rate by 50% in patients experiencing a mild or moderate (grade 1 or 2) infusion reaction for the duration of that infusion. • Terminate the infusion in patients experiencing severe infusion reactions. Depending on the severity and/or persistence of the reaction, permanently discontinue Vectibix®. Dose Modifications for Dermatologic Toxicity [see Boxed Warning, Warnings and Precautions (5.1), and Adverse Reactions (6.1, 6.3)] • Upon first occurrence of a grade 3 (NCI-CTC/CTCAE) dermatologic reaction, withhold 1 to 2 doses of Vectibix®. If the reaction improves to < grade 3, reinitiate Vectibix ® at the original dose. • Upon the second occurrence of a grade 3 (NCI-CTC/CTCAE) dermatologic reaction, withhold 1 to 2 doses of Vectibix®. If the reaction improves to < grade 3, reinitiate Vectibix® at 80% of the original dose. • Upon the third occurrence of a grade 3 (NCI-CTC/CTCAE) dermatologic reaction, withhold 1 to 2 doses of Vectibix®. If the reaction improves to < grade 3, reinitiate Vectibix® at 60% of the original dose. • Upon the fourth occurrence of a grade 3 (NCI-CTC/CTCAE) dermatologic reaction, permanently discontinue Vectibix®. Permanently discontinue Vectibix® following the occurrence of a grade 4 dermatologic reaction or for a grade 3 (NCI-CTC/CTCAE) dermatologic reaction that does not recover after withholding 1 or 2 doses. Preparation and Administration Do not administer Vectibix® as an intravenous push or bolus. CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS Dermatologic and Soft Tissue Toxicity In Study 1, dermatologic toxicities occurred in 90% of patients and were severe (NCI-CTC grade 3 and higher) in 15% of patients with mCRC receiving Vectibix ®. The clinical manifestations included, but were not limited to, acneiform dermatitis, pruritus, erythema, rash, skin exfoliation, paronychia, dry skin, and skin fissures. Monitor patients who develop dermatologic or soft tissue toxicities while receiving Vectibix® for the development of inflammatory or infectious sequelae. Life-threatening and fatal infectious complications including necrotizing fasciitis, abscesses, and sepsis have been observed in patients treated with Vectibix®. Life-threatening and fatal bullous mucocutaneous disease with blisters, erosions, and skin sloughing has also been observed in patients treated with Vectibix®. It could not be determined whether these mucocutaneous adverse reactions were directly related to EGFR inhibition or to idiosyncratic immunerelated effects (eg, Stevens-Johnson syndrome or toxic epidermal necrolysis). Withhold or discontinue Vectibix® for dermatologic or soft tissue toxicity associated with severe or life-threatening inflammatory or infectious complications [see Boxed Warning and Adverse Reactions (6.1, 6.3)]. Dose modifications for Vectibix® concerning dermatologic toxicity are provided [see Dosage and Administration (2.3)]. Increased Tumor Progression, Increased Mortality, or Lack of Benefit in Patients with RAS Vectibix® is not indicated for the treatment of patients with colorectal cancer that harbor somatic mutations in exon 2 (codons 12 and 13), exon 3 (codons 59 and 61), and exon 4 (codons 117 and 146) of either KRAS or NRAS and hereafter is referred to as “RAS ” [see Indications and Usage (1.1), Dosage and Administration (2.1), Clinical Pharmacology (12.1) and Clinical Studies (14)]. Retrospective subset analyses across several randomized clinical trials were conducted to investigate the role of RAS mutations on the clinical effects of anti-EGFR-directed monoclonal antibodies (panitumumab or cetuximab). Anti-EGFR antibodies in patients with tumors containing RAS mutations resulted in exposing those patients to anti-EGFR related adverse reactions without clinical benefit from these agents [see Indications and Usage (1.1), and Clinical Pharmacology (12.1)]. Additionally, in Study 3, 272 patients with RAS-mutant mCRC tumors received Vectibix® in combination with FOLFOX and 276 patients received FOLFOX alone. In an exploratory subgroup analysis, OS was shorter (HR = 1.21, 95% CI: 1.01-1.45) in patients with RAS-mutant mCRC who received Vectibix® and FOLFOX versus FOLFOX alone [see Indications and Usage (1.1)]. Electrolyte Depletion/Monitoring Progressively decreasing serum magnesium levels leading to severe (grade 3-4) hypomagnesemia occurred in up to 7% (in Study 2) of patients across clinical trials. Monitor patients for hypomagnesemia and hypocalcemia prior to initiating Vectibix® treatment, periodically during Vectibix® treatment, and for up to 8 weeks after the completion of treatment. Other electrolyte disturbances, including hypokalemia, have also been observed. Replete magnesium and other electrolytes as appropriate. Infusion Reactions In Study 1, 4% of patients experienced infusion reactions and 1% of patients experienced severe infusion reactions (NCI-CTC grade 3-4). Infusion reactions, manifesting as fever, chills, dyspnea, bronchospasm, and hypotension, can occur following Vectibix® administration [see Adverse Reactions (6.1, 6.3)]. Fatal infusion reactions occurred in postmarketing experience. Terminate the infusion for severe infusion reactions [see Dosage and Administration (2.3)]. Acute Renal Failure in Combination with Chemotherapy Severe diarrhea and dehydration, leading to acute renal failure and other complications, have been observed in patients treated with Vectibix® in combination with chemotherapy. Pulmonary Fibrosis/Interstitial Lung Disease (ILD) Fatal and nonfatal cases of interstitial lung disease (ILD) (1%) and pulmonary fibrosis have been observed in patients treated with Vectibix®. Pulmonary fibrosis occurred in less than 1% (2/1467) of patients enrolled in clinical studies of Vectibix®. In the event of acute onset or worsening of pulmonary symptoms, interrupt Vectibix® therapy. Discontinue Vectibix® therapy if ILD is confirmed. In patients with a history of interstitial pneumonitis or pulmonary fibrosis, or evidence of interstitial pneumonitis or pulmonary fibrosis, the benefits of therapy with Vectibix® versus the risk of pulmonary complications must be carefully considered. Photosensitivity Exposure to sunlight can exacerbate dermatologic toxicity. Advise patients to wear sunscreen and hats and limit sun exposure while receiving Vectibix®. Ocular Toxicities Keratitis and ulcerative keratitis, known risk factors for corneal perforation, have been reported with Vectibix® use. Monitor for evidence of keratitis or ulcerative keratitis. Interrupt or discontinue Vectibix® therapy for acute or worsening keratitis. Increased Mortality and Toxicity with Vectibix® in Combination with Bevacizumab and Chemotherapy In an interim analysis of an open-label, multicenter, randomized clinical trial in the first-line setting in patients with mCRC, the addition of Vectibix® to the combination of bevacizumab and chemotherapy resulted in decreased OS and increased incidence of NCI-CTC grade 3-5 (87% vs 72%) adverse reactions. NCI-CTC grade 3-4 adverse reactions occurring at a higher rate in Vectibix®-treated patients included rash/acneiform dermatitis (26% vs 1%), diarrhea (23% vs 12%), dehydration (16% vs 5%), primarily occurring in patients with diarrhea, hypokalemia (10% vs 4%), stomatitis/mucositis (4% vs < 1%), and hypomagnesemia (4% vs 0). NCI-CTC grade 3-5 pulmonary embolism occurred at a higher rate in Vectibix®-treated patients (7% vs 3%) and included fatal events in three (< 1%) Vectibix®-treated patients. As a result of the toxicities experienced, patients randomized to Vectibix®, bevacizumab, and chemotherapy received a lower mean relative dose intensity of each chemotherapeutic agent (oxaliplatin, irinotecan, bolus 5-FU, and/or infusional 5-FU) over the first 24 weeks on study compared with those randomized to bevacizumab and chemotherapy. ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: • Dermatologic and Soft Tissue Toxicity [see Boxed Warning, Dosage and Administration (2.3), and Warnings and Precautions (5.1)] • Increased Tumor Progression, Increased Mortality, or Lack of Benefit in RAS- and KRAS-Mutant mCRC [see Indications and Usage (1.1) and Warnings and Precautions (5.2)] • Electrolyte Depletion/Monitoring [see Warnings and Precautions (5.3)] • Infusion Reactions [see Dosage and Administration (2.3), and Warnings and Precautions (5.4)] • Acute Renal Failure in Combination with Chemotherapy [see Warnings and Precautions (5.5)] • Pulmonary Fibrosis/Interstitial Lung Disease (ILD) [see Warnings and Precautions (5.6)] • Photosensitivity [see Warnings and Precautions (5.7)] • Ocular Toxicities [see Warnings and Precautions (5.8)]

• Increased Mortality and Toxicity with Vectibix® in combination with Bevacizumab and Chemotherapy [see Warnings and Precautions (5.9)] Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates in the clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical studies does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates. Safety data are presented from two clinical trials in which patients received Vectibix®: Study 1, an openlabel, multinational, randomized, controlled, monotherapy clinical trial (N = 463) evaluating Vectibix® with best supportive care (BSC) versus BSC alone in patients with EGFR-expressing mCRC and Study 3, a randomized, controlled trial (N = 1183) in patients with mCRC that evaluated Vectibix® in combination with FOLFOX chemotherapy versus FOLFOX chemotherapy alone. Safety data for Study 3 are limited to 656 patients with wild-type KRAS mCRC. Vectibix® Monotherapy In Study 1, the most common adverse reactions (≥ 20%) with Vectibix® were skin rash with variable presentations, paronychia, fatigue, nausea, and diarrhea. The most common (> 5%) serious adverse reactions in the Vectibix® arm were general physical health deterioration and intestinal obstruction. The most frequently reported adverse reactions for Vectibix® leading to withdrawal were general physical health deterioration (n = 2) and intestinal obstruction (n = 2). For Study 1, the data described in Table 1 and in other sections below, except where noted, reflect exposure to Vectibix® administered to patients with mCRC as a single agent at the recommended dose and schedule (6 mg/kg every 2 weeks). Table 1: Adverse Reactions (≥ 5% Difference) Observed in Patients Treated with Vectibix® Monotherapy and Best Supportive Care Compared to Best Supportive Care Alone (Study 1)

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Direct From ASCO

Conquer Cancer Foundation Hosts Inaugural Scientific and Career Development Retreat

n October 2015, the Conquer Cancer Foundation of ASCO (CCF) hosted its first Scientific and Career Development Retreat at ASCO Headquarters in Alexandria, Virginia, for past recipients of the Young Investigator Award (YIA) and Career Development Award (CDA). The YIA provides funding to promising investigators during their transition from a fellowship program to a faculty appointment, to encourage and promote quality research in clinical oncology. The CDA is a 3-year grant awarded to clinical investigators who have already received their faculty appointment as they work to establish an independent clinical cancer research program with a patientoriented focus. The 2-day retreat opened with brief remarks from Nancy R. Daly, MS, MPH, CCF Executive Director and Chief Philanthropic Officer, and presentations on a few of the career development programs that ASCO offers. Jamie H. Von Roenn, MD, ASCO’s Director of Education, Science, and Professional Development, discussed the new Health Policy Fellowship, and Deborah Kamin, RN, PhD, Senior Director of Policy and Advocacy, discussed the Leadership Development Program. Awards were presented to participants who submitted high-quality abstracts to the retreat, including Nader Sanai, MD, a 2013 CDA recipient, of St. Joseph’s Hospital and Medical Center, and Filipa Lynce, MD, a 2013 YIA recipient, of Medstar Health Research Institute. The second day of the retreat included scientific sessions and sessions focusing on career development. Past YIA and CDA recipients shared new and unpublished findings from their CCF-funded research in oral abstract presentations and poster sessions. Career development talks addressed practical steps for a successful research career, with an emphasis on finding role models and mentors, maximizing scientific opportunities, building collaborations across disciplines, time management, and

achieving work-life balance. Dawn Hershman, MD, MS, of Columbia University Medical Center, gave an inspirational keynote address on the opportunities and challenges of a research career. Dr. Hershman provided an overview of the CCF grants she received—the 2002 Career Development Award, the 2007 Advanced Clinical Research Award in Breast Cancer, and the 2015 Comparative Effectiveness Research Professorship in Breast Cancer—and the critical role those grants played in her successful career development as a physician-scientist. She described the positive effects of the ASCO Leadership Development Program and how her volunteer experiences at ASCO have helped her in her career. ASCO President Julie M. Vose, MD, MBA, FASCO, discussed effective time management and work-life balance. Other presentations examined the role of intrinsic and extrinsic work values in career development and the importance of multidisciplinary collaborations in oncology research. Attendees also participated in small-group discussions on topics such as drug development, immunotherapy, health services research, and biomarkers, led by Richard Schilsky,

MD, FASCO, ASCO Chief Medical Officer; Eduardo Sotomayor, MD, Chair of the CCF Grants Selection Committee; Dr. Hershman; and Christina Annunziata, MD, PhD, of the National Cancer Institute. CCF is working to create a world free from the fear of cancer by funding breakthrough research, by sharing knowledge with physicians and patients worldwide, and by supporting initiatives to ensure that all people have access to high-quality cancer care. Working in close collaboration with a global network of top scientists

and clinicians, as well as leading advocacy and research organizations, CCF draws on the passion and expertise of nearly 40,000 oncology professionals who are members of its affiliate organization, ASCO. For more information, visit www.conquercancerfoundation.org. n Originally printed in ASCO Connection. © American Society of Clinical Oncology. “Conquer Cancer Foundation Hosts Inaugural Scientific and Career Development Retreat” connection.asco.org. 15 December 2015. All rights reserved.

CCF Names Thomas G. Roberts, Jr, MD, New Board of Directors Chair, Appoints Two New Leaders

homas G. Roberts, Jr, MD, a global investor and oncologist, has been named as the new Chair of the Conquer Cancer Foundation (CCF) Board of Directors. Two new members of the Board have also been announced: Margaret Tempero,

Thomas G. Roberts, Jr, MD

MD, FASCO, a Past President of ASCO and a pioneer in cancer treatment and research, and Alexander Casdin, an investor focused on the health-care sector, assumed their new roles alongside Dr. Roberts in January. In addition, the following mem-

Margaret Tempero, MD, FASCO

Alexander Casdin

bers of the CCF Board of Directors have been reappointed for another term: • Sandra M. Swain, MD, FACP, FASCO, Incoming 2016 Treasurer • Claire A. Huang, Incoming 2016 Secretary • Lawrence H. Einhorn, MD, FASCO • Thomas A. Marsland, MD, FASCO • Steven T. Rosen, MD, FASCO • Aaron A. Sasson To learn more, visit conquercancerfoundation.org/about/board-ofdirectors. n © 2016. American Society of Clinical Oncology. All rights reserved.

The ASCO Post | JANUARY 25, 2016

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Direct From ASCO

International Innovation Grant Supports Novel Breast Cancer Health Education Program in Mexico

Yanin Chávarri-Guerra, MD, MSc

he International Innovation Grant, funded by the Conquer Cancer Foundation (CCF) of ASCO, provides research funding in support of novel and innovative projects that can have a significant impact on cancer control in low- and middle-income countries. The grant is intended to support research that has the potential to reduce the cancer burden in local communities, while also being potentially transferable to other low- or middle-income settings. This 1-year research grant awards up to $20,000 paid directly to a nonprofit organization or governmental agency. In 2015, CCF awarded

International Innovation Grants to five researchers in Nigeria, Uganda, Mexico, India, and Romania. One of those researchers is Yanin Chávarri-Guerra, MD, MSc, a medical oncologist at Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán in Mexico City. Dr. Chávarri-Guerra is using the International Innovation Grant to fund a breast health educational program that uses intergenerational learning to increase breast cancer awareness among adolescents and their female relatives in low-income communities in Mexico. This program addresses an important educational need—Mexican women with breast cancer present at more advanced stages than those in high-resource countries due to delays in diagnosis and limited access to information. Dr. Chávarri-Guerra provided more insight on her plans for her project in the future below. ASCO: Describe your International Innovation Grant project. Yanin Chávarri-Guerra (YCG): We implemented a breast health educational program for adolescents enrolled

in a middle school in a rural community in Mexico. The program was aimed at increasing knowledge about breast health and promoting help-seeking behaviors, not only in adolescents but also in their female relatives, through intergenerational learning. The program consisted of culturally adapted breast health education sessions given by medical doctors, educators, and a breast cancer survivor. Women in low-income countries have very limited educational opportunities, and my project aims at

transforming young girls into health promoters within their households and communities in order to raise awareness of breast cancer. ASCO: What do you hope to achieve through the health education program? YCG: Our preliminary results, which we presented at the 2015 Breast Cancer Symposium, showed that it was feasible to implement our program at a school locatcontinued on page 83

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ASCO Submits Comments to CMS on EHR Stage 3 of Meaningful Use and Modifications Final Rule

n December 15, ASCO submitted comments to the Centers for Medicare & Medicaid Services (CMS) on the agency’s Electronic Health Record (EHR) Stage 3 of Meaningful Use and Modifications in 2015 through 2017. The Society’s comments provided recommendations to CMS regarding the implementation of the EHR incentive program within the context of the Medicare Access and CHIP Reauthorization Act of 2015 (MACRA). “ASCO is a strong advocate for the utilization of health information technology (HIT) to improve the quality

and value of cancer care services,” stated ASCO President Julie M. Vose, MD, MBA, FASCO, in the comment letter. “ASCO is working diligently to facilitate the oncology community’s adoption of HIT and cancer-specific interoperability standards.” The comment letter included the following recommendations to CMS: • Focus regulatory efforts on ensuring widespread interoperability between HIT products and reducing administrative burdens on providers in implementing MACRA. continued on page 83

by Omar Abdel-Rahman, et al

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Toward a Latin American Cancer Observatory by Eduardo Cazap, et al

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Development of a Breast Cancer Treatment Program in Portau-Prince, Haiti: Experiences From the Field by Vincent DeGennaro Jr, et al

ASCOPost.com | JANUARY 25, 2016

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Direct From ASCO International Innovation Grant continued from page 82

ed in a rural community, and that the students and their teachers were engaged in it and came away having learned important information. We were very pleased with the local community’s strong acceptance of a potentially delicate subject. For our final results, we are expecting that students and their relatives who participated in the educational sessions will show a 30% increase in content knowledge, based on tests given before and after the program. ASCO: How will these results translate into improved care for patients? YCG: Our project could potentially impact cancer control in Mexico by finding an innovative way to improve early detection of breast cancer

ASCO Comments to CMS continued from page 82

• Facilitate increased interoperability in the exchange of treatment information about cancer patients by implementing COTPS standards. • Clarify ambiguous regulatory language involving the Specialized Registry Reporting Measure of the Public Health Reporting objective as finalized in the Modifications for

through intergenerational education in rural communities with poor access to health information. The project also potentially represents a transferable educational intervention, which could be used to develop awareness of breast cancer among adolescents and their female relatives in other low- and middle-income countries outside of Mexico. In other Latin American countries, the program would need only minimal cultural and linguistic adaptations. In terms of intergenerational learning specifically, this could represent a valuable method for developing breast cancer awareness and improving the early detection of breast cancer and the downstaging of symptomatic disease in low-resource settings. Such an intergenerational intervention could also be scaled up and, after undergo2015–2017 to more clearly state that active engagement with clinical data registries will satisfy this measure. • Continue to promote the use of application programming interfaces to facilitate patient access to their health information is crucial to promoting innovation and interoperability in HIT. In the letter, Dr. Vose also reiterated ASCO’s plans for its electronic Quality

ing modifications, be applied to other common malignancies, cancers, and chronic diseases in low-resource countries (for example, skin, testicular, cervical, lung, and oral cancers, hypertension, and diabetes). ASCO: How did receiving the International Innovation Grant affect your career? YCG: This is the first academic and large prospective research study that I have personally led. Receiving the grant has allowed me to lay the foundation for future research in breast cancer disparities, to build connections with national and international researchers, and to plan ahead for new research projects. ASCO: Why is the Conquer Cancer Foundation Grants Program a valuOncology Practice Initiative (eQOPI) to be used to satisfy the Specialized Registry Reporting Measure in 2015 and beyond. “ASCO is currently piloting an electronic version of its eQOPI registry,” stated Dr. Vose. “Without clarifications that registries like eQOPI are satisfactory for meeting the Modified Stage 2 Objective 10 requirements, adoption of clinical data registries as powerful tools

able research funding mechanism? YCG: The Conquer Cancer Foundation Grants Program gives support to innovative, investigator-initiated cancer research, including studies carried out by international researchers. I believe supporting these types of research projects is enormously necessary to improve the care of patients with cancer worldwide. To learn more about the Conquer Cancer Foundation Grants and Awards program, visit conquercancerfoundation.org/grants-awards. n Originally printed in ASCO Connection. © American Society of Clinical Oncology. “International Innovation Grant Supports Novel Breast Cancer Health Education Program in Mexico” connection.asco.org 14 December 2015. All rights reserved.

for quality improvement, especially among oncology and other specialty providers, may stall.” To read the full letter, visit http:// w w w. a s c o. o r g / a d v o c a c y / a s c o submits-comments-cms-ehr-stage3-meaningful-use-and-modificationsfinal-rule. n © 2016. American Society of Clinical Oncology. All rights reserved.

Save the Date ASCO Quality Care Symposium

ASCO Annual Meeting

February 26-27, 2016

June 3-7, 2016

JW Marriott Phoenix Desert Ridge

McCormick Place

Phoenix, Arizona

Chicago, Illinois

Best of ASCO® Chicago

Best of ASCO® Washington, DC

June 24-25, 2016

July 15-16, 2016

Chicago, Illinois

Washington, DC

The ASCO Post | JANUARY 25, 2016

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Direct From ASCO

ASCO University Announces New Immuno-Oncology Program

SCO University has created a new multidisciplinary immunology program that provides a broad overview of immunobiology, as well as an in-depth focus on topics relevant to the practicing clinician, such as treatment, efficacy, monitoring, and management of immunobiologic agents. ASCO University’s Immuno-Oncology Program was developed by expert physicians and advanced practice providers whose careers focus on developing immunotherapies, treating patients with these new agents, and managing associated toxicities. The new program provides the most

also provides a post-test that features answer rationales and additional references, allowing participants to delve deeper into topics that they would like to learn more about. After successful completion of the post-test, participants are eligible to

claim both Continuing Medical Education credit and Maintenance of Certification Medical Knowledge points from the American Board of Internal Medicine. To learn more, visit university.asco. org/immuno-oncology-program. n

ADVERTORIAL ADVERTORIAL

Alexander E. Drilon, MD

current information on the exciting and fast-developing field of immunooncology, said Alexander E. Drilon, MD, an Associate Editor on the ASCO University Editorial Board. “The development of immune checkpoint inhibitors marked a major advance in the field of cancer therapeutics,” Dr. Drilon said. “These agents are clearly active in histologies such as melanoma and lung cancer and are now [U.S. Food and Drug Administration]-approved for the treatment of advanced disease. As patterns of response and the profile of adverse events of these treatments can differ substantially from chemotherapy and targeted therapy, clinicians, advanced practice providers, and providers in training will benefit from an educational course highlighting important issues in this space.” The program is made up of six sections focusing on key educational elements deemed most important by experts from the program’s planning group: • Cancer immunobiology • Classes of agents • Potential predictive biomarkers • Clinical activity • Response determination • Management of immune-related adverse events The online learning program includes audio commentary with hyperlinks to key articles and resources. It

CANCER STEM CELLS

SIGNALING PATHWAYS

CANCER STEM CELLS

SIGNALING PATHWAYS

Cancer Stem Cells and Their Role Cancer Stem Cells and Their Role Despite current advances in cancer therapy, tumor recurrence and metastasis a Despite current advances in cancerremain therapy, 1 stem cells are a subset clinical challenge. tumor recurrenceCancer and metastasis remain a 1 of the total cancerCancer cell population highly stem cellsthat are is a subset clinical challenge. 2,3 Chemotherapy and radiation have tumorigenic. of the total cancer cell population that is highly been shown 2,3 to Chemotherapy affect the primary buthave not and tumor, radiation tumorigenic. 4 Many patients with cancer, the cancer cell. the been shownstem to affect primary tumor, but not 4 even though diagnosed early, succumb to the the cancer stem cell. Many patients with cancer, 5,6 disease because of recurrence metastasis. even though diagnosed early,and succumb to the 5,6 Cancer stem cells are thoughtand to metastasis. contribute to disease because of recurrence 7 this recurrence andare metastasis. Cancer stem cells thought to contribute to

Most chemotherapeutic strategies target actively proliferating cancer cells, resulting bulk Most chemotherapeutic strategies target in actively tumor shrinkage. Cancer stem cells, however, proliferating cancer cells, resulting in bulk may beshrinkage. highly resistant thesecells, therapies and tumor Cancertostem however, may be nothighly be resistant eradicated during treatment, may to these therapies and 4,7 resulting metastasis. may not in be recurrence eradicated and during treatment, 4,7 Moreover, have resulting inchemotherapy recurrence and and radiation metastasis. the potentialchemotherapy to induce stemness properties in Moreover, and radiation have 2,9 non-stem cancer cells.stemness properties in the potential to induce

this recurrence and metastasis.7 Another characteristic of cancer stem cells is that they possess ofstemness. Stemness Another characteristic cancer stem cells distinguishes stem cells fromStemness ordinary is that they cancer possess stemness. cancer cells by their stem abilitycells to continually selfdistinguishes cancer from ordinary renew, intoability cancertocells, migrate,selfand cancer differentiate cells by their continually 7,8 regrow the tumor. into cancer cells, migrate, and renew, differentiate

non-stem cancer cells.2,9 Several signaling pathways are involved in the induction and maintenance of stemness in Several signaling pathways are involved in cancer stem and cells,maintenance including JAK/STAT, Wnt/ the induction of stemness in 10-12 β-catenin, Hedgehog, Notch, JAK/STAT, and Nanog. cancer stem cells, including Wnt/ 10-12 Targeting aberrant signaling pathways β-catenin, these Hedgehog, Notch, and Nanog. may resultthese in cancer stem cell apoptosis, while Targeting aberrant signaling pathways reducing toxicity stem to normal tissues that is may resultthe in cancer cell apoptosis, while 4 associated with chemotherapy. reducing the toxicity to normal tissues that is

regrow the tumor.7,8

associated with chemotherapy.4

ASCOPost.com | JANUARY 25, 2016

PAGE 85

Announcements

Raymond N. DuBois, MD, PhD, Named Dean of the MUSC College of Medicine

he Medical University of South Carolina (MUSC) has named Raymond N. DuBois, MD, PhD, as the next Dean of the College of Medicine. Dr. DuBois will assume his new role effective March 1, 2016, with an academic appointment as Professor

in the College of Medicine while also holding an appointment in the Hollings Cancer Center.

Current Appointments Dr. DuBois currently serves as Executive Director of the Biodesign Insti-

tute at Arizona State University, which focuses on health solutions and biomedical science through 14 research centers conducting broad-based interdisciplinary research. Prior to his appointment at Arizona State, Dr. DuBois was Provost and Executive Vice

President at The University of Texas MD Anderson Cancer Center, overseeing all research, education, training, and faculty development, including

Raymond N. DuBois, MD, PhD

REGROWTH

APOPTOSIS

REGROWTH

APOPTOSIS

in Recurrence and Metastasis in Recurrence and Metastasis Boston Biomedical is developing the next Boston Biomedical developingwith the next generation of cancer is therapeutics drugs generation cancer therapeutics drugs designed to of inhibit cancer stem cellwith pathways. designed to inhibit stem cellthepathways. Clinical trials are cancer underway with goal of Clinical trialsrecurrence are underway the goal of reducing and with metastasis. reducing recurrence and metastasis.

Learn more at www.bostonbiomedical.com Learn more at www.bostonbiomedical.com

References: 1. Li Y, Rogoff HA, Keates S, et al. Suppression of cancer relapse and metastasis by inhibiting cancer stemness. Proc Natl Acad Sci. 2015;112(6):1839-1844. 2. Hu X, Ghisolfi L, Keates AC, et al. Induction of cancer stemness by chemotherapy. Cell Cycle. 2012;11(14):2691-2698. 3. Clarke MF. Self-renewal solid-tumor stem S, cells. Biol Blood Marrow Transplant. 2005:11(2 suppl 2):14-16. 4. Boman BM, Huang E. Human colon cancer References: 1. Li and Y, Rogoff HA, Keates et al. Suppression of cancer relapse and metastasis by inhibiting cancer stemness. Proc Natl Acad Sci. stem cells: A new paradigm oncology. J Clin Oncol.of 2008;26(17):2828-2838. 5. Ahmad A. Pathways for2012;11(14):2691-2698. breast cancer recurrence. ISRN 2015;112(6):1839-1844. 2. Huin X,gastrointestinal Ghisolfi L, Keates AC, et al. Induction cancer stemness by chemotherapy. Cell Cycle. 3. Clarke Oncol. 2013;2013:290568. doi: 10.1155/2013/290568. 6. Hung JH, Wu YC. Stage 2005:11(2 I non-small cell lung cancer: recurrence factors and MF . Self-renewal and solid-tumor stem cells. Biol Blood Marrow Transplant. suppl 2):14-16. 4. Boman BM,patterns, Huang E.prognostic Human colon cancer survival. In:A Cardoso P, ed. in Topics in Thoracic oncology. Surgery. Shanghai, China: InTech; 2012:285-292. http://www.intechopen.com/books/topics-in-thoracicstem cells: new paradigm gastrointestinal J Clin Oncol. 2008;26(17):2828-2838. 5. Ahmad A. Pathways for breast cancer recurrence. ISRN surgery/stage-i-non-smallcell-lung-cancer-recurrence-patterns-prognostic-factors-and-survival. Accessed May 8, 2015. 7. Jordan CT, Guzman ML, Oncol. 2013;2013:290568. doi: 10.1155/2013/290568. 6. Hung JH, Wu YC. Stage I non-small cell lung cancer: recurrence patterns, prognostic factors and Noble M.In: Cancer stemP, cells. N EnglinJThoracic Med. 2006;355(12):1253-1261. 8. Gupta PB, Chaffer CL, Weinberg RA. Cancer stem cells: mirage or reality? Nat survival. Cardoso ed. Topics Surgery. Shanghai, China: InTech; 2012:285-292. http://www.intechopen.com/books/topics-in-thoracicMed. 2009;15(9):1010-1012. 9. Ghisolfi L, Keates AC, Hu X, Lee D, Li CJ. Ionizing radiation induces stemness in cancer cells. PLOS ONE. surgery/stage-i-non-smallcell-lung-cancer-recurrence-patterns-prognostic-factors-and-survival. Accessed May 8, 2015. 7. Jordan CT, 2012;7(8):1-11. Guzman ML, 10. Hoffmeyer K, Raggioli A, Rudloff et al. Wnt/β-catenin signaling regulates stem cells and cells. Science. 2012;336(6088):1549Noble M. Cancer stem cells. N Engl S, J Med. 2006;355(12):1253-1261. 8. Gupta telomerase PB, Chaffer in CL, Weinberg RA.cancer Cancer stem cells: mirage or reality? Nat 1554. 11. Bourguignon LYW,9.Earle C, Wong G, Spevak CC, K.CJ. Stem cell marker (Nanog) andstemness Stat-3 signaling promote MicroRNA-21 expression Med. 2009;15(9):1010-1012. Ghisolfi L, Keates AC, Hu X,Krueger Lee D, Li Ionizing radiation induces in cancer cells. PLOS ONE. 2012;7(8):1-11. and chemoresistance in hyaluronan/CD44-activated headsignaling and neckregulates squamous cell carcinoma Oncogene. 2012;31(2):149-160. 12. Espinoza I, 10. Hoffmeyer K, Raggioli A, Rudloff S, et al. Wnt/β-catenin telomerase in stemcells. cells and cancer cells. Science. 2012;336(6088):1549Pochampally R, Xing F,LYW, Watabe K,C, Miele L.G, Notch signaling: targeting cancer cells and epithelial-to-mesenchymal transition. Onco Targets Ther. 1554. 11. Bourguignon Earle Wong Spevak CC, Krueger K. Stem cellstem marker (Nanog) and Stat-3 signaling promote MicroRNA-21 expression 2013;6:1249-1259. and chemoresistance in hyaluronan/CD44-activated head and neck squamous cell carcinoma cells. Oncogene. 2012;31(2):149-160. 12. Espinoza I, Pochampally R, Xing F, Watabe K, Miele L. Notch signaling: targeting cancer stem cells and epithelial-to-mesenchymal transition. Onco Targets Ther. EDU-NPS-0027 12/2015 ©2015 Boston Biomedical 2013;6:1249-1259. EDU-NPS-0027

12/2015

collaborative agreements with more than 25 institutions globally. Prior to joining MD Anderson, Dr. DuBois was Professor at Vanderbilt University Medical Center, Nashville, in the departments of Internal Medicine and Cancer Biology, Director of the Vanderbilt-Ingram Cancer Center, and, prior to that, Chief of Gastroenterology, Hepatology, and Nutrition. He also currently serves on the Executive Management Committee for the Stand Up to Cancer Foundation and is the President and Chair of the American Association for Cancer Research (AACR) Foundation Board.

Past Accomplishments An active cancer researcher with more than 25 years of continuous funding from the National Institutes of Health, Dr. DuBois has an extensive list of scientific publications and has received numerous national and international honors. He has served in many leadership roles, among them as Past President of the AACR and the International Society for Gastrointestinal Cancer. Dr. DuBois will continue his leadership in cancer discovery through his ongoing research, engagement with the National Cancer Institute, and through partnership with the Hollings Cancer Center. Dr. DuBois received his PhD in biochemistry from The University of Texas Southwestern Medical Center at Dallas and his medical degree from the University of Texas Health Science Center at San Antonio. He completed his internship, residency, and fellowship training in gastroenterology at Johns Hopkins University Hospital. n

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Perspective

The Evolving Treatment Landscape of ALK-Positive NSCLC By Alice T. Shaw, MD, PhD

ince the initial discovery of ALK rearrangement in non–small cell lung cancer (NSCLC) in 2007,1 small molecule tyrosine kinase inhibitors of ALK have transformed the course of disease for those patients with ALK-rearranged (ie, ALK-positive) NSCLC. Crizotinib (Xalkori), a multitargeted tyrosine kinase inhibitor of ALK, ROS1, and CMET, was the first targeted therapy developed for patients with advanced ALK-positive NSCLC2 and has demonstrated superiority compared with first- and second-line chemotherapy in global randomized trials.3,4 However, patients invariably relapse on crizotinib, often within the first year of treatment. To address the growing issue of crizotinib resistance, multiple nextgeneration ALK inhibitors have been developed. The first of these new drugs—ceritinib (Zykadia)— showed significant clinical activity in a global phase I study,5 leading to its approval in the United States, Europe, and elsewhere. Alectinib (Alecensa) now joins ceritinib as another nextgeneration ALK inhibitor approved in the United States for patients with advanced ALK-positive NSCLC previously treated with crizotinib.

Supporting Clinical Data The approval of alectinib by the U.S. Food and Drug Administration (FDA) was based on two phase II studies: one conducted globally6 and one conducted in the United States and Canada.7 These studies are reviewed in this issue of The ASCO Post. Efficacy and safety results were similar between the two studies. Overall, alectinib was highly active in ALK-positive patients who had progressed on crizotinib, inducing responses in close to 50% of patients. Responses were durable, with median durations of response of 11.2 and 13.5 months in the global and U.S./Canadian studies, respectively.6,7 Median progression-free survival was also comparable at 8.9 and 8.1 months, respectively.6,7 Alectinib was associated with primarily grade 1 or 2 side effects, with the most common being Dr. Shaw is a thoracic oncologist at Harvard Medical School, Massachusetts General Hospital, Boston.

(across both studies) fatigue (41%), constipation (34%), edema (30%), and myalgias (29%).8

Focus on CNS Metastases Both studies also highlight one of the most important aspects of alectinib’s activity: namely, its efficacy in treating central nervous system (CNS) metastases. Unlike other studies of ALK inhibitors that have examined intracranial activity retrospectively, these two studies assessed CNS activity prospectively, and the results are included in the FDA label for alectinib. Across both studies, 60% of patients had known CNS metastases at the time of enrollment, and of these patients, 51 had baseline measurable CNS lesions. The response rate among these 51 patients was 61%, and median duration of intracranial response was 9.1 months.8

differ from patient to patient, with some patients developing a single site of relapse (for example, in the CNS), and others having more extensive relapse in the CNS, the body, or both. In addition, no randomized head-to-head trials comparing next-generation ALK inhibitors have been performed, making it difficult to compare efficacy or safety. Based on the available single-arm studies of alectinib and ceritinib in crizotinib-resistant disease, the systemic efficacy of these drugs may be roughly comparable. There may be potential advantages of alectinib over ceritinib, including alectinib’s documented intracranial activity and its favorable safety profile, but, ultimately, the choice of next-generation ALK inhibitor will need to be individualized for each patient. A related and perhaps more important question is whether patients could

Serial molecular genotyping of resistant tumors may potentially guide proper sequencing of next-generation ALK inhibitors, beginning at the initial selection of a next-generation inhibitor after crizotinib failure. —Alice T. Shaw, MD, PhD

CNS responses were observed in patients regardless of prior brain radiation status, including in those who had never received brain radiation. In addition, in separate studies, alectinib has been noted to have activity not only in parenchymal CNS metastases but also in leptomeningeal disease.9,10 Taken together, these results suggest that alectinib is highly effective in patients with progressive and untreated CNS metastases, including leptomeningeal disease.

Choice of ALK Inhibitor These two studies, along with the recent approval of alectinib, raise several important questions regarding the management of patients with advanced ALK-positive NSCLC. First, in a patient who has relapsed on crizotinib, which next-generation ALK inhibitor should be prescribed? This question does not have a simple answer, since the pattern of relapse can

benefit from both drugs, one given after the other. In the literature, there are data supporting the sequential use of alectinib after ceritinib, for example in the setting of progressive CNS disease, including in those with symptomatic disease10 or in patients who have developed the ceritinib resistance mutation F1174V.11 Similarly, ceritinib may be active after alectinib in patients who become resistant due to the alectinib resistance mutation I1171.12 Of note, both F1174 and I1171 mutations rarely emerge after crizotinib therapy. Thus, serial molecular genotyping of resistant tumors may potentially guide proper sequencing of nextgeneration ALK inhibitors, beginning at the initial selection of a next-generation inhibitor after crizotinib failure.

Comparing First-Line Options The second question that needs to be addressed is whether next-gen-

eration ALK inhibitors like alectinib should be used in the first-line setting in place of crizotinib. At present, the standard approach—sequential therapy with crizotinib followed by a next-generation ALK inhibitor—is associated with a combined median progression-free survival of 18 to 20 months.13 Whether first-line use of a next-generation ALK inhibitor can lead to a comparable outcome is not yet known. However, limited data with several of the next-generation ALK inhibitors suggest that this could be the case. In particular, in a small Japanese phase II study of 46 crizotinib-naive patients, the response rate with alectinib was 94%, and median progression-free survival was 28 months.14 In the global phase I study of ceritinib, median progression-free survival among 83 crizotinib-naive patients was also prolonged, at 18.4 months.15 Thus, single-arm studies suggest that first-line use of next-generation ALK inhibitors may be highly effective. To directly address the question of optimal first-line therapy for advanced ALK-positive NSCLC, two first-line studies comparing alectinib with crizotinib have recently completed enrollment: one conducted in Japan ( J-ALEX) and one conducted globally (ALEX). It is widely anticipated that these studies will be positive, favoring alectinib over crizotinib in terms of progression-free survival. However, what will be most important is the magnitude of progressionfree survival benefit. Since sequential therapy with crizotinib followed by alectinib provides a combined median progression-free survival of 18 to 20 months, the magnitude of benefit will need to be at least 6 months to justify a switch from first-line crizotinib to firstline alectinib. Unfortunately, the ALEX study does not incorporate a crossover design (ie, patients who progress on crizotinib will not automatically cross over to alectinib), thus precluding a direct comparison of first-line alectinib vs sequential crizotinib/alectinib.

The Issue of Resistance The third and final question concerns resistance to alectinib. As with other targeted therapies, all patients will relapse at some point on alec-

ASCOPost.com | JANUARY 25, 2016

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Perspective

tinib, including in the CNS. As previously mentioned, in some patients, resistance to alectinib may be due to a specific ALK resistance mutation affecting the I1171 residue.12 This is an important mutation to identify, since ceritinib has been reported to have activity against I1171 mutants.12 Another ALK resistance mutation that has been observed in alectinibresistant tumors is G1202R. This mutation confers resistance to almost all ALK inhibitors in the clinic, except for lorlatinib (PF-06463922). In early studies, lorlatinib demonstrated potent clinical activity against resistant tumors harboring the ALK G1202R mutation.16 Thus, for some patients relapsing on alectinib, another nextgeneration ALK inhibitor may represent an effective therapy. However, for likely a majority of alectinib-resistant cases, the tumors lack an ALK resistance mutation and have become ALK-independent. In these cases, patients may not benefit from another next-generation ALK inhibitor given as monotherapy. Instead, they may require combination strategies including a next-generation ALK inhibitor or standard therapies such as chemotherapy. Given its safety profile, alectinib may be a particularly attractive candidate for

combination approaches. Investigation of a few alectinibbased combinations is already underway in the clinic, including alectinib in combination with the programmed cell death ligand 1 (PD-L1) inhibitor atezolizumab and alectinib combined with bevacizumab (Avastin). Studies of these and other alectinib-based combinations should help to identify new therapeutic strategies that can overcome and even potentially prevent resistance. n Disclosure: Dr. Shaw reported no potential conflicts of interest.

References 1. Soda M, Choi YL, Enomoto M, et al: Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature 448:561-566, 2007. 2. Kwak EL, Bang YJ, Camidge DR, et al: Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med 363:1693-1703, 2010. 3. Shaw AT, Kim DW, Nakagawa K, et al: Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med 368:2385-2394, 2013. 4. Solomon BJ, Mok T, Kim DW, et al: First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med 371:2167-2177, 2014. 5. Shaw AT, Kim DW, Mehra R, et al:

Ceritinib in ALK-rearranged non-smallcell lung cancer. N Engl J Med 370:11891197, 2014. 6. Ou SI, Ahn JS, De Petris L, et al: Alectinib in crizotinib-refractory ALKrearranged non-small-cell lung cancer: A phase II global study. J Clin Oncol. November 23, 2015 (early release online). 7. Shaw AT, Gandhi L, Gadgeel S, et al: Alectinib in ALK-positive, crizotinibresistant, non-small-cell lung cancer: A single-group, multicentre, phase 2 trial. Lancet Oncol. December 18, 2015 (early release online). 8. Alecensa (alectinib) prescribing information, Genentech, 2015. Available at http://www.gene.com/download/pdf/ alecensa_prescribing.pdf. Accessed January 8, 2016. 9. Ou SH, Sommers KR, Azada MC, et al: Alectinib induces a durable (> 15 months) complete response in an ALKpositive non-small cell lung cancer patient who progressed on crizotinib with diffuse leptomeningeal carcinomatosis. Oncologist 20:224-226, 2015. 10. Gainor JF, Sherman CA, Willoughby K, et al: Alectinib salvages CNS relapses in ALK-positive lung cancer patients previously treated with crizotinib and ceritinib. J Thorac Oncol 10:232-236, 2015. 11. Ou SH, Milliken JC, Azada MC, et al: ALK F1174V mutation confers sensi-

tivity while ALK I1171 mutation confers resistance to alectinib: The importance of serial biopsy post progression. Lung Cancer 91:70-72, 2016. 12. Katayama R, Friboulet L, Koike S, et al: Two novel ALK mutations mediate acquired resistance to the next-generation ALK inhibitor alectinib. Clin Cancer Res 20:5686-5696, 2014. 13. Gainor JF, Tan DS, De Pas T, et al: Progression-free and overall survival in ALK-positive NSCLC patients treated with sequential crizotinib and ceritinib. Clin Cancer Res 21:2745-2752, 2015. 14. Tamura T, Seto T, Nakagawa K, et al: Updated data of a phase I/II study (AF-001JP) of alectinib, a CNS-penetrant, highly selective ALK inhibitor in ALK-rearranged advanced NSCLC. Int J Radiat Oncol Biol Phys 90:S6, 2014. 15. Felip E, Kim DW, Mehra R, et al: Efficacy and safety of ceritinib in patients with advanced anaplastic lymphoma kinase (ALK)-rearranged (ALK+) nonsmall cell lung cancer (NSCLC): An update of ASCEND-1. 2014 European Society for Medical Oncology Meeting. Poster presented September 2014. 16. Shaw AT, Bauer TM, Felip E, et al: Clinical activity and safety of PF06463922 from a dose escalation study in patients with advanced ALK+ or ROS1+ NSCLC. 2015 ASCO Annual Meeting. Abstract 8018. Presented May 29, 2015.

Don’t Miss These Important Reports in This Issue of The ASCO Post Heather Wakelee, MD, on Bevacizumab Plus Chemotherapy in Early-Stage Lung Cancer Survival see page 1

Hagop Kantarjian, MD, and Robert Chapman, MD, on the 340B Drug Pricing Program see page 1

Stephen J. Schuster, MD, on CAR-T Therapy in Lymphoma see page 3

Torsten O. Nielsen, MD, PhD, on Chemotherapy in Luminal A Breast Cancer see page 6

Cynthia Ma, MD, PhD, on Neoadjuvant Palbociclib and Anastrozole in Complete CellCycle Arrest see page 8

Sarat Chandarlapaty, MD, on Mutation Identification in BOLERO-2 Population see page 10

Barbara J. Gitlitz, MD, on ALK Rearrangements in Young Patients With Lung Cancer see page 24

Sébastien Maury, MD, on Rituximab in Adult B-Cell Precursor ALL see page 26

Visit The ASCO Post online at ASCOPost.com

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*

Laceration

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

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 92

The ASCO Post | JANUARY 25, 2016

Palliative Care in Oncology How Effective Communication Can Improve Patient Care—and Reduce Physician Burnout

A Conversation With James A. Tulsky, MD By Jo Cavallo

urveys conducted between 1950 and 1970 show that most physicians considered it inhumane to give patients with a poor cancer prognosis the bad news.1,2 Since then, it has been well established that open communication between physician and patient is an essential part of effective cancer care and can even improve patient adherence to treatment regimens and help oncologists and palliative care specialists experience greater professional fulfillment and avoid burnout, according to James A. Tulsky, MD. Dr. Tulsky, Chair, Department of Psychosocial Oncology and Palliative Care at Dana-Farber Cancer Institute, and Chief of the Division of Palliative Medicine at Brigham and Women’s Hospital, has been studying effective physician/patient communication for over 20 years and cofounded VitalTalk (vitaltalk.org), a nonprofit company that teaches advanced communication skills courses and faculty development courses to help clinicians deliver bad news and discuss goals of care in an empathic manner. Delivering bad news to patients, said

mnemonic SPIKES. They include: • Setup—The physician is prepared with the patient’s medical facts and has a plan for delivering the news. • Perception—Find out what the patient’s understanding is of the medical situation and how much information the patient wants. • Invitation—Ask permission about whether now is a good time to discuss the news. • Knowledge—Be direct in explaining the medical situation and use language that matches the patient’s level of education. • Empathize—Use empathic statements to respond to a patient’s emotions. For example, “I know this must be disappointing for you.” • Summarize and Strategize—Summarize the clinical information and make a plan for the next step, which may include further testing or a discussion about treatment options. To improve communication between oncologists and their patients, Dr. Tulsky has teamed up with the American Board of Internal Medicine

When oncologists communicate effectively with their patients, patients have greater feelings of trust and satisfaction. And if patients feel more trusting, they are more likely to adhere to the therapies being prescribed because they will believe in their effectiveness. —James A. Tulsky, MD

Dr. Tulsky, is something oncologists do thousands of times over their career and yet is a source of great stress that can linger for days after the initial conversation with patients and lead to physician burnout. However, when bad news is communicated in an empathic way it can reduce not only the patient’s feelings of anxiety and depression, but can alleviate the physician’s feelings of stress and sadness as well, he said. To build a coherent strategy for delivering bad news, Dr. Tulsky recommends using a series of six communication steps described in the

(ABIM) to study a computerized program called SCOPE in which oncologists audio record conversations with patients and then receive feedback on what went well and how they can improve in the future.3 Oncologists participating in the 3-year study will use the program as part of their ABIM Maintenance of Certification Program recertification process, and the researchers will test whether SCOPE improves oncologists’ communication skills and increases patients’ satisfaction.

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PAGE 93

Palliative Care in Oncology The ASCO Post talked with Dr. Tulsky about how developing effec tive communication skills improves patients’ understanding of their illness, increases patients’ adherence to treatment, and helps oncologists avoid professional burnout.

Improving Adherence and Patient Care How can good communication between patient and oncologist result in greater adherence to therapy and improve overall patient care? When oncologists communicate effectively with their patients, patients have greater feelings of trust and satisfaction. And if patients feel more trusting, they are more likely to adhere to the therapies being prescribed because they will believe in their effectiveness. The other piece is that patients frequently have concerns or questions about therapy, and better communication will lead them to a greater understanding of what the issues are with their treatment and allow them to express their concerns and to have those concerns addressed by the oncologist. All of this leads to greater treatment adherence, and greater adherence to treatment ought to lead to better outcomes.

Empathic Opportunities How can effective communication promote professional fulfillment and help oncologists avoid burnout? One of the major causes of burnout is the stress of dealing with patients who are very sick and ultimately die, which is exacerbated when it is also hard to communicate effectively with patients about their medical situation. There is a tremendous amount of emotional energy that goes into avoiding directly confronting patients with bad news, which then makes us feel less effective and more stressed. Also, patients living with advanced cancers have a lot of emotions, including anger, fear, and sadness, and those emotions enter into the clinical space, and we as health-care providers are the recipients of those emotions, which can be difficult to experience. When oncologists are better trained to manage these feelings and have the skills to respond to patients in a way that is effective and makes patients feel supported, then clinicians also feel better because their own stress level is reduced. Engaging in these conversations can also

make clinicians feel fulfilled because they allow physicians to feel helpful and get closer to their patients. What are the skills oncologists need to communicate more effectively with their patients? First of all, oncologists need to be able to elicit their patients’ concerns and correctly identify the emotional responses from patients. Some physicians have a hard time seeing the emotion a patient may be experiencing or interpreting it accurately, and then they need the skills to know what to do with that information (for example, how to make an empathic statement in response to a patient’s emotional concern). There are moments that arise in these conversations, we call them empathic opportunities, in which patients express negative emotion and the physician can respond either with an empathic statement, which identifies that he or she understands the patient’s position, or with what we call a “terminator,” in which the physician changes the topic or distances himself to avoid the emotion all together.

Ask-Tell-Ask Please explain the principle of “ask-tellask” when communicating with patients. This principle is based on understanding what the patient already knows about his or her situation before giving additional information. Oftentimes, we walk into the examination room armed with a lot of details, such as the status of the patient’s disease and treatment options, and the temptation is to launch into a long monologue. Yet, frequently, patients already know this information. Asking patients to describe their understanding of the issue allows clinicians to learn the patients’ level of knowledge, emotional state, and degree of education and then tailor their message based on their patients’ understanding. For example, a typical “ask” might be, “What have your doctors told you about your cancer?” or “What is your understanding of your illness right now?” Another “ask” might be for permission to give additional information. For example, “Would it be okay if we talked about the results of your cancer treatment and what your options might be?” Asking permission before telling a patient more information is a way of putting more control into the patient’s hands.

Delivering Bad News What is the most compassionate and effective way to give bad news? Clinicians can follow the SPIKES protocol, which starts by first checking the patient’s perspective about his or her situation and then asking permission to give additional news so the patient doesn’t feel overwhelmed. For example, you might say, “Is now a good time to share your test results?” And to prepare the patient for the bad news, it is a good idea to fire a warning shot first, for example, by saying, “The scan didn’t come back as we were hoping,” or “I wish I had better news to give you.” Then when the news is delivered it should be in short, clear, concise sentences. For example, “The biopsy showed that you have cancer.” “The scan shows the cancer has come back in your liver.” “Your treatment is no longer working.” Then I advocate being quiet and letting the patient absorb what has just been said. Often a patient will then say, “What is the next step?” And before I go into the next phase of presenting information, I immediately recognize the emotion the patient is feeling and I might say, “I wonder if you are feeling angry or afraid.” I try to address the emotion before going on with more facts. During that conversation is it appropriate to schedule another appointment with the patient to detail the next treatment plan rather than giving all the information at once? Yes, absolutely. If clinicians have the time in their schedule to have the patient come back to discuss options, especially if the options are complex and the likelihood that the patient will be able to absorb them are low, or if a decision has to be made between continuing active treatment or receiving palliative care only, it is best to separate the two conversations. The most important way to end the initial conversation is to give the patient a plan. The plan might be as simple as, “Let’s make an appointment for next Tuesday to discuss a new course of treatment and other concerns you may have.” The greatest antidote to patient anxiety is having a plan.

Maintaining Hope How can oncologists help their patients with advanced cancer maintain hope without giving them unrealistic hope? Being honest in their conversa-

GUEST EDITOR

Jamie H. Von Roenn, MD

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

tions about the patient’s prognosis is always best. I don’t think we can give or take away a patient’s hope. Hope is something that is a very internal resource. Hope is reliance, it is faith, and it is having trust in what the future holds. We can support our patients during this difficult time by expressing our concern and assuring them that we will be there for them during the course of their disease, no matter what happens. By using “I wish” statements, for example, “I wish I had a chemotherapy that could cure your metastatic cancer,” oncologists can acknowledge what patients are hoping for while also acknowledging that their hopes cannot be fulfilled. n

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

References 1. Oken D: What to tell cancer patients: A study of medical attitudes. JAMA 175:1120-1128, 1961. 2. Friedman HS: Physician management of dying patients: An exploration. Psychiatry Med 1:295-305, 1970. 3. Tulsky J: Improving communication between cancer patients and oncologists using patient feedback on actual conversations and the ABIM Maintenance of Certification program. Patient-Centered Outcomes Research Institute, 2014. Available at pcori.org/research-results/2014/ improving-communication-between-cancer-patients-and-oncologists-using-patient. Accessed January 8, 2016.

The ASCO Post | JANUARY 25, 2016

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News

E-Cigarette Advertisements Reach Nearly 7 in 10 Middle and High School Students

bout 7 in 10 middle and high school students—more than 18 million young people—see e-cigarette advertising in stores, online, in newspapers and magazines, or on television and in movies, according to a new Centers for Disease Control and Prevention (CDC) Vital Signs report.

ads in retail stores, and more than 6 million saw them on the Internet. • More than half of middle school students (6 million) saw e-cigarettes ads in retail stores, and more than 4 mil-

lion saw them on the Internet. • About 15% of all students (4.1 million) saw e-cigarette ads from all four sources: retail stores, the Internet, television/ movies, and magazines/newspapers.

Reducing Youth Access Proposed strategies to reduce youth access to e-cigarettes could include: • Limiting tobacco product sales to fa-

Thomas Frieden, MD, MPH

E-cigarette ads use many of the same themes—independence, rebellion, and sex—used to sell cigarettes and other conventional tobacco products. Advertising of tobacco products has been shown to cause youth to start using those products. The unrestricted marketing of e-cigarettes and the dramatic increases in their use by youth could reverse decades of progress in preventing tobacco use among youth. “The same advertising tactics the tobacco industry used years ago to get kids addicted to nicotine are now being used to entice a new generation of young people to use e-cigarettes,” said CDC Director Thomas Frieden, MD, MPH. “I hope all can agree that kids should not use e-cigarettes.”

Marketing Sources and Effect Data from the 2014 National Youth Tobacco Survey (NYTS) showed that 68.9% of middle and high school students see e-cigarettes ads from one or more media sources. More youth see e-cigarette ads in retail stores (54.8%) than online (39.8%), in television/movies (36.5%), or in newspapers and magazines (30.4%). In 2014, e-cigarettes became the most commonly used tobacco product among youth, surpassing conventional cigarettes. During 2011 to 2014, current ecigarette use among high school students soared from 1.5% to 13.4% and among middle school students from 1.6% to 3.9%. Spending on e-cigarette advertising rose from $6.4 million in 2011 to an estimated $115 million in 2014. Other key findings in the Vital Signs report showed that: • More than half of high school students (8.3 million) saw e-cigarette

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ASCOPost.com | JANUARY 25, 2016

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News

cilities that never admit youth; • Restricting the number of stores that sell tobacco and how close they can be to schools; • Requiring that e-cigarettes be sold only through face-to-face transactions, not on the Internet; • Requiring age verification to enter e-cigarette vendors’ websites, make

purchases, and accept deliveries of e-cigarettes. “States and communities can also help reduce youth tobacco use by funding tobacco prevention and control programs that address the diversity of tobacco products available on the market, including e-cigarettes,” said Corinne Graffunder, DrPH, Director of CDC’s Office on

Smoking and Health. “We know what works to effectively reduce youth tobacco use. If we were to fully invest in these proven strategies, we could significantly reduce the staggering toll that tobacco takes on our families and communities.” The 2009 Family Smoking Prevention and Tobacco Control Act gave the U.S. Food and Drug Administration

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(FDA) authority to regulate the manufacture, marketing, and sale of certain tobacco products. The FDA has announced its intention to regulate e-cigarettes and other currently unregulated tobacco products as part of this Act. The rule-making is currently under review at the Office of Management and Budget. n

The ASCO Post | JANUARY 25, 2016

PAGE 96

JCO Spotlight Hematology

Two Inherited Genetic Variants Predict Event-Free and Overall Survival in Diffuse Large B-Cell Lymphoma Treated With Immunochemotherapy By Matthew Stenger

n a genome-wide association study reported in Journal of Clinical Oncology, Hervé Ghesquieres, MD, PhD,

of Centre Léon Bérard, Lyon, France, and colleagues identified two inherited genetic variants that were associ-

ated with poorer event-free and overall survival in patients with diffuse large B-cell lymphoma treated with

immunochemotherapy.1 James R. Cerhan, MD, PhD, of Mayo Clinic, Rochester, is the corre-

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JCO Spotlight

sponding author for the Journal of Clinical Oncology article.

Study Details The study involved meta-analysis of genome-wide association study data sets from the LNH2003B trial (N = 540), a prospective clinical trial from the Lymphoma Study Association, and

the Molecular Epidemiology Resource study (N = 312), a prospective observational study from the University of Iowa-Mayo Clinic Lymphoma Specialized Program of Research Excellence. Top single-nucleotide polymorphisms were genotyped in independent cohorts of patients from the Specialized Program of Research Excellence (N = 391) and

the Groupe Ouest-Est des Leucémies Aiguës et Maladies du Sang-075 randomized trial (N = 294). Hazard ratios (HRs) for event-free and overall survival were calculated using a model adjusting for age, sex, and age-adjusted International Prognostic Index (IPI). In a meta-analysis of the four studies, the top loci associated with event-free

James R. Cerhan, MD, PhD

survival were marked by rs7712513 at 5q23.2, near SNX2 and SNCAIP (HR = 1.39, P = 2.08 × 10-7), and rs7765004 at 6q21, near MARCKS and HDAC2 (HR = 1.38, P = 7.09 × 10-7); however, neither reached the conventional threshold for genome-wide significance (P = 5 × 10-8). Both rs7712513 (HR = 1.49, P = 3.53 × 10-8) and rs7765004 (HR = 1.47, P = 5.36 × 10-7) were also associated with overall survival. In an exploratory analysis, a risk score based on the two single-nucleotide polymorphisms was highly predictive of event-free survival (P = 1.78 × 10-12) independent of treatment, IPI, and cell of origin. The investigators concluded: “Our study provides encouraging evidence for associations between loci at 5q23.2 and 6q21 with [event-free survival] and [overall survival] in patients with diffuse large B-cell lymphoma treated with immunochemotherapy, suggesting novel biology and the potential contribution of host genetics to the prognosis of this aggressive malignancy.” n

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Disclosure: The study was supported by National Cancer Institute Specialized Programs of Research Excellence (SPORE) in Human Cancer, Molecular Epidemiology of Non-Hodgkin Lymphoma Survival, National Center for Advancing Translational Science, Henry J. Predolin Foundation, Institut National du Cancer, Lymphoma Study Association, Fondation de France, and Philippe Foundation. For full disclosures of the study authors, visit jco.ascopubs.org.

Reference 1. Ghesquieres H1, Slager SL1, Jardin F, et al: Genome-wide association study of event-free survival in diffuse large B-cell lymphoma treated with immunochemotherapy. J Clin Oncol 33:3930-3937, 2015.

Genetic Variants in Diffuse Large B-Cell Lymphoma ■■ Loci at 5q23.2 and 6q21 were associated with event-free and overall survival. ■■ A risk score based on the two single-nucleotide polymorphisms was highly predictive of eventfree survival independent of treatment, IPI, and cell of origin.

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Physiatry in Discussion Roundtable Oncology Personalized Care

The New Frontiers of Breast Cancer

Three breast cancer experts discuss how precision medicine is leading to less aggressive treatment and better outcomes for patients with the disease. By Jo Cavallo

seismic shift is underway in screening and treatment approaches for breast cancer. These changes are being fueled by studies showing that mammography in younger women may do more harm than good and that advances in genomic testing and a better understanding of the biology of breast cancers may enable clinicians to prescribe more precise care for their patients, sparing them needless overtreatment. Six years after the U.S. Preventive Services Task Force (USPSTF) recommended that women start mammography screening at age 50 instead of age 40,1 the American Cancer Society (ASC) announced that it, too, was changing its recommendations2 for the start and frequency of mammography for women at average risk for breast cancer. The new recommendations call for average-risk women to begin annual screening at age 45, instead of age 40, and that the tests be done less frequently—every 2 years rather than yearly for women 55 and older. The ACS is also recommending ending clinical breast examinations as well as breast self-examinations. And while the changes in ACS policy did not stir up the same level of national uproar as the USPSTF’s did in 2009, they are still raising concern among some oncologists, advocacy groups, and patients who say that early detection improves survival. When to screen women for breast cancer and how aggressively to treat them when cancers are found—especially when the cancers are preinvasive and may never advance to become lifethreatening (eg, ductal carcinoma in situ [DCIS])—are issues at the center of a new debate among oncologists on how best to approach the disease. To learn what new research is showing on the most effective screening and treatment options for women with earlyand late-stage breast cancer and how the findings are impacting clinical care, The ASCO Post held a roundtable discussion with three leaders in the field: Laura J. Esserman, MD, MBA, Director of the Carol Franc Buck Breast Cancer Center and Co-Leader of the Breast Oncology Program at the University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center; Julie R. Gralow, MD, Jill Bennett Endowed Professor of Breast Medical Oncology at the University of Washington School of

About the Faculty

Laura J. Esserman, MD, MBA

Julie R. Gralow, MD

Marisa C. Weiss, MD

Director of the Carol Franc Buck Breast Cancer Center and Co-Leader of the Breast Oncology Program at the University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center

Jill Bennett Endowed Professor of Breast Medical Oncology at the University of Washington School of Medicine and Director of Breast Medical Oncology at Seattle Cancer Care Alliance

Director of Breast Radiation Oncology at Lankenau Medical Center in Philadelphia and Founder and Chief Medical Officer of Breastcancer.org.

Medicine and Director of Breast Medical Oncology at Seattle Cancer Care Alliance; and Marisa C. Weiss, MD, Director of Breast Radiation Oncology at Lankenau Medical Center in Philadelphia and Founder and Chief Medical Officer of Breastcancer.org.

third of cancers fall into the ultra–lowrisk or indolent category. We have to adopt screening and prevention strategies recognizing that these indolent lesions or less aggressive cancers exist and that they do not have to be aggressively treated. This is what personalizing therapy for patients is all about. If we recognize that there are indolent cancers, less aggressive treatment upfront is probably sufficient, especially for women with shortened life spans. And, certainly, we do not want to find precursors to those indolent cancers, because early intervention will just increase the morbidity rate (eg, low-grade DCIS). Dr. Gralow: We have known for some time basic ways of stratifying breast cancer—most importantly, by whether the cancer expresses the estrogen receptor or overexpresses HER2—and how to treat breast cancer based on those stratifications. With genomic testing and a better understanding of the biology of breast cancer, we are getting beyond estrogen receptor and HER2 disease and understand that even a subtype of breast cancer, such as triple-negative disease, encompasses multiple subtypes. We have a better understanding of what the drivers of these subsets are and what does or does not work, but we have not converted this information to the clinic yet. The more we look at these subsets, the more we understand that every breast cancer is unique. Dr. Weiss: I agree: There is no one-

size-fits-all approach to treating breast cancer. Each patient is unique and wants to take full advantage of the best relevant medical advances from multiple fronts. There is a better understanding of the cancer itself and how to determine a tailored, customized approach for each patient. The goal is to give the best treatment approach from the beginning— one that will provide the greatest benefit and least toxicity for each individual. But the approach to treating breast cancer is not just about looking behind the curtain to see what is driving the disease; it is about understanding each patient’s unique physical and emotional situation as well, including her overall health and goals. Women want a holistic approach to their personalized care.

Individualizing Care Advances in genomics and a greater understanding of the biology of different types of breast cancer are changing treatment strategies for the disease. What are you learning about the prevention, detection, diagnosis, and treatment of breast cancer; how is the treatment for breast cancer becoming more individualized; and what might the change mean for overall outcome and survival? Dr. Esserman: The most fundamental change in our understanding of breast cancer is that biology trumps stage, which to me means that size isn’t necessarily as important as the biology of the tumor. I have been very vocal about explaining that there are indolent cancers or even tumors that should not be called cancers— not just in breast cancer but across all cancer types—that may not need immediate treatment. Previously, we did not understand this nuance; you do not often see the manifestation of these indolent cancers until you screen for them. Redefining “what is cancer” in 2016 is an important scientific opportunity. If you screen for cancer, more cancers with a low-risk biology are going to surface. We think that probably one-

Achieving More by Doing Less Are advances being made in your ability to better determine who will benefit most from a specific treatment, thereby eliminating unnecessary aggressive treatment and toxicity? In other words, is it possible to do less and still achieve a good outcome? Dr. Esserman: We have found an ultra–low-risk threshold that we think defines indolent cancers, and I think that is where the opportunity is to feel comfortable giving less aggressive therapy. There is also the opportunity to understand who has the higher-risk type of lesions. Oftentimes, surgeons are the first physicians to see newly diagnosed patients, and when there is uncertainty about

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Physiatry in Discussion Roundtable Oncology whether the cancer is significant or consequential, surgery is sequenced first. When it is clear that the cancer is triplenegative, HER2-positive, or has spread to the lymph nodes, our concern is that the patient will die of systemic disease, so systemic therapy is most important in those situations, and understanding the impact of those systemic therapies is critical. My recommendation is that we flip the order of therapy. I am a big proponent of

tions regarding adjuvant treatment of breast cancer. The participants could not determine who would benefit most from chemotherapy and concluded that everyone should, therefore, get the therapy. We all knew that conclusion was wrong, but we could not change the strategy because we could not figure out who would and would not benefit from chemotherapy. Now we have profiling assays such as the Oncotype DX and MammaPrint

The most fundamental change in our understanding of breast cancer is that biology trumps stage, which to me means that size isn’t necessarily as important as the biology of the tumor.… There are indolent cancers or even tumors that should not be called cancers and that may not need immediate treatment. —Laura J. Esserman, MD, MBA

neoadjuvant therapy, whether it is chemotherapy or hormonal therapy. We started the I-SPY breast cancer trial to learn about tumor biomarkers and how to match combinations of drugs to provide the greatest benefit and least toxic side effects and to accelerate the pace of finding the right drug for the right patient. The next phase of that trial will investigate how to determine the right sequence of agents if a patient is not responding to treatment. When you have a patient with aggressive cancer, the big challenge is to prevent her death by accurately figuring out how to get the most effective therapy for her cancer upfront. Next-generation gene sequencing of the host is making it possible to identify people who clearly have a high risk of getting breast cancer, and we now know that there are genes associated with early-onset breast cancer. These are the people who should be given preventive interventions and intensive screenings at appropriate intervals. To give us the knowledge to determine a personalized approach to breast cancer screening for women, we have launched the WISDOM study (Women Informed to Screen Depending on Measures of Risk), which is enrolling 100,000 women 40 to 80 years old, to test a personalized schedule of screening based on each woman’s individual risk for breast cancer. We are going to let the science drive screening frequency. For women with very low risk for disease, we should screen them less often, and for women at high risk for disease, we should screen them more often. That is what personalized medicine is all about. Dr. Gralow: In 2000, the National Institutes of Health held a Consensus Development Conference3 to review ques-

genomic tests among others, to tell us which patients have good- or bad-risk cancers and which cancers respond more to chemotherapy or endocrine therapy, and we are absolutely giving less chemotherapy as a result. We are also learning more about defining populations of patients who do not benefit from adjuvant radiation after lumpectomy to ward off recurrence or who do not benefit from wholebreast irradiation and can have accelerated partial-breast irradiation instead. So “less is more” is a real trend in breast cancer treatment. Dr. Weiss: Yes, we are absolutely making advances in our knowledge of personalizing treatment for patients. Prior to treatment is selection. It is critical to take time upfront to fully define the extent and nature of the disease. In appropriate patients, it is also important to identify any potential inherited predisposition like BRCA1 or BRCA2 genetic mutations. In the setting of advanced disease, genetic testing of the cancer itself may reveal important clues for the role of targeted therapies against genetic drivers. Of course, it is also critical to understand the patient’s preferences and style of making decisions, as well as to assess her overall health and expected lifespan. There are also genetic changes that tell us how one form of treatment may be more problematic than another. For example, patients with the TP53 gene abnormality may have more issues with radiation therapy than patients without that mutation, and radiation therapy should be avoided in this group if possible. Regarding overdiagnosis, I believe a missed or delayed diagnosis is much more harmful than a false-positive mammography screening. And I worry

about using outdated historical analog mammography data to make futuristic guidelines for modern-day mammography, since medicine has marched forward and we have much better tools with which to make more accurate diagnoses and avoid overtreatment. Are women being overtreated? Yes, there is overdiagnosis and there is overtreatment since there are breast cancers that may never be life-threatening. But right now we do not know exactly which cancers will remain indolent and which ones will become aggressive. And the cancer needs to be removed in order to be fully defined and staged. For example, a core biopsy of a mass that shows just grade 1 DCIS may be a sampling error. The mass needs to be removed to be sure that there is no significant noninvasive or invasive disease present. Moreover, our data on the natural history of both DCIS and invasive breast cancer are from after lumpectomy with essentially clear margins. After a diagnosis, we now have the Oncotype DX test for DCIS and hormone receptor–positive early-stage invasive disease to help us make treatment choices, and there are more accurate tests in the pipeline. But right now, it is still a gamble to predict who does or does not need treatment or how aggressive treatment should be. Until we

Detected Lesions,4 and we are working to better define what I call IDLE (indolent lesion of epithelial origin) conditions vs aggressive cancers. We did not have the opportunity to understand and classify cancers differently in the past, but now that we are screening cancers and finding all the low-risk disease, we have the opportunity to consider that some of these cancers can be reclassified and called something else. This is just as essential as finding better ways to treat the aggressive cancers, because all of our interventions have complications, both psychological and physical. Personalized medicine does not just mean doing more for some; it also means doing less for others, and that is just as important and deserves as much attention as finding new treatments. Dr. Gralow: In breast cancer, the idea of active surveillance is a new concept. In cases of in situ disease, such as DCIS, there is undoubtedly a subset that will never evolve to invasive cancer, where watching it and not giving aggressive treatment is reasonable. Currently, however, I don’t think we are great at picking out which DCIS will go on over time to have another mutation and turn into invasive disease and which cases will not. If there is just a millimeter of DCIS, and it is low-grade and quiet, can you leave it and watch it? Yes, probably. But

We are paying more attention to overtreatment. With respect to these low-grade, early-stage tumors in older patients, based on age, comorbidities, and life expectancy, there is a group we should not be screening with mammography. —Julie R. Gralow, MD

have those more discriminating tests, we will probably continue to overtreat patients to reduce the risk of recurrence and treat more patients than we need to.

Watch and Wait When is active surveillance in breast cancer appropriate? Dr. Esserman: We are creating a DCIS registry across the five University of California medical centers to offer women with DCIS options, including active surveillance, chemoprevention, or surgery, and track their outcomes over decades. I do not believe that low-grade DCIS should be a target for screening, because we have not demonstrated that we are improving outcomes by going after it, and we have not lowered the rates of invasive cancer. I am a member of the Consortium for Molecular Characterization of Screen-

that is not what we usually find with DCIS. Is there any invasive disease we can just watch? I would say there are some low-risk, early-stage breast cancers, particularly in older women, where we can either leave it in place or just perform surgery (but not give radiation), and watch to see if the cancer grows. We are paying more attention to overtreatment. With respect to these low-grade, early-stage tumors in older patients, based on age, comorbidities, and life expectancy, there is a group we should not be screening with mammography. How do we define DCIS vs invasive breast cancer? That is what this whole question of the appropriateness of active surveillance is all about. Do we really want to be finding some of these early, nonaggressive tumors? We probably do not, but continued on page 106

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Physiatry in Discussion Roundtable Oncology New Frontiers of Breast Cancer continued from page 99

then how do we make sure that we find the more aggressive cancers that will impact a woman’s survival? Dr. Weiss: We already have a number of powerful tests that help us select people who need to be treated and those who do not. Those tests are getting better and smarter. My practice approach is to make sure that each woman gets the best customized treatment possible, whatever is most effective at reducing her risk of recurrence, and to avoid or minimize any associated side effects. Along the way, it is critical to offer the right medical expertise and support at the right time so the patient can make the best decisions possible with her doctor, which is exactly the mission of my organization, Breastcancer.org. We are getting smarter about figuring out the best treatments, but we do not yet know how to predict exactly how a particular cancer will behave, and we do not want to miss the opportunity to treat a patient for early-stage disease with reasonable and effective therapy.

Treating Metastatic Cancer How are treatment strategies changing for metastatic disease? Dr. Esserman: We are investigating how we can accelerate the prevention of metastatic disease and test new agents earlier in the disease course by testing new agents first in the neoadjuvant setting in the I-SPY 2 trial. Every year, we see one or two new treatments getting U.S. Food and Drug Administration approval for metastatic breast cancer. The Breast Cancer Research Foundation (bcrfcure.org) is putting a huge international effort into characterizing metastatic breast cancer to determine how to sequence and organize more effective therapies. I think we can look forward to a time when metastatic breast cancer becomes much more of a chronic disease. Dr. Gralow: When I started my oncology fellowship in 1992, we prescribed a lot of chemotherapy and had just a handful of endocrine therapies in our treatment arsenal. Now, we have many more endocrine therapies and new categories of targeted therapies that have been designed to overcome resistance to endocrine therapies. For the majority of patients with metastatic disease whose tumors express estrogen receptor, we have six lines of nonchemotherapy approaches that can give them years and sometimes decades without ever having chemotherapy. But we aren’t curing these women, and we need to do better, especially for women with triple-negative breast cancer.

About 15% to 20% of metastatic breast cancers are triple-negative, and we have not made huge gains in treating these women. This is a group of patients who could benefit from genomic profiling and enrollment in studies of targeted agents that match their tumor profile. For patients with estrogen receptor–positive and HER2-positive metastatic disease, we have a wide variety of drugs that are prolonging survival and that have a lot less toxicity than classic chemotherapy drugs. There are some very innovative trials looking at immunotherapies and PARP inhibitors. Dr. Weiss: In general, metastatic disease requires continuous treatment, and it is important to redefine the extent and nature of the recurrent and progressive disease. We can’t assume that the recurring disease is the same as the original cancer. It can be very helpful to biopsy the tumor to understand the type of cancer that has re-

My philosophy from the beginning has been based on a precision medicine approach—that is, the art of tailoring treatment to the cancer biology, patient preference, and clinical performance. You cannot force patients to do what they do not want to do, which is how I wound up not treating some patients with low-grade DCIS. They said to me, “I’m not convinced by this treatment, and I don’t want to have drastic interventions,” and they are fine 10 years later. Even among people who are at increased risk for cancer and breast cancer death, we have to resist the urge to be frightened and prescribe them everything. We need to know what will work to reduce that risk—and we need to find better alternatives that are less morbid. If you never try an alternative approach, you will never learn whether different approaches are successful. Dr. Gralow: For general screening

In general, metastatic disease requires continuous treatment, and it is important to redefine the extent and nature of the recurrent and progressive disease. We can’t assume that the recurring disease is the same as the original cancer. —Marisa C. Weiss, MD

curred, because it may have altered in some way, and then we can select the most effective treatment with the fewest side effects.

Looking Ahead What advances do you expect to see over the next 5 to 10 years in the screening and treatment of breast cancer? Will there be more effective screening methods and diagnostic tools over the next decade? Dr. Esserman: Yes, there will be more effective screening and diagnostic tools, and I think we will be able to make a lot of progress in this disease. We will start to understand and focus on how to better identify people at risk for consequential cancers. We will probably have blood tests that identify people at risk for breast cancer, and understanding the underlying risk factors of various populations will drive a lot of the innovation. The more we can narrow down the population vulnerable to the highest-risk cancers, the better we will be able to add new tools and technologies and study preventive approaches in these high-risk populations. We will successfully treat HER2positive breast cancer with less-toxic combinations of targeted therapies, and I hope that will be true for triple-negative and high-risk hormone-positive breast cancers as well.

for a first breast cancer, we are at the point where we are catching a lot of lesions we don’t necessarily want to catch. What we really want are good tools that find invasive cancers early. I think three-dimensional tomography is very promising compared to standard digital mammography, and researchers are working on noncontrast rapid breast magnetic resonance mammography, which will create highquality images of the breasts and have better sensitivity and specificity for the detection of breast cancer. We are also looking at automated breast ultrasound as another screening tool, especially for women with very dense breasts. In terms of diagnostic tools, we are looking at different kinds of blood tests, or liquid biopsies, that can find single cells or circulating cell-free DNA, which will detect cancer both at initial diagnosis and at recurrence. These blood assays can also allow us to do genomic profiling of the tumor. Then we have to prove that knowing there is a little bit of cancer and acting on it sooner makes a difference in survival, because that would be the next step. As far as more effective treatment, as I mentioned earlier, I do think a better understanding of the genetic and molecular changes that lead to each cancer

is going to lead to much more specific treatments for each patient, and that will lead to better outcomes. We will have more successes and some nonsuccesses, too, but we learn from it all. Dr. Weiss: I agree. Medicine is marching forward very quickly, and we are definitely getting better at determining risk factors and in screening and treating breast cancer, so I’m very optimistic that we will be able to do a better job in the prevention, early detection, treatment, and surveillance of women at high risk of getting the disease. We know a lot of the risk factors for breast cancer, including obesity, lack of physical activity, and alcohol consumption, and we have to do a better job of educating the public about these risk factors. If women at age 50 were to start making healthy lifestyle choices and sustain them over time, they could lower their incidence of breast cancer by 50%. And if girls lead healthy lives starting at age 2, they could lower their lifetime risk for breast cancer by 70%. Breast cancer is a serious problem, but there is a lot we can do to reduce individual risk. Just because the American Cancer Society’s mammography guidelines call for screening to begin at age 45 and then every other year at age 55 does not mean that breast cancer risk starts at that point. There are a lot of women who think that breast cancer risk starts when mammography begins, and that is not true. That misconception is a barrier to making progress on prevention and risk reduction. n

Disclosure: Dr. Esserman reported no potential conflicts of interest. Dr. Gralow has received research funding from Roche/ Genentech. Dr. Weiss is Founder and Chief Medical Officer of Breastcancer.org.

References 1. U.S. Preventive Services Task Force: Breast cancer screening, November 2009. Available at www.uspreventiveservicestaskforce.org/Page/Document/UpdateSummaryFinal/breast-cancer-screening. Accessed January 10, 2016. 2. American Cancer Society recommendations for early breast cancer detection in women without breast symptoms. Available at www.cancer.org/cancer/breastcancer/ moreinformation/breastcancerearlydetection/breast-cancer-early-detection-acsrecs. Accessed January 10, 2016. 3. Abrams JS: Adjuvant therapy for breast cancer: Results from the USA consensus conference. Breast Cancer 8:298-304, 2001. 4. National Cancer Institute Division of Cancer Prevention: Consortium for Molecular Characterization of Screen-Detected Lesions created: Eight grants awarded. Available at http://prevention.cancer.gov/ news-and-events/news/consortium-molecular. Accessed January 10, 2016.

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Announcements

Community Oncology Alliance Elects New Officers and Board Members for 2016

he Community Oncology Alliance (COA), a nonprofit organization dedicated to advocating for community oncology practices and the patients they serve, announced the election of a new Board of Directors and Executive Committee officers.

Bruce Gould, MD

“2016 is primed to be an important year for community oncology. We anticipate significant progress on payment reform initiatives such as the Oncology Medical Home (OMH) and ongoing examinations of the 340B drug program and more,” said Bruce Gould, MD, President of COA and a practicing oncologist with the Northwest Georgia Oncology Centers. “COA is strengthened by the very active involvement of its volunteer Board and Executive team. We welcome the new and continuing Board members. Their participation ensures that COA

will continue in its strivings for the betterment of community cancer care.” The following individuals were elected to serve as officers of COA and on the Executive Committee: • Bruce Gould, MD, President • Jeffrey Vacirca, MD, Vice President • Michael Diaz, MD, Secretary • Ricky Newton, CPA (Treasurer; ex officio) • Mark E. Thompson, MD (Immediate Past President) • David Eagle, MD (Past President) • Henry “Mac” Barnes, MD (Past President) • Miriam Atkins, MD (Officer-atLarge) • Ted Okon (Executive Director; ex officio) The following individuals were elected to serve a first-time term on the COA Board of Directors: • Bruce Burns, MD (Georgia) • Jose DeVilla, MD (Puerto Rico) • Deborah Patt, MD (Texas) • Jeffrey Patton, MD (Tennessee) COA is a nonprofit, 501.c.6 organization that is controlled by community oncologists. COA has an Executive Committee of Officers that reports to a Board of Directors, comprising volunteer representatives from community oncology, who di-

Michael Diaz, MD

Ricky Newton, CPA

Mark E. Thompson, MD

David Eagle, MD

Henry “Mac” Barnes, MD

Miriam Atkins, MD

Ted Okon

Bruce Burns, MD

Jeffrey Patton, MD

rect the management of COA by its Executive Director. The complete list of Officers and

Board members can be viewed at http://www.communityoncology.org/ site/form-of-organization.htm. n

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The ASCO Post | JANUARY 25, 2016

PAGE 108

Announcements

Terence S. Dermody, MD, Named Chair of Pediatrics at UPMC and Scientific Director of Children’s Hospital of Pittsburgh

erence S. Dermody, MD, has been named the Chair of the Department of Pediatrics at the University of Pittsburgh School of Medicine and Physician-in-Chief and Scientific Director at Children’s Hospital of Pittsburgh of the University of Pittsburgh Medical Center (UPMC). Dr. Dermody will officially begin in these new positions on June 1, 2016.

Terence S. Dermody, MD

He joins Children’s Hospital from Vanderbilt University, where he is the Dorothy Overall Wells Professor of Pediatrics, Director of the Division of Pediatric Infectious Diseases and Director of the Medical Scientist Training Program at Vanderbilt University School of Medicine. He also is Professor of Pathology, Microbiology, and Immunology at Vanderbilt.

Viral Pathogenesis and Vaccine Development Dr. Dermody is a virologist with interests in viral pathogenesis and vaccine development. He has focused mainly on reovirus, an important experimental model for studies of viral encephalitis in infants, and on chikungunya virus, an arthropod-borne virus that causes epidemics of febrile arthritis. The work in Dr. Dermody’s laboratory has encompassed several interrelated themes, including the structural basis of viral attachment and cell entry; mechanisms of genome replication and packaging; patterns of cell signaling and gene expression occurring in response to viral infection; mechanisms of virus-induced apoptosis and its significance in the viral life cycle; and the role of viral receptor distribution and utilization in disease pathology. Currently, the lab is developing viral vectors for oncolytic and vaccine applications. “I am honored to be able to join the team in Pittsburgh and be a part of this world-class pediatric facility dedicated to improving the lives of

children,” said Dr. Dermody. “I am eager to begin and have the opportunity to work with the talented physicians and scientists at Children’s Hospital. I feel honored and humbled to have

this opportunity.” Dr. Dermody succeeds David H. Perlmutter, MD, who recently left Children’s to become Executive Vice Chancellor for Medical Affairs and

Dean of Medicine at Washington University in St. Louis. Dr. Dermody’s research is supported by grants from the National Institutes of Health (NIH) and the Lamb

ASCOPost.com | JANUARY 25, 2016

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Announcements

Foundation. He currently holds five NIH grants, and the NIH has continually funded his research since 1987. He is a past President of the American Society for Virology, past Chair of the AAMC GREAT Group MD/ PhD Section Steering Committee, and current Chair of the Virology Division of the International Union of

Microbiological Societies. Dr. Dermody received his medical degree from Columbia University. He completed an internal medicine residency at Presbyterian Hospital in New York and fellowships in infectious diseases and molecular virology at Brigham and Women’s Hospital and Harvard Medical School. n

The ASCO Post Wants to Hear From You

We encourage readers to share their opinions and thoughts on issues of interest to the oncology community. Write to The ASCO Post at editor@ASCOPost.com

ASCOPost.com | JANUARY 25, 2016

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Journal Spotlight Hematology

Lenalidomide Plus Rituximab Highly Active in Initial Treatment of Mantle Cell Lymphoma By Matthew Stenger

n a phase II trial reported in The New England Journal of Medicine by Jia Ruan, MD, PhD, and colleagues, firstline treatment with the immunomodulatory agent lenalidomide (Revlimid) and the anti-CD20 antibody rituximab (Rituxan) followed by maintenance lenalidomide and rituximab produced a high response rate, prolonged remission, and promising survival outcomes in patients with mantle cell lymphoma.1 Initial treatment of mantle cell lymphoma is not standardized but generally includes cytotoxic chemotherapy; cure is seldom achieved.

Study Details In the single-group study, 38 patients enrolled at 4 U.S. sites between July 2011 and April 2014 received induction and maintenance treatment with lenalidomide and rituximab, During induction, lenalidomide was given at 20 mg daily (10 mg if creatinine clearance 30 to < 60 mL/min) on days 1 to 21 of 28-day cycles for 12 cycles, with the dose being escalated to 25 mg daily (15 mg) after the first cycle if no doselimiting adverse events occurred during the first cycle. Rituximab was given at 375 mg/ m2 during weeks 1, 2, 3, 4, 13, 21, 29, 37, and 45, for a total of nine doses. Starting with cycle 13, maintenance lenalidomide was given at 15 mg (5 mg) daily on days 1 to 21 of 28-day cycles, while maintenance rituximab was given every other cycle. Treatment was continued for at least 36 cycles or until disease progression, development of unacceptable adverse effects, or withdrawal from the study. Thromboprophylaxis with aspirin or low–molecular-weight heparin was administered to all patients unless treatment for known thrombosis was required. Asymptomatic hepatitis B virus carriers received antiviral therapy. Prophylactic growth factors were not empirically given. The primary endpoint was overall response rate. Patients had a median age of 65 years (range, 42–86 years), 71% were male, 97% had an Eastern Cooperative Oncology Group performance status of 0 or 1, 100% had Ann Arbor stage III or IV disease, 39% had an elevated lactate dehydrogenase level, and 89% had bone marrow involvement. In addition, 34% had low-risk,

34% intermediate-risk, and 32% highrisk disease on Mantle Cell Lymphoma International Prognostic Index (MIPI) scores; 47% had low-intermediate risk, 26% had high-intermediate risk, and 11% had high-risk disease on the International Prognostic Index (IPI); and Ki67 index was < 30% in 68% and ≥ 30% in 21%. The most common indications for treatment were symptomatic lymphadenopathy (53%), cytopenias (18%), and bulky disease (13%).

Responses and Survival At a median follow-up of 30 months, the overall response rate among 36 evaluable patients was 92% (95% confidence interval [CI] = 78%–98%), with a complete response rate of 64% (95% CI = 46%–79%).

Combination Biologic Therapy for Mantle Cell Lymphoma ■■ Among evaluable patients who received lenalidomide and rituximab for mantle cell lymphoma, the response rate was 92%, with a complete response rate of 64%. ■■ The number of complete responses increased over time with continuous treatment. ■■ A total of 78% of patients were in remission without disease progression at last follow-up.

ceived study treatment for 3 years and was no longer receiving therapy while remaining in complete remission.

Adverse Events For both treatment phases, the most common adverse events of any grade were neutropenia (74%) and anemia (60%) among hematologic ad-

Combination biologic therapy consisting of lenalidomide plus rituximab was active as initial therapy for mantle cell lymphoma. —Jia Ruan, MD, PhD, and colleagues

The number of complete responses increased over time with continuous treatment. Median time to partial response was 3 months (range, 3–13) months, and median time to complete response was estimated at 11 months (range, 3–22 months). Median progression-free survival and overall survival had not been reached. Two-year progression-free survival was 85% (95% CI = 67%– 94%), and 2-year overall survival was 97% (95% CI = 79%–99%). MIPI and IPI scores and Ki67 index were not correlated with response or progressionfree survival; high-risk disease on MIPI was associated with unfavorable overall survival (P = .05). Among the 36 evaluable patients, 78% were in remission without disease progression at last analysis, including 26 who had completed induction therapy and were receiving maintenance therapy, 1 who had almost completed induction therapy, and 1 who had re-

verse events and fatigue (74%), rash (66%), fever (58%), cough (55%), diarrhea (55%), and hyperglycemia (50%) among nonhematologic adverse events. Grade 1 or 2 infections included upper respiratory tract infection (39%), urinary tract infection (18%), and sinusitis (11%). The most common grade 3 or 4 adverse events were neutropenia (50%), rash (29%), thrombocytopenia (13%), an inflammatory syndrome (“tumor flare”; 11%), and anemia (11%). Secondary cancers were observed, consisting primarily of noninvasive skin cancers requiring local therapy, including squamous cell carcinoma in two patients, basal cell carcinoma in one patient, and melanoma in situ in two patients. Merkel cell carcinoma developed in an 86-yearold patient after 18 months of treatment, and pancreatic cancer was diagnosed in a 68-year-old patient after 12 months of treatment.

Among the 33 patients with normal renal function, 36% had no unacceptable side effects associated with dose escalation from 20 mg to 25 mg, and 42% required a dose reduction from 20 mg to ≤ 15 mg. During induction therapy, rituximab was discontinued in two patients with serum sickness–like symptoms. During maintenance therapy, six patients received modified therapy during remission. Rituximab was discontinued in two patients with hypogammaglobulinemia, and lenalidomide was discontinued in four patients, due to investigator discretion for two patients, after asymptomatic grade 4 liver function abnormality in one patient, and due to a reversible grade 4 ventricular arrhythmia in a patient with a history of dysrhythmia. Quality of life assessed by Functional Assessment of Cancer Therapy–Lymphoma (FACT-Lym) showed trends toward improvement among patients completing the instrument at baseline and month 12 (P = .04) and baseline and month 21 (P = .06). The investigators concluded: “Combination biologic therapy consisting of lenalidomide plus rituximab was active as initial therapy for mantle cell lymphoma.” n

Disclosure: The study was funded by Celgene and a Weill Cornell Medical College Clinical Translational Science Center grant. For full disclosures of the study authors, visit www. nejm.org.

Reference 1. Ruan J, Martin P, Shah B, et al: Lenalidomide plus rituximab as initial treatment for mantle-cell lymphoma. N Engl J Med 373:1835-1844, 2015. See commentary by Michael Wang, MD, PhD, on page 112.

The ASCO Post | JANUARY 25, 2016

PAGE 112

Perspective

Winning the Battle at the Front Lines: Lenalidomide Plus Rituximab— A Promising Initial Treatment for Mantle Cell Lymphoma By Michael Wang, MD

antle cell lymphoma is a pernicious, incurable disease. Frontline therapies for this disease are not currently standardized; however, novel therapies for relapsed or refractory mantle cell lymphoma can ideally be

by Wiernik and colleagues in 2008.4 In 49 patients, the objective response rate was 35%; however, in the 15 enrolled patients with mantle cell lymphoma, the objective response rate was 53%. Based on these promising results,

Starting with the auspicious efforts of Ruan and colleagues, multiple chemotherapy-free regimens for newly diagnosed patients with mantle cell lymphoma are on the verge of becoming standardized therapies. —Michael Wang, MD

translated into beneficial treatments for newly diagnosed patients, as clearly demonstrated by the phase II study of lenalidomide (Revlimid) and rituximab (Rituxan) by Ruan and colleagues recently reported in The New England Journal of Medicine.1 As reviewed in this issue of The ASCO Post, Ruan and colleagues rapidly and effectively transferred the findings of a multi-institutional study of rituximab and lenalidomide for relapsed or refractory mantle cell lymphoma into the front-line setting and achieved a striking objective response rate of 92%—which is a major step forward in the fight against mantle cell lymphoma.

Recap of Lymhoma Studies Lenalidomide was first approved by the U.S. Food and Drug Administration (FDA) for relapsed myeloma therapy in combination with dexamethasone.2 However, based on preclinical findings, lenalidomide was proposed to be a potentially effective treatment for lymphoma. With the preclinical work performed by Hernandez-Ilizaliturri et al3 and after approval of this agent by the FDA, Celgene initiated the lymphoma efforts. Lenalidomide was first studied as a single agent in non-Hodgkin lymphoma Dr. Wang is Professor, Department of Lymphoma/Myeloma, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.

my colleague, Dr. Liang Zhang, and I conducted preclinical experiments to test the activity of lenalidomide and rituximab in mantle cell lymphoma cell lines, primary mantle cell lymphoma cells, and mantle cell lymphoma–bearing patient-derived xenograft mice. The combination was shown to be effective preclinically, which led us to propose our phase I/II clinical trial testing the combination in patients with relapsed or refractory mantle cell lymphoma.5 It is somewhat funny that I missed the initial deadline to submit a letter of intent to Celgene; however, I believed strongly in our preclinical data and predicted that this combination would exceed the efficacy of the currently approved bortezomib (Velcade), which had a response rate of 33% in relapsed/refractory mantle cell lymphoma.6 Although my letter of intent was past due, Celgene provided me with a moderate budget for my first investigator-initiated trial. In this trial, we enrolled 52 patients, and in the phase II portion, with 44 patients, an overall response rate of 57% was obtained.5 These promising results led the MD Anderson Cancer Center to expand the testing of this combination to follicular lymphoma or chronic lymphocytic leukemia.

Front-Line Setting The trial by Ruan and colleagues quickly applied these findings in patients with relapsed or refractory mantle cell lymphoma to newly diagnosed patients

with mantle cell lymphoma. They conducted a multicenter phase II trial with 38 patients with induction/maintenance phases, closely following the same dosing and scheduling previously published for relapsed or refractory mantle cell lymphoma with minor modifications.1 At the median follow-up of 30 months, the overall response rate was 92%, with a complete response rate of 64%, and no unexpected adverse events. Strikingly, the 2-year progression-free survival among the patients with mantle cell lymphoma who received this initial combination was 85%, which is in marked contrast to the median progression-free survival of 16 to 35 months witnessed in patients with mantle cell lymphoma who received initial therapy consisting of chemotherapy.7 Furthermore and encouragingly, the patients who progressed on this treatment responded favorably to subsequent therapeutic regimens. Nevertheless, in this trial, grade 3 toxicities were still numerous, including neutropenia (50%), rash (29%), thrombocytopenia (13%), and pneumonia (8%),1 suggesting that lenalidomide still causes severe adverse events in the front-line setting and may not be the miracle drug that we hoped.

Ibrutinib-Based Combinations These results by Ruan and colleagues clearly demonstrate that treatment already shown to be effective in the relapsed/refractory setting should be tested in the front-line setting. We recently showed that the combination of ibrutinib (Imbruvica) and rituximab is efficacious in relapsed/refractory mantle cell lymphoma, with an overall response rate of 88% and a complete response rate of 40%.8 In support of this shift in the way mantle cell lymphoma is treated, we have opened two trials testing the combination of ibrutinib and rituximab in the front-line setting. First, we are testing the ibrutinib and rituximab combination as an initial treatment in older patients with mantle cell lymphoma (> 65 years of age) whose Ki67 levels are less than 50%; currently, 20 of 50 patients have been enrolled. Second, for younger patients (< 65 years of age), we designed the twopart Window protocol: ibrutinib and

rituximab followed by R-hyper-CVAD (rituximab plus hyper-cyclophosphamide, vincristine, doxorubicin, and dexamethasone) alternating with the regimen of rituximab plus methotrexate and cytarabine for fewer cycles if the patient demonstrates a good response in part 1. To date, for the Window study, 30 of 50 patients have been enrolled. These trials testing novel front-line treatment combinations are creating a shift in the treatment of mantle cell lymphoma. Starting with the auspicious efforts of Ruan and colleagues, multiple chemotherapy-free regimens for newly diagnosed patients with mantle cell lymphoma are on the verge of becoming standardized therapies. This is an exciting time in the treatment of mantle cell lymphoma—one in which we may be able to battle this disease successfully at the front line with multiple novel combinations of agents. n

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

References 1. Ruan J, et al: Lenalidomide plus rituximab as initial treatment for mantle-cell lymphoma. N Engl J Med 373:1835-1844, 2015. 2. Weber DM, et al: Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America. N Engl J Med 357:2133-2142, 2007. 3. Hernandez-Ilizaliturri FJ, et al: Immunomodulatory drug CC-5013 or CC4047 and rituximab enhance antitumor activity in a severe combined immunodeficient mouse lymphoma model. Clin Cancer Res 11:5984-5992, 2005. 4. Wiernik PH, et al: Lenalidomide monotherapy in relapsed or refractory aggressive non-Hodgkin’s lymphoma. J Clin Oncol 26:4952-4957, 2008. 5. Wang M, et al: Lenalidomide in combination with rituximab for patients with relapsed or refractory mantle-cell lymphoma. Lancet Oncol 13:716-723, 2012. 6. Fisher RI, et al: Multicenter phase II study of bortezomib in patients with relapsed or refractory mantle cell lymphoma. J Clin Oncol 24:4867-4874, 2006. 7. Howard OM, et al: Rituximab and CHOP induction therapy for newly diagnosed mantle-cell lymphoma. J Clin Oncol 20:1288-1294, 2002. 8. Wang ML, et al: Ibrutinib in combination with rituximab in relapsed or refractory mantle cell lymphoma. Lancet Oncol. November 27, 2015 (early release online).

Image not intended to depict total daily dose. Number of tablets may vary depending on prescribed dose. Tablets shown are not actual size.

Introducing

NOW APPROVED Please see Important Safety Information and brief summary of Prescribing Information on the following pages.

The ASCO Post | JANUARY 25, 2016

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Announcements LARGE TRIM: 8.125” BLEED:8.5”

New Society of Breast Imaging Website Seeks to End Confusion Surrounding Mammography Screening SMALL TRIM:7.875” SAFETY:6.875”

reast cancer is the second-leading cause of cancer deaths among women in the United States. In 2015, according to the National Cancer In-

stitute, 231,840 women were to be diagnosed with the disease and 40,290 were to die from it. The death rate is highest among women who are not

screened regularly and present with advanced cancers. Despite these data and the clear advantages of mammography as a key component of preventive

health care, many women are confused by widespread variance in guidelines on when and how frequently to get a mammogram.

NOW APPROVED Indication LONSURF® (trifluridine and tipiracil) is indicated for the treatment of patients with metastatic colorectal cancer who have been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF biological therapy, and if RAS wild type, an anti-EGFR therapy. Important Safety Information WARNINGS AND PRECAUTIONS Severe Myelosuppression: In Study 1, LONSURF caused severe and life-threatening myelosuppression (Grade 3-4) consisting of anemia (18%), neutropenia (38%), thrombocytopenia (5%), and febrile neutropenia (3.8%). One patient (0.2%) died due to neutropenic infection. In Study 1, 9.4% of LONSURF-treated patients received granulocyte-colony stimulating factors. Obtain complete blood counts prior to and on day 15 of each cycle of LONSURF and more frequently as clinically indicated. Withhold LONSURF for febrile neutropenia, Grade 4 neutropenia, or platelets less than 50,000/mm3. Upon recovery, resume LONSURF at a reduced dose. Embryo-Fetal Toxicity: LONSURF can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment with LONSURF. USE IN SPECIFIC POPULATIONS Lactation: It is not known whether LONSURF or its metabolites are present in human milk. There are no data to assess the effects of LONSURF or its metabolites on the breast-fed infant or the effects on milk production. Because of the potential for serious adverse reactions in breast-fed infants, advise women not to breast-feed during treatment with LONSURF and for 1 day following the final dose.

Male Contraception: Advise males with female partners of reproductive potential to use condoms during treatment with LONSURF and for at least 3 months after the final dose. Geriatric Use: Grade 3 or 4 neutropenia and thrombocytopenia and Grade 3 anemia occurred more commonly in patients 65 years or older who received LONSURF. Renal Impairment: Patients with moderate renal impairment may require dose modifications for increased toxicity. No patients with severe renal impairment were enrolled in Study 1. Hepatic Impairment: Patients with moderate or severe hepatic impairment were not enrolled in Study 1. ADVERSE REACTIONS Most Common Adverse Drug Reactions in Patients Treated With LONSURF (≥5%): The most common adverse drug reactions in LONSURF-treated patients vs placebo-treated patients with refractory mCRC, respectively, were asthenia/fatigue (52% vs 35%), nausea (48% vs 24%), decreased appetite (39% vs 29%), diarrhea (32% vs 12%), vomiting (28% vs 14%), abdominal pain (21% vs 18%), pyrexia (19% vs 14%), stomatitis (8% vs 6%), dysgeusia (7% vs 2%), and alopecia (7% vs 1%). Additional Important Adverse Drug Reactions: The following occurred more frequently in LONSURF-treated patients compared to placebo: infections (27% vs 15%) and pulmonary emboli (2% vs 0%). Interstitial lung disease (0.2%), including fatalities, has been reported in clinical studies and clinical practice settings in Asia. Laboratory Test Abnormalities in Patients Treated With LONSURF: Laboratory test abnormalities in LONSURF-treated patients vs placebo-treated patients with refractory mCRC, respectively, were anemia (77% vs 33%), neutropenia (67% vs 1%), and thrombocytopenia (42% vs 8%).

Please see brief summary of Prescribing Information on the following pages.

Learn more at LONSURFhcp.com/new

09/2015

LON-PM-US-0035

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Announcements LARGE TRIM: 8.125” BLEED:8.5”

To address this, the Society of Breast Imaging created End the Confusion, a campaign to inform and engage providers, stakeholders, and the public on the benefits of breast cancer screening. “I have read patient mammograms that detected cancers early, when treatment is most effective. I have patients who are alive today because they fol-

SMALL TRIM:7.875”

lowed the advice of respected organizations like the Society of Breast Imaging. Ultimately, this is the reason for End the Confusion; to save lives through early detection,” said Society of Breast Imaging President Elizabeth A. Morris, MD, FACR. End the Confusion hosts resources, including multimedia presentations,

SAFETY:6.875”

Elizabeth A. Morris, MD, FACR

LONSURF (trifluridine and tipiracil) tablets, for oral use Initial U.S. Approval: 2015 Brief Summary of Prescribing Information For complete Prescribing Information, consult official package insert.

Table 1 Per Patient Incidence of Adverse Drug Reactions (≥5%) in Study 1 Occurring More Commonly (>2%) than in Patients Receiving Placebo. LONSURF (N=533)

Adverse Reactions

All Grades

Placebo (N=265)

Grades 3-4* All Grades

1 INDICATIONS AND USAGE LONSURF is indicated for the treatment of patients with metastatic colorectal cancer who have been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF biological therapy, and if RAS wild-type, an anti-EGFR therapy.

Gastrointestinal disorders

4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Severe Myelosuppression In Study 1, LONSURF caused severe and life-threatening myelosuppression (Grade 3-4) consisting of anemia (18%), neutropenia (38%), thrombocytopenia (5%) and febrile neutropenia (3.8%). One patient (0.2%) died due to neutropenic infection. In Study 1, 9.4% of LONSURF-treated patients received granulocyte-colony stimulating factors.

General disorders and administration site conditions

Obtain complete blood counts prior to and on Day 15 of each cycle of LONSURF and more frequently as clinically indicated. Withhold LONSURF for febrile neutropenia, Grade 4 neutropenia, or platelets less than 50,000/mm3. Upon recovery resume LONSURF at a reduced dose. [see Dosage and Administration (2.2) in the full Prescribing Information] 5.2 Embryo-Fetal Toxicity Based on animal studies and its mechanism of action, LONSURF can cause fetal harm when administered to a pregnant woman. Trifluridine/tipiracil caused embryo-fetal lethality and embryo-fetal toxicity in pregnant rats when orally administered during gestation at dose levels resulting in exposures lower than those achieved at the recommended dose of 35 mg/m2 twice daily.

In Study 1, 3.6% of patients discontinued LONSURF for an adverse event and 13.7% of patients required a dose reduction. The most common adverse reactions leading to dose reduction were neutropenia, anemia, febrile neutropenia, fatigue, and diarrhea.

24%

32%

12%

<1%

Vomiting

28%

14%

<1%

Abdominal pain

21%

18%

Stomatitis

<1%

Asthenia/fatigue

52%

35%

Pyrexia

19%

14%

<1%

29%

Metabolism and nutrition disorders Decreased appetite

39%

Nervous system disorders Dysgeusia

Skin and subcutaneous tissue disorders Alopecia

*No Grade 4 definition for nausea, abdominal pain, or fatigue in National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.03.

Table 2 Laboratory Test Abnormalities LONSURF (N=533*) Laboratory Parameter

Placebo (N=265*)

Grade† All %

3 %

Grade† 4 %

All %

3 %

4 % N/A

Blood and lymphatic system disorders Anemia‡

N/A#

Neutropenia

Thrombocytopenia

*% based on number of patients with post-baseline samples, which may be less than 533 (LONSURF) or 265 (placebo) Terminology Criteria for Adverse Events (CTCAE), v4.03 ‡ Anemia: No Grade 4 definition for these laboratory parameters in CTCAE, v4.03 # One Grade 4 anemia adverse reaction based on clinical criteria was reported † Common

In Study 1, infections occurred more frequently in LONSURF-treated patients (27%) compared to those receiving placebo (15%). The most commonly reported infections which occurred more frequently in LONSURF-treated patients were nasopharyngitis (4% versus 2%), and urinary tract infections (4% versus 2%). In Study 1, pulmonary emboli occurred more frequently in LONSURFtreatment patients (2%) compared to no patients on placebo.

Additional Clinical Experience Interstitial lung disease was reported in fifteen (0.2%) patients, three of which were fatal, among approximately 7,000 patients exposed to LONSURF in clinical studies and clinical practice settings in Asia. 7 DRUG INTERACTIONS No pharmacokinetic drug-drug interaction studies have been conducted with LONSURF. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Based on animal data and its mechanism of action, LONSURF can cause fetal harm. LONSURF caused embryo-fetal lethality and embryo-fetal toxicity in pregnant rats when given during gestation at doses resulting in exposures lower than or similar to exposures at the recommended dose in humans. [see Data] There are no available data on LONSURF exposure in pregnant women. Advise pregnant women of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

LARGE TRIM: 10.875”

The most common adverse drug reactions or laboratory abnormalities (all Grades and greater than or equal to 10% in incidence) in patients treated with LONSURF at a rate that exceeds the rate in patients receiving placebo were anemia, neutropenia, asthenia/fatigue, nausea, thrombocytopenia, decreased appetite, diarrhea, vomiting, abdominal pain, and pyrexia.

48%

Diarrhea

BLEED:11.25”

The data described below are from Study 1, a randomized (2:1), doubleblind, placebo-controlled trial in which 533 patients (median age 63 years; 61% men; 57% White, 35% Asian, 1% Black) with previously treated metastatic colorectal cancer received LONSURF as a single agent at a dose of 35 mg/m2/dose administered twice daily on Days 1 through 5 and Days 8 through 12 of each 28-day cycle. The mean duration of LONSURF therapy was 12.7 weeks.

Nausea

SAFETY:9.5”

6 ADVERSE REACTIONS 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Grades 3-4*

SMALL TRIM:10.5”

LARGE TRIM: 10.875”

BLEED:11.25”

SAFETY:9.5”

SMALL TRIM:10.5”

Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment with LONSURF. [see Use in Specific Populations (8.1, 8.3), Clinical Pharmacology (12.1) in the full Prescribing Information]

fact sheets, and relevant articles. The site provides women with clear and accurate information on mammography screening so they are prepared to make informed decisions in partnership with their health-care providers. The End the Confusion website can be accessed at www.endtheconfusion. org. n

The ASCO Post | JANUARY 25, 2016

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NCCN Awards Research Grants to Five Investigators to Study Effectiveness of Enzalutamide in Various Cancers SMALL TRIM:7.875” SAFETY:6.875”

he National Comprehensive Cancer Network (NCCN) Oncology Research Program (ORP) has awarded five grants to investigators to evaluate and define the preclinical and clinical effective-

ness of enzalutamide (Xtandi) in mantle cell lymphoma and endometrial, hepatocellular, and prostate cancers. These grants are made possible through funding from Astellas Pharma, Inc. and Medivation, Inc.

8.7 Renal Impairment No dedicated clinical studies have been conducted to evaluate the effect of renal impairment on the pharmacokinetics of LONSURF. In Study 1, patients with moderate renal impairment (CLcr = 30 to 59 mL/min, n= 47) had a higher incidence (difference of at least 5%) of ≥ Grade 3 adverse events, serious adverse events, and dose delays and reductions compared to patients with normal renal function (CLcr ≥ 90 mL/min, n= 306) or patients with mild renal impairment (CLcr = 60 to 89 mL/min, n= 178). No dose adjustment to the starting dose of LONSURF is recommended in patients with mild or moderate renal impairment (CLcr of 30 to 89 mL/min); however patients with moderate renal impairment may require dose modification for increased toxicity. No patients with severe renal impairment (CLcr < 30 mL/min) were enrolled in Study 1. [ see Clinical Pharmacology (12.3) in the full Prescribing Information] 8.8 Ethnicity There were no clinically meaningful differences in Study 1 between Western and Asian subgroups with respect to overall incidence of adverse events or ≥ Grade 3 adverse events in either the LONSURF or placebo groups. 10 OVERDOSAGE The highest dose of LONSURF administered in clinical studies was 180 mg/m2 per day. There is no known antidote for LONSURF overdosage. 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Severe Myelosuppression: Advise the patient to immediately contact their healthcare provider if they experience signs or symptoms of infection and advise patients to keep all appointments for blood tests. [see Warnings and Precautions (5.1)]

Advise the patient that anyone else who handles their medication should wear gloves. [see References (15) in the full Prescribing Information] Embryo-Fetal Toxicity: Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment with LONSURF. [see Warnings and Precautions (5.2) and Use in Specific Populations (8.3)] Lactation: Advise women not to breastfeed during treatment with LONSURF and for one day following the final dose. [see Use in Specific Populations (8.2)] © TAIHO ONCOLOGY, INC. 09/2015

LARGE TRIM: 10.875”

Advise the patient to take LONSURF within 1 hour after eating their morning and evening meals. [see Dosage and Administration (2.1) in the full Prescribing Information]

BLEED:11.25”

Administration Instructions: Advise the patient that LONSURF is available in two strengths and they may receive both strength tablets to provide the prescribed dose. Advise the patient of the importance of reading prescription labels carefully and taking the appropriate number of tablets.

SAFETY:9.5”

Gastrointestinal toxicity: Advise patients to contact their healthcare provider for severe or persistent nausea, vomiting, diarrhea, or abdominal pain. [see Adverse Reactions (6.1)]

agent,” said Robert C. Young, MD, Interim Vice President, NCCN ORP. The following proposals have been awarded funding: • Albert Chang, MD, PhD UCSF Helen Diller Family Comprehensive Cancer Center “Phase II Trial of Dose Escalated Radiotherapy with Leuprolide and Enzalutamide in Patients with Very High Risk or Pelvic Node Positive Prostate Cancer” • Ajay Gopal, MD Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance “Androgen Receptor Targeting in Mantle Cell Lymphoma: A Pilot Phase II Trial of Enzalutamide” • James Harding, MD Memorial Sloan Kettering Cancer Center “A Multi-Center Phase I/II Study of Enzalutamide with and without Sorafenib in Advanced Hepatocellular Carcinoma Patients” • Gustavo Leone, PhD The Ohio State University Comprehensive Cancer Center–Arthur G. James Cancer Hospital and Richard J. Solove Research Institute “Evaluating the Efficacy of Enzalutamide Therapy in Preventing Tumor Progression in a Preclinical Mouse Model of Type 1 Endometrial Carcinoma” • Shannon Westin, MD, MPH The University of Texas MD Anderson Cancer Center “A Phase II Study with a Limited Safety Lead-In of Enzalutamide in Combination with Carboplatin and Paclitaxel in Advanced Stage or Recurrent Endometrial Cancer” The awardees responded to a Request for Proposals issued by the NCCN ORP to the 26 NCCN member institutions. Submissions were peer-reviewed by the NCCN Enzalutamide Scientific Review Committee. The funded concepts were selected based on several criteria, including scientific merit, existing data, and the types of studies necessary to further evaluate the efficacy of enzalutamide. The NCCN ORP draws on the expertise of the investigators of the NCCN member institutions and NCCN Affiliate Research Consortium to facilitate all phases of clinical research. This research is made possible by collaborations with pharmaceutical and biotechnology companies in order to advance therapeutic options for patients with cancer. For more information about NCCN ORP, visit NCCN.org/ORP. n SMALL TRIM:10.5”

Data Animal Data Trifluridine/tipiracil was administered orally once daily to female rats during organogenesis at dose levels of 15, 50, and 150 mg/kg [trifluridine (FTD) equivalent]. Decreased fetal weight was observed at FTD doses greater than or equal to 50 mg/kg (approximately 0.33 times the exposure at the clinical dose of 35 mg/m2 twice daily). At the FTD dose of 150 mg/kg (approximately 0.92 times the FTD exposure at the clinical dose of 35 mg/m2 twice daily) embryolethality and structural anomalies (kinked tail, cleft palate, ectrodactyly, anasarca, alterations in great vessels, and skeletal anomalies) were observed. 8.2 Lactation Risk Summary It is not known whether LONSURF or its metabolites are present in human milk. In nursing rats, trifluridine and tipiracil or their metabolites were present in breast milk. There are no data to assess the effects of LONSURF or its metabolites on the breastfed infant or the effects on milk production. Because of the potential for serious adverse reactions in breastfeeding infants, advise women not to breastfeed during treatment with LONSURF and for one day following the final dose. Data Radioactivity was excreted in the milk of nursing rats dosed with trifluridine/ tipiracil containing 14C-FTD or 14C-tipiracil (TPI). Levels of FTD-derived radioactivity were as high as approximately 50% of the exposure in maternal plasma an hour after dosing with trifluridine/tipiracil and were approximately the same as those in maternal plasma for up to 12 hours following dosing. Exposure to TPI-derived radioactivity was higher in milk than in maternal plasma beginning 2 hours after dosing and continuing for at least 12 hours following administration of trifuridine/tipiracil. 8.3 Females and Males of Reproductive Potential Contraception Females LONSURF can cause fetal harm when administered to a pregnant woman. [see Use in Specific Populations (8.1)] Advise females of reproductive potential to use effective contraception during treatment. Males Because of the potential for genotoxicity, advise males with female partners of reproductive potential to use condoms during treatment with LONSURF and for at least 3 months after the final dose. [see Nonclinical Toxicology (13.1) in the full Prescribing Information] 8.4 Pediatric Use Safety and effectiveness of LONSURF in pediatric patients have not been established. Animal Data Dental toxicity including whitening, breakage, and malocclusion (degeneration and disarrangement in the ameloblasts, papillary layer cells and odontoblasts) were observed in rats treated with trifluridine/tipiracil at doses greater than or equal to 50 mg/kg (approximately 0.33 times the exposure at the clinical dose of 35 mg/m2 twice daily). 8.5 Geriatric Use In Study 1, 533 patients received LONSURF; 44% were 65 years of age or over, while 7% were 75 and over. No overall differences in effectiveness were observed in patients 65 or older versus younger patients, and no adjustment is recommended for the starting dose of LONSURF based on age. Patients 65 years of age or older who received LONSURF had a higher incidence of the following compared to patients younger than 65 years: Grade 3 or 4 neutropenia (48% vs 30%), Grade 3 anemia (26% vs 12%), and Grade 3 or 4 thrombocytopenia (9% vs 2%). 8.6 Hepatic Impairment No dedicated clinical studies have been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of LONSURF. No dose adjustment is recommended for patients with mild hepatic impairment (total bilirubin (TB) less than or equal to the upper limit of normal (ULN) and AST greater than ULN or TB less than 1 to 1.5 times ULN and any AST). Patients with moderate (TB greater than 1.5 to 3 times ULN and any AST) or severe (TB greater than 3 times ULN and any AST) hepatic impairment were not enrolled in Study 1. [see Clinical Pharmacology (12.3) in the full Prescribing Information]

“These five studies selected through peer review represent an excellent mix of both clinical and preclinical projects, which will further elucidate the activity and utility of this important therapeutic

ASCOPost.com | JANUARY 25, 2016

PAGE 117

Journal Spotlight Hematology

Phase III Trial Shows Improved Progression-Free Survival With Ibrutinib vs Temsirolimus in Relapsed/Refractory Mantle Cell Lymphoma By Matthew Stenger

n a phase III trial reported in The Lancet and at the recent American Society of Hematology Annual Meeting and Exposition, Martin Dreyling, MD, of the European Mantle Cell Lymphoma Network, and colleagues found that ibrutinib (Im-

81% and 85%; histology was nonblastoid in 88% in both; and the risk group was low in 32% and 30%, intermediate in 47% and 49%, and high in 22% and 21%. The median number of previous lines of therapy was two in both groups, with 68% and 66% having one or two

Ibrutinib treatment resulted in significant improvement in progression-free survival and better tolerability vs temsirolimus in patients with relapsed or refractory mantle-cell lymphoma. These data lend further support to the positive benefit-risk ratio for ibrutinib in relapsed or refractory mantle-cell lymphoma. —Martin Dreyling, MD, and colleagues

bruvica) was associated with improved progression-free survival vs temsirolimus (Torisel) in patients with relapsed or refractory mantle cell lymphoma.1

Study Details In this open-label trial, 280 patients from 21 countries who had received at least one rituximab (Rituxan)-containing treatment were randomly assigned between December 2012 and November 2013 to receive oral ibrutinib at 560 mg daily (n = 139) or intravenous temsirolimus at 175 mg on days 1, 8, and 15 of cycle 1 and 75 mg on days 1, 8, and 15 of subsequent 21-day cycles (n = 141). The primary endpoint was progression-free survival assessed by masked independent review committee. The trial is ongoing. For the ibrutinib and temsirolimus groups: median age was 67 and 68 years; 72% and 77% of patients were male; 83% and 91% were white, and 12% and 4% were Asian. Almost all patients (99% in both groups) had an Eastern Cooperative Oncology Group performance status of 0 or 1. Disease stage was III in 12% and 10% and IV in

prior treatments; 74% and 67% had relapsed disease, and 26% and 33% had refractory disease.

Progression-Free Survival Median treatment duration was 14.4 months in the ibrutinib group vs 3.0 months in the temsirolimus group. After median follow-up of 20 months, median progression-free survival was 14.6 months (95% confidence interval [CI] = 10.4 months to not estimable) in the ibrutinib group vs 6.2 months (95% CI = 4.2–7.9 months) in the temsirolimus group (hazard ratio [HR] = 0.43, P < .0001). Hazard ratios consistently favored ibrutinib in subgroup analyses, although less of a benefit was observed among the 33 patients with blastoid histology. Two-year progression-free survival was 41% vs 7%.

Response Rate, Overall Survival Overall response rate on independent review was 72% vs 40% (P < .0001), including complete response in 19% vs 1%. At the time of data cutoff, median duration of response was not reached in the ibrutinib group vs 7.0 months in the temsirolimus group; response was ongoing in 59% of responders in the ibrutinib group. Median overall survival was not reached in the ibrutinib group vs 21.3 months in the temsirolimus group (HR = 0.76, P = .1324). A total of 23% of patients in the temsirolimus group crossed over to ibrutinib at progression. Overall, subsequent therapy was received by 32% of the ibrutinib group, with the most common treatments being rituximab (15%), bendamustine (Bendeka, Treanda; 11%), and cyclophosphamide (9%), and by 58% of patients in the temsirolimus group, with the most common being rituximab (26%), ibrutinib, bendamustine (16%), and cyclophosphamide (13%). One-year survival was 68% vs 61%. As assessed by the Functional Assessment of Cancer Therapy-Lymphoma questionnaire, clinically meaningful improvement in lymphoma symptoms was reported in 62% vs 35% of patients, with median time to improvement of 6.3 vs 57.3 weeks (P < .0001), and clinically meaningful worsening occurred in 27% vs 52%, with median time to worsening of not reached vs 9.7 weeks (P < .0001).

Adverse Events The most common adverse events of any grade in the ibrutinib group were diarrhea (29% vs 31%), cough

Ibrutinib vs Temsirolimus in Relapsed/Refractory Mantle Cell Lymphoma ■■ Ibrutinib significantly prolonged progression-free survival vs temsirolimus.

(22% vs 22%), and fatigue (22% vs 29%), and the most common in the temsirolimus group were thrombocytopenia (56% vs 18%), anemia (43% vs 18%), diarrhea, fatigue, neutropenia (26% vs 16%), epistaxis (24% vs 9%), cough, peripheral edema (22% vs 13%), nausea (22% vs 14%), pyrexia (21% vs 17%), and stomatitis (21% vs 3%). Grade ≥ 3 adverse events occurred in 68% of the ibrutinib group vs 87% of the temsirolimus group, including neutropenia in 13% vs 17%, thrombocytopenia in 9% vs 42%, anemia in 8% vs 20%, atrial fibrillation in 4% vs 1%, fatigue in 4% vs 7%, and diarrhea in 3% vs 4%. Major bleeding occurred in 10% vs 6%. New malignancies were observed in 4% vs 3%. Adverse events led to discontinuation of treatment in 6% vs 26%. During the first 6 months of treatment, 6% of patients in the ibrutinib group and 8% in the temsirolimus group had a treatment-emergent adverse event leading to death. The investigators concluded: “Ibrutinib treatment resulted in significant improvement in progression-free survival and better tolerability versus temsirolimus in patients with relapsed or refractory mantle-cell lymphoma. These data lend further support to the positive benefit-risk ratio for ibrutinib in relapsed or refractory mantle-cell lymphoma.” n

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

Reference 1. Dreyling M, Jurczak W, Jerkeman M, et al: Ibrutinib versus temsirolimus in patients with relapsed or refractory mantle-cell lymphoma: An international, randomised, open-label, phase 3 study. Lancet. December 7, 2015 (early release online). See commentary by Mitchell R. Smith, MD, PhD, on page 118.

■■ Ibrutinib treatment was better tolerated.

Visit The ASCO Post website at ASCOPost.com

The ASCO Post | JANUARY 25, 2016

PAGE 118

Perspective

Ibrutinib in Relapsed Mantle Cell Lymphoma By Mitchell R. Smith, MD, PhD

reatment of mantle cell lymphoma continues to evolve, both in the front-line and relapsed settings. Key advances include better use of established agents, such as the incorporation of high-dose cytarabine into initial induction regimens and application of rituximab (Rituxan) consolidation/ maintenance following response to initial therapy. More excitement has been generated by new, and now not so new, targeted agents with demonstrated activity in the relapsed setting. They are quickly being moved into earlier lines of therapy in combination with, or replacing, standard cytotoxic immunochemotherapy.

New Targeted Agents For patients with previously treated mantle cell lymphoma, there are now four approved drugs, including bortezomib (Velcade), lenalidomide (Revlimid), and ibrutinib (Imbruvica) in the United States and ibrutinib and temsirolimus (Torisel) in Europe. The proteasome inhibitor bortezomib was approved almost a decade ago as treatment for relapsed or refractory mantle cell lymphoma based on the single-arm phase II PINNACLE trial, demonstrating an overall response rate of 33%, median time to progression of 6 months, and median duration of response of 9 months. The immune-modulatory agent lenalidomide was approved for treatment of bortezomib-exposed mantle cell lymphoma patients based on the single-arm phase II EMERGE trial, with a response rate of 28%, median time to progression of 4 months, but median duration of response of 17 months. The mTOR inhibitor temsirolimus was approved in Europe based on the randomized three-arm phase III trial of temsirolimus at two different doses vs investigator’s choice of single-agent chemotherapy. In that study, temsirolimus was administered weekly at 175 mg for 3 weeks, then weekly at either 25 mg or 75 mg. In the 175/75 cohort, the response rate was 22%, median progression-free survival was 5 months, and median duration of response was 5 months. Dr. Smith is Director, Lymphoid Malignancy Program, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio.

Most recently, the Bruton tyrosine kinase inhibitor ibrutinib has been approved for relapsed/refractory mantle cell lymphoma based on a single-arm phase Ib/II trial, with a response rate

For the primary endpoint, median progression-free survival was 14.6 vs 6.2 months. Median duration of response was not yet reached for ibrutinib; response of ≥ 18 months occurred

Ibrutinib is a marvelous addition to mantle cell lymphoma treatment options. There remains room for improvement, however, as mantle cell lymphoma in one of three patients does not respond to ibrutinib, and with median follow-up of 20 months fewer than 50% of patients remain on ibrutinib therapy. —Mitchell R. Smith, MD, PhD

of 67%, median progression-free survival of 14 months, and median duration of response of 18 months. These trial outcomes cannot be directly compared given differences in patient populations, including age and number and types of prior therapy, but certainly the sense is that the ibrutinib response rates and duration were superior to those of the other agents.

Phase III Study of Ibrutinib vs Temsirolimus As summarized in this issue of The ASCO Post, Dreyling and colleagues recently reported the first phase III randomized trial comparing any of these approved single agents in relapsed or refractory mantle cell lymphoma—in this case, the two approved in Europe, ibrutinib and temsirolimus.1 The study enrolled patients with mantle cell lymphoma who had received at least one prior rituximab-chemotherapy regimen (median number of prior regimens was two). Notable strengths of the study include the phase III design and the international cooperation and rapid accrual (280 patients in < 1 year), making this a contemporary trial. The median age of 68 years suggests a “real-world” patient cohort, although all had an Eastern Cooperative Oncology Group performance status of 0 or 1. Central review of pathology was another vital component. The response rate was 72% with ibrutinib vs 40% with temsirolimus.

in 58% of ibrutinib responders vs 20% of temsirolimus responders. An important component of this study was acquisition of patient-reported outcomes on the Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) scale, demonstrating faster and more marked improvement with ibrutinib treatment. Thus, the improved outcomes with ibrutinib, assessed as response rate, progression-free survival, and duration of response, also improve quality of life.

Key Implications These data clearly support the already generally accepted concept of ibrutinib as the better choice for therapy in patients with previously treated mantle cell lymphoma. Although not surprising, the results of this trial are important, since phase III trials do not always confirm early-phase data in terms of efficacy or toxicity. It is comforting that in this study the response, progression-free survival, and duration of response outcomes in the ibrutinib group closely match the phase Ib/II data, and no new safety signals were observed. Further, the FACT-Lym data are new. We should also not ignore the temsirolimus data, since a 40% response rate in a rigorously designed and executed phase III trial represents significant activity in 139 patients (only 54 patients were treated with this temsirolimus dose in the trial leading to approval in this setting). This implicates

PI3K/AKT/mTOR as useful targets in mantle cell lymphoma, as new agents affecting this pathway reach the clinic. There are other bits of informative data in this report. Importantly, patients with mantle cell lymphoma or chronic lymphocytic leukemia (CLL) who came off or “failed” ibrutinib in early studies have very poor outcomes, with survival measured in months and concerns for aggressive disease such as Richter’s transformation in CLL and blastoid mantle cell lymphoma. Whether this was due to the heavy pretreatment in patients in those studies or some biologic selection for aggressive clones has not been clear. Supplementary data (Figure 3) in the Dreyling et al report demonstrate encouraging second progression-free survival (ie, time from the start of therapy to progression after the next therapy) in the ibrutinib group, which exceeded that observed in the temsirolimus group. This finding suggests that ibrutinib “failure” does not necessarily confer dismal prognosis in this perhaps less heavily pretreated population. In addition, subgroup analysis, though with small numbers, suggests that patients with blastoid mantle cell lymphoma remain an unmet need, having poor outcomes even with ibrutinib. Note that presumably they were blastoid at diagnosis, as we have disappointingly few data on serial biopsies of mantle cell lymphoma; such data will become very important to collect as patients cycle through different targeted therapies. Ibrutinib is a marvelous addition to mantle cell lymphoma treatment options. There remains room for improvement, however, as mantle cell lymphoma in one of three patients does not respond to ibrutinib, and with median follow-up of 20 months fewer than 50% of patients remain on ibrutinib therapy. We await additional data on combination regimens in the relapsed as well as front-line settings. n

Disclosure: Dr. Smith has received research support from Abbvie and is on the advisory boards of Celgene, Genentech, and Seattle Genetics.

ASCOPost.com | JANUARY 25, 2016

PAGE 119

Journal Spotlight

Study Reveals Potential Therapy Targets for Triple-Negative Breast Cancer

multi-institutional international investigation led by scientists at The University of Texas MD Anderson Cancer Center, Houston, has revealed new information about how molecules called long noncoding

ing therapeutic treatment targets.” The team identified an lncRNA known as LINK-A, which activates HIF-1 signaling in triple-negative breast cancer. “Our study delineates an lncRNAprotein kinase module that regulates

HIF-1,” said Dr. Yang. “The LINK-A–dependent HIF-1 signalizing cascade and the consequent effects on cancer cells implicate LINK-A and LINK-A–interacting kinases and receptors as promising therapeutic targets for triple-negative

breast cancer,” he concluded. n Reference 1. Lin A, Li C, Xing Z, et al: The LINKA lncRNA activates normoxic HIFα signaling in triple-negative breast cancer. Nat Cell Biol. January 11, 2016 (early release online).

In EGFRm+ advanced NSCLC,

NEARLY 2 OUT OF 3 CASES OF PROGRESSION WITH FIRSTGENERATION EGFR TKIs ARE RELATED TO THE T790M MUTATION1,2 Liuqing Yang, PhD

RNAs (lncRNA) interact with HIF1, a signaling pathway that is overexpressed in many cancers. HIF-1 has been shown to regulate breast cancer progression.

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

Need for Biomarkers and Therapeutic Targets

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

The team’s findings, published by Lin et al in Nature Cell Biology,1 explored the role of HIF-1 in triplenegative breast cancer. The study analyzed data from The Cancer Genome Atlas, a research program supported by the National Cancer Institute and National Human Genome Research Institute within the National Institutes of Health that is looking at genomic changes in more than 20 different types of cancer. “Triple-negative breast cancer continues to be a severe health problem, demanding the consideration of emerging long noncoding RNAs as biomarkers and therapeutic targets in combating this disease,” said L iuqing Yang, PhD, Assistant Professor in the Department of Molecular & Cellular Oncology. Dr. Yang and coauthor Chunru Lin, PhD, confirmed four sites for phosphorylation, impacting key cellular functions.

The majority of tumors will acquire EGFR TKI–resistance mutations

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%)

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

LINK-A Pathway

AstraZeneca is a leader in lung cancer research

“Our study identified four previously unknown phosphorylation sites in a LINK-A–regulated signaling pathway,” said Dr. Lin. “These events predict a worse outcome in patients with triple-negative breast cancer, suggesting that the LINK-A pathway plays a critical role in this disease and may provide wide-rang-

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 | JANUARY 25, 2016

PAGE 120

Integrative Oncology Acupuncture for Cancer Symptom Clusters By Lora M. A. Thompson, PhD, and Peter A. S. Johnstone, MD, FACR

cupuncture has been practiced for thousands of years in Eastern Asian cultures as a component of traditional Chinese medicine.1 In the United States, acupuncture became known to the public as a complementary and alternative medicine technique in the 1970s, but it took many years before it was recognized as a legitimate health practice. Events that moved the field of acupuncture forward were the reclassification of acupuncture needles as medical devices by the U.S. Food and Drug Administration in 19962 and the release of the National Institute of Health (NIH) consensus statement in 1997 declaring that sufficient evidence was available to support the usefulness of acupuncture as a therapeutic intervention.3 Acupuncture is increasingly integrated into conventional health practice. According to the most recent National Health Interview Survey (NHIS), the use of acupuncture among U.S. adults rose significantly from 2002 to 2012.4 NHIS data also suggested that individuals with cancer are more likely to have used a complementary and alternative medicine technique, such as acupuncture, than individuals without cancer.5 Acupuncture rates among patients with cancer are estimated to be as high as 17%, based on a review of studies published in English.6 Patients with cancer often experience multiple concurrent physical and emotional symptoms. Interventions are needed to manage these symptoms and to improve patients’ quality of life. This article provides an introduction to the use of acupuncture in cancer symptom management and its potential use as a treatment for symptom clusters.

Acupuncture Research Research on the use of acupuncture to treat cancer-related symptoms is relatively new, and early studies suffered from a number of limitations, such as a small sample size; lack of a control group; and failure to report methodologic details, including the style of acupuncture (eg, traditional Chinese medicine, Korean), needling procedures, the frequency and duration of treatment, or the provider’s training.3,7,8 To date, the Dr. Thompson is Director of Integrative Medicine and Dr. Johnstone is a radiation oncologist at H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.

design of an appropriate placebo control group remains a challenge, as acupuncture providers cannot be blinded and sham procedures themselves may have a therapeutic effect.9,10 Sham needling involves placement of a sham needle, which does not pierce the skin, or placement of a penetrating needle at a site on the body that is an incorrect point or a nonacupuncture point.11 The placebo effect is well documented in medical and psychological research,12 and it is also a known factor affecting acupuncture clinical trials.13,14 For example, Bao et al found that patients with breast cancer treated with an aromatase inhibitor reported reductions in hot flashes after receiving either real or sham acupuncture treatment for

ous, and evidence has slowly accumulated to support the use of acupuncture for treatment of specific cancer-related symptoms such as pain,16,17 nausea,18 and hot flashes.19,20

Evidenced-Based Guidelines for Clinical Practice Integrative medicine is a treatment approach that incorporates “nonmainstream” complementary health practices into conventional health care.21 In 2007, the Society for Integrative Oncology convened a group of experts in integrative medicine and oncology to review the evidence on integrative health techniques and to develop clinical guidelines for the use of these techniques in patients with cancer.22

Acupuncture is safe for most patients, and growing evidence demonstrates its potential effectiveness as an adjunct intervention. Further integration of practitioners trained in traditional Chinese medicine into mainstream cancer care will open new doors to cross-cutting symptom management in our patients. —Lora M. A. Thompson, PhD, and Peter A. S. Johnstone, MD, FACR

8 weeks.13 One possible explanation for the placebo effect is response expectancy, or the belief that an intervention will have the desired effect. In a randomized controlled trial of women receiving electroacupuncture or sham acupuncture for treatment of aromatase inhibitor–related joint pain, Bauml and colleagues found that pain relief was moderated by response expectancy.15 Although pain relief between the two groups was similar, in the sham acupuncture group, only women who expected acupuncture to be effective reported clinically significant pain relief. Clinically significant pain relief experienced by women in the electroacupuncture group was unrelated to response expectancy. Clinical trials are increasingly rigor-

The consensus for acupuncture was that it is safe for use in oncology when conducted by a trained provider. It can be recommended as a complementary treatment for radiation-induced xerostomia and inadequately controlled cancer-related symptoms, including pain, chemotherapy-induced neuropathy, postoperative nausea and vomiting, chemotherapy-related nausea and vomiting, severe hot flashes, dyspnea, and fatigue. The guidelines caution against the use of acupuncture in individuals with hematologic conditions (eg, neutropenia, thrombocytopenia), in tumor sites, or in limbs affected by lymphedema. More recently, disease-specific guidelines for the use of acupuncture have been published for patients with

lung cancer23 and patients with breast cancer.24 These guidelines are generally consistent with the original guidelines. To date, however, these guidelines provide recommendations for treatment of individual symptoms.

Cancer Symptom Clusters Patients with cancer often experience multiple symptoms related to the disease process or its treatment. Findings from a review of 18 studies by Esther Kim indicated that fatigue, dry mouth, insomnia, drowsiness, mood disturbance, and pain were the most common symptoms experienced by patients with cancer during treatment.25 Further, more than five concurrent symptoms were experienced by 22% to 30% of the patients. The concept of cancer symptom clusters, first introduced by Dodd et al in 2001,26 is defined as the cooccurrence of two or more related symptoms.27 Clusters may occur if symptoms share a similar etiology (eg, circadian-signaling inhibition resulting in sleep disruption, fatigue, and poor appetite28), if one symptom causes or worsens another symptom (eg, uncontrolled worrying leads to inability to sleep), or if the treatment of one symptom causes a new symptom (eg, opioid management of pain causes fatigue).29,30 Although there is no consensus as to which symptoms constitute a particular symptom cluster, several studies have identified similar co-occurring symptoms, such as pain/fatigue/sleep,31-33 depression/anxiety,33-35 nausea/vomiting,36,37 dyspnea/cough/fatigue,38 and weight/food intake.33,34 The presence of multiple concurrent symptoms may increase the symptom burden and may have a greater negative effect on functional status,39 psychological well-being,33,40 and quality of life40,41 than do individual symptoms.25

Acupuncture Treatment of Symptom Clusters There are obvious benefits to treating cancer symptom clusters with a single intervention. This approach has the potential to reduce polypharmacy and drug interactions, decrease the risk of side effects, and reduce the cost of treatment to the patient.29,30,42 A critical understanding of the potential role of acupuncture under these circumstances is to understand that its effect may be general as well as specific. For example, the Ming Men ap-

ASCOPost.com | JANUARY 25, 2016

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Integrative Oncology proach targets acupuncture points in the lower torso to strengthen Qi (“vital energy” in traditional Chinese medicine). Stimulation of these acupuncture points for fatigue in patients with breast cancer may also reduce distress from hot flashes. In traditional Chinese medicine, hot flashes may be described as “kidney water exhausted,”43 signifying a deficiency as the cause for hot flashes; for this diagnosis, there are many potentially logical acupuncture points and treatment regimens. Use of the Ming Men technique to treat hot flashes will also relax and energize patients because it engages acupuncture points associated with various traditional Chinese medicine organ systems, including the kidneys, lungs, and triple burner [the flow of energy through all 12 vital organs]. We have published objective responses in both hot flashes and sleep in patients with breast cancer.44 Unique to this study was the use of a cadre of community acupuncturists selecting acupuncture points they considered appropriate given each patient’s unique symptom constellation. Oddly to the Western-trained physician, of the 38 points used in the study, 70% of treatments involved the acupoint Lu (lung) unilaterally on the left. This properly points out the vast differences in perspective between traditional Chinese medicine practitioners and physicians— even physician acupuncturists. Those trained in traditional Chinese medicine are far more informed on the lore and artistic nature of the craft than those of us who are not, who tend to think practically in terms of points and effects.

Study Findings Although no published studies have examined cancer symptom clusters as

a primary outcome, studies have been conducted to evaluate the effect of acupuncture on multiple symptoms.25 For example, in 2013, Kasymjanova et al conducted an observational study of 33 patients with lung cancer who received at least four sessions of acupuncture for symptom control.45 Significant improvements were seen in pain, nausea, appetite, nervousness, and well-being. In an observational study by DeanClower et al in 2010, 26 women with advanced gynecologic or breast cancer completed up to 8 weeks of acupuncture treatment.46 Among those who reported baseline symptoms, the severity of anxiety, depression, fatigue, and pain decreased over the course of the acupuncture treatment. In 2014, Garcia and colleagues conducted a study in which patients with cancer patients who had uncontrolled pain participated in up to 10 sessions of acupuncture with or without electrical stimulation.47 Acupuncture points were selected by the provider based on patients’ pain location, pain type, other symptoms, and medical history. Patients completed measures assessing the severity of pain and other cancerrelated symptoms as well as the extent to which these symptoms interfered with daily activities. In addition to significant reductions in pain, patients also reported improved overall quality of life and less symptom interference. In a pragmatic controlled trial conducted in 2012, Molassiotis et al randomized patients with breast cancer to 6 weeks of acupuncture or usual care (ie, educational booklet on fatigue) for the treatment of cancer-related fatigue.48 The acupuncture intervention targeted three acupuncture points to

GUEST EDITOR

ntegrative Oncology is guest edited by Barrie R. Cassileth, MS, PhD, Former Chief of the Integrative Medicine Service and Former Laurance S. Rockefeller Chair in Integrative Medicine at Memorial Sloan Kettering Cancer Center, New York. The Integrative Medicine Service at Memorial Sloan Kettering Cancer Center developed and Barrie R. Cassileth, MS, PhD maintains a free website—About Herbs (www. mskcc.org/aboutherbs)—that provides objective and unbiased information about herbs, vitamins, minerals, and other dietary supplements, and unproved anticancer treatments. Each of the close to 300 and growing number of entries offers health-care professional and patient versions, and entries are regularly updated with the latest research findings. In addition, the About Herbs app, Memorial Sloan Kettering Cancer Center’s very first mobile application, can be downloaded at http://itunes.apple. com/us/app/about-herbs/id554267162?mt=8. The app is compatible with iPad, iPhone, and iPod Touch devices. treat fatigue, and providers choose two substitute points if the target points could not be accessed. In addition to improvement in the primary outcome of fatigue, women also reported improvement in physical and emotional well-being.

Closing Thoughts Oncologists should be alert to the potential of acupuncture to relieve cancer-related symptom clusters. Acupuncture is safe for most patients, and growing evidence demonstrates its potential effectiveness as an adjunct intervention. Research into the role of response expectancy is ongoing and should inform the true role of “placebo” across all interventions, including radiotherapy and chemotherapy. Further integration of practitioners trained in traditional Chinese medicine into

mainstream cancer care will open new doors to cross-cutting symptom management in our patients. n

Disclosure: Drs. Thompson and Johnstone reported no potential conflicts of interest.

References 1. Lu DP, Lu GP: An historical review and perspective on the impact of acupuncture on U.S. medicine and society. Med Acupunct 25:311-316, 2013. 2. U.S. Food and Drug Administration: CFR - Code of Federal Regulations Title 21. Available at https://www.accessdata.fda. gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch. cfm. Accessed October 1, 2015. 3. NIH Consensus Conference: Acupuncture. JAMA 280:1518-1524, 1998. 4. Clarke TC, Black LI, Stussman BJ, et al: Trends in the use of complementary health approaches among adults: United continued on page 124

Learn More About

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

www.mskcc.org/aboutherbs

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PV STATE OF

MIND

Polycythemia vera:

Emerging diagnostic and risk stratiﬁcation criteria

Polycythemia vera (PV) is a myeloproliferative neoplasm (MPN) that reduces overall life expectancy, primarily by hemostatic complications, including thrombosis, and development of secondary malignancies.1,2 Conventional models are designed to assess the risk for thrombotic complications3 but do not provide hematologists and oncologists the ability to predict disease progression, hematologic transformation, or overall survival. New models are being explored that reﬂect our updated understanding of risk factors, integrate more molecular data, and provide a more accurate prognosis.4-6

Diagnosis may evolve to address a new element of risk

Assessing risk

PV is a Philadelphia chromosome–negative MPN. Erythrocytosis is the hallmark of PV and is associated with increased thrombotic events, the primary factor in morbidity and mortality.9,10 Most patients with PV are diagnosed by chance during a routine blood testing, after a thrombotic event, or upon presenting with a diseaserelated symptom.11 7,8

The diagnosis and risk assessment of PV are evolving fields, and investigations into risk factors may inspire significant changes. Current diagnostic criteria for PV include hemoglobin (Hb) levels >18.5 g/dL in men and >16.5 g/dL in women7,8 or hematocrit (Hct) levels >52% in men and >48% in women.12 Revisions to the World Health Organization (WHO) diagnostic criteria have been proposed that include lower Hb thresholds (>16.5 g/dL in men, >16 g/dL in women) and lower Hct thresholds (>49% in men, >48% in women).13 These lower cutoffs may help establish a diagnosis of PV in individuals with borderline Hb and Hct test results despite an elevated red cell mass masked by plasma volume expansion. Published literature suggests that some patients with PV have Hb and Hct values below current cutoffs.14

The conventional risk factors of age and thrombotic history estimate the risk for thrombosis to help determine the therapeutic approach.5,15 In the landmark European Collaboration on Low-Dose Aspirin in Polycythemia Vera (ECLAP) observational study, age ≥65 years and a thrombotic event before recruitment each doubled the rate of thrombotic events; the rate of events was approximately 4-fold higher in patients with both criteria.16 Studies have examined factors that may predict not only thrombosis but also other outcomes, including disease complications, hematologic transformation, and overall survival. These investigational risk factors raise the question of whether thrombosis per se is the only relevant outcome in PV or whether we now have the tools to construct models that can reliably predict survival as well (Table 1).4,5,17 Table 1: Potential Risk Factors That May Predict Complications in PV 18-25

• Erythrocytosis

• Thrombocytosis

• Leukocytosis

• Hydroxyurea resistance

• Mutational profile

Paid Advertisement

This article, sponsored by Incyte Corporation, is based on a paid interview with

Rami S. Komrokji, MD,

of Moffitt Cancer Center, Tampa, Florida, conducted on May 4, 2015.

Building prognostic models that predict outcomes

References: 1. Passamonti F et al. Am J Med. 2004;117(10): 755-761. 2. Falanga A et al. Hematology Am Soc Hematol Educ Program. 2012;2012:571-581. 3. Tefferi A et al. Am J Hematol. 2015;90(2):163-173. 4. Tefferi A et al. Leukemia. 2013;27(9):1874-1881. 5. Passamonti F et al. Best Pract Res Clin Haematol. 2014;27(2):121-127. 6. Alvarez-Larrán A et al. Am J Hematol. 2014;89(5): 517-523. 7. Vardiman JW et al. Blood. 2009;114(5): 937-951. 8. Tefferi A et al. Leukemia. 2008;22(1):14-22. 9. Tefferi A et al. Semin Hematol. 2005;42(4):206-220. 10. Falanga A et al. Semin Thromb Hemost. 2014;40(3): 348-358. 11. Passamonti F. Blood. 2012;120(2):275-284. 12. McMullin MF et al. Br J Haematol. 2007;138(6): 821-822. 13. Tefferi A et al. Leukemia. 2014;28(7): 1407-1413. 14. Barbui T et al. Am J Hematol. 2014;89(2):199-202. 15. Tefferi A et al. [Article published online April 14, 2015]. Am J Hematol. doi:10.1002/ajh.24037. 16. Marchioli R et al. J Clin Oncol. 2005;23:2224-2232. 17. Stein BL et al. J Natl Compr Canc Netw. 2015;13(4):424-434. 18. Marchioli R et al. N Engl J Med. 2013;368(1):22-33. 19. Landolfi R et al. Blood. 2007;109(6):2446-2452. 20. Gangat N et al. Br J Haematol. 2007;138(3):354-358. 21. Chou YS et al. Eur J Haematol. 2013;90(3):228-236. 22. Passamonti F et al. Leukemia. 2010;24(9):1574-1579. 23. Vannucchi AM et al. Leukemia. 2007;21(9):1952-1959. 24. Takata Y et al. [Article published online November 11, 2013]. Kurume Med J. 2014;60(3-4):89-97. 25. Alvarez-Larrán A et al. Blood. 2012;119(6):1363-1369. 26. Barosi G et al. Br J Haematol. 2009;148(6):961-963. 27. Barbui T et al. J Clin Oncol. 2011;29(6):761-770.

The Cytoreductive Therapy in Polycythemia Vera (CYTO-PV) trial demonstrated that an Hct level >45% was associated with an increased rate of death from cardiovascular causes or major thrombotic events.18 More recently, several investigators have explored the possibility that other factors, including leukocytosis,19-21 mutational profile (especially the presence and burden of the JAK2V617F mutation),6,22-24 and abnormal karyotype,4,13 may also be predictive of thrombohemorrhagic complications and shortened survival. In a retrospective analysis, Alvarez-Larrán et al demonstrated that resistance to hydroxyurea (HU) is a highly significant risk factor in PV, increasing risk for death 5.6-fold and increasing risk for transformation to acute myelogenous leukemia or myelofibrosis by a factor of 6.8.25 Resistance may take various forms: failure to maintain Hct <45% with excessive phlebotomies, failure to control platelet count >400 × 109/L and white blood cell count >10 × 109/L, or failure to control splenomegaly or its related symptoms.26,27 New models are evolving that include these and other factors to better predict clinical outcomes. It may be that more than one model is needed to capture thrombotic risk, disease progression, and overall survival.

Essential updates

Hematologists are actively working to update diagnostic and risk stratification criteria in PV. Proposed diagnostic criteria may, in some cases, identify patients with borderline red cell parameters who may be at increased risk for thrombotic events. Although standard risk factors of age and vascular history will maintain their significance, new models are being evaluated that will hopefully improve patient care and outcomes in this challenging cancer.

Dr Komrokji was compensated for his participation in this interview. He has also received clinical research funding from and served as a consultant for Incyte Corporation (Wilmington, DE).

Download the full article at PVStateOfMind.com Brought to you by Incyte Corporation

The ASCO Post | JANUARY 25, 2016

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Integrative Oncology Acupuncture continued from page 121

States, 2002-2012. Natl Health Stat Report 79:1-16, 2015. 5. Anderson JG, Taylor AG: Use of complementary therapies by individuals with or at risk for cardiovascular disease: Results of the 2007 National Health Interview Survey. J Cardiovasc Nurs 27:96-102, 2012. 6. Carmady B, Smith CA: Use of Chinese medicine by cancer patients: A review of surveys. Chin Med 6:22, 2011. 7. Lian WL, Pan MQ, Zhou DH, et al: Effectiveness of acupuncture for palliative care in cancer patients: A systematic review. Chin J Integr Med 20:136-147, 2014. 8. MacPherson H, Thomas K, Walters S, et al: A prospective survey of adverse events and treatment reactions following 34,000 consultations with professional acupuncturists. Acupunct Med 19:93-102, 2001. 9. Haddad NE, Palesh O: Acupuncture in the treatment of cancer-related psychological symptoms. Integr Cancer Ther 13:371-385, 2014. 10. Moffet HH: Sham acupuncture may be as efficacious as true acupuncture: A systematic review of clincial trials. J Altern Complement Med 15:213-216, 2009. 11. Langevin HM, Wayne PM, MacPherson H, et al: Paradoxes in acupuncture research: Strategies for moving forward. Evid Based Complement Alternat Med 2011:180805, 2011. 12. Colagiuri B, Schenk LA, Kessler MD, et al: The placebo effect: From concepts to genes. Neuroscience 307:171-190, 2015. 13. Bao T, Cai L, Snyder C, et al: Patientreported outcomes in women with breast cancer enrolled in a dual-center, double-

blind, randomized controlled trial assessing the effect of acupuncture in reducing aromatase inhibitor-induced musculoskeletal symptoms. Cancer 120:381-389, 2014. 14. Rostock M, Jaroslawski K, Guethlin C, et al: Chemotherapy-induced peripheral neuropathy in cancer patients: A four-arm randomized trial on the effectiveness of electroacupuncture. Evid Based Complement Alternat Med 2013:349653, 2013. 15. Bauml J, Xie SX, Farrar JT, et al: Expectancy in real and sham electroacupuncture: Does believing make it so? J Natl Cancer Inst Monogr 2014:302-307, 2014. 16. Alimi D, Rubino C, Pichard-Léandri E, et al: Analgesic effect of auricular acupuncture for cancer pain: A randomized, blinded, controlled trial. J Clin Oncol 21:4120-4126, 2003. 17. Garcia MK, McQuade J, Lee R, et al: Acupuncture for symptom management in cancer care: An update. Curr Oncol Rep 16:418, 2014. 18. Ezzo JM, Richardson MA, Vickers A, et al: Acupuncture-point stimulation for chemotherapy-induced nausea or vomiting. Cochrane Database Syst Rev Apr 19(2):CD002285, 2006. 19. Frisk J, Spetz AC, Hjertberg H, et al: Two modes of acupuncture as a treatment for hot flushes in men with prostate cancer—A prospective multicenter study with long-term follow-up. Eur Urol 55:156163, 2009. 20. Walker EM, Rodriguez AI, Kohn B, et al: Acupuncture versus venlafaxine for the management of vasomotor symptoms in patients with hormone receptor-positive breast cancer: A randomized controlled trial. J Clin Oncol 28:634-640, 2010. 21. National Center for Complementary

and Integrative Health: What is complementary, alternative, or integrative health? Available at https://nccih.nih.gov/health/ integrative-health. Accessed October 17, 2015. 22. Deng GE, Frenkel M, Cohen L, et al: Evidence-based clinical practice guidelines for integrative oncology: Ceomplementary therapies and botanicals. J Soc Integr Oncol 7:85-120, 2009. 23. Deng GE, Rausch SM, Jones LW, et al: Complementary therapies and integrative medicine in lung cancer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidencebased clinical practice guidelines. Chest 143:e420S-e436S, 2013. 24. Greenlee H, Balneaves LG, Carlson LE, et al: Clinical practice guidelines on the use of integrative therapies as supportive care in patients treated for breast cancer. J Natl Cancer Inst Monogr 2014:346-358, 2014. 25. Esther Kim JE, Dodd MJ, Aouizerat BE, et al: A review of the prevalence and impact of multiple symptoms in oncology patients. J Pain Symptom Manag 37:715736, 2009. 26. Dodd M, Janson S, Facione N, et al: Advancing the science of symptom management. J Adv Nurs 33:668-676, 2001. 27. Kim HJ, McGuire DB, Tulman L, et al: Symptom clusters: Concept analysis and clinical implications for cancer nursing. Cancer Nurs 28:270-282, 2005. 28. Rich TA: Analyzing the symptoms in cancer patients: Disrupted circadian signaling by the epidermal growth factor receptor. IEEE Eng Med Biol Mag 27:25-28, 2008. 29. Kwekkeboom KL, Cherwin CH, Lee JW, et al: Mind-body treatments for the pain-fatigue-sleep disturbance symptom cluster in persons with cancer. J Pain Symptom Manage 39:126-138, 2010. 30. Williams LA: Clinical management of symptom clusters. Semin Oncol Nurs 23:113-120, 2007. 31. Beck SL, Dudley WN, Barsevick A: Pain, sleep disturbance, and fatigue in patients with cancer: Using a mediation model to test a symptom cluster. Oncol Nurs Forum 32:542, 2005. 32. Hoffman AJ, Given BA, von Eye A, et al: Relationships among pain, fatigue, insomnia, and gender in persons with lung cancer. Oncol Nurs Forum 34:785-792, 2007. 33. Thomas BC, Waller A, Malhi RL, et al: A longitudinal analysis of symptom clusters in cancer patients and their sociodemographic predictors. J Pain Symptom Manage 47:566-578, 2014. 34. Breen SJ, Baravelli CM, Schofield PE, et al: Is symptom burden a predictor of anxiety and depression in patients with cancer about to commence chemotherapy?

Med J Aust 190:S99-S104, 2009. 35. Chow E, Fan G, Hadi S, et al: Symptom clusters in cancer patients with bone metastases. Support Care Cancer 15:10351043, 2007. 36. Aktas A, Walsh D, Hu B: Cancer symptom clusters: An exploratory analysis of eight statistical techniques. J Pain Symptom Manage 48:1254-1266, 2014. 37. Walsh D, Rybicki L: Symptom clustering in advanced cancer. Support Care Cancer 14:831-836, 2006. 38. Cheville AL, Novotny PJ, Sloan JA, et al: Fatigue, dyspnea, and cough comprise a persistent symptom cluster up to five years after diagnosis with lung cancer. J Pain Symptom Manage 42:202-212, 2011. 39. Dodd MJ, Miaskowski C, Paul SM: Symptom clusters and their effect on the functional status of patients with cancer. Oncol Nurs Forum 28:465-470, 2001. 40. Portenoy RK, Thaler HT, Kornblith AB, et al: The Memorial Symptom Assessment Scale: An instrument for the evaluation of symptom prevalence, characteristics and distress. Eur J Cancer 30A:1326-1336, 1994. 41. Chang VT, Hwang SS, Feuerman M, et al: Symptom and quality of life survey of medical oncology patients at a veterans affairs medical center: A role for symptom assessment. Cancer 88:1175-1183, 2000. 42. Johnstone PA: Acupuncture as cancer symptom therapy: What a difference a decade makes. J Acupunct Meridian Stud 4:209-213, 2011. 43. Kaptchuk TJ: The Web That Has No Weaver: Understanding Chinese Medicine, 2nd ed. Chicago, IL, Contemporary Books, 2000. 44. Otte JL, Carpenter JS, Zhong X, et al: Feasibility study of acupuncture for reducing sleep disturbances and hot flashes in postmenopausal breast cancer survivors. Clin Nurse Spec 25:228-236, 2011. 45. Kasymjanova G, Grossman M, Tran T, et al: The potential role for acupuncture in treating symptoms in patients with lung cancer: An observational longitudinal study. Curr Oncol 20:152-157, 2013. 46. Dean-Clower E, Doherty-Gilman AM, Keshaviah A, et al: Acupuncture as palliative therapy for physical symptoms and quality of life for advanced cancer patients. Integr Cancer Ther 9:158-167, 2010. 47. Garcia MK, Driver L, Haddad R, et al: Acupuncture for treatment of uncontrolled pain in cancer patients: A pragmatic pilot study. Integr Cancer Ther 13:133-140, 2014. 48. Molassiotis A, Bardy J, FinneganJohn J, et al: Acupuncture for cancer-related fatigue in patients with breast cancer: A pragmatic randomized controlled trial. J Clin Oncol 30:4470-4476, 2012.

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News

Stage Increase in Lung Cancer More Frequent After Open vs Closed Thoracic Surgery

n increase in the stage of non–small cell lung cancer (NSCLC) due to cancer-positive lymph node discovery was more common following open chest surgery for lung lobe removal of early-stage lung cancer compared to the closed-chest procedure known as video-assisted thoracic surgery (VATS). The standard and often most effective treatment for early-stage lung cancer is surgical removal of the tumor and a portion of the lung, with open thoracotomy the traditional method of choice. Thoracotomies do pose some risk, especially in patients with other health problems. VATS is a less invasive approach that has fewer complications, less pain, improved lung function, shorter recovery periods, and lower acute care costs. However, incomplete lymph node staging by VATS could compromise survival by leaving residual cancer and altering optimal postsurgical treatment because of inaccurate understaging. The National Cancer Data Base was examined for NSCLC patients who underwent lobectomy between 2010 and 2011 for tumors < 7 cm and no apparent lymph node involvement prior to surgery. Statistical analyses were performed to compare nodal upstaging in VATS vs open thoracotomies and to determine if there were differences depending on surgical center.

thors note, “Standardized quality assurance of lymph node staging during VATS lobectomy is needed to achieve the goal of eliminating differences in staging, and there needs to be an anal-

ysis of differences in long-term survival rates between VATS and open thoracotomy for lobectomy to ensure that minimally invasive approaches provide tumor control equivalent to

that provided by open approaches.” n Reference 1. Medbery R, et al: J Thorac Oncol. January 11, 2016 (early release online).

When oneonedidn’t exist, When didn’t exist, Dana-Farber Dana-Farber created a pathway created a pathway tototreat children with treat children with rare rarebrain braincancers. cancers.

Study Results The results published by Medbery et al in the Journal of Thoracic Oncology1 show a total of 16,983 lobectomies were performed, 29.1% using VATS. Of all 4,935 VATS, 4.9% were performed at community centers, 50% at comprehensive community cancer programs, and 45.1% at academic or research centers. Upstaging because of the discovery of cancer in lymph nodes during surgery was more frequent in the open vs closed group (12.8% vs 10.3%; P < .001), even though a greater number of lymph nodes (≥9 LNs, 43.7% vs 38.8%; P < .001) were sampled using VATS. The open approach resulted in longer length of hospital stay (mean, 7.4 vs 6.1 days, P < .001), and a higher 30-day mortality rate (2.1% vs 1.3%; P < .001), whereas VATS was more likely to lead to an unplanned 30day readmission (6.9% vs 5.9%; P = .014). The authors suggest that, “nodal upstaging appears to be affected by facility type, which may represent a surrogate for expertise in minimally invasive surgical procedures.” The au-

Researchers at Dana-Farber have been studying some of the rarest and most dangerous childhood brain cancers, hoping to develop new, more effective approaches treatment. Ourofwork with cancers likedangerous DIPG, a brain stem glioma that affects Researchers at Dana-Farber have beentostudying some the rarest and most childhood brain cancers, hoping onlyto200 children each year and AT/RT, a lethaltobrain tumor that 100cancers annually, creating a better develop new, more effective approaches treatment. Our affects work with likeisDIPG, a brain stemunderstanding glioma that affects of how attack theseeach diseases. Taking on rare childhood cancers helped open new pathwaysa in the study of onlyto200 children year and AT/RT, a lethal brain tumor thathas affects 100usannually, is creating better understanding many adult cancers as well, including ovarian, breast, colon and possibly pancreatic cancer. While the biology of cancer of how to attack these diseases. Taking on rare childhood cancers has helped us open new pathways in the study of remains we believe even small steps can breast, lead to colon giant leaps forwardpancreatic toward a brighter children, manycomplex, adult cancers as well, including ovarian, and possibly cancer. future While for theour biology of cancer and remains for everyone. complex, we believe even small steps can lead to giant leaps forward toward a brighter future for our children, and for everyone. See videos, whitepapers and more at DiscoverCareBelieve.org/DIPG. See videos, whitepapers and more at DiscoverCareBelieve.org/DIPG.

The ASCO Postâ&#x20AC;&#x201A; | â&#x20AC;&#x201A; JANUARY 25, 2016

PAGE 126

Global Cancer Burden World Health Organization Region: South-East Asia Country: Afghanistan

Cancer on the Global Stage: Incidence and Cancer-Related Mortality in Afghanistan By Chandrakanth Are, MBBS, MBA, FRCS, FACS The ASCO Post is pleased to introduce this special focus on the worldwide cancer burden, beginning in this issue with a close look at the cancer incidence and mortality rates in the United States. The aim of this special feature is to highlight the global cancer burden for various countries of the world. For the convenience of the reader, each issue will focus on one country from one of the six regions of the world as defined by the World Health Organization (ie, Africa, the Americas, South-East Asia, Europe, Eastern Mediterranean, and Western Pacific). Each section will focus on the general aspects of the country followed the current and predicted rates of incidence and cancer-related mortality. It is hoped that through these issues, we can increase awareness and shift public policy and funds toward proactively addressing this lethal disease on the global stage. Disclaimer: This commentary represents the views of the author and may not necessarily reflect the views of ASCO.

fghanistan, with a population of nearly 32.5 million, is the 41st most populous nation in the world. The median age is very young, at 18.4 years, with a high population growth rate of 2.32% (34th in the world), a high birth rate of 38.57/1,000 population (11th in the world), and an even higher death rate of 13.89 deaths/100,000 population (9th in the world). This contributes to a very low life expectancy of 51 years (222nd rank in the world). Although Afghanistan spends nearly 8.5% of its gross domestic product on health care (ranked 46th in the world), this does not seem to translate to real benefits. The physician density of 0.27 physicians/1,000 population and the hospital bed density of 0.5 beds/1,000 population stand in stark contrast to the figures in the United States of 2.45 physicians/1,000 population and 2.9 beds/1,000 population, respectively. The cancer profile in Afghanistan is very different from the profile in high-income countries such as the United States. The most common

GUEST EDITOR Chandrakanth Are, MBBS, MBA, FRCS, FACS

Dr. Are is Jerald L & Carolynn J. Varner Professor of Surgical Oncology & Global Health, Vice Chair of Education, Program Director, General Surgery Residency, University of Nebraska Medical Center, Omaha.

ASCOPost.com | JANUARY 25, 2016

PAGE 127

Focus: Afghanistan cancers seen in Afghanistan by incidence include breast, stomach, esophagus, and lip/oral cavity. Cancers of the breast, stomach, esophagus, and lungs contribute the most to cancer-related mortality in this country. In addition, although the overall incidence may seem low, the overall cancerrelated mortality is very high when compared with the overall incidence. For example, in the year 2015, there were 19,656 new cancer cases and 15,211 cancer-related deaths in Afghanistan, accounting for nearly 78% of the incidence. In contrast, for the United States in 2015, there were 1,730,861 new cancer cases and 667,333 cancer-related death, accounting for 38% of the incidence. There are several issues associated with cancer care in Afghanistan. The primary one consists of the unavailability of accurate data on the actual burden of cancer. Some of the data obtained from GLOBOCAN is not directly from Afghanistan but based on extrapolation from data from neighboring countries. There is no national cancer policy or action plan, and similarly there is a lack of robust cancer registries. Screening for early detection of breast, cervical, and colorectal cancers is not generally available at the public primary healthcare level. Similarly, radiotherapy or chemotherapy is universally unavailable at the public primary health-care level. Although some facilities existed in the past, the intervening war years destroyed most facilities capable of treating patients with cancer. As a result, many patients travel outside the country to receive cancer care. Efforts are underway to address the rising cancer burden. The first world cancer day in Afghanistan was held on February 6, 2013, in Kabul to express commitment and dedication to improve health status as well as to reduce mortality and morbidity—not only of communicable diseases but also noncommunicable diseases such as cancer. A national strategy (2013–2018) for prevention and control of noncommunicable diseases underscores the importance placed on control of diseases such

Table 1: General Facts

Additional Readings 1. http://www.who.int/nmh/countries/afg_en.pdf 2. http://www.emro.who.int/afg/afghanistan-news/world-cancer-day-2013.html 3. http://www.who.int/nmh/ncd-tools/en/ 4. https://www.iaea.org/newscenter/news/world-cancer-day-afghanistan-looks-opencancer-care-centre

Note to Readers: If you are interested in participating in this continuing series on the global cancer burden and have an interesting perspective to share about a particular region of the world, contact Dr. Are at care@unmc.edu.

Population

32.5 million (2015)

Median age

18.4 years

Population growth rate

2.32% (2015)

Birth rate per 1,000 population

38.57 (2015)

Death rate per 1,000 population

13.89 (2015)

Life expectancy at birth

50.87 years

Health expenditure as % of GDP

8.1% (2013)

Physicians per 1,000 population

0.27 (2013)

Hospital bed density per 1,000 population

0.5 beds (2012)

Obesity prevalence rate

2.4% (2014)

Mobile telephones

23.4 million (2014)

Land lines

100,000 (2014)

as cancer. Recent attempts are underway in conjunction with the International Atomic Energy Agency to open a radiotherapy facility to re-establish cancer care in Kabul. Cancer is blind to war and peace and strikes just as hard in conflict-free and conflict-ridden zones of the world. It is hoped that through these efforts and resolution of conflict, appropriate measures can be taken to deliver compassionate and timely cancer care to these patients in dire need. n

3,500

1,800

3,000

1,600 1,400

2,500

1,200

2,000

1,000

1,500

800 600

1,000

400

500 0

200 0 Breast

Stomach

Esophagus

Lip, Oral Cavity

Lung

Non-Hodgkin Colorectum Lymphoma

Cervix Uteri

Brain, Nervous Systerm

Liver

Fig. 1: Top 10 Cancers by Incidence—Current Rates in Afghanistan.

Breast

Stomach

Esophagus

Lung

Lip, Oral Cavity

NonColorectum Hodgkin Lymphoma

Liver

Brain, Nervous System

Leukemia

Fig. 2: Top 10 Cancers by Mortality—Current Rates in Afghanistan.

45,000

35,000

40,000

30,000

35,000

25,000

30,000 25,000

20,000

15,000

10,000

5,000 0

5,000 0 2015

2020

2025

2030

Fig. 3: Trends in the Incidence of New Cancer Cases in Afghanistan: 2015–2035.

2035

2015

2020

2025

Fig. 4: Trends in Cancer-Related Mortality in Afghanistan: 2015–2035.

2030

2035

i am proof of extended survival in newly diagnosed GBM

Actor portrayal

Optuneâ&#x201E;˘ is intended as a treatment for adult patients (22 years of age or older) with histologically-confirmed glioblastoma multiforme (GBM). Optune with temozolomide is indicated for the treatment of adult patients with newly diagnosed, supratentorial glioblastoma following maximal debulking surgery, and completion of radiation therapy together with concomitant standard of care chemotherapy. Optune was studied in the EF-14 trial, a prospective, international, multicenter, open-label, randomized, controlled, phase 3 trial in newly diagnosed GBM patients comparing Optune + TMZ with TMZ alone (N=700). The prespecified interim analysis occurred when the first 315 patients completed 18 months of follow-up. The primary endpoint was PFS (ITT); OS (per protocol) was a powered secondary endpoint; 1- and 2-year survival rates, PFS6, QoL, and radiological response rates, along with safety, were also secondary endpoints. The final analysis included all patients randomized to EF-14 who had CRF information available at the database cutoff of December 3, 2014. This included 695 of the 700 patients randomized at that time: 466 patients in the Optune + TMZ arm and 229 patients in the TMZ-alone arm.1,2

Please see the following Summary of Important Safety Information for Optune and visit www.Optune.com/IFU for Optune Instructions for Use for complete information regarding the deviceâ&#x20AC;&#x2122;s indication, contraindications, warnings and precautions. CI, confidence interval; CRF, case report form; GBM, glioblastoma; HR, hazard ratio; ITT, intent to treat; OS, overall survival; PFS, progression-free survival; PFS6, progression-free survival at 6 months; QoL, quality of life; TMZ, temozolomide. References: 1. Optune Instructions for Use. Novocure 2015. 2. Novocure Data on File. OPT-103.

Optune + TMZ significantly extended median overall survival by 4.9 months and median PFS by 3.2 months 1 20.5 months median OS with Optune + TMZ1

Fraction Survival

Overall Survival (interim analysis)1 1.0

Median OS from randomization (months)1

0.9

Log-rank P-value1

0.0042

HR (95% CI)1

0.666 (0.495-0.898)

0.8

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0.7

20.5 MONTHS

0.6 0.5

20.5

Median OS from diagnosis (months)2

Median OS

24.4

15.6

19.4

Per Protocol population

0.4

TMZ alone

Optune + TMZ (n=196)

0.3

15.6

TMZ alone (n=84)

MONTHS

0.2 0.1 + Censored

0.0 0

Overall Survival (months)

* In the final analysis (n=695), Optune + TMZ extended median OS by 4.4 months, and this was consistent with the interim analysis (n=315).1

Overall Survival (months)

Median PFS improved by >3 months with Optune + TMZ1

Fraction Survival

Progression-free Survival (interim analysis)1 1.0

Median PFS from randomization (months)1

7.2

0.9

Log-rank P-value1

0.0013

HR (95% CI)1

0.621 (0.468-0.823)

0.8

Optune + TMZ

0.7

7.2 MONTHS

0.6 0.5

Median PFS from diagnosis (months)2

Median PFS

0.4

TMZ alone

0.3

4.0

11.0

4.0

Median time from diagnosis to randomization was

7.8

3.8 months1

ITT population

Optune + TMZ (n=210) TMZ alone (n=105)

MONTHS

0.2 0.1

â&#x20AC;

+ Censored

0.0 0

Progression-free Survival (months)

In the final analysis (n=695), Optune + TMZ extended median PFS by 2.9 months, and this was consistent with the interim analysis (n=315).1

Progression-free Survival (months)

SELECTED SAFETY INFORMATION Do not use Optune in patients with an active implanted medical device, a skull defect (such as, missing bone with no replacement), or bullet fragments. Use of Optune together with implanted electronic devices has not been tested and may theoretically lead to malfunctioning of the implanted device. Use of Optune together with skull defects or bullet fragments has not been tested and may possibly lead to tissue damage or render Optune ineffective. Learn more at Optune.com ÂŠ2015 Novocure. All rights reserved. Optune and Novocure are trademarks of Novocure. OPT-117

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The ASCO Post | JANUARY 25, 2016

Book Review INDICATIONS FOR USE Optune™ is intended as a treatment for adult patients (22 years of age or older) with histologicallyconfirmed glioblastoma multiforme (GBM). Optune with temozolomide is indicated for the treatment of adult patients with newly diagnosed, supratentorial glioblastoma following maximal debulking surgery, and completion of radiation therapy together with concomitant standard of care chemotherapy. SUMMARY OF IMPORTANT SAFETY INFORMATION Contraindications Do not use Optune in patients with an active implanted medical device, a skull defect (such as, missing bone with no replacement), or bullet fragments. Use of Optune together with implanted electronic devices has not been tested and may theoretically lead to malfunctioning of the implanted device. Use of Optune together with skull defects or bullet fragments has not been tested and may possibly lead to tissue damage or render Optune ineffective. Do not use Optune in patients that are known to be sensitive to conductive hydrogels. In this case, skin contact with the gel used with Optune may commonly cause increased redness and itching, and rarely may even lead to severe allergic reactions such as shock and respiratory failure. Warnings and Precautions Optune can only be prescribed by a healthcare provider that has completed the required certification training provided by Novocure (the device manufacturer). Do not prescribe Optune for patients that are pregnant, you think might be pregnant or are trying to get pregnant, as the safety and effectiveness of Optune in these populations have not been established. The most common (≥10%) adverse events involving Optune in combination with temozolomide were thrombocytopenia, nausea, constipation, vomiting, fatigue, medical device site reaction, headache, convulsions, and depression. Use of Optune in patients with an inactive implanted medical device in the brain has not been studied for safety and effectiveness, and use of Optune in these patients could lead to tissue damage or lower the chance of Optune being effective. If the patient has an underlying serious skin condition on the scalp, evaluate whether this may prevent or temporarily interfere with Optune treatment. Please see the Optune Instructions for Use (IFU) for complete information regarding the device’s indication, contraindications, warnings, and precautions at Optune.com/IFU.

Saving Children Orphaned by AIDS in South Africa By Ronald Piana

Bookmark Title: Empty Hands, A Memoir: One Woman’s Journey to Save Children Orphaned by AIDS in South Africa Author: Sister Abegail Ntleko Publisher: North Atlantic Books Publication date: September 1, 2015 Price: $12.95; paperback, 176 pages

ith the development of the multidrug highly active antiretroviral therapy regimen and concerted prevention initiatives, the devastation of the HIV/AIDS pandemic has been largely curtailed, especially in Western industrialized nations. Given the success on the awareness and therapeutic fronts it is difficult to comprehend the grim mortality facts coming out of South Africa, sub-Sahara’s most industrialized country: The leading cause of yearly deaths among men and women is HIV/AIDS. This human tragedy is compounded by the clinical reality that the country’s leading cause of death is preventable. As in many human catastrophes, children are the innocent victims. A compelling new memoir called Empty Hands, A Memoir, by Sister Abegail Ntleko, tells her journey to save children orphaned by AIDS in South Africa. In the book’s forward by Desmond Tutu, the South African Anglican bishop and social rights activist who rose to worldwide prominence as an early opponent of apartheid, he writes: “We sometimes accomplish great things regardless of where and how we grew up, regardless of what we were told was possible…. The life and work of Sister Abegail Ntleko show that.” After reading this slim, powerful memoir, Desmond Tutu’s praise of Sister Abegail Ntleko is an understatement.

The Simplest of Language “I always loved the smell of fresh cow dung. Some families preferred mud, but we always used dung. To

keep our floor tidy, we would rub in a new layer each week,” so begins Empty Hands, A Memoir. This opening brings the reader into a wildly foreign land, and it also speaks volumes about the narrator’s character. You want to read more, and you should. The telling of this remarkable story is done in the simplest of language: so simple that the reader might find it offputting, but that judgment will quickly fade, as the author tells of growing up in a poor, rural village with an alcoholic father who did not believe in educating girls. In the face of brutal oppression, Ms. Ntleko earned a nursing degree and became a community nurse and educator, dedicating herself to those at the lowest station in life.

Overcoming Poverty, Racism, Sexism In chapter three, “Hands to Hold,” the author writes: “I was 32 and just shy of 3 years into nursing school when something unexpected happened: I fell in love with a child…. The little girl was only a few months old, a beautiful mix of an Indian mother and a black South African father. The poor little one was an outcast before she could even walk.” The girl’s father had become mentally ill and began horribly abusing the mother. The mother, being Indian, retreated to the “colored section” of town but she couldn’t bring her daughter because she was black. The poor child is tossed about and finally discarded, until the author adopted her—hardly a common occurrence at the time for

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an unmarried woman to have a child. Reading this story is a sobering experience, as it should be. After overcoming poverty, racism, and violent sexism, the author becomes a mother, a nurse, an Anglican Sister, and a savior for children orphaned by AIDS. Reading about the early days of the African AIDS epidemic is riveting. The author writes: “Over the course of the early years of the AIDS epidemic, the flames of distrust and blame were further fanned by racial tensions underlying the Apartheid policies. Rumors and conspiracy theories were rampant; blacks thought whites were deliberately infecting them.”

The Indomitable Human Spirit And in the epicenter of this surreal environment, Sister Ntleko not only keeps her humanity intact, she turns hate and craziness into a positive way forward, developing a program to help the frailest of all: disposed children. “Many of the children who came to us had suffered greatly. They had been through the death of their parents, abject poverty, and all kinds of abuse, including sexual,” writes the author in this sliver of a book that celebrates the indomitable human spirit. In 2009, Sister Abegail Ntleko received the Unsung Heroes of Compassion Award from the Dalai Lama,

There may be many secrets to happiness. Here is mine: Every night I empty my hands. And every day, I try to fill them with love and then spend all the love until my hands are empty again. —Sister Abegail Ntleko

which Sister Abegail Ntleko graciously accepted. However, her words at the close of this fine book tell more about her than any award could: “There may be many secrets to happiness, I don’t know. Here is mine: Every night I empty my hands. And every day, I try to fill them with love

and then spend all the love until my hands are empty again.” This 121-page saga drills down into the heart of disease, the people the disease affects, and those who fight against the disease and its victims. Empty Hands, A Memoir is recommended for readers of The ASCO Post. n

News Epidemiology

Cancer Incidence in Indigenous People in Australia, New Zealand, Canada, and the United States

n a population-based study reported in The Lancet Oncology, Suzanne P. Moore, PhD, of Charles Darwin University, Northern Territory, Australia, and colleagues compared cancer incidence in indigenous people in Australia, New Zealand, Canada, and the United States with the incidence in nonindigenous counterparts.1 The overall rate of cancer in indigenous populations was lower in the United States except in Alaska, similar or slightly lower in Australia and Canada, and higher in New Zealand.

Study Details In the study, incidence data were derived from population-based cancer registries in Queensland, Western Australia, and the Northern Territory in Australia, New Zealand, Alberta in Canada, and Contract Health Service Delivery Areas in the United States; the U.S. regions used in comparisons consisted of Alaska, the United States except Alaska, Northern Plains, Pacific Coast, East, and Southwest. Data for First Nations and Inuit in Alberta were provided directly by Alberta Health Services. Age-standardized rates by registry, sex, cancer site, and ethnicity were compared for all incident cancer cases (except nonmelanoma skin cancers) diagnosed between 2002 and 2006. Rates were compared for the indigenous and nonindigenous populations of each jurisdiction, except for comparison of the Alaska Native population with the white U.S. population. The analysis included

24,815 cases of cancer in indigenous people and 5,685,264 in nonindigenous people from all regions (except Alberta).

Cancer Risk The overall rate of cancer in indigenous populations was lower in the United States except in Alaska, similar or slightly

(0.51), U.S.-Pacific Coast (0.50), U.S.-except Alaska (0.49), and U.S.-East (0.27). Among men, standardized rate ratios were higher for Māori men (standardized rate ratios = 1.07, 95% confidence interval = 1.03–1.11); standardized rate ratios were lower for indigenous populations in the U.S.-East (0.27), U.S. except

Our findings highlight the need for much-improved, targeted programs of screening, vaccination, and smoking cessation, among other prevention strategies. Governments and researchers need to work in partnership with indigenous communities to improve cancer surveillance in all jurisdictions and facilitate access to cancer data. —Suzanne P. Moore, PhD, and colleagues

lower in Australia and Canada, and higher in New Zealand compared with non-indigenous counterparts. Among women, standardized rate ratios for all cancers combined were higher for Alaska native women (1.30, 95% confidence interval [CI] = 1.21–1.40) and Māori women (1.29, 95% CI = 1.24–1.33), similar in Alberta (1.00), Queensland (0.92), and Australia-Northern Territory (1.01), and lower in Western Australia (0.86), U.S. Southwest (0.65), U.S.-Northern Plains

Alaska (0.44), U.S.-Pacific coast (0.45), U.S.-Northern Plains (0.54), U.S.-Southwest (0.57), Western Australia (0.73), and Queensland (0.80) and similar for Alberta (0.98), Australia-Northern Territory (0.96), and Alaska (0.98). In women, breast cancer was the most common cancer in all regions except Alberta (colorectal cancer). In men, lung cancer was the most common cancer in New Zealand, all Australian regions, and Alaska; prostate can-

cer was the most common in other U.S. regions; and colorectal cancer was the most common in Alberta. Standardized rate ratios for lung cancer were higher in indigenous men in New Zealand (2.55), Queensland (1.77), AustraliaNorthern Territory (1.64), and Alaska (1.45). standardized rate ratios for breast cancer in women were lower in all indigenous populations except New Zealand (1.23) and Alaska (1.14). The incidence of cervical cancer was significantly or nonsignificantly higher in indigenous women in most regions. The investigators concluded: “There are clear differences in the scale and profile of cancer in indigenous and nonindigenous populations in Australia, New Zealand, Canada, and the United States. Our findings highlight the need for much-improved, targeted programs of screening, vaccination, and smoking cessation, among other prevention strategies. Governments and researchers need to work in partnership with indigenous communities to improve cancer surveillance in all jurisdictions and facilitate access to cancer data.” n

Disclosure: The study was funded by the International Agency for Research on Cancer– Australia Fellowship. For full disclosures of the study authors, visit www.thelancet.com.

Reference 1. Moore SP, Antoni S, Colquhoun A, et al: Cancer incidence in indigenous people in Australia, New Zealand, Canada, and the USA: A comparative population-based study. Lancet Oncol 16:1483-1492, 2015.

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Book Review

A Noted Breast Surgeon’s Book of Solid Advice By Ronald Piana

hen a new book on breast cancer is published, the first question that comes to mind is: Why should this book be added to the already crowded shelves of breast cancer books? A new book on breast cancer by Elisa Port, MD, deserves a prominent place among recently published books in this genre because it lives up to its subtitle: How to Navigate Your Diagnosis and Treatment Options—and Remain Optimistic—in an Age of Information Overload. Moreover, the author is eminently qualified to speak directly to women with breast cancer and those at risk. Dr. Port is Chief of Breast Surgery at Mount Sinai Medical Center and Director of the Dubin Breast Center, a state-of-the-art facility opened in Manhattan in 2011. She is also a frequent contributor to print, radio, and television media.

Screening and Early Detection The book is organized into 20 chapters, ending with two highly informative appendices. To her credit, Dr. Port leads off with a chapter about screening and early detection. As with prostate-specific antigen screening, mammography has been scrutinized for its worth vs the downsides of overdiagnosis and false-positive results. Organizations as diverse as the Affordable Care Act and the U.S. Preventive Services Task Force (USPSTF) have altered their screening recommendations over the years, adding confusion to an issue that is vital for breast health. Dr. Port is a true advocate for breast health, traveling the country leading seminars and general public education workshops, during which she has to field questions from concerned women. For example, “My sister was diagnosed with breast cancer when she felt a lump one month after a normal mammogram. Why should I get one if it didn’t work for her?” This is a tough question for a clinician/advocate, but given the level of understandable anxiety produced by the continuing debate over the value of mammography, Dr. Port is firm. And that’s a good thing for women. “Mammograms are not flawless—no test is…but even when all the variables are taken into account, mammograms are still the best tool currently available for identifying breast cancer in the majority of women.” Another reason this book deserves a prominent position in the crowded world of breast cancer books is its unparalleled readability and structure. In the opening chapter on breast cancer screening, Dr.

Port breaks down the various screening methods along with risk factors. Smartly, she uses callout boxes to illustrate her points. For example, in one callout titled “Need to Know: What is the appropriate screening regimen for the average woman,” she gives her recommendations, backed by the best available data, without overloading the reader with statistics. Dr. Port follows this with a Myths and Facts callout. “Myth: If you don’t have a family history of breast cancer… the reality is that 80% to 90% of women diagnosed with breast caner have no special risk factors.” This simple and straightforward delivery style is one of the many strong points of this book.

Bookmark Title: The New Generation Breast Cancer Book: How to Navigate Your Diagnosis and Treatment Options— and Remain Optimistic—in an Age of Information Overload Author: Elisa Port, MD Publisher: Ballantine Books Publication date: September 2015 Price: $20.00; paperback, 320 pages

Diagnosis and Treatment The chapters dealing with diagnosis and treatment are handled with care and clarity. Again, Dr. Port takes difficult clinical issues and drills down to their core messages. A surgeon herself, Dr. Port advises women with breast cancer to spend some time thinking carefully about their surgeon. “A surgeon isn’t just the person you are going to trust with your operation. A good breast surgeon will provide you with critical information that you need to make the right decisions,” she writes. In her section on needle biopsy, along

lumpectomy and mastectomy. In this section, Dr. Port uses strategically placed Word to the Wise callout boxes that give patients invaluable advice on how to put a surgical team together and make tough clinical decisions. Perhaps the best part of this section is one that is often overlooked in books for the lay public: when a second opinion is needed. Throughout the book, Dr. Port has indicated when a second opinion is needed. Here, Dr. Port takes on the understandable mindset that prior to breast

If your surgeon or facility does not meet the standards that I have outlined, then a second opinion is probably an excellent idea. —Elisa Port, MD

with her step-by-step clinical explanation of the procedure, the author also tackles common myths that cause needless confusion for patients with breast cancer, such as needle biopsy can spread cancer. “Somehow, at some point, someone came up with the misinformation that needle biopsies can spread cancer—and if a needle biopsy is done and shows cancer, surgery needs to be done quickly to contain the cancer and reduce the risk of spread caused by the needle,” writes Dr. Port, as she debunks this misinformation that vulnerable patients with breast cancer can find on irresponsible cancer-information Internet websites.

Seeking a Second Opinion One of the most difficult choices newly diagnosed patients with breast cancer face is the choice between

cancer surgery, the patient must have a second opinion, which is often guided by well-meaning family and friends. And, as Dr. Port points out, this approach can be misguided. She illustrates her point with an actual case history in which one of her patients was persuaded by a friend to see the surgeon who had performed her double mastectomy. Dr. Port’s patient was being pressured by her friend to have a double mastectomy, “as that’s what worked for her.” However, no two cancers are alike, and Dr. Port suggests that even if a patient seeks a second opinion, it is important to make the choice based on the criteria she has outlined in the preceding chapter. “If your surgeon or facility does not meet the standards that I have outlined, then a second opinion is probably an excellent idea,” writes Dr. Port.

Clinical Trial Participation Yet another issue that many cancer books fail to address in depth is clinical trial participation. Dr. Port again uses a case history to illustrate her messages. After surgery, her 59-year-old patient saw a medical oncologist who strongly recommended that she go on a clinical trial. “I explained to her that every standard treatment for breast cancer was once an experiment and part of a clinical trial. I am extremely supportive of clinical trials, but only when they are appropriate for a particular patient, and in this case it was,” writes the author.

Other Featured Topics She then elucidates a complicated issue that is largely misunderstood by the lay public, using the excellent callout boxes and shaded subheads that have made this book a cut above most others. Advantages and disadvantages, questions to ask, red flags, and a note on financial compensation are explained in this section. Dr. Port also discusses genetic and lifestyle factors that increase the risk of breast cancer. She also devotes a full chapter to male breast cancer, followed by a description of standard chemotherapies and a look into the future. This is the only section where the layperson might have difficulty. The end of the book deals with recurrence and end-of-life care, replete with online resources. Appendices on Myth and Truth and Frequently Asked Questions are so good they could be published as stand-alone pamphlets. The New Generation Breast Cancer Book may not dazzle The ASCO Post readers with new information, but it will give aspiring authors a level of excellence to strive for. n

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Announcements

Ravi Salgia, MD, PhD, Joins City of Hope

edical oncologist and researcher Ravi Salgia, MD, PhD, has joined City of Hope as Professor and Chair in the Department of Medical Oncology & Therapeutics Research. He will play a key leadership role in the expansion of clinical programs at City of Hope’s Duarte campus and in its clinics throughout

Ravi Salgia, MD, PhD

Southern California, as well as enhance the integration of state-of-the-art therapeutics with leading-edge research. At City of Hope, Dr. Salgia will work closely with faculty to support both basic research and clinical studies aimed at discovering new cancer treatments. Beyond his role as the Arthur & Rosalie Kaplan Endowed Chair in Medical Oncology, he will also serve as Associate Director for Clinical Sciences in the institution’s Comprehensive Cancer Center. Dr. Salgia joins City of Hope from the University of Chicago Medical Center and Pritzker School of Medicine, where he was Professor of Medicine, Pathology, and Dermatology; Director of the Thoracic Oncology Program; Vice Chair of Medicine; and Associate Director of Translational Sciences for the Comprehensive Cancer Center.

Major Research During his 12 years with the University of Chicago, Dr. Salgia identified several novel targets in oncology and led a strong clinical and research group. His laboratory conducted research on how the receptor tyrosine kinases, which are abundant in lung cancer cells, affect cell growth and may have potential use in treatment. Dr. Salgia is also utilizing various strategies to understand tumor heterogeneity, including the role of cellsignaling pathways, mitochondria, immunology, and mathematical modeling. Dr. Salgia’s most recent work has focused on the development of biomarkers for early diagnosis, as well as prognosis and therapeutic monitoring of thoracic cancers. His goal is to develop novel therapeutics with minimal side effects. “City of Hope embodies the commitment to discovering new treatments that enhance quality of life for

cancer patients,” said Dr. Salgia, whose research has been funded by the National Cancer Institute, the American Cancer Society, and the Mesothelioma Applied Research Foundation, among other organizations. “It is a privilege to join a multidisciplinary team of physi-

cians, nurse practitioners, scientists, and other health professionals who are dedicated to providing the highest quality cancer treatment and care.” Dr. Salgia has published more than 200 journal articles, contributed to 34 books related to thoracic diseases, and served as an

editor and associate editor for six journals. He received his medical degree and PhD in biochemistry and biophysics from Loyola University Stritch School of Medicine and completed his internship and residency in internal medicine at John Hopkins Hospital. n

Our commitment to cancer research

Merck is passionate about improving health and is committed to helping people with cancer. Keynote is a series of investigational trials studying pembrolizumab (MK-3475)—a type of investigational immunotherapy that works by targeting the PD-1 pathway. Merck has investigational clinical trials underway or planned in multiple cancer types.

If you have patients who may be eligible for a trial, visit

www.keynoteclinicaltrials.com

for more information about this ongoing research.

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2016

2016 Oncology Meetings January 2016 8th Annual T-Cell Lymphoma Forum January 28-30 • San Francisco, California For more information: www.tcellforum.com/

3rd Annual University of Southern California Multidisciplinary Breast Cancer Symposium January 30 • Los Angeles, California For more information: http://keck.usc. edu/About/Administrative_Offices/ Office_of_Continuing_Education/ Courses/~/media/Office%20of%20 CME/FINAL_brochure_2016%20 breast%20cancer.pdf

18th Annual Symposium on Anti-Angiogenesis and Immune Therapies for Cancer: Recent Advances and Future Directions in Basic and Clinical Cancer Research February 4-6 • San Diego, California For more information: www.imedex.com/antiangiogenesis-and-immunetherapies/

4th State of the Science Cancer Survivorship Research Symposium February 4 • Houston, Texas For more information: www.mdanderson.org Scripps’ 36th Annual Conference: Clinical Hematology & Oncology February 4 • Houston, Texas For more information: http://www.mdanderson.org/ education-and-research/educationand-training/schools-and-programs/ cme-conference-management/ conferences/cme/conferencemanagement-fourth-state-of-thescience-cancer-survivorship-researchsymposium.html

Cancer Center Business Summit February 24-25 • Phoenix, Arizona For more information: http://cancerbusinesssummit.com

Advances in Systemic Therapy for Breast Cancer 2016 February 12-13 • Ponte Vedra Beach, Florida For more information: https://ce.mayo.edu/node/5816 10th AACR-JCA Joint Conference on Breakthroughs in Cancer Research: From Biology to Therapeutics February 16-20 • Maui, Hawaii For more information: www.aacr.org

February 27th International Congress of AntiCancer Treatment (ICACT) February 2-4 • Paris, France For more information: http://www.icact.fr

3rd Annual International Conference on Advances in Cancer Medical Research (ACMR 2016) February 22-23 • Singapore For more information: http://cancerresearch-conf.org/

The Biomarker Conference February 18-20 • San Diego, California For more information: www.mnmconferences.com/thebiomarker-conference-florida.html Multidisciplinary Head and Neck Cancer Symposium February 18-20 • Scottsdale, Arizona For more information: www.headandnecksymposium.org 25th Conference of the Asian Pacific Association for the Study of the Liver February 20-24 • Tokyo, Japan For more information: http://www.apasl2016.org

22nd Annual Blood-Brain Barrier and Neuro-oncology Meeting March 3-5 • Stevenson, Washington For more information: www.ohsu.edu/bbb 4th Annual UC San Diego Essentials and Advances in Apheresis Therapies March 3-5 • San Diego, California For more information: https://cme.ucsd.edu/apheresis/ 8th Annual Asian Oncology Summit March 3-6 • Kyoto, Japan For more information: www.asianoncologysummit.com

ASCO Quality Care Symposium February 26-27 • Phoenix, Arizona For more information: http://quality.asco.org Winship Cancer Institute 2016 Melanoma Conference February 27 • Atlanta, Georgia For more information: www .winshipmelanomaconference.com AACR Precision Medicine Series: Cancer Cell Cycle–Tumor Progression and Therapeutic Response February 28-March 2 • Maui, Hawaii For more information: www.aacr.org/Meetings/ Pages/MeetingDetail. aspx?EventItemID=76#.Vbb2qKTbJjo 6th World Congress on Cell & Stem Cell Research February 29-March 2 • Philadelphia, Pennsylvania For more information: http://stemcell.omicsgroup.com/

March Society of Surgical Oncology Annual Cancer Symposia March 2-5 • Boston, Massachusetts For more information: www.surgonc.org

Hematology and Medical Oncology Board Review: Contemporary Practice From Memorial Sloan Kettering Cancer Center March 4-7 • New York, New York For more information: www.mskcc.org/event/hematologyand-medical-oncology-boardreview-contemporary-practice Second Annual New Treatments in Oncology March 5-6 • Scottsdale, Arizona For more information: www.cvent.com/events/annualnew-treatments-in-oncologyconference-presented-by-cancertreatment-centers-of-america-/ event-summary-2fb116562f6447cca4 92c89064760b02.aspx American Association of Physicists in Medicine Spring Clinical Meeting March 5-8 • Salt Lake City, Utah For more information: http://www.aapm.org/ meetings/2016SCM/ ILCA School of Liver Cancer 2016 March 7-8 • Barcelona, Spain For more information: www.ilcaonline.org/sitecore/content/bebruga/ilca-online/School%20of%20 Liver%20Cancer/2016.aspx

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2016

2016 Oncology Meetings Moffitt Cancer Center Neuro-Oncology Conference March 10-11 • Clearwater Beach, Florida For more information: http://myana.org/events/moffittcancer-center-neuro-oncologyconference 3rd St. Gallen International Gastrointestinal Cancer Conference March 10-12 • St. Gallen, Switzerland For more information: www.oncoconferences.ch/dynasite .cfm?dsmid=500294

33rd Annual Miami Breast Cancer Conference March 10-13 • Miami, Florida For more information: www.gotoper.com/conferences/ mbcc/meetings/33rd-Annual-MiamiBreast-Cancer-Conference 2016 ASTRO Annual Refresher Course March 11-13 • La Jolla, California For more information: www.astro.org/Meetings-andEvents/2016-Annual-RefresherCourse/Index.aspx Annual European Association of Urology Congress March 11-15 • Munich, Germany For more information: http://eaumunich2016.uroweb.org

40th Annual American Society of Preventive Oncology (ASPO) Conference March 12-15 • Columbus, Ohio For more information: https://aspo.org/annual-meeting 2016 Methods in Clinical Research Workshop for Minority Physicians March 17-20 • Fort Lauderdale, Florida For more information: www.roswellpark.edu/education/ diversity-clinical-research-workshop The 16th Multidisciplinary Management of Cancers: A Case-Based Approach March 18-20 • Napa, California For more information: https://med.stanford.edu/cme/ courses/2016/multicancer2016.html Society of Gynecologic Oncology Annual Meeting on Women’s Cancer March 19-22 • San Diego, California For more information: www.sgo.org

April New Frontiers in Diagnosis, Screening, and Management of Inherited Cancer Syndromes April 8-9 • Chicago, Illinois For more information: https://cme.uchicago.edu/NFD2016 Gastrointestinal Cancer Multidisciplinary Symposium 2016: Current Update on State of the Art Screening, Diagnosis and Treatment April 9 • Columbus, Ohio For more information: https://ccme.osu.edu/ 26th Annual Interdisciplinary Breast Cancer Center Conference April 9-13 • Las Vegas, Nevada For more information: http://www2.breastcare.org/ welcome-to-the-24th-annualnational-interdisciplinary-breastcenter-conference/

International Conference on Pancreatic and Colorectal Cancer March 29-30 • Atlanta, Georgia For more information: http://pancreatic-colorectal .cancersummit.org

American Association of Cancer Research Annual Meeting April 16-20 • New Orleans, Louisiana For more information: www.aacr.org 16th Pan Arab Cancer Conference April 28-30 • Cairo, Egypt For more information: www.pacc16.org 2016 Head and Neck Cancer Symposium Fifth Annual April 30 • Miami, Florida For more information: http://cme.baptisthealth.net/ headneckcancer/pages/index.aspx

May Markers in Cancer Diagnostic Development Tutorial May 2-3 • Bethesda, Maryland For more information: http://markersincancer.org

European Lung Cancer Conference April 13-16 • Geneva, Switzerland For more information: www.esmo.org/Conferences/ ELCC-2016-Lung-Cancer

NCCN 21st Annual Conference: Advancing the Standard of Cancer CareTM March 31-April 2 • Hollywood, Florida For more information: www.nccn.org

Clinical Immunology Society Annual Meeting April 14-17 • Boston, Massachusetts For more information: www.clinimmsoc.org/education/ meetings/2016-annual-meeting

American Society for Colposcopy and Cervical Pathology (ASCCP) Annual Meeting April 13-16 • New Orleans, Louisiana For more information: www.asccp.org/2016annualmeeting

Palliative Care Education and Practice (PCEP) May 4-10 • Cambridge, Massachusetts For more information: www.hms.harvard.edu/pallcare/ PCEP/PCEP.htm 19th SIS World Congress on Breast Healthcare May 5-8 • Warsaw, Poland For more information: www.siscongress.org

November 3-6, 2016 Washington, DC

Gaylord National Hotel | National Harbor, MD

Brief Summary: Consult package insert for complete Prescribing Information INDICATIONS AND USAGE: Bone Metastasis from Solid Tumors Xgeva is indicated for the prevention of skeletal-related events in patients with bone metastases from solid tumors. Limitation of Use: Xgeva is not indicated for the prevention of skeletal-related events in patients with multiple myeloma. Giant Cell Tumor of Bone Xgeva is indicated for the treatment of adults and skeletally mature adolescents with giant cell tumor of bone that is unresectable or where surgical resection is likely to result in severe morbidity. Hypercalcemia of Malignancy Xgeva is indicated for the treatment of hypercalcemia of malignancy refractory to bisphosphonate therapy. DOSAGE AND ADMINISTRATION: Important Administration Instructions Xgeva is intended for subcutaneous route only and should not be administered intravenously, intramuscularly, or intradermally. Recommended Dosage: Bone Metastasis from Solid Tumors: The recommended dose of Xgeva is 120 mg administered as a subcutaneous injection every 4 weeks in the upper arm, upper thigh, or abdomen. Administer calcium and vitamin D as necessary to treat or prevent hypocalcemia. Giant Cell Tumor of Bone: The recommended dose of Xgeva is 120 mg administered every 4 weeks with additional 120 mg doses on Days 8 and 15 of the first month of therapy. Administer subcutaneously in the upper arm, upper thigh, or abdomen. Administer calcium and vitamin D as necessary to treat or prevent hypocalcemia. Hypercalcemia of Malignancy: The recommended dose of Xgeva is 120 mg administered every 4 weeks with additional 120 mg doses on Days 8 and 15 of the first month of therapy. Administer subcutaneously in the upper arm, upper thigh, or abdomen. CONTRAINDICATIONS: Hypocalcemia. Pre-existing hypocalcemia must be corrected prior to initiating therapy with Xgeva. Hypersensitivity. Xgeva is contraindicated in patients with known clinically significant hypersensitivity to Xgeva. WARNINGS AND PRECAUTIONS: Drug Products with Same Active Ingredient. Xgeva includes the same active ingredient (denosumab) found in Prolia. Patients receiving Xgeva should not take Prolia. Hypersensitivity. Clinically significant hypersensitivity including anaphylaxis has been reported with use of Xgeva. Reactions may include hypotension, dyspnea, upper airway edema, lip swelling, rash, pruritus, and urticaria. If an anaphylactic or other clinically significant allergic reaction occurs, initiate appropriate therapy and discontinue Xgeva therapy permanently. Hypocalcemia. Xgeva can cause severe symptomatic hypocalcemia, and fatal cases have been reported. Correct pre-existing hypocalcemia prior to Xgeva treatment. Monitor calcium levels, throughout Xgeva therapy, especially in the first weeks of initiating therapy, and administer calcium, magnesium, and vitamin D as necessary. Monitor levels more frequently when Xgeva is administered with other drugs that can also lower calcium levels. In the postmarketing setting, severe symptomatic hypocalcemia has been reported. Advise patients to contact a healthcare professional for symptoms of hypocalcemia. An increased risk of hypocalcemia has been observed in clinical trials of patients with increasing renal dysfunction, most commonly with severe dysfunction (creatinine clearance less than 30 mL/minute and/or on dialysis), and with inadequate/no calcium supplementation. Monitor calcium levels and calcium and vitamin D intake. Osteonecrosis of the Jaw. Osteonecrosis of the jaw (ONJ) has been reported in patients receiving Xgeva, manifesting as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration, or gingival erosion. Persistent pain or slow healing of the mouth or jaw after dental surgery may also be manifestations of ONJ. In clinical trials, in patients with osseous metastasis, the incidence of ONJ was higher with longer duration of exposure. Seventy-nine percent of patients with ONJ had a history of tooth extraction, poor oral hygiene, or use of a dental appliance as a predisposing factor. Other risk factors for the development of ONJ include immunosuppressive therapy, treatment with angiogenesis inhibitors, systemic corticosteroids, diabetes, and gingival infections. Perform an oral examination and appropriate preventive dentistry prior to the initiation of Xgeva and periodically during Xgeva therapy. Advise patients regarding oral hygiene practices. Avoid invasive dental procedures during treatment with Xgeva. Consider temporary discontinuation of Xgeva therapy if an invasive dental procedure must be performed. There are no data available to suggest the optimal duration of treatment interruption. Patients who are suspected of having or who develop ONJ while on Xgeva should receive care by a dentist or an oral surgeon. In these patients, extensive dental surgery to treat ONJ may exacerbate the condition. Clinical judgment of the treating physician should guide the management plan of each patient based on individual risk/benefit assessment. Atypical Subtrochanteric and Diaphyseal Femoral Fracture. Atypical femoral fracture has been reported with Xgeva. These fractures can occur anywhere in the femoral shaft from just below the lesser trochanter to above the supracondylar flare and are transverse or short oblique in orientation without evidence of comminution. Atypical femoral fractures most commonly occur with minimal or no trauma to the affected area. They may be bilateral and many patients report prodromal pain in the affected area, usually presenting as dull, aching thigh pain, weeks to months before a complete fracture occurs. A number of reports note that patients were also receiving treatment with glucocorticoids (e.g. prednisone) at the time of fracture. During Xgeva treatment, patients should be advised to report new or unusual thigh, hip, or groin pain. Any patient who presents with thigh or groin pain should be suspected of having an atypical fracture and should be evaluated to rule out an incomplete femur fracture. Patient presenting with an atypical femur fracture should also be assessed for symptoms and signs of fracture in the contralateral limb. Interruption of Xgeva therapy should be considered, pending a risk/benefit assessment, on an individual basis. EMBRYO-FETAL TOXICITY: Xgeva can cause fetal harm when administered to a pregnant woman. Based on findings in animals, Xgeva is expected to result in adverse reproductive effects. In utero denosumab exposure in cynomolgus monkeys resulted in increased fetal loss, stillbirths, and postnatal mortality, along with evidence of absent peripheral lymph nodes, abnormal bone growth, and decreased neonatal growth. Advise females of reproductive potential to use highly effective contraception during therapy, and for at least 5 months after with the last dose of Xgeva. Apprise the patient of the potential hazard to a fetus if Xgeva is used during pregnancy or if the patient becomes pregnant while patients are exposed to Xgeva. Advise patients to contact their healthcare provider if they become pregnant or a pregnancy is suspected during this time. ADVERSE REACTIONS: The following adverse reactions are discussed below and elsewhere in the labeling: • Hypocalcemia • Osteonecrosis of the Jaw The most common adverse reactions in patients receiving Xgeva (per-patient incidence greater than or equal to 25%) were fatigue/asthenia, hypophosphatemia, and nausea (see Table 1). The most common serious adverse reaction in patients receiving Xgeva was dyspnea. The most common adverse reactions resulting in discontinuation of Xgeva were osteonecrosis and hypocalcemia. Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in practice. The safety of Xgeva was evaluated in three randomized, double-blind, double-dummy trials in which a total of 2841 patients with bone metastasis from prostate cancer, breast cancer, or other solid tumors, or lytic bony lesions from multiple myeloma received at least one dose of Xgeva. In Trials 1, 2, and 3, patients were randomized to receive either 120 mg of Xgeva every 4 weeks as a subcutaneous injection or 4 mg (dose adjusted for reduced renal function) of zoledronic acid every 4 weeks by intravenous (IV) infusion. Entry criteria included serum calcium (corrected) from 8 to 11.5 mg/dL (2 to 2.9 mmol/L) and creatinine clearance 30 mL/min or greater. Patients who had received IV bisphosphonates were excluded, as were patients with prior history of ONJ or osteomyelitis of the jaw, an active dental or jaw condition requiring oral surgery, non-healed dental/oral surgery, or any planned invasive dental

procedure. During the study, serum chemistries including calcium and phosphorus were monitored every 4 weeks. Calcium and vitamin D supplementation was recommended but not required. The median duration of exposure to Xgeva was 12 months (range: 0.1 – 41) and median duration on-study was 13 months (range: 0.1 – 41). Of patients who received Xgeva, 46% were female. Eighty-five percent were White, 5% Hispanic/Latino, 6% Asian, and 3% Black. The median age was 63 years (range: 18 – 93). Seventy-five percent of patients who received Xgeva received concomitant chemotherapy. Table 1. Per-patient Incidence of Selecteda Adverse Reactions of Any Severity (Trials 1, 2, and 3) Zoledronic Acid Xgeva n = 2836 Body System n = 2841 % % GASTROINTESTINAL 32 31 Nausea 19 20 Diarrhea GENERAL Fatigue/ Asthenia 45 46 IN VESTIGATIONS Hypocalcemiab 9 18 20 32 Hypophosphatemiab NEUROLOGICAL Headache 13 14 RESPIRATORY 18 21 Dyspnea 15 15 Cough Adverse reactions reported in at least 10% of patients receiving Xgeva in Trials 1, 2, and 3, and meeting one of the following criteria: • At least 1% greater incidence in Xgeva-treated patients, or • Between-group difference (either direction) of less than 1% and more than 5% greater incidence in patients treated with zoledronic acid compared to placebo (US Prescribing Information for zoledronic acid) b Laboratory-derived and below the central laboratory lower limit of normal [8.3 – 8.5 mg/dL (2.075 – 2.125 mmol/L) for calcium and 2.2 – 2.8 mg/dL (0.71 – 0.9 mmol/L) for phosphorus] Severe Mineral/Electrolyte Abnormalities • Severe hypocalcemia (corrected serum calcium less than 7 mg/dL or less than 1.75 mmol/L) occurred in 3.1% of patients treated with Xgeva and 1.3% of patients treated with zoledronic acid. Of patients who experienced severe hypocalcemia, 33% experienced 2 or more episodes of severe hypocalcemia and 16% experienced 3 or more episodes. • Severe hypophosphatemia (serum phosphorus less than 2 mg/dL or less than 0.6 mmol/L) occurred in 15.4% of patients treated with Xgeva and 7.4% of patients treated with zoledronic acid. Osteonecrosis of the Jaw In the primary treatment phases of Trials 1, 2, and 3, ONJ was confirmed in 1.8% of patients in the Xgeva group (median exposure of 12.0 months; range 0.1 – 40.5) and 1.3% of patients in the zoledronic acid group. The trials in patients with breast (Trial 1) or prostate (Trial 3) cancer included an Xgeva open label extension treatment phase where patients were offered Xgeva 120 mg once every 4 weeks (median overall exposure of 14.9 months; range 0.1 – 67.2). The patient-year adjusted incidence of confirmed ONJ was 1.1% during the first year of treatment and 4.1% thereafter. The median time to ONJ was 20.6 months (range: 4 – 53). Atypical Subtrochanteric and Diaphyseal Fracture Atypical femoral fracture has been reported with Xgeva. Giant Cell Tumor of Bone The safety of Xgeva was evaluated in two single arm trials (Trials 4 and 5) in which a total of 304 adult or skeletally mature adolescent patients with giant cell tumor of bone received at least 1 dose of Xgeva. Patients received 120 mg Xgeva subcutaneously every 4 weeks with additional 120 mg doses on Days 8 and 15 of the first month of therapy. Patients receiving concurrent bisphosphonate therapy were excluded from enrollment in both studies. Patients with prior history of ONJ or osteomyelitis of the jaw, an active dental or jaw condition requiring oral surgery, non-healed dental/oral surgery, or any planned invasive dental procedure were excluded from enrollment in Trial 5. During the trial, serum chemistries including calcium and phosphorus were monitored every 4 weeks. Calcium and vitamin D supplementation was recommended but not required. Of the 304 patients who received Xgeva, 145 patients were treated with Xgeva for ≥ 1 year, 44 patients for ≥ 2 years, and 15 patients for ≥ 3 years. The median number of doses received was 14 (range: 1 to 60 doses) and the median number of months on study was 11 (range: 0 to 54 months). Fifty-eight percent of the enrolled patients were women and 80% were White. The median age was 33 years (range: 13 to 83 years); a total of 10 patients were skeletally mature adolescents (13 to 17 years of age). The adverse reaction profile of Xgeva in patients with giant cell tumor of bone was similar to that reported in Trials 1, 2, and 3. The most common adverse reactions in patients (per-patient incidence ≥ 10%) were arthralgia, headache, nausea, back pain, fatigue, and pain in extremity. The most common serious adverse reactions were osteonecrosis of the jaw and osteomyelitis (per-patient incidence of 0.7%). The most common adverse reactions resulting in discontinuation of Xgeva were osteonecrosis of the jaw (per-patient incidence of 0.7%), and tooth abscess or tooth infection (per-patient incidence of 0.7%). The adverse reaction profile appeared similar in skeletally mature adolescents and adults. Hypocalcemia and Hypophosphatemia • Moderate hypocalcemia (corrected serum calcium less than 8 to 7 mg/dL or less than 2 to 1.75 mmol/L) occurred in 2.6% of patients treated with Xgeva. • Severe hypophosphatemia (serum phosphorus less than 2 to 1 mg/dL or less than 0.6 to 0.3 mmol/L) occurred in 29 patients (9.5%). Osteonecrosis of the Jaw (ONJ) In Trials 4 and 5, ONJ was confirmed in 4 of 304 (1.3%) patients who received Xgeva. The median time to ONJ was 16 months (range: 13 to 20 months) [see Warnings and Precautions (5.4)]. Hypercalcemia of Malignancy Xgeva was evaluated in an open-label, single-arm trial (Trial 6) in which 33 patients with hypercalcemia of malignancy (with or without bone metastases) refractory to treatment with intravenous bisphosphonate therapy were enrolled. The adverse reaction profile of Xgeva in patients with hypercalcemia of malignancy was similar to that reported in Trials 1, 2, 3, 4, and 5. Adverse reactions occurring in greater than 20% of patients were nausea (30%), dyspnea (27%), decreased appetite (24%), headache (24%), peripheral edema (24%), vomiting (24%), anemia (21%), constipation (21%), and diarrhea (21%). The following adverse reactions of Grade 3 or greater severity related to study therapy were reported on study: fatigue (3%) and infection (6%). Grade 3 laboratory abnormalities included hypomagnesemia (3%), hypokalemia (3%), and hypophosphatemia (76%) of patients. No deaths on study were related to Xgeva therapy. Postmarketing Experience. Because postmarketing reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The following adverse reactions have been identified during post approval use of Xgeva: • Hypocalcemia: Severe symptomatic hypocalcemia, including fatal cases. • Hypersensitivity, including anaphylactic reactions. • Musculoskeletal pain, including severe musculoskeletal pain. Positive rechallenge has been reported. Immunogenicity. As with all therapeutic proteins, there is potential for immunogenicity. Using an electrochemiluminescent bridging immunoassay, less than 1% (7/2758) of patients with osseous metastases treated with denosumab doses ranging from 30-180 mg every 4 weeks or every 12 weeks for up to 3 years and none of the 304 patients with giant cell tumor of bone in Trials 4 and 5 tested positive for binding antibodies. No patient with positive binding antibodies tested positive for neutralizing antibodies as a

assessed using a chemiluminescent cell-based in vitro biological assay. There was no evidence of altered pharmacokinetic profile, toxicity profile, or clinical response associated with binding antibody development. The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of a positive antibody (including neutralizing antibody) test result may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of antibodies to denosumab with the incidence of antibodies to other products may be misleading. DRUG INTERACTIONS: No formal drug-drug interaction trials have been conducted with Xgeva. There was no evidence that various anticancer treatments affected denosumab systemic exposure and pharmacodynamic effect. Serum denosumab concentrations at 1 and 3 months and reductions in the bone turnover marker uNTx/Cr (urinary N-terminal telopeptide corrected for creatinine) at 3 months were similar in patients with and without prior intravenous bisphosphonate therapy and were not altered by concomitant chemotherapy and/or hormone therapy. USE IN SPECIFIC POPULATIONS: Pregnancy: Category D. Risk Summary: Xgeva can cause fetal harm when administered to a pregnant woman based on findings in animals. In utero denosumab exposure in cynomolgus monkeys resulted in increased fetal loss, stillbirths, and postnatal mortality, along with evidence of absent lymph nodes, abnormal bone growth and decreased neonatal growth. There are no adequate and well-controlled studies with Xgeva in pregnant women. Women should be advised not to become pregnant when taking Xgeva. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women who become pregnant during Xgeva treatment are encouraged to enroll in Amgen’s Pregnancy Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll. Clinical Considerations: The effects of Xgeva are likely to be greater during the second and third trimesters of pregnancy. Monoclonal antibodies are transported across the placenta in a linear fashion as pregnancy progresses, with the largest amount transferred during the third trimester. If the patient becomes pregnant during Xgeva therapy, consider the risks and benefits in continuing or discontinuing treatment with Xgeva. Animal Data: The effects of denosumab on prenatal development have been studied in both cynomolgus monkeys and genetically engineered mice in which RANK ligand (RANKL) expression was turned off by gene removal (a “knockout mouse”). In cynomolgus monkeys dosed subcutaneously with denosumab throughout pregnancy at a pharmacologically active dose, there was increased fetal loss during gestation, stillbirths, and postnatal mortality. Other findings in offspring included absence of axillary, inguinal, mandibular, and mesenteric lymph nodes; abnormal bone growth, reduced bone strength, reduced hematopoiesis, dental dysplasia and tooth malalignment; and decreased neonatal growth. At birth out to one month of age, infants had measurable blood levels of denosumab (22621% of maternal levels). Following a recovery period from birth out to 6 months of age, the effects on bone quality and strength returned to normal; there were no adverse effects on tooth eruption, though dental dysplasia was still apparent; axillary and inguinal lymph nodes remained absent, while mandibular and mesenteric lymph nodes were present, though small; and minimal to moderate mineralization in multiple tissues was seen in one recovery animal. There was no evidence of maternal harm prior to labor; adverse maternal effects occurred infrequently during labor. Maternal mammary gland development was normal. There was no fetal NOAEL (no observable adverse effect level) established for this study because only one dose of 50 mg/kg was evaluated. In RANKL knockout mice, absence of RANKL (the target of denosumab) also caused fetal lymph node agenesis and led to postnatal impairment of dentition and bone growth. Pregnant RANKL knockout mice showed altered maturation of the maternal mammary gland, leading to impaired lactation. Nursing Mothers. It is not known whether Xgeva is excreted into human milk. Measurable concentrations of denosumab were present in the maternal milk of cynomolgus monkeys up to 1 month after the last dose of denosumab (≤ 0.5% milk:serum ratio). Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Xgeva, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. Maternal exposure to Xgeva during pregnancy may impair mammary gland development and lactation based on animal studies in pregnant mice lacking the RANK/RANKL signaling pathway that have shown altered maturation of the maternal mammary gland, leading to impaired lactation postpartum. However, in cynomolgus monkeys treated with denosumab throughout pregnancy, maternal mammary gland development was normal, with no impaired lactation. Mammary gland histopathology at 6 months of age was normal in female offspring exposed to denosumab in utero; however, development and lactation have not been fully evaluated. Pediatric Use. The safety and efficacy of Xgeva have not been established in pediatric patients except in skeletally mature adolescents with giant cell tumor of bone. Xgeva is recommended only for treatment of skeletally mature adolescents with giant cell tumor of bone. Xgeva was studied in an open-label trial that enrolled a subset of 10 adolescent patients (aged 13-17 years) with giant cell tumor of bone who had reached skeletal maturity, defined by at least 1 mature long bone (e.g., closed epiphyseal growth plate of the humerus), and had a body weight ≥ 45 kg. A total of two of six (33%) evaluable adolescent patients had an objective response by retrospective independent assessment of radiographic response according to modified Response Evaluation Criteria in Solid Tumors (RECIST 1.1) criteria. The adverse reaction profile and efficacy results appeared to be similar in skeletally mature adolescents and adults. Treatment with Xgeva may impair bone growth in children with open growth plates and may inhibit eruption of dentition. In neonatal rats, inhibition of RANKL (the target of Xgeva therapy) with a construct of osteoprotegerin bound to Fc (OPG-Fc) at doses ≤ 10 mg/kg was associated with inhibition of bone growth and tooth eruption. Adolescent primates treated with denosumab at doses 5 and 25 times (10 and 50 mg/ kg dose) higher than the recommended human dose of 120 mg administered once every 4 weeks, based on body weight (mg/kg), had abnormal growth plates, considered to be consistent with the pharmacological activity of denosumab. Cynomolgus monkeys exposed in utero to denosumab exhibited bone abnormalities, reduced hematopoiesis, tooth malalignment, decreased neonatal growth, and an absence of axillary, inguinal, mandibular, and mesenteric lymph nodes. Some bone abnormalities recovered once exposure was ceased following birth; however, axillary and inguinal lymph nodes remained absent 6 months post-birth. Geriatric Use. Of patients who received Xgeva in Trials 1, 2, and 3, 1260 (44%) were 65 years of age or older. No overall differences in safety or efficacy were observed between these patients and younger patients. Renal Impairment. Two clinical trials were conducted in patients without cancer and with varying degrees of renal function. In one study, patients (N=55) with varying degrees of renal function (ranging from normal through end-stage renal disease requiring dialysis) received a single 60 mg subcutaneous dose of denosumab. In a second study, patients (N=32) with severe renal dysfunction (creatinine clearance less than 30 mL/minute and/or on dialysis) were given two 120 mg subcutaneous doses of denosumab. In both studies, greater risk of developing hypocalcemia was observed with increasing renal impairment, and with inadequate/no calcium supplementation. Hypocalcemia was mild to moderate in severity in 96% of patients. Monitor calcium levels and, calcium and vitamin D intake. Females and Males of Reproductive Potential. Contraception Females: Counsel patients on pregnancy planning and prevention. Advise females of reproductive potential to use highly effective contraception during therapy, and for at least 5 months after the last dose of Xgeva. Advise patients to contact their healthcare provider if they become pregnant, or a pregnancy is suspected, during treatment or within 5 months after the last dose of Xgeva. Males: The extent to which denosumab is present in seminal fluid is unknown. There is potential for fetal exposure to denosumab when a male treated with Xgeva has unprotected sexual intercourse with a pregnant partner. Advise males of this potential risk. 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. USA-162x-104118

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Announcements

American Psychosocial Oncology Society Endorses Psychosocial Standards of Care for Children With Cancer and Their Families

he American Psychosocial Oncology Society (APOS) has endorsed the “Psychosocial Standards of Care for Children With Cancer and Their Families,” which were published in a December 2015 special supplement of Pediatric Blood & Cancer. The scientific, evidence-based psychosocial standards define the psychosocial care that all children with cancer and their families should receive. More than 60 clinicians and researchers from the United States, Canada, and the Netherlands developed the standards over 3 years following rigorous research and academic requirements and processes.

Need for Psychosocial Care The Mattie Miracle Cancer Foundation spearheaded the effort to create and implement Standards of Care to ensure patients and families have access to a minimum level of psychosocial care from the time of diagnosis, through survivorship or end-of-life and bereavement care. “We are proud that APOS collaborated with us on the development of the Standards. Having lost our only child to cancer, we know there is a medical standard of care for children, but there were no national psychosocial standards to guide cancer treatment,” said Victoria Sardi-Brown and Peter Brown, Co-Founders of The Mattie Miracle Cancer Foundation and parents of Mattie Brown, who lost his

life to a 14-month battle with childhood cancer on September 8, 2009. They added that “our mission was to change this because childhood cancer is not just about the medicine. The psychological impact of childhood cancer is just as real as the physical consequences, and these issues do not end once the medical treatment stops.”

Lori Wiener, PhD, DCSW

Mattie Brown died at the age of 7 following a 14-month battle with childhood cancer. Photo from the Mattie Miracle Foundation. Visit www.mattiemiracle.com.

Lori Wiener, PhD, DCSW, CoDirector of the Pediatric Oncology Branch at the National Cancer Institute, federal liaison to the APOS Board of Directors, and APOS Fellow, was instrumental in developing the pediatric psychosocial standards. Dr. Wiener stated, “These standards were developed, in large part, during APOS annual conferences from 2012–2015, when leaders in the field came together in separate think tanks to address current knowledge, needs, and how to strategically develop evidence-based standards of care pertaining to pediatric psychosocial data.” Dr. Wiener praised Paul Jacobsen, PhD, FAPOS, of H. Lee Moffitt Can-

Paul Jacobsen, PhD, FAPOS

cer Center, for his guidance prior to and during each think tank. The development of the Psychosocial Standards of Care is a major step forward in addressing the needs of children with cancer and their families. The integration of psychosocial care along with disease-directed treatment improves the quality of life across the cancer trajectory. Depression and other psychosocial concerns can affect adherence to treatment regimens and decrease coping abilities. Therefore, making psychosocial care part of standard treatment maximizes positive treatment outcomes. The Mattie Miracle Cancer Foundation and the team of pediatric oncology experts will work to encourage the rapid adoption of the Standards in clinical sites throughout the country. Learn more at www.mattiemiracle.com. The Pediatric Blood & Cancer special supplement can be viewed at http:// onlinelibrary.wiley.com/doi/10.1002/ pbc.v62.S5/issuetoc. To learn more about the Mattie Miracle Foundation, visit www.mattiemiracle.com n

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Art of Oncology Pieces of Grief Erica C. Kaye, MD The ASCO Post is pleased to reproduce installments of the “Art of Oncology” as published previously in the Journal of Clinical Oncology ( JCO). These articles focus on the experience of suffering from cancer or of caring for people diagnosed with cancer, and they include narratives, topical essays, historical vignettes, poems, and photographic essays. To read more, visit http://jco. ascopubs.org/ and search “Art of Oncology.”

struggle to remember Taylor’s face as he died. I piece together kaleidoscope fragments, but they blur in and out of focus: his sunken eyes, the sharp angle of his jaw, his cold fingers, the sucking spaces between his ribs. I’ve grown used to how the broken shards of people become embedded in my subconscious. I am careful— paranoid, even—about handling each memory fragment gingerly, lest it slice into a place within myself where it might linger like a splinter.

Starting to Unravel The end of Taylor’s life intersected with the end of my first year of pediatric hematology-oncology fellowship. Taylor was 15 years old, he had lymphoma, and he was dying. Many of my patients could be reduced to similar sound bites: age, disease, and acuity captured in quick one-liners. Initially, I rebelled against these synopses, injecting flowery language into my verbal and written reports in an effort to capture the spirit of my patients beyond their illnesses. I grew particularly fond of using adjectives like “feisty” or “precocious” to describe my patients, and I gladly accepted the inevitable teasing of my colleagues in return. Yet as I cared for increasing numbers of patients, I found it difficult to genuinely know children and families in a meaningful way that transcended their diseases and treatments. In the late evenings, I would try to circle back to the bedside in search of a few nonmedical moments. I remember these visits vividly: We sang, played board games, talked about life beyond the hospital. Often, I did not begin writing notes until after midnight. It did not take long before this pattern became unsustain-

able, and I started to unravel. Exhausted and anxious to prove my competence, I learned to prioritize proficiency and productivity. There were too many patients and too few hours in the day, with each shift morphing into a zero-sum game governed by meticulous triage calculations. To maximize efficiency, I mastered the art of collapsing patients into their disparate parts: vital signs, pain scores, input/output, laboratory values, medication doses, imaging studies. Over time, I started to believe that the key to healing my patients lay in these details, if only I were smarter or faster in gathering and deciphering the essential pieces.

Emotional Self-Regulation In the midst of this incessant data collection, I also was a front-seat witness to horror and heartbreak on a daily basis. Each layer of tragedy felt more raw and unbearable than the last, and I struggled to empathize deeply without falling apart. Coping might be easier, I thought, if I could figure out how to strip suffering down to objective, depersonalized data and then methodically process it. To achieve this goal, I deliberately tried to observe grief from a bird’s-eye view, using distance as a protective shield against the anguish of individual faces and stories. I knew that sadness was intrinsic to my chosen career, and I began to wonder if detachment might be a partial antidote to—or better yet, a preemptive strike against— grief. The culture of oncology has a long history of stigmatizing death and the dying process as well as condemning emotion as weakness.1 Sensitive to this stigma and eager to fit in, I became preoccupied with learning how to turn my emotions on and off, akin to flipping a light switch. Yet as I ran from one terrible death to another, I struggled to slip into autopilot. Ironically, the more I strove for emotional self-regulation, the more emotionally unbalanced I became. On a subliminal level, I think I was afraid that, should I succeed in turning off my emotions, I might forget how to turn them back on. Or, perhaps worse, I might not want to. Secretly, I envied my colleagues who seemed able to move gracefully between devastating events, their objectivity and empathy unclouded by the surrounding emotional turmoil. I, on the other hand, absorbed the emotions of my patients and their families with an intensity that both blinded and consumed me. In pub-

lic, I strove to maintain a facade of composure, busying myself by accounting for every medical detail. Yet privately, I wept in my car on the drive to and from the hospital. In the rare hours that I slept, my nightmares were filled with montages of vital signs and laboratory values splayed across disembodied organs, all of the images nameless and faceless.

Drowning in Unresolved Grief In retrospect, in my drive to compute medical minutiae, I gradually lost count of what mattered. Faced with relentlessly high patient numbers and acuity, just completing the requisite daily tasks was

scious, but I doubt that it was accidental. In difficult moments, depersonalized suffering is simply easier to tolerate. Pediatric oncology fellows admit to becoming increasingly desensitized toward death and dying throughout their training,2 and this is not a problem that trainees outgrow; oncologists likewise use words like “denial” and “dissociation” to describe how they cope with the death of their patients, and they report burnout secondary to their inability to compartmentalize grief or create sustainable emotional boundaries.4 By the end of my first year of fellowship, I had reached a breaking point. I

Slowly, I am learning to cope and grieve—not despite, but rather in honor of, all of the pieces that embody our humanity. —Erica C. Kaye, MD

often unfeasible; finding time or a quiet place to reflect on the life and death of each child simply did not make my todo list. At the time, I thought that I was suffocating underneath an impossible workload; in retrospect, I was drowning in unresolved, cumulative grief. My experience is not unique. When pediatric oncology fellows at two academic centers were interviewed about their experiences with the deaths of their patients, they endorsed feelings of sadness, guilt, failure, and helplessness.2 Fellows also expressed feeling vulnerable, inexperienced, unable to cope, and alone in their reactions to death, and they attributed their negative experiences to inadequate modeling of coping strategies, lack of grief counseling and other supportive resources, and extensive ward duties that exhausted their physical and emotional reserves.3 Not every oncologist suffers from extreme grief, yet many do experience at least some degree of these feelings at some point in their careers, suggesting the importance of making room for such emotions in our clinical practice. Personally, my default survival strategy was to focus on the objective data; yet the more I concentrated on my patients’ diseases, treatments, and complications, the more I lost sight of their humanity, and my own. My behavior was subcon-

had enough insight to recognize that I was a shell of my former self, but allowing myself time to reflect on the reasons felt like a luxury that I didn’t deserve and couldn’t afford. Whenever I felt the familiar lump swell in my throat, I redirected my emotional energy into productivity, checking off boxes on my to-do list robotically until the waves of hurt subsided. After nearly 12 months of accumulated grief, however, the dam was beginning to crack and I struggled to plug the leaks. After one particularly difficult overnight shift during which several children died, I was numbly marching through morning rounds when I suddenly felt ill. I excused myself with the pretense of using the restroom, and I barely made it there before the tears began to fall. For a few minutes, I sat on the floor beside the sink, weeping with my face pressed against my knees. Then I wiped my eyes, practiced a smile, and returned to finish rounds. Around this time I began to realize that I had unwittingly trapped myself in a false dichotomy: competent professional detachment on one end vs inefficient empathy on the other. Unable to reconcile what I thought were diametrically opposed aptitudes, I focused on analyzing the medical data, believing this would enable me to see the full story and be the best possible doctor. In doing so, I

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Art of Oncology conflated problem-solving with healing. Worse still, I failed to celebrate my patients as unique souls, each shaped, but not defined, by their illness journeys.

An Intimate Moment In this fragile mindset, I met Taylor. It was only a few hours before he died. As I stood in the hallway of the intensive care unit and observed him through the sliding glass door, I remember thinking that I was gathering the information I needed to know: the skin hanging loosely over protruding bones, the blue-gray tinge of his lips, the shallow laboring of his sunken chest. Silently, I aggregated his physical appearance with the information obtained in my chart review: The sum of his data pointed to imminent death. Taylor’s eyes were closed when I entered the room, but I could tell that he was not asleep. I knelt beside him and placed my hand over his. Introducing myself, I asked him if there was anything he needed. With effort, Taylor opened his eyes and looked steadily into mine. Please keep holding my hand, he said. Don’t let go. His hand was cold and frail. My own sweating and pulsing. I won’t let go, I told him. My voice faltered, and silence wrapped around us. Taylor’s eyes closed, as tears filled mine. I don’t know how long I crouched in front of him, holding his hand. Neither of us spoke again. I remember trying to memorize his face, piece by piece, hoping somehow to capture the whole of him, to reconcile this intimate moment with the fact that I had no idea who he was. Only a few moments earlier, I had presumed to know Taylor’s story from outside the glass door; the realization of my gross error was bitterly painful and shameful in its sudden clarity as his life slipped away. As I held his hand, I thought about everything that I did not know and would never have a chance to learn about Taylor. I felt his humanity eclipse his illness, and I let myself cry without feeling ashamed. I was stunned to realize that, when I stopped hiding behind the medical data and simply stood still in that painful moment, I felt a sense of purpose and peace that had eluded me for months. Taylor reminded me that knowing a patient’s medical story in fastidious detail is not the same thing as knowing his story. When we miss the opportunity to learn who our patients are—their likes, dislikes, hopes, fears, dreams—we also miss an opportunity to find meaning in our work, to grieve, and to achieve the closure requisite to career longevity and sustainability.

The Sum of Their Parts I fixed nothing, and Taylor died. But in bearing witness during those few moments, I felt like more of a healer than I had during all of the preceding year. It took me months to reach this realization, but I finally found myself able to grieve, openly and vulnerably, for the senseless loss of a beautiful young man and all of the mysterious parts of his unique personhood. More than a year later, glimpses of Taylor still flash behind my eyes in unexpected moments, intermingling

with fragmented memories of the other children who have died. My mind whirs in a frantic effort to aggregate the sum of their parts. Even now, I am haunted by the pieces that are missing. Slowly, though, I am learning how to cope and grieve—not despite, but rather in honor of, all of the pieces that embody our humanity. n References 1. Granek L, Krzyzanowska MK, Tozer R, et al: Difficult patient loss and physician culture for oncologists grieving patient loss. J

Palliat Med 15:1254-1260, 2012. 2. Granek L, Bartels U, Scheinemann K, et al: Grief reactions and impact of patient death on pediatric oncologists. Pediatr Blood Cancer 62:134-142, 2015. 3. Granek L, Bartels U, Barrera M, et al: Challenges faced by pediatric oncology fellows when patients die during their training. J Oncol Pract 11:e182-e189, 2015. 4. Granek L, Tozer R, Mazzotta P, et al: Nature and impact of grief over patient loss on oncologists’ personal and professional lives. Arch Intern Med 172:964-966, 2012.

! W NE

Special Issue Coming in April VOL 7

Highlights From the 2015 JADPRO Live at APSHO Annual Conference

NO 3

| APR 2016

Highlights From the 2015 JADPRO Live at APSHO Conference The Science Behind Biologics and Biosimilars Kelley D. Mayden

Review of Newly Approved Oncologic Therapies: 2014–2015 Patrick Medina, Monique Giordana

Updates in the Treatment of Metastatic Colorectal Cancer John Marshall, Robin Sommers

This exciting BONUS issue of JADPRO will include summaries of each session presented at the 2015 JADPRO Live at APSHO conference.

Benign Hematology: Bleeding Disorders Ravi Krishnadasan

Evolving Paradigms in Melanoma Therapy Anthony J. Olszanski, Brianna Hoffner

Management of Dermatologic Toxicities From Targeted Therapies Mario E. Lacouture

Non–Small Cell Lung Cancer: Immunotherapy Suzanne Walker

Management of Locally Advanced and Metastatic HER2-Positive Breast Cancer Melanie E. Royce, Karen Herold

advancedpractitioner.com

For more information, contact Betty Ann Gilchrist at bettyann@harborsidepress.com

The ASCO Post | JANUARY 25, 2016

PAGE 142

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 Woodburytype, Philadelphia, 1869

Mastectomy Healed by Earth Dressing Patient of Addinell Hewson, MD

nfection was the roadblock to the advancement of surgery. The lengthy and complicated operations that anesthesia permitted often resulted in high morbidity and mortality. Every operation was expected to cause an infection. The most common hospital infections were erysipelas, hospital gangrene, and pyemia (septicemia), with mortality rates of over 90%. If the patient contracted one of these infections, death was the usual outcome. One Philadelphia surgeon, however, bucked the odds. His patients didn’t get infections, and they healed their wounds by primary intention.

Joseph Lister, MD

During the Civil War, the research conclusions of Louis Pasteur, stating that putrefaction and bacteria caused fermentation, were published. English surgeon Joseph Lister, MD (1827– 1912), implemented Pasteur’s idea into a landmark medical proposal. Since foreign matter, bacteria, dirt, etc. were the culprits in wound infection, he recognized that by keeping a wound clean, it would heal without infection. Dr. Lister’s antiseptic wound treatment and surgical antiseptic procedures were the second greatest medical innovation of the 19th century. With the knowledge of the fatality rate from secondary infec-

tions during the Civil War and in light of both Pasteur’s and Lister’s work, physicians were certainly not responsive to the therapy suggestions of Philadelphia surgeon Addinell Hewson, MD (1828–1889). Dr. Hewson proposed an innovative wound treatment using earth as the dressing. A fascinating aspect of medical history is that occasionally great ideas and advances lay hidden in old books and journals; however, open minds and new technologies are sometimes necessary to understand and implement the discoveries of the past. In 1872, Dr. Hewson published Earth as a Topical Application in Surgery. He described his treatment of wounds and operative cases using an application of earth as a dressing with its accompanying acceleration of the healing process. He detailed 93 cases, including ulcers, burns, gunshot wounds, and operations such as this mastectomy. The cases were all treated during a 6-month period in 1869 at the Pennsylvania Hospital. All wounds were dressed with his special dirt and all healed quickly, most within 15 days. Dr. Hewson attributed this healing to the action of the ozone, deoxygenating, and released ammonia. It was more likely that the infection was inhibited by the presence of a naturally occurring antibacterial agent in the soil such as bacitracin. Unfortunately for Dr. Hewson, his work appeared at the same time that Dr. Lister’s antiseptic surgical technique was being promoted. Packing wounds with dirt made no sense to a profession recently advised of the necessity for cleanliness. Had Dr. H ewson’s findings been evaluated more seriously, the

age of antibiotics might have dawned a half-century sooner. This photograph is one of two he published showing his success with mastectomy. “Hannah C. admitted to the hospital on the 12th of February for a scirrhous tumor of the right mamma.” The 41-year-old widow with three children presented with the cachexia of cancer. “Operation of excision of the whole gland was performed before the class of the hospital on the 17th of Feb-

ruary over 40 square inches of wound surface (had) to be healed. Dry earth was spread over the breast, and retained by some pieces of white unglazed paper and a roller around the chest.” The earth dressing was renewed daily and on the 24th the gauze was removed, “and found union firm and complete.” On the 27th of February, this photograph was taken. “In January, 1871 nearly 3 years after the operation, there was no return of disease.” n

FOR UNRESECTABLE OR METASTATIC LIPOSARCOMA OR LEIOMYOSARCOMA AFTER ANTHRACYCLINE

THERE IS A NEW OPTION

INDICATIONS

YONDELIS速 (trabectedin) is indicated for the treatment of patients with unresectable or metastatic liposarcoma or leiomyosarcoma who received a prior anthracycline-containing regimen.

IMPORTANT SAFETY INFORMATION CONTRAINDICATIONS

YONDELIS速 is contraindicated in patients with known severe hypersensitivity, including anaphylaxis, to trabectedin.

Please see the following pages for additional Important Safety Information and a Brief Summary of the full Prescribing Information.

NOW APPROVED

PROPEL TREATMENT FORWARD WITH 45%

REDUCTION OF RISK vs dacarbazine

YONDELIS® ( trabectedin) SIGNIFICANTLY IMPROVED PROGRESSION-FREE SURVIVAL (PFS) YONDELIS® resulted in a 45% reduction in the risk of disease progression or death compared with dacarbazine in a phase 3, open-label study • YONDELIS® improved median PFS* vs dacarbazine: 4.2 months with YONDELIS® vs 1.5 months for dacarbazine (hazard ratio [HR]†=0.55; 95% CI: 0.44, 0.70; P<0.001‡)

Kaplan-Meier Curve of PFS 100

Dacarbazine YONDELIS® Censored in dacarbazine Censored in YONDELIS®

90 80

Subjects, %

70 60 50 40 30 20 10 0 0

0 5

Progression-Free Survival, Months NUMBER OF SUBJECTS AT RISK: Dacarbazine YONDELIS®

173 345

35 133

10 71

2 29

1 10

*An exploratory analysis of independent radiology committee–determined PFS, in a subgroup consisting of approximately 60% of the total population, provided similar results to the investigator-determined PFS. †HR is estimated using Cox proportional hazards model with treatment group as the only covariate. ‡P value is based on unstratified log-rank test.

Study Design YONDELIS® was studied in a phase 3 randomized, open-label, active-controlled, multicenter trial of patients with unresectable, locally advanced or metastatic leiomyosarcomas (73%) or liposarcomas (27%).

IMPORTANT SAFETY INFORMATION WARNINGS AND PRECAUTIONS

Neutropenic sepsis, including fatal cases, can occur. In Trial 1, the incidence of Grade 3 or 4 neutropenia, based on laboratory values, was 43% (161/378). Median time to the first occurrence of Grade 3 or 4 neutropenia was 16 days (range: 8 days to 9.7 months). Median time to complete resolution of neutropenia was 13 days (range: 3 days to 2.3 months). Febrile neutropenia (fever ≥38.5°C with Grade 3 or 4 neutropenia) occurred in 18 patients (5%). Ten patients (2.6%) experienced neutropenic sepsis, 5 of whom had febrile neutropenia, which was fatal in 4 patients (1.1%). Assess neutrophil count prior to administration of each dose of YONDELIS® and periodically throughout the treatment cycle. Withhold YONDELIS® for neutrophil counts of less than 1500 cells/microliter on the day of dosing. Permanently reduce the dose of YONDELIS® for life-threatening or prolonged, severe neutropenia in the preceding cycle. Rhabdomyolysis—YONDELIS® can cause rhabdomyolysis and musculoskeletal toxicity. In Trial 1, rhabdomyolysis leading to death occurred in 3 (0.8%) of the 378 patients. Elevations in creatine phosphokinase (CPK) occurred in 122 (32%) of the 378 patients receiving YONDELIS®, including Grade 3 or 4 CPK elevation in 24 patients (6%), compared to 15 (9%) of the 172 patients receiving dacarbazine with any CPK elevation, including 1 patient (0.6%) with Grade 3 CPK elevation. Among the 24 patients receiving YONDELIS® with Grade 3 or 4 CPK elevation, renal failure occurred in 11 patients (2.9%); rhabdomyolysis with the complication of renal failure occurred in 4 of these 11 patients (1.1%). Median time to first occurrence of Grade 3 or 4 CPK elevations was 2 months (range: 1 to 11.5 months). Please see the following pages for additional Important Safety Information and a Brief Summary of the full Prescribing Information.

YONDELIS®

13.7 months

The median overall survival was 13.7 months for patients treated with YONDELIS® vs 13.1 months for patients treated with dacarbazine in the pivotal trial (HR=0.93; 95% CI: 0.75, 1.15; P=0.49)

S:13 IN

T:14 IN

B:14.25 IN

2.7 months

Median duration of response was 2.7 months longer for YONDELIS® vs dacarbazine (6.9 months vs 4.2 months, respectively)

13 weeks

The median duration of treatment with YONDELIS® was 13 weeks (range, 1 to 127 weeks), with 30% of patients treated for more than 6 months and 7% for more than 1 year Liposarcoma and leiomyosarcoma are two of the most common subtypes of soft tissue sarcomas.1,2 References: 1. Blay J-Y, Sleijfer S, Schöffski P, et al. International expert opinion on patient-tailored management of soft tissue sarcomas. Eur J Cancer. 2014;50(4):679-689. 2. Ducimetière F, Lurkin A, Ranchère-Vince D, et al. Incidence of sarcoma histotypes and molecular subtypes in a prospective epidemiological study with central pathology review and molecular testing. PLoS One. 2011;6(8):e20294.

Median time to complete resolution was 14 days (range: 5 days to 1 month). Assess CPK levels prior to each administration of YONDELIS®. Withhold YONDELIS® for serum CPK levels more than 2.5 times the upper limit of normal. Permanently discontinue YONDELIS® for rhabdomyolysis. Hepatotoxicity, including hepatic failure, can occur. Patients with serum bilirubin levels above the upper limit of normal or AST or ALT levels > 2.5 x ULN were not enrolled in Trial 1. In Trial 1, the incidence of Grade 3-4 elevated liver function tests (defined as elevations in ALT, AST, total bilirubin, or alkaline phosphatase) was 35% (134/378). Median time to development of Grade 3-4 elevation in ALT or AST was 29 days (range: 3 days to 11.5 months). Of the 134 patients with Grade 3 to 4 elevations in LFTs, 114 (85%) experienced complete resolution with the median time to complete resolution of 13 days (range: 4 days to 4.4 months). In Trial 1, the incidence of drug-induced liver injury (defined as concurrent elevation in ALT or AST of more than three times the upper limit of normal, alkaline phosphatase less than two times the upper limit of normal, and total bilirubin at least two times the upper limit of normal) was 1.3% (5/378). ALT or AST elevation greater than eight times the ULN occurred in 18% (67/378) of patients. Assess LFTs prior to each administration of YONDELIS®. Manage elevated LFTs with treatment interruption, dose reduction, or permanent discontinuation NOW APPROVED based on severity and duration of LFT abnormality.

IMPORTANT SAFETY INFORMATION Cardiomyopathy, including cardiac failure, congestive heart failure, ejection fraction decreased, diastolic dysfunction, or right ventricular dysfunction can occur. In Trial 1, patients with a history of New York Heart Association Class II to IV heart failure or abnormal left ventricular ejection fraction (LVEF) at baseline were ineligible. In Trial 1, cardiomyopathy occurred in 23 patients (6%) receiving YONDELIS® and in four patients (2.3%) receiving dacarbazine. Grade 3 or 4 cardiomyopathy occurred in 15 patients (4%) receiving YONDELIS® and 2 patients (1.2%) receiving dacarbazine; cardiomyopathy leading to death occurred in 1 patient (0.3%) receiving YONDELIS® and in none of the patients receiving dacarbazine. The median time to development of Grade 3 or 4 cardiomyopathy in patients receiving YONDELIS® was 5.3 months (range: 26 days to 15.3 months). Assess left ventricular ejection fraction (LVEF) by echocardiogram or multigated acquisition (MUGA) scan before initiation of YONDELIS® and at 2- to 3-month intervals thereafter until YONDELIS® is discontinued. Withhold YONDELIS® for LVEF below lower limit of normal. Permanently discontinue YONDELIS® for symptomatic cardiomyopathy or persistent left ventricular dysfunction that does not recover to lower limit of normal within 3 weeks. Extravasation Resulting in Tissue Necrosis—Extravasation of YONDELIS®, resulting in tissue necrosis requiring debridement, can occur. Evidence of tissue necrosis can occur more than 1 week after the extravasation. There is no specific antidote for extravasation of YONDELIS®. Administer YONDELIS® through a central venous line. Embryofetal Toxicity—Based on its mechanism of action, YONDELIS® can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during therapy and for at least 2 months after the last dose of YONDELIS®. Advise males with female partners of reproductive potential to use effective contraception during therapy and for at least 5 months after the last dose of YONDELIS®. Adverse Reactions—The most common (≥20%) adverse reactions were nausea (75%), fatigue (69%), vomiting (46%), constipation (37%), decreased appetite (37%), diarrhea (35%), peripheral edema (28%), dyspnea (25%), and headache (25%). The most common (≥5%) grades 3-4 laboratory abnormalities are: neutropenia (43%), increased ALT (31%), thrombocytopenia (21%), anemia (19%), increased AST (17%), and increased creatine phosphokinase (6.4%). Effect of Cytochrome CYP3A Inhibitors—Avoid use of strong CYP3A inhibitors (e.g., oral ketoconazole, itraconazole, posaconazole, voriconazole, clarithromycin, telithromycin, indinavir, lopinavir, ritonavir, boceprevir, nelfinavir, saquinavir, telaprevir, nefazodone, conivaptan) in patients taking YONDELIS®. Avoid taking grapefruit or grapefruit juice. If a strong CYP3A inhibitor for short-term use (i.e., less than 14 days) must be used, administer the strong CYP3A inhibitor 1 week after the YONDELIS® infusion, and discontinue it the day prior to the next YONDELIS® infusion. Effect of Cytochrome CYP3A Inducers—Avoid administering strong CYP3A inducers (e.g., rifampin, phenobarbital, St. John’s wort) to patients who are taking YONDELIS®. Please see the following pages for Brief Summary of the full Prescribing Information.

NOW APPROVED

040598-150918

DRUG INTERACTIONS

YONDELIS (trabectedin) for injection, for intravenous use Brief Summary of Full Prescribing Information INDICATIONS AND USAGE YONDELIS® is indicated for the treatment of patients with unresectable or metastatic liposarcoma or leiomyosarcoma who received a prior anthracycline-containing regimen [see Clinical Studies (14) in Full Prescribing Information]. CONTRAINDICATIONS YONDELIS is contraindicated in patients with known severe hypersensitivity, including anaphylaxis, to trabectedin. WARNINGS AND PRECAUTIONS Neutropenic Sepsis: Neutropenic sepsis, including fatal cases, can occur with YONDELIS. In Trial 1, the incidence of Grade 3 or 4 neutropenia, based on laboratory values, in patients receiving YONDELIS was 43% (161/378). The median time to the first occurrence of Grade 3 or 4 neutropenia was 16 days (range: 8 days to 9.7 months); the median time to complete resolution of neutropenia was 13 days (range: 3 days to 2.3 months). Febrile neutropenia (fever ≥38.5°C with Grade 3 or 4 neutropenia) occurred in 18 patients (5%) treated with YONDELIS. Ten patients (2.6%) experienced neutropenic sepsis, 5 of whom had febrile neutropenia, which was fatal in 4 patients (1.1%). Assess neutrophil count prior to administration of each dose of YONDELIS and periodically throughout the treatment cycle. Withhold YONDELIS for neutrophil counts of less than 1500 cells/microliter on the day of dosing. Permanently reduce the dose of YONDELIS for life-threatening or prolonged, severe neutropenia in the preceding cycle [see Dosage and Administration (2.3) in Full Prescribing Information]. Rhabdomyolysis: YONDELIS can cause rhabdomyolysis and musculoskeletal toxicity. In Trial 1, rhabdomyolysis leading to death occurred in 3 (0.8%) of the 378 patients receiving YONDELIS. Elevations in creatine phosphokinase (CPK) occurred in 122 (32%) of the 378 patients receiving YONDELIS, including Grade 3 or 4 CPK elevation in 24 patients (6%), compared to 15 (9%) of the 172 patients receiving dacarbazine with any CPK elevation, including 1 patient (0.6%) with Grade 3 CPK elevation. Among the 24 patients receiving YONDELIS with Grade 3 or 4 CPK elevation, renal failure occurred in 11 patients (2.9%); rhabdomyolysis with the complication of renal failure occurred in 4 of these 11 patients (1.1%). The median time to first occurrence of Grade 3 or 4 CPK elevations was 2 months (range: 1 to 11.5 months). The median time to complete resolution was 14 days (range: 5 days to 1 month). Assess CPK levels prior to each administration of YONDELIS. Withhold YONDELIS for serum CPK levels more than 2.5 times the upper limit of normal. Permanently discontinue YONDELIS for rhabdomyolysis [see Dosage and Administration (2.3) in Full Prescribing Information]. Hepatotoxicity: Hepatotoxicity, including hepatic failure, can occur with YONDELIS. Patients with serum bilirubin levels above the upper limit of normal or AST or ALT levels >2.5 x ULN were not enrolled in Trial 1. In Trial 1, the incidence of Grade 3-4 elevated liver function tests (defined as elevations in ALT, AST, total bilirubin, or alkaline phosphatase) was 35% (134/378) in patients receiving YONDELIS. The median time to development of Grade 3-4 elevation in ALT or AST was 29 days (range: 3 days to 11.5 months). Of the 134 patients with Grade 3-4 elevations in LFTs, 114 (85%) experienced complete resolution with the median time to complete resolution of 13 days (range: 4 days to 4.4 months). In Trial 1, the incidence of drug-induced liver injury (defined as concurrent elevation in ALT or AST of more than three times the upper limit of normal, alkaline phosphatase less than two times the upper limit of normal, and total bilirubin at least two times the upper limit of normal) was 1.3% (5/378) in patients receiving YONDELIS. ALT or AST elevation greater than eight times the ULN occurred in 18% (67/378) of patients receiving YONDELIS. Assess LFTs prior to each administration of YONDELIS. Manage elevated LFTs with treatment interruption, dose reduction, or permanent discontinuation based on severity and duration of LFT abnormality [see Dosage and Administration (2.3) in Full Prescribing Information]. Cardiomyopathy: Cardiomyopathy including cardiac failure, congestive heart failure, ejection fraction decreased, diastolic dysfunction, or right ventricular dysfunction can occur with YONDELIS. In Trial 1, patients with a history of New York Heart Association Class II to IV heart failure or abnormal left ventricular ejection fraction (LVEF) at baseline were ineligible. In Trial 1, cardiomyopathy occurred in 23 patients (6%) receiving YONDELIS and in four patients (2.3%) receiving dacarbazine. Grade 3 or 4 cardiomyopathy occurred in 15 patients (4%) receiving YONDELIS and 2 patients (1.2%) receiving dacarbazine; cardiomyopathy leading to death occurred in 1 patient (0.3%) receiving YONDELIS and in none of the patients receiving dacarbazine. The median time to development of Grade 3 or 4 cardiomyopathy in patients receiving YONDELIS was 5.3 months (range: 26 days to 15.3 months). Assess left ventricular ejection fraction (LVEF) by echocardiogram or multigated acquisition (MUGA) scan before initiation of YONDELIS and at 2- to 3-month intervals thereafter until YONDELIS is discontinued. Withhold YONDELIS for LVEF below lower limit of normal. Permanently discontinue YONDELIS for symptomatic cardiomyopathy or persistent left ventricular dysfunction that does not recover to lower limit of normal within 3 weeks [see Dosage and Administration (2.3) in Full Prescribing Information]. Extravasation Resulting in Tissue Necrosis: Extravasation of YONDELIS, resulting in tissue necrosis requiring debridement, can occur. Evidence of tissue necrosis can occur more than 1 week after the extravasation. There is no specific antidote for extravasation of YONDELIS. Administer YONDELIS through a central venous line [see Dosage and Administration (2.5) in Full Prescribing Information]. Embryofetal Toxicity: Based on its mechanism of action, YONDELIS can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during therapy and for at least 2 months after the last dose of YONDELIS. Advise males with female partners of reproductive potential to use effective contraception during therapy and for at least 5 months after the last dose of YONDELIS [see Use in Specific Populations].

YONDELIS® (trabectedin) for injection intravenous infusion over 20 to 120 minutes once every 3 weeks (n=172) [see Clinical Studies (14) in Full Prescribing Information]. All patients treated with YONDELIS were required to receive dexamethasone 20 mg intravenous injection 30 minutes prior to start of the YONDELIS infusion. In Trial 1, patients had been previously treated with an anthracycline- and ifosfamide-containing regimen or with an anthracycline-containing regimen and one additional cytotoxic chemotherapy regimen. The trial excluded patients with known central nervous system metastasis, elevated serum bilirubin or significant chronic liver disease, such as cirrhosis or active hepatitis, and history of myocardial infarction within 6 months, history of New York Heart Association Class II to IV heart failure, or abnormal left ventricular ejection fraction at baseline. The median age of patients in Trial 1 was 57 years (range: 17 to 81 years), with 69% female, 77% White, 12% Black or African American, 4% Asian, and <1% American Indian or Alaska Native. The median duration of exposure to trabectedin was 13 weeks (range: 1 to 127 weeks) with 30% of patients exposed to YONDELIS for greater than 6 months and 7% of patients exposed to YONDELIS for greater than 1 year. In Trial 1, adverse reactions resulting in permanent discontinuation of YONDELIS occurred in 26% (98/378) of patients; the most common were increased liver tests (defined as ALT, AST, alkaline phosphatase, bilirubin) (5.6%), thrombocytopenia (3.4%), fatigue (1.6%), increased creatine phosphokinase (1.1%), and decreased ejection fraction (1.1%). Adverse reactions that led to dose reductions occurred in 42% (158/378) of patients treated with YONDELIS; the most common were increased liver tests (24%), neutropenia (including febrile neutropenia) (8%), thrombocytopenia (4.2%), fatigue (3.7%), increased creatine phosphokinase (2.4%), nausea (1.1%), and vomiting (1.1%). Adverse reactions led to dose interruptions in 52% (198/378) of patients treated with YONDELIS; the most common were neutropenia (31%), thrombocytopenia (15%), increased liver tests (6%), fatigue (2.9%), anemia (2.6%), increased creatinine (1.1%), and nausea (1.1%). The most common adverse reactions (≥20%) were nausea, fatigue, vomiting, constipation, decreased appetite, diarrhea, peripheral edema, dyspnea, and headache. The most common laboratory abnormalities (≥20%) were increases in AST or ALT, increased alkaline phosphatase, hypoalbuminemia, increased creatinine, increased creatine phosphokinase, anemia, neutropenia, and thrombocytopenia. Table 1: Selected Adverse Reactionsa occurring in ≥10% of Patients receiving YONDELIS and at a higher incidence than in the Control Arm - Trial 1 System Organ Class Adverse Reaction

Gastrointestinal disorders Nausea 75 Vomiting 46 Constipation 37 Diarrhea 35 General disorders and administration site conditions 69 Fatiguec Peripheral edema 28 Metabolism and nutrition disorders Decreased appetite 37 Respiratory, thoracic and mediastinal disorders Dyspnea 25 Nervous system disorders Headache 25 Musculoskeletal and connective tissue disorders Arthralgia 15 Myalgia 12 Psychiatric disorders Insomnia 15 a

b c

Dacarbazine (N=172) All Grades Grades 3-4 (%) (%)

7 6 0.8 1.6

50 22 31 23

1.7 1.2 0.6 0

8 0.8

52 13

1.7 0.6

1.9

0.6

4.2

1.2

0.3

0 0

8 6

1.2 0

0.3

Limited to adverse reactions at a rate of ≥10% in the trabectedin arm and at a rate higher in the trabectedin arm compared with dacarbazine arm by ≥5% in overall incidence or by ≥2% for Grade 3-4 adverse reactions. Toxicity grade is based on NCI common toxicity criteria, version 4.0. Fatigue is a composite of the following adverse event terms: fatigue, asthenia, and malaise.

Other clinically important adverse reactions observed in <10% of patients (N=755) with soft tissue sarcoma receiving YONDELIS were: Nervous system disorders: peripheral neuropathy, paresthesia, hypoesthesia. Respiratory, thoracic, and mediastinal disorders: pulmonary embolism. Table 2: Incidence of Selected Treatment-Emergent Laboratory Abnormalitiesa - Trial 1 Laboratory Abnormalities Chemistry Increased ALT Increased AST Increased alkaline phosphatase Hypoalbuminemia Increased creatinine Increased creatine phosphokinase Hyperbilirubinemia Hematology Anemia Neutropenia Thrombocytopenia

ADVERSE REACTIONS The following adverse reactions are discussed in more detail in other sections of the labeling: • Anaphylaxis [see Contraindications] • Neutropenic Sepsis [see Warnings and Precautions] • Rhabdomyolysis [see Warnings and Precautions] • Hepatotoxicity [see Warnings and Precautions] • Cardiomyopathy [see Warnings and Precautions] • Extravasation Resulting in Tissue Necrosis [see Warnings and Precautions] Adverse Reactions in Clinical Trials: 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 below reflect exposure to YONDELIS in 755 patients with soft tissue sarcoma including 197 (26%) patients exposed to YONDELIS for greater than or equal to 6 months and 57 (8%) patients exposed to YONDELIS for greater than or equal to 1 year. The safety of YONDELIS was evaluated in six open-label, single-arm trials, in which 377 patients received YONDELIS and one open-label, randomized, active-controlled clinical trial in which 378 patients received YONDELIS (Trial 1). All patients received YONDELIS at the recommended dosing regimen of 1.5 mg/m2 administered as an intravenous infusion over 24 hours once every 3 weeks (q3wk, 24-h). The median age was 54 years (range: 18 to 81 years), 63% were female, and all patients had metastatic soft tissue sarcoma. Tables 1 and 2 present selected adverse reactions and laboratory abnormalities, respectively, observed in Trial 1, an open-label, randomized (2:1), active-controlled trial in which 550 patients with previously treated leiomyosarcoma or liposarcoma (dedifferentiated, myxoid round cell, or pleomorphic) received YONDELIS 1.5 mg/m2 intravenous infusion over 24 hours once every 3 weeks (n=378) or dacarbazine 1000 mg/m2

YONDELIS (N=378) Grades 3-4 All Gradesb (%) (%)

YONDELIS All Grades Grades 3-4 (%) (%)

Dacarbazine All Grades Grades 3-4 (%) (%)

90 84 70 63 46 33 13

31 17 1.6 3.7 4.2 6.4 1.9

33 32 60 51 29 9 5

0.6 1.2 0.6 3.0 1.2 0.6 0.6

96 66 59

19 43 21

79 47 57

12 26 20

Treatment-emergent laboratory abnormalities including those higher in the trabectedin arm compared with the dacarbazine arm by ≥5% (all Grades) or by ≥2% (Grade 3-4). Incidence based on number of patients who had both baseline and at least one on-study laboratory measurement YONDELIS group (range: 373 to 377 patients) and dacarbazine group (range: 166 to 168 patients). a

DRUG INTERACTIONS Effect of Cytochrome CYP3A Inhibitors: Coadministration of YONDELIS with ketoconazole, a strong CYP3A inhibitor, increases systemic exposure of trabectedin by 66%. Avoid use of strong CYP3A inhibitors (e.g., oral ketoconazole, itraconazole, posaconazole, voriconazole, clarithromycin, telithromycin, indinavir, lopinavir, ritonavir, boceprevir, nelfinavir, saquinavir, telaprevir, nefazodone, conivaptan) in patients taking YONDELIS. Avoid taking grapefruit or grapefruit juice during YONDELIS treatment. If a strong CYP3A

YONDELIS® (trabectedin) for injection inhibitor for short-term use (i.e., less than 14 days) must be used, administer the strong CYP3A inhibitor 1 week after the YONDELIS infusion, and discontinue it the day prior to the next YONDELIS infusion [see Clinical Pharmacology (12.3) in Full Prescribing Information]. Effect of Cytochrome CYP3A Inducers: Coadministration of YONDELIS with rifampin, a strong CYP3A inducer, decreased systemic exposure of trabectedin by 31%. Avoid administering strong CYP3A inducers (e.g., rifampin, phenobarbital, St. John’s wort) to patients who are taking YONDELIS [see Clinical Pharmacology (12.3) in Full Prescribing Information]. USE IN SPECIFIC POPULATIONS Pregnancy: Risk Summary: Based on its mechanism of action, trabectedin can cause fetal harm when administered during pregnancy [see Clinical Pharmacology (12.1) in Full Prescribing Information]. There are no available data with the use of YONDELIS during pregnancy. Animal reproductive and developmental studies at relevant doses have not been conducted with trabectedin; however, placental transfer of trabectedin was demonstrated in pregnant rats. Advise pregnant woman of the potential risk to a fetus. The background risk of major birth defects and miscarriage for the indicated population are unknown; however, the background risk in the U.S. general population of major birth defects is 2 to 4% and of miscarriage is 15 to 20% of clinically recognized pregnancies. Lactation: Risk Summary: There are no data on the presence of trabectedin in human milk, the effects on the breastfed infant, or the effects on milk production. Because of the potential for serious adverse reactions from YONDELIS in breastfed infants, advise a nursing woman to discontinue nursing during treatment with YONDELIS. Females and Males of Reproductive Potential: Contraception: Females: Advise female patients of reproductive potential to use effective contraception during and for 2 months after the last dose of YONDELIS [see Use in Specific Populations]. Males: YONDELIS may damage spermatozoa, resulting in possible genetic and fetal abnormalities. Advise males with a female sexual partner of reproductive potential to use effective contraception during and for 5 months after the last dose of YONDELIS [see Nonclinical Toxicology (13.1) in Full Prescribing Information]. Infertility: YONDELIS may result in decreased fertility in males and females [see Nonclinical Toxicology (13.1) in Full Prescribing Information]. Pediatric Use: Safety and effectiveness in pediatric patients have not been established. Geriatric Use: Clinical studies of YONDELIS did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Hepatic Impairment: The pharmacokinetics of trabectedin has not been evaluated in patients with a total bilirubin greater than the upper limit of normal [see Clinical Pharmacology (12.3) in Full Prescribing Information]. Renal Impairment: No dose adjustment is recommended in patients with mild [creatinine clearance (CLcr) 60-89 mL/min] or moderate (CLcr of 30-59 mL/min) renal impairment. The pharmacokinetics of trabectedin has not been evaluated in patients with severe renal impairment (CLcr <30 mL/min) or end stage renal disease [see Clinical Pharmacology (12.3) in Full Prescribing Information]. OVERDOSAGE There is no specific antidote for YONDELIS. Hemodialysis is not expected to enhance the elimination of YONDELIS because trabectedin is highly bound to plasma proteins (97%) and not significantly renally excreted. PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Myelosuppression: Inform patients of the risks of myelosuppression. Instruct patients to immediately contact their healthcare provider for fever or unusual bruising, bleeding, tiredness, or paleness. Rhabdomyolysis: Advise patients to contact their healthcare provider if they experience severe muscle pain or weakness. Hepatotoxicity: Advise patients to contact their healthcare provider immediately for yellowing of skin and eyes (jaundice), pain in the upper right quadrant, severe nausea or vomiting, difficulty in concentrating, disorientation, or confusion. Cardiomyopathy: Advise patients to contact their healthcare provider for new onset chest pain, shortness of breath, fatigue, lower extremity edema, or heart palpitations. Hypersensitivity: Advise patients to seek immediate medical attention for symptoms of allergic reactions including difficulty breathing, chest tightness, wheezing, severe dizziness or lightheadedness, swelling of the lips or skin rash. Extravasation: Inform patients of the risks of extravasation and to notify their healthcare provider for redness, swelling, itchiness and discomfort or leakage at the injection site. Embryofetal toxicity: Advise pregnant women of the potential risk to a fetus. Advise females to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, during treatment with YONDELIS [see Warnings and Precautions and Use in Specific Populations]. Females and males of reproductive potential: Advise females of reproductive potential to use effective contraception during treatment with YONDELIS and for at least 2 months after last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with YONDELIS and for at least 5 months after the last dose [see Warnings and Precautions and Use in Specific Populations]. Lactation: Advise females not to breastfeed during treatment with YONDELIS [see Use in Specific Populations].

PAGE 148

The ASCO Post | JANUARY 25, 2016

Announcements

Rakesh Jain, PhD, and Mary-Claire King, PhD, Awarded the National Medal of Science

akesh Jain, PhD, the A. Werk Cook Professor of Radiation Oncology (Tumor Biology) at Harvard Medical School and Massachusetts General Hospital, and Mary-Claire King, PhD, Professor of Genome Sciences and Medicine (Medical Genetics) at the University of Washington, have been selected as recipients of the National Medal of Science by President Barack Obama. “Science and technology are fundamental to solving some of our nation’s biggest challenges,” President Obama said. “The knowledge produced by these Americans today will carry our country’s legacy of innovation forward and continue to help countless others around the world. Their work is a testament to American ingenuity.” The National Medal of Science was created by statute in 1959 and is administered for the White House by the National Science Foundation. Awarded annually, the Medal recognizes individuals who have made outstanding contributions to science and engineering. The President receives nominations from a committee of Presidential appointees based on their extraordinary knowledge in and contributions to chemistry; engineering; computing; mathematics; and the biologic, behavioral/social, and physical sciences.

Rakesh Jain, PhD Dr. Jain is a chemical engineer who has applied his training to the service of cancer research. His laboratory at Massachu-

Manufactured by: Baxter Oncology GmbH Halle/Westfalen Germany Manufactured for: Janssen Products, LP Horsham, PA © Janssen Products, LP. 2015 Under license from Pharma Mar, S.A. 042354-151026

Rakesh Jain, PhD

setts General focuses on normalizing tumor vessels and their microenvironment. Using mathematical models, animal models and advanced imaging techniques, Dr. Jain has mapped blood vessel growth in tumors, pointing colleagues to new therapies for cancer. In 2001, Dr. Jain advanced a hypothesis on the normalization of blood vessels in tumors, suggesting that re-engineering—rather than re-

pressing—blood vessel growth deterred tumor metastasis. This insight has been confirmed in mouse models and is being tested in human clinical trials. Dr. Jain’s work also led to the discovery of an alternative use of bevacizumab (Avastin) as an inhibitor for blood vessel growth necessary for tumor growth. Dr. Jain was elected to the National Academy of Sciences, the Institute of Medicine, and the National Academy of Engineering. He is a past recipient of the Outstanding Achievement Award from the Society of American Asian Scientists in Cancer Research and the Alpha Chi Sigma Award from the American Institute of Chemical Engineers. Dr. Jain received his doctorate in chemical engineering from the University of Delaware.

Mary-Claire King, PhD Dr. King is a world leader in cancer genetics and in the application of genetics to resolution of human rights abuses.

Mary-Claire King, PhD

She was the first to demonstrate that a genetic predisposition for breast cancer exists, as the result of inherited mutations in the gene she named BRCA1. She built upon that body of work to discover the BRCA2 breast cancer gene. More recently she has devised with a scheme to screen for all genes that predispose to breast and ovarian cancers. Dr. King was elected to the National Academy of Sciences, the Institute of Medicine, the American Academy of Arts and Sciences, and as a Fellow of the American Association for the Advancement of Science. She was also named as honorary chair for the state of Washington at the 50th Anniversary of the United Nations. She is a past recipient of the Heineken Prize, the Gruber Prize in Genetics, the Weizmann Award, the Pearl Mesiter Greengard Prize, and the Lasker Award. Dr. King received her doctorate in genetics from the University of California at Berkeley. n

ASCOPost.com | JANUARY 25, 2016

PAGE 149

In the News Gynecologic Oncology

Could a Screening Test That Would Reduce Deaths From Ovarian Cancer Be on the Way? By Charlotte Bath

“A

solid triple but not a home run” is how Karen H. Lu, MD, characterized a study in The Lancet reporting a reduction in deaths from ovarian cancer with the use of multimodal ovarian cancer screening.1 Dr.

a patented Risk of Ovarian Cancer algorithm, with women triaged to one of three risk groups: normal (annual screening), intermediate (repeat CA125 testing in 3 months), and elevated (repeat CA-125 testing and transvagi-

In 3 years, we should have a pretty firm answer about whether ovarian cancer screening reduces death from the disease. —Karen H. Lu, MD

Lu’s remark was one of several, mostly but not universally, favorable and optimistic comments included in an article on the study in The New York Times.2 In a follow-up interview with The ASCO Post, Dr. Lu, Chair of the Department of Gynecologic Oncology and Reproductive Medicine, Division of Surgery, at The University of Texas MD Anderson Cancer Center, Houston, explained what it would take to make it to home plate. The authors of The Lancet study acknowledged that they need 3 additional years to allow the mortality data to mature, Dr. Lu noted. “So in 3 years, we should have a pretty firm answer about whether ovarian cancer screening reduces death from the disease—which would be a home run.” One of the strengths of the study is its large scale, with more than 200,000 participants. Dr. Lu said that there are many other strengths as well. “The reason it is so powerful,” she pointed out, “is that the goal was to reach a gold standard for determining whether screening will be effective in terms of public health, which is seeing fewer deaths from the disease because of screening.”

Three Study Groups The study reported in The Lancet randomly assigned 202,638 postmenopausal women aged 50 to 74 from 13 centers in the National Health Service Trusts in England, Wales, and Northern Ireland to multimodal screening, transvaginal ultrasound screening, or no screening in a 1:1:2 ratio. The multimodal screening used serum CA125 testing interpreted over time by

nal ultrasound screening as a secondline test in 6 weeks). Dr. Lu is principal investigator of a single-arm study based on the same screening algorithm. Results in the transvaginal ultrasound–screening groups were classified as normal (annual screening), unsatisfactory (scan repeated in 3 months), or abnormal (scan repeated within 6 weeks by a senior ultrasonographer). In both screening groups, women with persistent abnormalities had clinical assessment and additional tests by a trial clinician. Women in the multimodal- and

ultrasound-screening groups were compared separately with women in the noscreening group. At a median follow-up of 11.1 years, ovarian cancer was diagnosed in 1,282 (0.6%) women: 338 (0.7%) in the multimodal-screening group, 314 (0.6%) in the ultrasoundscreening group, and 630 (0.6%) in the no-screening group. Among these women, deaths due to ovarian cancer occurred in 148 (0.29%) in the multimodal-screening group, 154 (0.30%) in the ultrasound-screening group, and 347 (0.34%) in the no-screening group.

Primary and Secondary Analyses The relative mortality reductions of 15% in the multimodal- and 11% in the ultrasound-screening groups were not significant in the primary analysis. “In retrospect, it would have been preferable to specify a primary analysis that was weighted to reflect the predictable delay in mortality reduction in a screening trial of this type,” the authors stated. A prespecified secondary subgroup analysis excluding women who had an estimated change point in their CA-125 profile before randomization (prevalent cases) did find a significant mortality reduction in the multimodal-screening group, with an overall reduction in mortality of 20%,

and 28% after 7 years of screening. Commenting on the differing primary and subgroup analyses, Dr. Lu said that the study investigators “have done a tremendous job in carrying out and interpreting the study. I think that the results were very balanced, but we need to wait a little bit longer, and 3 years is a very short amount of time. Then we will hopefully have an answer.”

Roll Out in the United States Results from a single-arm study at MD Anderson and six other sites using the same Risk of Ovarian Cancer algorithm has shown that the multimodal screening “really is quite practical,” Dr. Lu noted. “The vast majority of women—over 90%—just need to come back once a year for a blood test, and they could get that at their annual exam. It is a very small percentage, really less than 1% to 2%, that need to go on to have an ultrasound,” she said. A report on the first 11 years of that study, published in Cancer in 2013,3 concluded the screening strategy “demonstrated excellent specificity and positive predictive value” in a population of U.S. women at average risk for ovarian cancer but could not be considered practice-changing at that time. “One of the things that we wanted continued on page 150

Same Study, Different Interpretations By Charlotte Bath

n article in The New York Times1 about an ovarian cancer screening study published in The Lancet2 is headlined, “Early Detection of Ovarian Cancer May Become Possible,” and leads with the promise of reduced mortality with multimodal screening for ovarian cancer. An article in MedPage Today3 about the same study is headlined, “Ovarian Cancer Screening Study Falls Short,” and leads with the failure of the study to demonstrate a significant difference in mortality. The experts quoted in the two articles respectively range from mildly optimistic to decidedly pessimistic, although all agreed that further follow-up is needed before multimodal screening could be recommended for routine use.

“With any kind of medical reporting, whether it is for screening or for treatment,” there is always the concern about creating unrealistic expectations, according to Karen H. Lu, MD, Chair of the Department of Gynecologic Oncology and Reproductive Medicine, Division of Surgery, at The University of Texas MD Anderson Cancer Center, Houston. “The interpretation of a study can be difficult, and even two very well-qualified individuals can interpret studies differently,” she added. Dr. Lu is lead investigator of a multicenter study using the same screening strategy used in the study reported in The Lancet and was among those experts expressing optimism that the strategy might prove effective in re-

ducing ovarian cancer deaths. Still, she noted, “I am someone who is always very cautious about not overpromising.” n

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

References 1. Grady D: Early detection of ovarian cancer may become possible. The New York Times, December 17, 2015. 2. Jacobs IJ, Menon U, Ryan A, et al: Ovarian cancer screening and mortality in the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS): A randomised controlled trial. Lancet. December 17, 2015 (early release online). 3. Bankhead C: Ovarian cancer screening study falls short. MedPage Today, December 17, 2015.

The ASCO Post | JANUARY 25, 2016

PAGE 150

In the News Ovarian Cancer Screening continued from page 149

to potentially be prepared for is if the UK study is positive, could this roll out in the United States, where the healthcare system is less centralized? Would we get the same results, given that it is a much less coordinated health-care system? We’ve got to figure out how to deliver this type of personalized screening strategy to assure that our outcomes will be the same. That is one of the reasons we are conducting this study, to see if we can do that,” Dr. Lu said. “And we are doing that in multiple locations. It is going on simultaneously in New Jersey, Rhode Island, Miami, and Houston, and so far we have had similar findings.”

Balancing Benefit With Harm In both the single-arm study led by Dr. Lu and the three-arm study reported in The Lancet, the multimodalscreening strategy is limited to postmenopausal women and should remain so, according Dr. Lu. “We know that ovarian cancer is a relatively rare cancer and that the incidence increases with age. In women under 50, the likelihood of ovarian cancer is quite low. We are always balancing benefit, which is detecting the cancer early, with harm, which is unnecessary surgery. That ratio will

change when you start to screen women in whom ovarian cancer is less common,” Dr. Lu explained. “If you look at the big picture, the vast majority of women who present to their physicians, present with very late-stage disease, and we have not been able to change that paradigm. So this would be a very important step forward. There have been incremental improvements in treatment over the past 20 years, but if we are going to make a home run, we really need an early-detection strategy,” Dr. Lu stated. “Certainly there are women between the ages of 40 and 50 in whom early detection is important as well, but we need to be a little more cautious,” she said, about extending screening strategies to these women. They would include younger women considered at higher risk of ovarian cancer because of family history and BRCA mutations. “But I am also a very strong believer that in women with a family history of ovarian cancer, or of breast cancer at a young age, genetic testing is a powerful way to identify whether they are at high risk for ovarian cancer,” Dr. Lu stated. “For women with a BRCA mutation, their risk for ovarian cancer can be as high as 40% to 50%. In the average population, lifetime risk is about 1% or 1.5%. There is a huge difference between

lifetime risks of 1.5% and 40%, and that is why we need to identify those at high risk,” Dr. Lu said. “It is a small number of individuals, but if we can identify those individuals who have a BRCA mutation, then we can really make an impact in terms of risk-reducing surgery.”

Very Low Complication Rates “Both venipuncture and transvaginal ultrasound used in the multimodal screening were associated with minor complications and very low complication rates,” the study authors reported. “Most postmenopausal women found transvaginal ultrasound screening acceptable, with 3.5% reporting moderate or severe pain during the scan.” Dr. Lu agreed that the complications were “very minor. I would say that the main issues are: (1) We always want to be cautious about having too many unnecessary surgeries, and we haven’t really seen that. So that’s been important. And: (2) Some women naturally have a higher CA-125. They just run high, and it can cause anxiety, but it may not actually be ovarian cancer.” In general, however, neither the study cited in The Lancet nor the single-arm study led by Dr. Lu has shown an increase in anxiety among the women screened. The authors of The Lancet article

reported 14 false-positive surgeries per 10,000 screens in the multimodalscreening group and 50 false-positive surgeries in the ultrasound group. Dr. Lu said that is consistent with what is normally seen but pointed out: “When we say unnecessary surgery in our study, these were still women who had ovarian masses. It’s just that they turned out not to be cancer. We don’t know whether they ultimately would have developed symptoms or more worrisome disease.” n Disclosure: Dr. Lu Reported no potential conflicts of interest.

References 1. Jacobs IJ, Menon U, Ryan A, et al: Ovarian cancer screening and mortality in the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS): A randomised controlled trial. Lancet. December 17, 2015 (early release online). 2. Grady D: Early detection of ovarian cancer may become possible. The New York Times, December 17, 2015. 3. Lu KH, Skates A, Hernandez MA, et al: A 2-stage ovarian cancer screening strategy using the Risk of Ovarian Cancer Algorithm (ROCA) identifies earlystage incident cancers and demonstrates high positive predictive value. Cancer 119:3454-3461, 2013.

Expect Questions About Ovarian Cancer Screening By Charlotte Bath

he authors of an ovarian cancer screening study published in The Lancet1 and many of the experts commenting on the study in the media agree that the results of multimodal screening are encouraging and could reduce mortality from ovarian cancer, but further follow-up is needed. Considering that the U.S. Preventive Services Task Force recommends against routine screening of women at average risk of ovarian cancer, what can patients who may have heard or read about the study and are concerned about testing for ovarian cancer do in the meantime? “We would recommend that they participate in an ovarian cancer screening study,” said Karen Lu, MD, Chair of the Department of Gyneco-

logic Oncology and Reproductive Medicine, Division of Surgery, at The University of Texas MD Anderson Cancer Center, Houston, in an interview with The ASCO Post.

Ongoing Study Dr. Lu is also lead investigator of a multicenter ovarian cancer screening study that uses the same Risk of Ovarian Cancer Algorithm (ROCA) used in the study reported in The Lancet. Based on a patient’s age and CA125 score, study participants are triaged to one of three risk groups: low-risk women, who receive annual CA-125 screening; intermediaterisk women, who have repeat CA125 tests in 3 months; and high-risk

women, who receive repeat CA-125 and transvaginal ultrasound and are referred to a gynecologic oncologist. Preliminary data from that study were first presented at the 2010 ASCO Annual Meeting, and updated findings were published in Cancer.2 The multicenter study involves seven sites across the country. Dr. Lu noted that screening studies have been conducted at other institutions as well, including the Fred Hutchinson Cancer Research Center in Seattle. While the algorithm used in the MD Anderson study is based on CA-125 testing, Dr. Lu stressed that women should be cautious about independently pursuing CA-125 testing. “Even going from two different labs, you can also have variations in

CA-125,” Dr. Lu said. In addition, “some women naturally have a higher CA-125.” n

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

References 1. Jacobs IJ, Menon U, Ryan A, et al: Ovarian cancer screening and mortality in the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS): A randomised controlled trial. Lancet. December 17, 2015 (early release online). 2. Lu KH, Skates A, Hernandez MA, et al: A 2-stage ovarian cancer screening strategy using the Risk of Ovarian Cancer Algorithm (ROCA) identifies earlystage incident cancers and demonstrates high positive predictive value. Cancer 119:3454-3461, 2013.

Visit The ASCO Post website at ASCOPost.com

ASCOPost.com | JANUARY 25, 2016

PAGE 151

Letters to the Editor

Keeping Up With How Drugs Work

love reading The ASCO Post, but I have a suggestion. For your reports on drug development, how about making it a policy to note the class or type of any new agent being discussed—ie, a brief description of the drug’s mechanism of action? For example, a recent issue included a nice article summarizing the approval

of daratumumab (Darzalex), but nowhere in the piece was there any mention of what type of drug daratumumab is. It would be a great learning opportunity and improve the summary if you offered a simple statement like: “Daratumumab is a human IgG1k mono-

clonal antibody that binds with high affinity to the transmembrane ectoenzyme CD38 on the surface of multiple myeloma cells. It is postulated to induce rapid tumor cell death through diverse mechanisms of action.” Similarly, a recent article on TAS-

102 was intriguing but does not describe what the drug is. Who can keep track of all the hundreds of agents being studied in oncology? n —Lou Vaickus, MD, FACP President and Founder akta Pharmaceutical Development (aktaPD)

Editor’s Reply

t is, in fact, the policy of The ASCO Post to describe a drug’s class or mechanism of action, particularly in articles reporting on investigational or newly approved agents, but we appreciate Dr. Vaickus’ keeping us on our toes. TAS-102 is an orally administered combination of trifluridine (a thymidine-based nucleoside analog) and tipiracil (a thymidine phosphorylase inhibitor). The combination increases trifluridine exposure by inhibiting its metabolism by thymidine phosphorylase. After uptake into cancer cells, trifluridine is incorporated into DNA, interfering with DNA synthesis and inhibiting cell proliferation. (The trifluridine/ tipiracil combination was approved by the U.S. Food and Drug Administration as Lonsurf in September 2015.) n

The ASCO Post Wants to Hear From You

We encourage readers to share their opinions and thoughts on issues of interest to the oncology community.

NCCN 10th Annual Congress:

Hematologic Malignancies™ Earn CME/CNE/CPE credit online with recordings from the October 2015 meeting in San Francisco, CA.

Recorded Presentations education.nccn.org/hem2015 Earn up to 8 credits online! Treatment of hematologic malignancies is increasingly complex. Participate in online activities to learn about the latest advances in hematologic malignancies. Supported by educational funding provided by Amgen. Supported by an independent educational grant from Incyte Corporation. Supported by educational grants from AbbVie Inc.; Actelion Pharmaceuticals US, Inc.; Astellas Scientific and Medical Affairs, Inc.; Bristol-Myers Squibb; Celgene Corporation; Genentech; Gilead Sciences, Inc.; Novartis Pharmaceuticals Corporation; Pfizer; Pharmacyclics LLC, An AbbVie Company and Janssen Biotech, Inc., administered by Janssen Scientific Affairs, LLC; Seattle Genetics; Spectrum Pharmaceuticals, Inc.; and Takeda Oncology.

The NCCN Value Initiative: Using NCCN Evidence Blocks™ in Clinical Decisions education.nccn.org/evidence-blocks NCCN Evidence Blocks™ are intended as a visual representation of five key measures that provide important information about specific recommendations contained within the NCCN Guidelines®. View a recording of the live symposium held at the Hematologic Malignancies meeting to learn more and earn credit.

Integrating Emerging Evidence into the Management of Patients with Chronic Lymphocytic Leukemia education.nccn.org/cll View a recording of the live symposium held at the Hematologic Malignancies meeting and learn to improve the ability to optimize therapy and incorporate clinical advances into the management of patients with chronic lymphocytic leukemia. This activity is supported by educational grants from AbbVie Inc.; Genentech; and Pharmacyclics LLC, an AbbVie Company, and Janssen Biotech, Inc.

Write to The ASCO Post at editor@ASCOPost.com Phone: 631.692.0800 Fax: 631.692.0805 www.ASCOPost.com

S AV E T H E D AT E ! Sponsorship and exhibit opportunities available! For more information, e-mail exhibits@nccn.org.

These activities are approved for AMA PRA Category 1 Credit(s)™. Nursing and pharmacy (ACPE) credits are also provided. Complete accreditation details are provided online.

The ASCO Post | JANUARY 25, 2016

PAGE 152

In Memoriam

Nationally Regarded Cancer Advocate Ellen Stovall Dies By Ronald Piana

assion is a much-needed virtue in one who seeks to change the world for the better. When you combine intelligence, stamina, iron-willed determination, the grace of an ambassador, and simple human likability with passion, you get that rare person who can turn words and ideas into reality. Such a person was Ellen Stovall, nationally regarded cancer advocate whose tireless work helped drive the survivorship movement that focused on adapting to life with, through, and beyond cancer, rather than treating a diagnosis as a death sentence. Ms. Stovall died on January 5, 2016, at age 69. Ms. Stovall was reared in Honesdale, Pennsylvania, in a loving family devoted to community service and leadership. Her mother volunteered for the Red Cross, and her aunt was a Girl Scout leader. Other relatives served as lay rabbis in Honesdale’s lone synagogue. “In my family, becoming the president of this and chair of that was a natural way of being,” said Ms. Stovall during an interview. She briefly studied music at West Chester State College and then spent 5 years at Penn State University, as she described, moving from one field of study to the next, largely because “I didn’t feel well.” Her malaise was caused by the nascent disease that would eventually change her life forever. By then, Ms. Stovall had married and moved to Washington, DC. Soon after giving birth to her son, she was diagnosed with Hodgkin lymphoma. She was 24 years old, a young mother with cancer and no support groups to lean on. That disparity of care would plant the seed for her life’s work.

Resolve to Make a Difference After her final treatments, Ms. Stovall founded a support group for young cancer survivors. The uncertainty of survivorship spurred her into further single-minded action. She beat the pavement, seeking donations to support the Leukemia & Lymphoma Society, and became a full-time volunteer at the American Cancer Society. She attributed her resolve to make a

difference, in part, to the mortality issue all survivors share. “I didn’t know how long I’d be around, but I knew this is how I wanted to spend my time,” she related during an interview. Unfortunately, Ms. Stovall’s cancer recurred. Seeking counseling to help her cope, she saw a psychiatrist, and while in the office, she noticed a pamphlet in which the word ”survivor” was used to describe a person diagnosed with cancer. She would later say that on

honest and have a frank conversation with their patients, starting with explaining whether their cancer is curable or incurable, and what the available options are. This lays the groundwork for a shared decision-making conversation that addresses the patient’s needs and values moving forward.” Ms. Stovall was also a founding member of the Institute of Medicine’s National Cancer Policy Board and its successor, the National Cancer Policy

I live my life and take pleasure in the littlest things. Cancer has taught me humility, and if there’s anything I’ve learned, it’s about not sweating the small stuff. —Ellen Stovall

that single day, she was set “on fire,” feeling empowered by a word that did not connote “victim.” It was during her second cancer recurrence that Ms. Stovall discovered the National Coalition for Cancer Survivorship (NCCS), and in 1988, she was elected to the Coalition’s Board of Directors. In 1992, NCCS moved its headquarters to Washington, DC, and it was that same year that Ms. Stovall became its President and CEO, positions she held until 2008. From there, she served NCCS as its senior health policy advisor.

Health-Care Expertise Ms. Stovall was more than an ebullient cheerleader; she was an astute expert on health care. For example, during the heated conversations about overtreatment and value, she told The ASCO Post, “At NCCS, our main focus is on cancer care planning, both in the delivery of care and on payment reforms. We look at this in four buckets: the patient, reimbursement, providers, and our central goal, which is cancer care planning at diagnosis and major transition points during treatment and survivorship.” She added, “Physicians need to be

Forum. Prior to the establishment of the Forum, she was Vice-Chair of the National Cancer Policy Board and co-chaired its Committee on Cancer Survivorship. In that capacity, she coedited the Institute of Medicine’s report “From Cancer Patient to Cancer Survivor: Lost in Transition,” which addressed the issues adult cancer survivors face. Her relentless and impassioned advocacy reached from small cancer support groups to Capitol Hill. She served on several advisory panels, working groups, and committees of the National Cancer Institute (NCI), American Association for Cancer Research, and ASCO. Ms. Stovall also served a 6-year term on the NCI’s National Cancer Advisory Board, an appointment she received in 1992 from President Bill Clinton.

Fond Remembrances A person’s life and accomplishments are also measured by human associations and how those associations help the greater good. Noted cancer advocate Carolyn “Bo” Aldigé, President and founder of the Prevent Cancer Foundation, reflected on Ms. Stovall: “I wish I had the words to

In Memoriam

 Ellen Stovall 

December 2, 1946 – January 5, 2016

capture what my heart is feeling over the loss of Ellen. I always felt a special bond with her, even though our respective organizations’ missions were at opposite ends of the spectrum. She always respected everyone’s ideas and opinions, whether she shared them or not, and she was indeed the ultimate collaborator. I have so many happy memories of times working together on both policy and projects—the Clinical Trials Summit, the Tour of Hope, Breakaway From Cancer. Rest in peace, dear Ellen; you are and will be forever missed.” Former ABC News anchor and melanoma survivor, Sam Donaldson, paid tribute to Ms. Stovall: “When I was diagnosed with melanoma in 1995, one of the first calls I received was from Ellen. I’d never met her, but she warmly offered her help and told me about her group. It was uplifting for me, and I truly appreciated it. I got to know Ellen and saw the dynamic things she did for people with cancer. I also knew her through some of her own battles with cancer, and the fact that she lived as long as she did is a testament to her tenacity and bravery. The whole cancer community is better for having had Ellen administer to us all these years. I’m just terribly sorry we lost her.”

Common Thread These heartfelt tributes are but a small fraction of the outpouring of sadness at Ms. Stovall’s passing. But more important, each one shares a common thread—the unbreakable spirit of Ms. Stovall’s energy connects them. And her own words, simple and straightforward, say it best: “I live my life and take pleasure in the littlest things. Cancer has taught me humility, and if there’s anything I’ve learned, it’s about not sweating the small stuff.” Ms. Stovall’s lasting message, which was the heart of her life’s work, is critical for cancer patients and their loved ones: All of us, the well included, only have the moment of time that we are living in. Strive to overcome the challenges of living with cancer, and make the most of it. She always did. n

ASCOPost.com | JANUARY 25, 2016

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News Gastrointestinal Oncology

Pilot Study Indicates Little Activity of Vemurafenib in Metastatic BRAF-Mutated Colorectal Cancer By Matthew Stenger

n a phase II pilot study reported in the Journal of Clinical Oncology, Scott Kopetz, MD, PhD, of The University of

Texas MD Anderson Cancer Center, and colleagues found little clinical activity of vemurafenib (Zelboraf) in patients with

metastatic BRAF-mutated colorectal cancer.1 The BRAF V600E mutation is found in approximately 5% to 8% of pa-

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tients with metastatic colorectal cancer and is associated with poor prognosis.

Low Response Rate In the study, 21 patients with BRAF V600E-positive metastatic colorectal cancer received oral vemurafenib at 960 mg twice daily. Twenty patients had received at least one prior chemotherapy regimen for metastatic disease. Partial response was observed in one patient (5%, 95% confidence in-

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Scott Kopetz, MD, PhD

terval [CI] = 1%–24%), and stable disease was observed in seven (33%). Median progression-free survival was 2.1 months. There was no association of clinical benefit with patterns of concurrent mutations, microsatellite instability status, CpG island methylation status, PTEN loss, EGFR expression, or copy number alterations.

Low-Frequency Mutations Low-frequency KRAS or NRAS mutations were found in 9 (56%) of 16 evaluable tumors, with a median allele frequency of 0.21%. These mutations appeared to be mechanisms of acquired resistance in vemurafenib-sensitive patient-derived xenografts. The investigators concluded: “In marked contrast to the results seen in patients with BRAF V600E–mutant melanoma, single-agent vemurafenib did not show meaningful clinical activity in patients with BRAF V600E–mutant colorectal cancer. Combination strategies are now under development and may be informed by the presence of intratumor heterogeneity of KRAS and NRAS mutations.” n

Disclosure: The study was supported by Plexxikon and Roche and by the National Institutes of Health and National Cancer Institute. For full disclosures of the study authors, visit jco.ascopubs.org.

Reference 1. Kopetz S, et al: J Clin Oncol 33:40324038, 2015.

The ASCO Post | JANUARY 25, 2016

PAGE 154

In Memoriam

Famed Cancer Biostatistician, Norman Breslow, PhD, Dies By Ronald Piana

“A

longitudinal case-controlled analysis of the probability of attaining normality after achieving 60: A perspective from the social sciences based on expert ethnographic insights.” So begins a long and charmingly erudite birthday card to internationally regarded biostatistician Norman Breslow, PhD, in celebration of his 60th birthday. The authors of the card were his two

Norman Breslow, PhD

daughters, Sara and Lauren. Dr. Breslow kept an electronic copy of the birthday card on his homepage at the University of Washington, where he was Professor Emeritus in the Department of Biostatistics. He died of prostate cancer on December 9, 2015, at the age of 74.

Son of a Famous Father Dr. Breslow was born on February 21, 1941, in Minneapolis and grew up in the Bay Area. His mother was Alice Philip Breslow, and his father was Lester Breslow, PhD, an epidemiologist and public health leader whose early work scientifically proved that healthier lifestyles lead to longer lives. Dr. Breslow’s father, famous in his day as “Mr. Public Health,” was born in 1915 and became an antismoking advocate after what he described as a bad experience with corncob pipes. The elder Breslow ended up popularizing what is now folksy-seeming health advice—exercise, don’t smoke, and eat right. Dr. Breslow graduated from Berkeley High School and went to Reed College, Portland, Oregon, where he graduated with a BA in Mathematics. In 1961, he entered Stanford University,

California, where he received a PhD in statistics in 1967. That same year, Dr. Breslow joined the University of Washington, where he quickly rose through the ranks, becoming the Chairman of the Biostatistical Department in 1983, a position he served in for 10 years. Inspired by his father’s career, Dr. Breslow used the application of biostatistics to inform the analysis of epidemiologic data, and since the early 1970s, Dr. Breslow made enormous contributions to statistical theory and its applications in cancer epidemiology. In fact, much of what is now known about the causes and risk factors for cancer and other diseases was derived, in part, using his formulas. Moreover, the math Dr. Breslow perfected and formalized was the basis for what are now standard methods to filter out stray factors in “case-controlled” health studies.

True to the Discipline Biostatistics is a discipline with a multitude of potential career paths, and many biostatisticians use the core discipline to become, for example, epidemiologists or managers of clinical trial data centers or

veloped have concentrated on two of the most important areas of biomedical science where statistical thinking is fundamental: clinical trials and chronic disease epidemiology.”

The Human Factor Dr. Breslow’s work also had a profound affect on the lives of thousands of young cancer patients by helping to found and lead the National Wilms Tumor Study Group and its data and statistical center, a Fred Hutchinson– based national registry dedicated to improving the treatment of this rare kidney cancer, which tends to strike children under the age of 5. And although Dr. Breslow was both brilliant and bold, he also had a soft, compassionate side—especially for children. Longtime colleague Giulio D’Angio, MD, Professor of Pediatrics at the University of Pennsylvania and Former Head of the Wilms Tumor Study Group, wrote in memorial of Dr. Breslow: “I think of him in Italian as Il Gigante Dolce—the giant without sharp edges. The success of the study was in large measure because of his invaluable

I think of him in Italian as Il Gigante Dolce—the giant without sharp edges. His enduring legacy will be the children. Thousands on thousands of them around the world, and their children, are alive and thriving because of Il Gigante Dolce. —Giulio D’Angio, MD

move into population genetics. Not Dr. Breslow. Although he became deeply involved in a range of biomedical applications, he remained focused throughout his career on the development of the core statistical discipline. According to colleague and coauthor on two books, Statistical Methods in Cancer Research, I and II, Nick E. Day, PhD, “Applications of the biostatistical methods that Dr. Breslow de-

guidance and surveillance. His enduring legacy will be the children. Thousands on thousands of them around the world, and their children, are alive and thriving because of Il Gigante Dolce.”

An Honored Scholar Adventurer Dr. Breslow was a tall and trim lover of the outdoors. At the age of 16, he climbed the Matterhorn in Europe. He

 In Memoriam

Norman Breslow, PhD February 21, 1941 – December 9, 2015



valued being in the mountains and was a member of the Seattle Mountaineers Club, the Sierra Club, and Club Alpin Francais. Growing up in the San Francisco area, he learned to hike and ski in the Sierra Nevada Mountains. He explored the Himalayas in both Tibet and Nepal and often traveled to England, Germany, Switzerland, and France for work. He and his wife, Gayle, spent part of each year in Provence, France, where they maintained a second home. Dr. Breslow’s many honors include the Spiegelman Gold Medal from the American Public Health Association, the Marvin Zelen Leadership award in Statistical Science from Harvard University, the Snedecor and R.A. Fisher awards from the Council of Presidents of Statistical Societies, and the Medal of Honor from the International Agency for Research on Cancer. He also had the singular distinction of simultaneous membership in the American Association for the Advancement of Science with his late father.

A Standard Bearer Dr. Breslow’s commitment to the highest quality science by adhering to rigorous standards is one of his strongest legacies. As President of the International Biometric Society in 2002, he said in response to concerns about medical research quality: “To correct these unfortunate perceptions, we would do well to follow more closely our own teachings: conduct larger, fewer studies designed to test specific hypotheses; follow strict protocols for study design and analysis; better integrate statistical findings with those from the laboratory; and exercise greater caution in promoting apparently positive results.” Dr. Breslow is survived by his wife, Gayle; daughters, Lauren Basson and Sara Jo Breslow; grandchildren, Benjamin and Ayelet Basson; brothers, Jack and Stephen; nephew, Paul; and stepmother, Devra Breslow. n

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The ASCO Post | JANUARY 25, 2016

PAGE 156

Perspective Hagop Kantarjian, MD Robert Chapman, MD continued from page 1

and Services Administration (HRSA) administers 340B.3 Drug manufacturers participating in Medicaid or Medicare Part B programs give 20% to 50% discounts on outpatient drugs (based on an average manufacturer price). In return, pharmaceutical companies are able to participate in Medicaid, thereby expanding their patient bases significantly. This mutually beneficial agreement allows 340B health-care organizations to stretch resources to help more patients and provide more comprehensive services. To be eligible for 340B status, hospitals must show that about 30% of their patient load makes use of Medicaid or Medicare Supplemental Security Income (ie, benefits low-income elderly patients). Freestanding children’s and cancer hospitals as well as rural hospitals (25 beds or less, including rural referral centers, sole community hospitals, and critical access hospitals) have different eligibility requirements. The premise behind 340B is to enhance these organizations’ ability to continue to provide needed comprehensive services to rural, uninsured, and underserved populations.

billion total U.S. drug spending in 2013, or about $7 billion.8,9 Curtailing 340B would allow companies to sell their drugs at higher prices and increase their already large profits (profit margins of 20%–30%, among the highest of any industry).10 To accomplish this, the drug industry relies on the most powerful lobby of any industry in the United States. In 2014, this formidable group spent $229 million on lobbying and another $32 million in campaign contributions to the 2014 elections.10 Drug companies pursue their aims by creating coalitions or front groups (with lofty titles that include words such as “concerned citizens,” “public interest,” “American,” “choice,” “freedom,” “institute,” and “integrity”) that

insurers through negotiated rates, thereby accessing savings. Hospitals use the savings to treat low-income patients, offset disproportionate levels of uncompensated care, and support unprofitable public health services that other hospitals do not provide. Other concerns: (1) 340B may have caused the shift in private oncology practices to hospital settings through acquisitions of and mergers with community cancer clinics, with the goal of increasing profits from use of oncology products16,17; (2) the number of 340B hospitals continues to expand,18 340B locations (contract pharmacies dispensing 340B drugs) are increasing,19 and 340B sales may continue to

The 340B Drug Pricing Program is a medical lifeline that should be maintained, nurtured, and expanded—but certainly not curtailed. —Hagop Kantarjian, MD, and Robert Chapman, MD

Does 340B Fulfill Its Intended Role? In creating the program, Congress stated that the purpose of 340B is “to enable [covered entities] to stretch scarce Federal resources as far as possible, reaching more eligible patients and providing more comprehensive services.”4 Confirmation that the 340B program is fulfilling its role is provided by the following observations: (1) The load of lowincome patients in 340B hospitals is twice that of non-340B hospitals; (2) 340B hospitals account for one-third of all disproportionate share hospitals but provide nearly 60% of all uncompensated care; and (3) more 340B disproportionate share hospitals than non-340B hospitals provide specialized services, which are often not profitable. The 2011 Government Accountability Report on the program stated that 340B providers are using their savings to benefit vulnerable patients, consistent with the congressional intent.3

Recent Discussions Concerning 340B A recent wave of concerns, criticisms, and analyses has swirled around 340B.5-7 The question is: Why so much interest now? The simple answer is: Follow the money. Drug sales under the 340B program were 2.3% of the $329

program, most with 25 beds or less. Third, 340B drug sales still account for only 2% of the $329 billion drug market in the United States—an insignificant amount, considering drug companies’ big profit margins and the fact that 340B is benefiting millions of Americans.8 Fourth, allowing 340B providers to contract with retail pharmacies gives vulnerable patients easier access to needed drugs, without necessarily increasing the volume of 340B sales.6 Finally, expanding Medicaid under the Affordable Care Act will help millions of vulnerable patients and save tens of thousands of American lives every year, without necessarily increasing the number of 340B hospitals. For example, when Massachusetts expanded insurance coverage to the previously uninsured, most vulnerable patients continued care with the same safety-net providers, citing convenience, affordability, and availability of nonmedical services.20 In response to some of the concerns related to the 340B program, discussions about policy changes were reflected in publications by ASCO5 and the Association of Community Cancer Centers.21 The HRSA, which monitors eligibility and ensures compliance with 340B requirements, can address these concerns and other perceived “abuses” of 340B.

Conclusions

recruit third parties as members; write letters to the editor, op-eds, analyses, and publications; influence the tone and content of the articles; and spin messages and talking points.11,12 Many of the reports criticizing the 340B program are directly or indirectly associated with the Alliance for Integrity and Reform of 340B,13 a group of mostly drug manufacturers and trade associations as well as other interest groups that might benefit financially from reducing the scope of 340B. Their arguments have been addressed by reports from 340B Health, which represents more than 1,000 hospitals participating in the 340B program.14,15

What Are the Concerns Related to 340B? A major concern is that 340B hospitals provide discounted drugs to insured patients. In fact, this is exactly what Congress intended.1,2 Hospitals are able to stretch their scarce resources because they buy drugs at discounted rates but receive reimbursement from

increase; and (3) Medicaid expansion under the Affordable Care Act will allow more hospitals to treat Medicaid patients and qualify for 340B. Here is why we believe these concerns are not problematic. First, hospitals are purchasing oncology practices regardless of their 340B status. The shift in cancer care to hospital-based settings is due to declining oncology practice revenues and declining reimbursements for visits and procedures, payment models that do not reflect the complexities of cancer care in community practices, and the need for a wider array of services and infrastructures (social workers, nutritionists, support groups, others) that hospitals are better equipped to provide than private oncology practices.6 Second, while the number of 340B hospitals is increasing, this is almost entirely due to congressional expansion of the program to rural and cancer hospitals in 2010.18 This is good for cancer care and for patients with cancer. Since 2010, and as of October 2015, 1,193 rural and cancer hospitals have joined the 340B

The 340B Drug Pricing Program is a critical program that allows organizations caring for large proportions of vulnerable, poor, underserved, or rural populations to access badly needed health care while remaining solvent. The disproportionate amount of uncompensated care that 340B hospitals provide affirms that they deserve the 340B status and that they use their program savings well. Restricting 340B may help increase the already astounding profits of drug companies, but it will harm millions of Americans. The 340B Drug Pricing Program is a medical lifeline that should be maintained, nurtured, and expanded—but certainly not curtailed. n

Disclosure: Drs. Kantarjian and Chapman reported no potential conflicts of interest.

Note: For interested readers, two articles discussing various aspects and issues related to 340B in more detail were recently published in the Journal of Oncology Practice and in JAMA Oncology (references 6 and 7). References 1. 340B Drug Pricing Program. Wikipedia, December 3, 2015. Available at https:// en.wikipedia.org/wiki/340B_Drug_Pricing_Program. Accessed January 6, 2016.

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Perspective

2. Veterans Health Care Act of 1992. Pub L No. 102-585, 42 USC §256b. Available at https://www.gpo.gov/fdsys/pkg/STATUTE-106/pdf/STATUTE-106-Pg4943. pdf. Accessed January 6, 2016. 3. U.S. Government Accountability Office: Drug pricing: Manufacturer discounts in the 340B program offer benefits, but federal oversight needs improvement. Available at www.gao.gov/assets/330/323802. pdf. Accessed January 6, 2016. 4. Health Resources and Services Administration: 340B Drug Pricing Program. Available at http://www.hrsa.gov/opa/index.html. Accessed January 6, 2016. 5. American Society of Clinical Oncology: Policy Statement on the 340B Drug Pricing Program by the American Society of Clinical Oncology. J Oncol Pract 10:259263, 2014. 6. Kantarjian HM, Chapman R: Role of the 340B drug discount program in recent cancer care trends. J Oncol Pract 11:303-307, 2015. 7. Kantarjian H, Chapman R: Value of the 340B drug discount program. JAMA Oncol 1:1029-1030, 2015. 8. Fein AJ: 340B sales totaled $7.5 billion in 2013, Apexus says. Drug Discount Monitor. February 14, 2014. 9. IMS Health: Medicine use and shifting costs of healthcare: A review of the use of medicines in the United States in 2013. Available at www.imshealth.com/en/thought-leadership/ ims-institute/reports/use-of-medicines-inthe-us-2013. Accessed January 6, 2016. 10. A brief guide to Big Pharma. The Week. October 17, 2015. Available at http:// theweek.com/articles/583337/brief-guidebig-pharma. Accessed January 6, 2016. 11. Potter W: Deadly Spin: An Insurance Company Insider Speaks Out on How Corporate PR Is Killing Health Care and Deceiving Americans, pp 222-224. New York, Bloomsbury Press, 2011. 12. Robert Kenner (director): Merchants of Doubt. Sony Pictures Classics, 2014. 13. Alliance for Integrity and Reform: AIR 340B. Available at www.340BReform. org. Accessed January 6, 2016. 14. 340B Health: Hospital group refutes misleading study on cancer costs. May 6, 2014. Available at http://www.snhpa.org/news/ hospital-group-refutes-misleading-study-oncancer-costs. Accessed January 6, 2016. 15. Safety Net Hospitals for Pharmaceutical Access: Setting the record straight on 340B: A response to critics. July 2013. Available at www.snhpa.org/files/Setting_the_Record_Straight_Report.pdf. Accessed January 6, 2016. 16. IMS Health: Innovation in cancer care and implications for health systems: Global oncology trend report. Available at http:// www.imshealth.com/en/thought-leadership/ims-institute/reports/global-oncologytrend-report-2014. Accessed January 6, 2016.

17. Berkeley Research Group: 340B covered entity acquisitions of physicianbased oncology practices. April 22, 2014. Available at www.thinkbrg.com/media/ publication/449_340B%20Physicianbased%20Oncology%20Practice%20Acquisitions.pdf. Accessed January 6, 2016. 18. HRSA Office of Pharmacy Affairs 340 B Database. Available at https://opa-

net.hrsa.gov/340B/Views/CoveredEntity/ CESearch. Accessed January 6, 2016. 19. HRSA Office of Pharmacy Affairs: Contract pharmacy oversight. Available at www.hrsa.gov/opa/updates/contractpharmacy02052014.html. Accessed January 6, 2016. 20. Ku L, Jones E, Shin P, et al: Safetynet providers after health care reform: Les-

sons from Massachusetts. Arch Intern Med 171:1379-1384, 2011. 21. Association of Community Cancer Centers: Association of Community Cancer Centers Position Paper on the 340B Drug Discount Program. October 2013. Available at https://www.accc-cancer.org/ advocacy/pdf/2013-position-paper-340B. pdf. Accessed January 6, 2016.

NEW IN 2016 Journal of Oncology Practice now includes highly practical clinical reviews Editor-in-Chief: John V. Cox, DO, MBA, FACP, FASCO; University of Texas Southwestern Medical Center, Dallas, Texas Deputy Editor: James O. Armitage, MD; University of Nebraska Medical Center, Omaha, Nebraska

JOP has expanded editorially to include highly practical clinical content. Increasing in frequency from bimonthly to monthly, JOP’s clinical expansion is anchored by practical clinical reviews written specifically for busy, practicing clinicians who treat patients on a daily basis, including:

New Clinical Content Led by Deputy Editor James O. Armitage, MD, the JOP Clinical Expansion will feature clinical reviews, expert commentaries, and case reports: • Clinical Reviews are focused, authoritative, and practical reviews addressing a distinct clinical issue in oncology relevant to the practicing oncologist. • Each review will be accompanied by Commentaries providing a personal perspective and expert opinion. • Case Reports are concise reports telling the clinical story of a challenging case from the author’s own experience.

ReCAP: A New Format for Original Research Original research papers will be presented in print as short, structured summaries called ReCAP (Research Contributions Abbreviated for Print). ReCAP distills the practical takeaways of an article into a single page. Each paper will be published in full online.

To Access Issues or Subscribe Visit JOP.ascopubs.org

The ASCO Post | JANUARY 25, 2016

PAGE 158

JOP Spotlight

Journal of Oncology Practice Increases Frequency, Adds Clinical Reviews

SCO recently announced that the Journal of Oncology Practice (JOP) will be printed on a monthly basis and offer new resources to supply oncology professionals with cutting-edge information on cancer care delivery. Doubling its content, the expanded journal also features clinical information from a multidisciplinary care team perspective led by JOP’s new Deputy Editor, James O. Armitage, MD, FASCO. “The Journal of Oncology Practice seeks not only to provide valuable information to oncologists, but also to respond to the changing landscape of cancer care,” said John V. Cox, DO, MBA, FACP, FASCO, and Editor-in-Chief of JOP. “Recognizing the shifting needs of the modern cancer community, JOP is expanding on its previous framework to make research findings more accessible and to provide oncologists with information covering all aspects of cancer care.” The expanded content and frequency will be delivered by Harborside Press, publisher of The ASCO Post in partnership with ASCO. Herewith, The ASCO Post is pleased to share the inaugural “Editor’s Desk” letter from Dr. Cox and Dr. Armitage as published in the January edition of JOP. Volume 12 / Issue 1 / January 2016

The Authoritative Resource for Practicing Oncology

Curing Metastatic Breast Cancer George W. Sledge Jr, MD Commentaries by Daniel F. Hayes, MD Nancy E. Davidson, MD

Clinical Insights Into the Biology and Treatment of Pancreatic Cancer

Surgical Management of Liver Metastases From Colorectal Cancer

The ASCO Oncology Composite Provider Utilization File: New Data, New Insights

N.B. Mettu and J.L. Abbruzzese

M. Dhir and A.R. Sasson

T.R. Barr and E.L. Towle

Kikuchi’s Disease Masquerading as Refractory Lymphoma

Improving Price Transparency in Cancer Care

A. Kallam, P. Bierman, and R.G. Bociek

N.B. Henrikson and V. Shankaran

Social Media Use Among Physicians and Trainees: Results of a National Medical Oncology Physician Survey R. Adilman et al

jop.ascopubs.org

Evolution By John V. Cox, DO, MBA, FACP, FASCO and James O. Armitage, MD, FASCO

en years ago, ASCO created the Journal of Oncology Practice to address a gap in the literature; there were no peer-reviewed journals dedicated to the practical issues of delivering quality oncology care. The original research and editorials published in JOP focus on care delivery topics such as practice operations, efficiency of service provision, health outcomes and health services research, quality of care and access to care, health policy and socioeconomics of cancer care, cost-benefit and cost-effectiveness analyses, and use of technology. Over the years, JOP has evolved and grown—from receiving a handful of pertinent research articles in its inaugural year to receiving approximately 400 submissions, including nearly 300 original reports, in 2015. Submissions were received from more than 20 countries, clearly emphasizing the global relevance of our content. The value of the journal to the oncology community continues to grow, as evidenced by increasing online use and growing readership scores. Yet we know we can do better. Beginning in this, our 11th volume, readers will find significant changes to the content and format of JOP. Our efforts are designed to address the expressed needs of our readers for new, highly practical clinical content and for more accessible, synoptic presentation of the care delivery research. We believe the result will be a unique oncology journal, bridging the gap between clinical challenges and the mechanisms of care delivery. Within this issue, readers will find three compelling clinical reviews, each with commentary highlighting key questions and opinions about a discrete clinical problem. Readers will appreciate recognized leaders in our profession weighing in on managing pancreatic cancer, dealing with liver metastasis of colorectal cancer, and potentially curing metastatic breast cancer. Four past ASCO presidents are contributing authors to this issue. We believe these and future reviews by authors who are master teachers in

Dr. Cox is with Parkland Health System; University of Texas Southwestern Medical Center, Dallas, Texas; and Dr. Armitage is with the University of Nebraska Medical Center, Omaha, Nebraska.

our field will be compelling reads for busy clinicians and, it is hoped, provide fodder for discussion. JOP will continue to present original research focusing on care delivery—providing care delivery researchers a robust forum within which to share their work. Over the years, two-thirds of our original research has been published as onlineonly/Web-exclusive content. Now, all original research articles will be presented in print as short, structured summaries: ReCAPs (Research Contributions Abbreviated for Print). A ReCAP will distill the practical takeaways of an article into a single page and highlight a single table or graphic from the article. The full manuscript will be published online (http://jop. ascopubs.org). The online manu-

Sagar Lonial, and Arif Kamal join as associate editors. Drs. Armitage, Ganti, and Lonial will guide the development of the clinical reviews and commentary, in addition to providing extra expertise in the care delivery mission of the journal. Dr. Kamal will attempt to fill the shoes of longtime JOP Associate Editor Pat Legant, who is retiring. Congratulations, Pat! Readers will appreciate the new look and feel of the journal. This is the result of a new collaborative publishing arrangement between the production teams of ASCO and Harborside Press, publishers of The ASCO Post. Visible to readers will be the enthusiasm and excitement over the evolution of our journal. We undertake these changes—more frequent publication, expanded clinical content,

[The JOP expansion addresses] expressed needs of our readers for new, highly practical clinical content and for more accessible, synoptic presentation of the care delivery research. We believe the result will be a unique oncology journal, bridging the gap between clinical challenges and the mechanisms of care delivery. —John V. Cox, DO, MBA, FACP, FASCO and James O. Armitage, MD, FASCO

script will be the citable article of record and the manuscript that will be identified by indexing services. The journal will move from being published six times per year to once per month and will no longer be bundled with the Journal of Clinical Oncology but instead mailed independently. All of our content is peer reviewed. Nearly all of our content is published online ahead of print. With the monthly print schedule, we expect to be able to shorten the time from acceptance to publication, both online and in print. To produce the reformatted and expanded JOP, new editorial expertise is needed. Dr. James Armitage, a former ASCO president who is well known to our readers, joins the journal as deputy editor. Drs. Apar Ganti,

synoptic presentation of original research, and new format—to meet the needs of our readers and provide our authors with a larger audience. Furthermore, initiatives are ongoing to improve our Web presence and the usability of our manuscript submission systems and editorial review tools. We encourage readers to subscribe to JOP podcasts, which highlight interesting and impactful content from the journal. We welcome comments—both formal letters to the editors and less formal feedback—on the journal at jopcontact@asco.org. n Reprinted from Cox J, Armitage J: Evolution. J Oncol Pract 12:1–2, 2016. ©American Society of Clinical Oncology 2016.

ASCOPost.com | JANUARY 25, 2016

PAGE 159

News Breast Cancer

USPSTF Recommendation Confirms Value of Screening Mammography

he recently updated U.S. Preventive Services Task Force (USPSTF) recommendation once again confirmed the value of screening mammography, concluding that the benefit of mammography outweighs the harms of screening in all age groups from age 40 through age 74. It emphasizes that both women and clinicians providing primary care to women need to understand the benefits and harms of screening. Compared to the initial draft recommendation, the USPSTF now places greater emphasis on the importance of making a personal, informed decision about when to start screening. The new language adds greater clarity regarding the higher risk of developing breast cancer in the late 40s compared to the early 40s and endorses a woman starting to screen any time in that decade if she believes screening is right for her.

Agreements and Differences The American Cancer Society (ACS) guideline and the USPSTF recommendation statement include similar recommendations, but there are a few areas of important differences, including the age by which all women should have started screening, the frequency of screening mammography, and at what age screening should stop. While differences exist among recommendations from the USPSTF, the ACS, and other organizations, each confirms the importance and value

The ASCO Post

of regular screening mammography. Our nation has a vital opportunity to further reduce mortality from breast cancer by reducing barriers to screening for all women, and in particular to improve access to high-quality mammography to the more than one-third

of women who are not being regularly screened. The Affordable Care Act tied health insurance coverage policies to USPSTF guidelines. However, recent action in Congress placed a 2-year moratorium on this breast cancer screening guide-

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Jame Abraham, MD Cleveland Clinic, Cleveland, Ohio

Alok A. Khorana, MD Cleveland Clinic, Cleveland, Ohio

targeting the epidermal growth factor receptor (EGFR) and angiogenesis, and determine which agents and combination regimens are good first-line options for selected patients with mCRC. benefits of surgical resection of the primary tumor and/or metastases.

PROGRAM CHAIR

@ASCOPost

NOWNOW AVAILABLE

Emerging Approaches in First-line Therapy for Metastatic Colorectal Cancer

AUDIENCE

line. While insurance coverage for women who choose to have mammography in their 40s should not be interrupted in the next 2 years, concern remains about the implications of this updated guideline on insurance coverage decisions in the future. n

The Cleveland Clinic Center for Continuing Education acknowledges educational grants for support of this activity from Lilly and AMGEN

Visit www.ccfcme.org/tumorboard for access to Cleveland Clinic tumor board programs:

Management of Locally Advanced HER2-Positive Breast Cancer March 2015 – March 2016

Emerging Approaches in First-line Therapy for Metastatic Colorectal Cancer December 2015 – December 2016

www.ccfcme.org/MCRC

Current and Future Treatment Options for Advanced Melanoma COMING IN 2016

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The ASCO Post

News

ASCO Praises President’s Sharp Focus on Cancer Statement From ASCO Chief Medical Officer Richard L. Schilsky, MD, FACP, FASCO

‘Big Data’ Initiatives We must recommit to vastly speeding the discovery of new cancer treatments and enabling the possibility of precision medicine for every individual with cancer. With the effective application of “big data” initiatives, such as ASCO’s CancerLinQ rapid-learning system, insights that have taken years to discern could happen much more quickly, helping us to better understand which treatments work best for each patient and the high-impact areas where additional research is critically needed. As the world’s leading professional organization representing nearly 40,000 physicians and other health-care professionals who care for people with cancer, ASCO’s mission is to conquer cancer through research education and promotion of high-quality cancer care that is accessible to all Americans. ASCO stands ready to fully support President Obama and Vice President Biden in this critically important endeavor as we strive to realize our vision of a world where cancer is prevented or cured and every survivor is healthy. n

WARNING: GASTROINTESTINAL PERFORATIONS, SURGERY AND WOUND HEALING COMPLICATIONS, and HEMORRHAGE Gastrointestinal Perforations The incidence of gastrointestinal perforation, some fatal, in Avastin‑treated patients ranges from 0.3 to 3.2%. Discontinue Avastin in patients with gastrointestinal perforation. [See Dosage and Administration (2.4), Warnings and Precautions (5.1).] Surgery and Wound Healing Complications The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Avastin‑treated patients. Discontinue Avastin in patients with wound dehiscence. The appropriate interval between termination of Avastin and subsequent elective surgery required to reduce the risks of impaired wound healing/ wound dehiscence has not been determined. Discontinue at least 28 days prior to elective surgery. Do not initiate Avastin for at least 28 days after surgery and until the surgical wound is fully healed. [See Dosage and Administration (2.4), Warnings and Precautions (5.2), Adverse Reactions (6.1).] Hemorrhage Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, central nervous systems (CNS) hemorrhage, epistaxis, and vaginal bleeding occur up to five‑fold more frequently in patients receiving Avastin. Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis. [See Dosage and Administration (2.4), Warnings and Precautions (5.3), Adverse Reactions (6.1).] 1 INDICATIONS AND USAGE 1.1 Metastatic Colorectal Cancer (mCRC) Avastin is indicated for the first‑ or second‑line treatment of patients with metastatic carcinoma of the colon or rectum in combination with intravenous 5‑fluorouracil–based chemotherapy. Avastin, in combination with fluoropyrimidine‑irinotecan‑ or fluoropyrimidine‑ oxaliplatin‑based chemotherapy, is indicated for the second‑line treatment of patients with metastatic colorectal cancer who have progressed on a first‑line Avastin‑containing regimen. Limitation of Use: Avastin is not indicated for adjuvant treatment of colon cancer. [See Clinical Studies (14.2).] 1.2 Non‑Squamous Non–Small Cell Lung Cancer (NSCLC) Avastin is indicated for the first‑line treatment of unresectable, locally advanced, recurrent or metastatic non–squamous non–small cell lung cancer in combination with carboplatin and paclitaxel. 1.3 Glioblastoma Avastin is indicated for the treatment of glioblastoma with progressive disease in adult patients following prior therapy as a single agent. The effectiveness of Avastin in glioblastoma is based on an improvement in objective response rate. There are no data demonstrating an improvement in disease‑related symptoms or increased survival with Avastin. [See Clinical Studies (14.4).] 1.4 Metastatic Renal Cell Carcinoma (mRCC) Avastin is indicated for the treatment of metastatic renal cell carcinoma in combination with interferon alfa. 1.5 Persistent, Recurrent, or Metastatic Carcinoma of the Cervix Avastin in combination with paclitaxel and cisplatin or paclitaxel and topotecan is indicated for the treatment of persistent, recurrent, or metastatic carcinoma of the cervix. [See Clinical Studies (14.6).] 1.6 Platinum‑Resistant Recurrent Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer Avastin in combination with paclitaxel, pegylated liposomal doxorubicin or topotecan is indicated for the treatment of patients with platinum‑ resistant recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer who received no more than 2 prior chemotherapy regimens. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Gastrointestinal Perforations and Fistulae Serious and sometimes fatal gastrointestinal perforation occurs at a higher incidence in Avastin treated patients compared to controls. The incidence of gastrointestinal perforation ranged from 0.3 to 3.2% across clinical studies. [See Adverse Reactions (6.1).] From a clinical trial in patients with persistent, recurrent, or metastatic cervical cancer (Study 9), gastrointestinal perforations were reported in 3.2% of Avastin treated patients, all of whom had a history of prior pelvic radiation. Fatal outcome was reported in <1% of Avastin‑treated patients. In a platinum‑resistant ovarian cancer trial (Study 10), the incidence of GI perforation was 1.7% (3/179). In this trial, patients with evidence of recto‑sigmoid involvement by pelvic examination or bowel involvement on CT scan or clinical symptoms of bowel obstruction were excluded. The typical presentation may include abdominal pain, nausea, emesis, constipation, and fever. Perforation can be complicated by intra‑abdominal abscess, fistula formation, and the need for diverting ostomies. The majority of cases occurred within the first 50 days of initiation of Avastin. Avoid use of Avastin in patients with ovarian cancer who have evidence of recto‑sigmoid involvement by pelvic examination or bowel involvement on CT scan or clinical symptoms of bowel obstruction. Permanently discontinue Avastin in patients with gastrointestinal perforation. In Avastin clinical trials, gastrointestinal fistulae have been reported with an incidence of up to 2% in patients with metastatic colorectal cancer and ovarian cancer. In a cervical cancer trial (Study 9), the incidence of gastrointestinal‑vaginal fistulae was 8.3% in Avastin‑treated patients and 0.9% in control patients, all of whom had a history of prior pelvic radiation. Patients who develop GI vaginal fistulas may also have bowel obstructions and require surgical intervention as well as diverting ostomies. [See Boxed Warning, Dosage and Administration (2.4).] 5.2 Non‑Gastrointestinal Fistulae Serious and sometimes fatal fistula formation involving tracheo‑ esophageal, bronchopleural, biliary, vaginal, renal and bladder sites occurs at a higher incidence in Avastin‑treated patients compared to controls. Uncommon (<1%) reports of fistulae that involve areas of the body other than the gastrointestinal tract were observed in clinical trials across various indications and have also been reported in post‑ marketing experience. Most events occurred within the first 6 months of Avastin therapy. From a clinical trial in patients with persistent, recurrent, or metastatic cervical cancer (Study 9), 1.8% of Avastin‑treated patients and 1.4% of control patients were reported to have had non‑gastrointestinal vaginal, vesical, or female genital tract fistulae. Permanently discontinue Avastin in patients with tracheoesophageal (TE) fistula or any Grade 4 fistula. Discontinue Avastin in patients with fistula formation involving an internal organ. [See Dosage and Administration (2.4).] 5.3 Surgery and Wound Healing Complications Avastin impairs wound healing in animal models. [See Nonclinical Toxicology (13.2).] In clinical trials, administration of Avastin was not allowed until at least 28 days after surgery. In a controlled clinical trial, the incidence of wound healing complications, including serious and fatal complications, in patients with mCRC who underwent surgery during the course of Avastin treatment was 15% and in patients who did not receive Avastin, was 4%. [See Adverse Reactions (6.1).] Avastin should not be initiated for at least 28 days following surgery and until the surgical wound is fully healed. Discontinue Avastin in patients with wound healing complications requiring medical intervention. The appropriate interval between the last dose of Avastin and elective surgery is unknown; however, the half‑life of Avastin is estimated to be 20 days. Suspend Avastin for at least 28 days prior to elective surgery. Do not administer Avastin until the wound is fully healed. [See Boxed Warning, Dosage and Administration (2.4).] Necrotizing fasciitis including fatal cases, has been reported in patients treated with Avastin; usually secondary to wound healing complications, gastrointestinal perforation or fistula formation. Discontinue Avastin therapy in patients who develop necrotizing fasciitis. [See Adverse Reactions (6.3).] 5.4 Hemorrhage Avastin can result in two distinct patterns of bleeding: minor hemorrhage, most commonly Grade 1 epistaxis; and serious, and in some cases fatal,

AVASTIN® (bevacizumab) hemorrhagic events. Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, hematemesis, CNS hemorrhage, epistaxis, and vaginal bleeding occurred up to five‑fold more frequently in patients receiving Avastin compared to patients receiving only chemotherapy. Across indications, the incidence of Grade ≥ 3 hemorrhagic events among patients receiving Avastin ranged from 0.4 to 6.9 %. [See Adverse Reactions (6.1).] Serious or fatal pulmonary hemorrhage occurred in four of 13 (31%) patients with squamous cell histology and two of 53 (4%) patients with non‑ squamous non‑small cell lung cancer receiving Avastin and chemotherapy compared to none of the 32 (0%) patients receiving chemotherapy alone. In clinical studies in non−small cell lung cancer where patients with CNS metastases who completed radiation and surgery more than 4 weeks prior to the start of Avastin were evaluated with serial CNS imaging, symptomatic Grade 2 CNS hemorrhage was documented in one of 83 Avastin‑treated patients (rate 1.2%, 95% CI 0.06%−5.93%). Intracranial hemorrhage occurred in 8 of 163 patients with previously treated glioblastoma; two patients had Grade 3−4 hemorrhage. Do not administer Avastin to patients with recent history of hemoptysis of ≥ 1/2 teaspoon of red blood. Discontinue Avastin in patients with hemorrhage. [See Boxed Warning, Dosage and Administration (2.4).] 5.5 Arterial Thromboembolic Events Serious, sometimes fatal, arterial thromboembolic events (ATE) including cerebral infarction, transient ischemic attacks, myocardial infarction, angina, and a variety of other ATE occurred at a higher incidence in patients receiving Avastin compared to those in the control arm. Across indications, the incidence of Grade ≥ 3 ATE in the Avastin containing arms was 2.6% compared to 0.8% in the control arms. Among patients receiving Avastin in combination with chemotherapy, the risk of developing ATE during therapy was increased in patients with a history of arterial thromboembolism, diabetes, or age greater than 65 years. [See Use in Specific Populations (8.5).] The safety of resumption of Avastin therapy after resolution of an ATE has not been studied. Discontinue Avastin in patients who experience a severe ATE. [See Dosage and Administration (2.4).] 5.6 Venous Thromboembolic Events Patients treated for persistent, recurrent, or metastatic cervical cancer with Avastin may be at increased risk of venous thromboembolic events (VTE). From a clinical trial in patients with persistent, recurrent, or metastatic cervical cancer (Study 9), Grade ≥ 3 VTE were reported in 10.6% of patients treated with chemotherapy and Avastin compared with 5.4% in patients receiving chemotherapy alone. Permanently discontinue Avastin in patients with life‑threatening (Grade 4) VTE, including pulmonary embolism. [See Dosage and Administration (2.4), Adverse Reactions (6.1).] 5.7 Hypertension The incidence of severe hypertension is increased in patients receiving Avastin as compared to controls. Across clinical studies the incidence of Grade 3 or 4 hypertension ranged from 5‑18%. Monitor blood pressure every two to three weeks during treatment with Avastin. Treat with appropriate anti‑hypertensive therapy and monitor blood pressure regularly. Continue to monitor blood pressure at regular intervals in patients with Avastin‑induced or ‑exacerbated hypertension after discontinuation of Avastin. Temporarily suspend Avastin in patients with severe hypertension that is not controlled with medical management. Discontinue Avastin in patients with hypertensive crisis or hypertensive encephalopathy. [See Dosage and Administration (2.4).] 5.8 Posterior Reversible Encephalopathy Syndrome (PRES) PRES has been reported with an incidence of < 0.5% in clinical studies. The onset of symptoms occurred from 16 hours to 1 year after initiation of Avastin. PRES is a neurological disorder which can present with headache, seizure, lethargy, confusion, blindness and other visual and neurologic disturbances. Mild to severe hypertension may be present. Magnetic resonance imaging (MRI) is necessary to confirm the diagnosis of PRES. Discontinue Avastin in patients developing PRES. Symptoms usually resolve or improve within days, although some patients have experienced ongoing neurologic sequelae. The safety of reinitiating Avastin therapy in patients previously experiencing PRES is not known. [See Dosage and Administration (2.4).] 5.9 Proteinuria The incidence and severity of proteinuria is increased in patients receiving Avastin as compared to controls. Nephrotic syndrome occurred in < 1% of patients receiving Avastin in clinical trials, in some instances with fatal outcome. [See Adverse Reactions (6.1).] In a published case series, kidney biopsy of six patients with proteinuria showed findings consistent with thrombotic microangiopathy. Monitor proteinuria by dipstick urine analysis for the development or worsening of proteinuria with serial urinalyses during Avastin therapy. Patients with a 2 + or greater urine dipstick reading should undergo further assessment with a 24‑hour urine collection. Suspend Avastin administration for ≥ 2 grams of proteinuria/24 hours and resume when proteinuria is < 2 gm/24 hours. Discontinue Avastin in patients with nephrotic syndrome. [See Dosage and Administration (2.4).] Data from a postmarketing safety study showed poor correlation between UPCR (Urine Protein/Creatinine Ratio) and 24 hour urine protein (Pearson Correlation 0.39 (95% CI 0.17, 0.57). [See Use in Specific Populations (8.5).] 5.10 Infusion Reactions Infusion reactions reported in the clinical trials and post‑marketing experience include hypertension, hypertensive crises associated with neurologic signs and symptoms, wheezing, oxygen desaturation, Grade 3 hypersensitivity, chest pain, headaches, rigors, and diaphoresis. In clinical studies, infusion reactions with the first dose of Avastin were uncommon ( < 3%) and severe reactions occurred in 0.2% of patients. Stop infusion if a severe infusion reaction occurs and administer appropriate medical therapy. [See Dosage and Administration (2.4).] 5.11 Embryo‑fetal Toxicity Avastin may cause fetal harm based on the drug’s mechanism of action and findings from animal studies. Congenital malformations were observed with the administration of bevacizumab to pregnant rabbits during organogenesis every 3 days at a dose as low as a clinical dose of 10 mg/kg. Furthermore, animal models link angiogenesis and VEGF and VEGF Receptor 2 (VEGFR2) to critical aspects of female reproduction, embryo‑fetal 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 and for 6 months after the last dose of Avastin. [See Use in Specific Populations (8.1, 8.3), Clinical Pharmacology (12.1).] 5.12 Ovarian Failure The incidence of ovarian failure was higher (34% vs. 2%) in premenopausal women receiving Avastin in combination with mFOLFOX chemotherapy as compared to those receiving mFOLFOX chemotherapy alone for adjuvant treatment for colorectal cancer, a use for which Avastin is not approved. Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin. [See Adverse Reactions (6.1), Use in Specific Populations (8.3).] 6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the label: • Gastrointestinal Perforations and Fistulae [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.1).] • Non‑Gastrointestinal Fistulae [See Dosage and Administration (2.4), Warnings and Precautions (5.2).] • Surgery and Wound Healing Complications [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.3).] • Hemorrhage [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.4).] • Arterial Thromboembolic Events [See Dosage and Administration (2.4), Warnings and Precautions (5.5).] • Venous Thromboembolic Events [See Dosage and Administration (2.4), Warnings and Precautions (5.6).] • Hypertensive Crisis [See Dosage and Administration (2.4), Warnings and Precautions (5.7).] • Posterior Reversible Encephalopathy Syndrome [See Dosage and Administration (2.4), Warnings and Precautions (5.8).] • Proteinuria [See Dosage and Administration (2.4), Warnings and Precautions (5.9).] • Infusion Reactions [See Dosage and Administration (2.4), Warnings and Precautions (5.10).] • Ovarian Failure [See Warnings and Precautions (5.12), Use in Specific Populations (8.1).]

AVASTIN® (bevacizumab) The most common adverse reactions observed in Avastin patients at a rate > 10% and at least twice the control arm rate, are epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain and exfoliative dermatitis Some of the adverse reactions are commonly seen with chemotherapy; however, Avastin may exacerbate these reactions when combined with chemotherapeutic agents. Examples include palmar‑plantar erythrodysaesthesia syndrome with pegylated liposomal doxorubicin or capecitabine peripheral sensory neuropathy with paclitaxel or oxaliplatin, and nail disorders or alopecia with paclitaxel. Across all studies, Avastin was discontinued in 8.4 to 21% of patients because of adverse reactions. 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data below reflect exposure to Avastin in 4996 patients with CRC, non‑squamous NSCLC, glioblastoma, mRCC, or cervical cancer or platinum‑ resistant recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer including controlled (Studies 1, 2, 4, 5, 8 9 and 10) or uncontrolled, single arm trials (Study 6) treated at the recommended dose and schedule for a median of 6 to 23 doses of Avastin. [See Clinical Studies (14).] The population was aged 18‑89 years (median 60 years), 42% male and 86% White. The population included 2184 first‑ and second‑line mCRC patients who received a median of 10 doses of Avastin, 480 first‑line metastatic NSCLC patients who received a median of 8 doses of Avastin, 163 glioblastoma patients who received a median of 9 doses of Avastin, 337 mRCC patients who received a median of 16 doses of Avastin, 218 cervical cancer patients who received a median of 6 doses of Avastin and 179 platinum‑resistant recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer patients who received a median of 6 doses of Avastin. These data also reflect exposure to Avastin in 363 patients with metastatic breast cancer (MBC) who received a median of 9.5 doses of Avastin, 1338 adjuvant CRC patients, including 669 female patients, who received a median of 23 doses of Avastin, and 403 previously untreated patients with diffuse large B‑cell lymphoma (DLBCL) who received a median of 8 doses of Avastin. Avastin is not approved for use in MBC, adjuvant CRC, or DLBCL. Surgery and Wound Healing Complications The incidence of post‑operative wound healing and/or bleeding complications was increased in patients with mCRC receiving Avastin as compared to patients receiving only chemotherapy. Among patients requiring surgery on or within 60 days of receiving study treatment, wound healing and/or bleeding complications occurred in 15% (6/39) of patients receiving bolus‑IFL plus Avastin as compared to 4% (1/25) of patients who received bolus‑IFL alone. In Study 6, events of post‑operative wound healing complications (craniotomy site wound dehiscence and cerebrospinal fluid leak) occurred in patients with previously treated glioblastoma: 3/84 patients in the Avastin alone arm and 1/79 patients in the Avastin plus irinotecan arm. [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.3).] Hemorrhage The incidence of epistaxis was higher (35% vs. 10%) in patients with mCRC receiving bolus‑IFL plus Avastin compared with patients receiving bolus‑IFL plus placebo. All but one of these events were Grade 1 in severity and resolved without medical intervention. Grade 1 or 2 hemorrhagic events were more frequent in patients receiving bolus‑IFL plus Avastin when compared to those receiving bolus‑IFL plus placebo and included gastrointestinal hemorrhage (24% vs. 6%), minor gum bleeding (2% vs. 0), and vaginal hemorrhage (4% vs. 2%). [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.4).] Venous Thromboembolic Events The overall incidence of Grade 3–4 venous thromboembolic events in Study 1 was 15.1% in patients receiving bolus‑IFL plus Avastin and 13.6% in patients receiving bolus‑IFL plus placebo. In Study 1, more patients in the Avastin containing arm experienced deep venous thrombosis (34 vs. 19 patients ) and intra‑abdominal venous thrombosis (10 vs. 5 patients). The risk of developing a second thromboembolic event while on Avastin and oral anticoagulants was evaluated in two randomized studies. In Study 1, 53 patients (14%) on the bolus‑IFL plus Avastin arm and 30 patients (8%) on the bolus‑IFL plus placebo arm received full dose warfarin following a venous thromboembolic event (VTE). Among these patients, an additional thromboembolic event occurred in 21% (11/53) of patients receiving bolus‑IFL plus Avastin and 3% (1/30) of patients receiving bolus‑IFL alone. In a second, randomized, 4‑arm study in 1401 patients with mCRC, prospectively evaluating the incidence of VTE (all grades), the overall incidence of first VTE was higher in the Avastin containing arms (13.5%) than the chemotherapy alone arms (9.6%). Among the 116 patients treated with anticoagulants following an initial VTE event (73 in the Avastin plus chemotherapy arms and 43 in the chemotherapy alone arms), the overall incidence of subsequent VTEs was also higher among the Avastin treated patients (31.5% vs. 25.6%). In this subgroup of patients treated with anticoagulants, the overall incidence of bleeding, the majority of which were Grade 1, was higher in the Avastin treated arms than the chemotherapy arms (27.4% vs. 20.9%). From a clinical trial in patients with persistent, recurrent, or metastatic cervical cancer (Study 9), Grade 3 or 4 VTE have been reported in 10.6% of patients treated with chemotherapy and Avastin compared with 5.4% in patients receiving chemotherapy alone. There were no patients with Grade 5 VTE. [See Dosage and Administration (2.4), Warnings and Precautions (5.6).] Neutropenia and Infection The incidences of neutropenia and febrile neutropenia are increased in patients receiving Avastin plus chemotherapy compared to chemotherapy alone. In Study 1, the incidence of Grade 3 or 4 neutropenia was increased in mCRC patients receiving IFL plus Avastin (21%) compared to patients receiving IFL alone (14%). In Study 5, the incidence of Grade 4 neutropenia was increased in NSCLC patients receiving paclitaxel/carboplatin (PC) plus Avastin (26.2%) compared with patients receiving PC alone (17.2%). Febrile neutropenia was also increased (5.4% for PC plus Avastin vs. 1.8% for PC alone). There were 19 (4.5%) infections with Grade 3 or 4 neutropenia in the PC plus Avastin arm of which 3 were fatal compared to 9 (2%) neutropenic infections in patients receiving PC alone, of which none were fatal. During the first 6 cycles of treatment, the incidence of serious infections including pneumonia, febrile neutropenia, catheter infections and wound infections was increased in the PC plus Avastin arm [58 patients (13.6%)] compared to the PC alone arm [29 patients (6.6%)]. In Study 6, one fatal event of neutropenic infection occurred in a patient with previously treated glioblastoma receiving Avastin alone. The incidence of any grade of infection in patients receiving Avastin alone was 55% and the incidence of Grade 3–5 infection was 10%. Proteinuria Grade 3–4 proteinuria ranged from 0.7 to 7.4% in Studies 1, 2, 4, 5, 8 and 10. The overall incidence of proteinuria (all grades) was only adequately assessed in Study 8, in which the incidence was 20%. Median onset of proteinuria was 5.6 months (range 15 days to 37 months) after initiation of Avastin. Median time to resolution was 6.1 months (95% CI 2.8 months, 11.3 months). Proteinuria did not resolve in 40% of patients after median follow up of 11.2 months and required permanent discontinuation of Avastin in 30% of the patients who developed proteinuria (Study 8). In an exploratory, pooled analysis of 8,273 patients treated in 7 randomized clinical trials, 5.4% (271 of 5037) of patients receiving Avastin in combination with chemotherapy experienced Grade ≥ 2 proteinuria. The Grade ≥ 2 proteinuria resolved in 74.2% (201 of 271) of patients. Avastin was re‑initiated in 41.7% (113 of 271) of patients. Of the 113 patients who re‑initiated Avastin, 47.8% (54 of 113) experienced a second episode of Grade ≥ 2 proteinuria. [See Warnings and Precautions (5.9).] Congestive Heart Failure (CHF) The incidence of Grade ≥ 3 left ventricular dysfunction was 1.0% in patients receiving Avastin compared to 0.6% in the control arm across indications. In patients with metastatic breast cancer (MBC), an indication for which Avastin is not approved, the incidence of Grade 3–4 CHF was increased in patients in the Avastin plus paclitaxel arm (2.2%) as compared to the control arm (0.3%). Among patients receiving prior anthracyclines for MBC, the rate of CHF was 3.8% for patients receiving Avastin as compared to 0.6% for patients receiving paclitaxel alone. The safety of continuation or resumption of Avastin in patients with cardiac dysfunction has not been studied.

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SCO applauds President Obama for his bold vision to launch a national effort on cancer, which he described during his State of the Union address on January 12, 2016. We also join him in recognizing Vice President Biden’s leadership in calling for a “moonshot” that will reduce the cancer-related human suffering and loss of life that impacts millions of Americans each year. With nearly 1.7 million people in the United States diagnosed with cancer each year, and the incidence of cancer expected to rise to 2.3 million cases per year by 2030, it is imperative that we do all we can to bring more effective treatments from the laboratory bench to the patient’s bedside as quickly as possible. We agree with President Obama when he asserted that “…we can do so much more. For the loved ones we’ve all lost, for the family we can still save, let’s make America the country that cures cancer once and for all,” said President Obama.

AVASTIN® (bevacizumab) Solution for intravenous infusion Initial U.S. Approval: 2004 This is a brief summary of information about AVASTIN. Before prescribing, please see full Prescribing Information.

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AVASTIN® (bevacizumab) In previously untreated patients with diffuse large B‑cell lymphoma (DLBCL), an indication for which Avastin is not approved, the incidence of CHF and decline in left‑ventricular ejection fraction (LVEF) were significantly increased in the Avastin plus R‑CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) arm (n=403) compared to the placebo plus R‑CHOP arm (n=379); both regimens were given for 6 to 8 cycles. At the completion of R‑CHOP therapy, the incidence of CHF was 10.9% in the Avastin plus R‑CHOP arm compared to 5.0% in the R‑CHOP alone arm [relative risk (95% CI) of 2.2 (1.3, 3.7)]. The incidence of a LVEF event, defined as a decline from baseline of 20% or more in LVEF or a decline from baseline of 10% or more to a LVEF value of less than 50%, was also increased in the Avastin plus R‑CHOP arm (10.4%) compared to the R‑CHOP alone arm (5.0%). Time to onset of left‑ventricular dysfunction or CHF was 1‑6 months after initiation of therapy in at least 85% of the patients and was resolved in 62% of the patients experiencing CHF in the Avastin arm compared to 82% in the control arm. Ovarian Failure The incidence of new cases of ovarian failure (defined as amenorrhoea lasting 3 or more months, FSH level ≥ 30 mIU/mL and a negative serum β‑HCG pregnancy test) was prospectively evaluated in a subset of 179 women receiving mFOLFOX chemotherapy alone (n = 84) or with Avastin (n = 95). New cases of ovarian failure were identified in 34% (32/95) of women receiving Avastin in combination with chemotherapy compared with 2% (2/84) of women receiving chemotherapy alone [relative risk of 14 (95% CI 4, 53)]. After discontinuation of Avastin treatment, recovery of ovarian function at all time points during the post‑treatment period was demonstrated in 22% (7/32) of the Avastin‑treated women. Recovery of ovarian function is defined as resumption of menses, a positive serum β‑HCG pregnancy test, or a FSH level < 30 mIU/mL during the post‑treatment period. Long term effects of Avastin exposure on fertility are unknown. [See Warnings and Precautions (5.12), Use in Specific Populations (8.3).] Post-Treatment Vascular Events In an open‑label, randomized, controlled trial of Avastin in adjuvant colorectal cancer, an indication for which Avastin is not approved, the overall incidence rate of post‑treatment Grade ≥ 3 vascular events was 3.1% (41 of 1338) among patients receiving mFOLFOX6 plus Avastin, compared to 1.6% (21 of 1349) among patients receiving mFOLFOX6 alone. Post‑treatment vascular events included arterial and venous thromboembolic events, ischemic events, and vascular aneurysms. Metastatic Colorectal Cancer (mCRC) The data in Table 1 and Table 2 were obtained in Study 1, a randomized, double‑blind, controlled trial comparing chemotherapy plus Avastin with chemotherapy plus placebo. Avastin was administered at 5 mg/kg every 2 weeks. All Grade 3–4 adverse events and selected Grade 1–2 adverse events (hypertension, proteinuria, thromboembolic events) were collected in the entire study population. Severe and life‑threatening (Grade 3–4) adverse events, which occurred at a higher incidence ( ≥ 2%) in patients receiving bolus‑IFL plus Avastin as compared to bolus‑IFL plus placebo, are presented in Table 1. Table 1 NCI‑CTC Grade 3−4 Adverse Events in Study 1 (Occurring at Higher Incidence [ ≥ 2%] Avastin vs. Control) Arm 1 IFL + Placebo (n = 396)

System Organ Class/ IFN‑α + Placebo IFN‑α + Avastin Preferred terma (n = 304) (n = 337) Gastrointestinal disorders Diarrhea 16% 21% General disorders and administration site conditions Fatigue 27% 33% Investigations Weight decreased 15% 20% Metabolism and nutrition disorders Anorexia 31% 36% Musculoskeletal and connective tissue disorders Myalgia 14% 19% Back pain 6% 12% Nervous system disorders Headache 16% 24% Renal and urinary disorders Proteinuria 3% 20% Respiratory, thoracic and mediastinal disorders Epistaxis 4% 27% Dysphonia 0% 5% Vascular disorders Hypertension 9% 28%

Arm 2 IFL + Avastin (n = 392)

74%

87%

7% 5% 5%

10% 8% 8%

2% 5% 1% 1%

12% 9% 3% 3%

25% 2%

34% 4%

31% 14%

37% 21%

Central laboratories were collected on Days 1 and 21 of each cycle. Neutrophil counts are available in 303 patients in Arm 1 and 276 in Arm 2.

Grade 1–4 adverse events which occurred at a higher incidence ( ≥ 5%) in patients receiving bolus‑IFL plus Avastin as compared to the bolus‑IFL plus placebo arm are presented in Table 2. Grade 1–4 adverse events were collected for the first approximately 100 patients in each of the three treatment arms who were enrolled until enrollment in Arm 3 (5‑FU/LV + Avastin) was discontinued. Table 2 NCI‑CTC Grade 1‑4 Adverse Events in Study 1 (Occurring at Higher Incidence [≥ 5%] in IFL + Avastin vs. IFL) Arm 1 Arm 2 Arm 3 IFL + Placebo IFL + Avastin 5‑FU/LV + Avastin (n = 98) (n = 102) (n = 109) Body as a Whole Pain Abdominal Pain Headache Cardiovascular Hypertension Hypotension Deep Vein Thrombosis Digestive Vomiting Anorexia Constipation Stomatitis Dyspepsia GI Hemorrhage Weight Loss Dry Mouth Colitis Hemic/Lymphatic Thrombocytopenia Nervous Dizziness Respiratory Upper Respiratory Infection Epistaxis Dyspnea Voice Alteration Skin/Appendages Alopecia Skin Ulcer Special Senses Taste Disorder Urogenital Proteinuria

55% 55% 19%

61% 61% 26%

62% 50% 26%

14% 7% 3%

23% 15% 9%

34% 7% 6%

47% 30% 29% 18% 15% 6% 10% 2% 1%

52% 43% 40% 32% 24% 24% 15% 7% 6%

47% 35% 29% 30% 17% 19% 16% 4% 1%

20%

26%

19%

39% 10% 15% 2%

47% 35% 26% 9%

40% 32% 25% 6%

26% 1%

32% 6%

6% 6%

14%

21%

24%

36%

Avastin in Combination with FOLFOX4 in Second-line mCRC Only Grade 3‑5 non‑hematologic and Grade 4–5 hematologic adverse events related to treatment were collected in Study 2. The most frequent adverse events (selected Grade 3–5 non‑hematologic and Grade 4–5 hematologic adverse events) occurring at a higher incidence ( ≥ 2%) in 287 patients receiving FOLFOX4 plus Avastin compared to 285 patients receiving FOLFOX4 alone were fatigue (19% vs. 13%), diarrhea (18% vs. 13%), sensory neuropathy (17% vs. 9%), nausea (12% vs. 5%), vomiting (11% vs. 4%), dehydration (10% vs. 5%), hypertension (9% vs. 2%), abdominal pain (8% vs. 5%), hemorrhage (5% vs. 1%), other neurological (5% vs. 3%), ileus (4% vs. 1%) and headache (3% vs. 0%). These data are likely to under‑estimate the true adverse event rates due to the reporting mechanisms used in Study 2. Avastin in Combination with Fluoropyrimidine-Irinotecan or FluoropyrimidineOxaliplatin Based Chemotherapy in Second-line mCRC Patients who have Progressed on an Avastin Containing Regimen in First-line mCRC: No new safety signals were observed in Study 4 when Avastin was administered in second line mCRC patients who progressed on an Avastin containing regimen in first line mCRC. The safety data was consistent with the known safety profile established in first and second line mCRC.

Adverse events were encoded using MedDRA, Version 10.1.

The following adverse events were reported at a 5‑fold greater incidence in the IFN‑α plus Avastin arm compared to IFN‑α alone and not represented in Table 3: gingival bleeding (13 patients vs. 1 patient); rhinitis (9 vs. 0 ); blurred vision (8 vs. 0); gingivitis (8 vs. 1); gastroesophageal reflux disease (8 vs. 1 ); tinnitus (7 vs. 1); tooth abscess (7 vs. 0); mouth ulceration (6 vs. 0); acne (5 vs. 0); deafness (5 vs. 0); gastritis (5 vs. 0); gingival pain (5 vs. 0) and pulmonary embolism (5 vs. 1). Persistent, Recurrent, or Metastatic Carcinoma of the Cervix All grade adverse reactions were collected in Study 9. Grade 1‑4 adverse reactions occurring where the incidence difference is ≥ 5% in patients receiving Avastin plus chemotherapy compared to chemotherapy alone are presented in Table 4. Table 4 NCI‑CTC Grades 1‑4 and 3‑4 Adverse Reactions in Study 9 (Incidence Difference of ≥ 5% Between Treatment Arms in Chemo + Avastin vs. Chemo Alone) Grade 1‑4 Grade 3‑4 reactions reactions Chemo Chemo+ Chemo Chemo+ Alone Avastin Alone Avastin (n=222) (n=218) (n=222) (n=218) Metabolism and Nutrition Disorders Decreased Appetite 26% 34% Hyperglycemia 19% 26% Hypomagnesemia 15% 24% Hyponatremia 10% 19% Hypoalbuminemia 11% 16% General Disorders and Administration Site Conditions Fatigue 75% 80% Edema Peripheral 22% 15% Investigations Weight Decreased 7% 21% Blood Creatinine Increased 10% 16% Infections and Infestations Urinary Tract Infection 14% 22% Infection 5% 10% Vascular Disorders Hypertension 6% 29% 0.5% 11.5% Thrombosis 3% 10% 2.7% 8.3% Nervous System Disorders Headache 13% 22% Dysarthria 1% 8% Gastrointestinal Disorders Stomatitis 10% 15% Proctalgia 1% 6% Anal Fistula — 6% Blood and Lymphatic System Disorders Neutropenia 6% 12% Lymphopenia 5% 12% Psychiatric Disorders Anxiety 10% 17% Reproductive System and Breast Disorders Pelvic Pain 8% 14% Respiratory, Thoracic and Mediastinal Disorders Epistaxis 1% 17% Renal and Urinary Disorders Proteinuria 3% 10%

AVASTIN® (bevacizumab) Grade 3 or 4 adverse reactions occurring at a higher incidence ( ≥2%) in 218 patients receiving chemotherapy plus Avastin compared to 222 patients receiving chemotherapy alone were abdominal pain (11.9% vs. 9.9%), diarrhea (5.5% vs. 2.7%), anal fistula (3.7% vs. 0%), proctalgia (2.8% vs. 0%), urinary tract infection (8.3% vs. 6.3%), cellulitis (3.2% vs. 0.5%), fatigue (14.2% vs. 9.9%), hypokalemia (7.3% vs. 4.5%), hyponatremia (3.7% vs. 1.4%), dehydration (4.1% vs. 0.5%), neutropenia (7.8% vs. 4.1%), lymphopenia (6.0% vs. 3.2%), back pain (5.5% vs. 3.2%), and pelvic pain (5.5% vs. 1.4%). There were no Grade 5 adverse reactions occurring at a higher incidence ( ≥2%) in patients receiving chemotherapy plus Avastin compared to patients receiving chemotherapy alone. Platinum-Resistant Recurrent Epithelia Ovarian, Fallopian Tube, or Primary Peritoneal Cancer Patients with evidence of recto‑sigmoid involvement by pelvic examination or bowel involvement on CT scan or clinical symptoms of bowel obstruction were excluded in this study. Grade 2‑4 adverse events occurring at a higher incidence (≥5%) in patients receiving Avastin plus chemotherapy compared to patients receiving chemotherapy alone are presented in Table 5. Table 5 Grade 2−4 Adverse Events Occurring at Higher Incidence [≥5%] in Chemo + Avastin vs. Chemo Safety−Evaluable Patients System Organ Class Preferred Term Blood And Lymphatic System Disorders Neutropenia General Disorders And Administration Site Conditions Mucosal Inflammation Infections And Infestations Infection Nervous System Disorders Peripheral Sensory Neuropathy Renal And Urinary Disorders Proteinuria Respiratory, Thoracic and Mediastinal Disorders Epistaxis Skin And Subcutaneous Tissue Disorders Palmar−Plantar Erythrodysaesthesia Syndrome Vascular Disorders Hypertension

Chemo Chemo + Avastin (n = 181) (n = 179) 25.4%

30.7%

5.5%

12.8%

4.4%

10.6%

7.2%

17.9%

0.6%

12.3%

0.0%

5.0%

10.6%

5.5%

19.0%

Grade 3−4 adverse events occurring at a higher incidence (≥2%) in 179 patients receiving Avastin plus chemotherapy compared to 181 patients receiving chemotherapy alone were hypertension (6.7% vs. 1.1%) and palmar‑plantar erythrodysaesthesia syndrome (4.5% vs. 1.7%). There were no Grade 5 events occurring at a higher incidence (≥2%) in patients receiving Avastin plus chemotherapy compared to patients receiving chemotherapy alone. 6.2 Immunogenicity As with all therapeutic proteins, there is a potential for an immune response to Avastin. In clinical trials of adjuvant colon carcinoma, 14 of 2233 evaluable patients (0.63%) tested positive for treatment‑emergent anti‑bevacizumab antibodies detected by an electrochemiluminescent (ECL) based assay. Among these 14 patients, three tested positive for neutralizing antibodies against bevacizumab using an enzyme‑linked immunosorbent assay (ELISA). The clinical significance of these anti‑ product antibody responses to bevacizumab is unknown. Immunogenicity assay results are highly dependent on the sensitivity and specificity of the test method and may be influenced by several factors, including sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Avastin with the incidence of antibodies to other products may be misleading. 6.3 Postmarketing Experience The following adverse reactions have been identified during post‑approval use of Avastin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Body as a Whole: Polyserositis Cardiovascular: Pulmonary hypertension, PRES, Mesenteric venous occlusion Eye disorders (from unapproved intravitreal use for treatment of various ocular disorders): Permanent loss of vision; Endophthalmitis (infectious and sterile); Intraocular inflammation; Retinal detachment; Increased intraocular pressure; Hemorrhage including conjunctival, vitreous hemorrhage or retinal hemorrhage; Vitreous floaters; Ocular hyperemia; Ocular pain or discomfort Gastrointestinal: Gastrointestinal ulcer, Intestinal necrosis, Anastomotic ulceration Hemic and lymphatic: Pancytopenia Hepatobiliary disorders: Gallbladder perforation Infections and infestations: Necrotizing fasciitis, usually secondary to wound healing complications, gastrointestinal perforation or fistula formation Musculoskeletal and Connective Tissue Disorders: Osteonecrosis of the jaw; Non‑mandibular osteonecrosis (cases have been observed in pediatric patients who have received Avastin) Neurological: Posterior Reversible Encephalopathy Syndrome (PRES) Renal: Renal thrombotic microangiopathy (manifested as severe proteinuria) Respiratory: Nasal septum perforation, dysphonia Systemic Events (from unapproved intravitreal use for treatment of various ocular disorders): Arterial thromboembolic events, Hypertension, Gastrointestinal perforation, Hemorrhage 7 DRUG INTERACTIONS A drug interaction study was performed in which irinotecan was administered as part of the FOLFIRI regimen with or without Avastin. The results demonstrated no significant effect of bevacizumab on the pharmacokinetics of irinotecan or its active metabolite SN38. In a randomized study in 99 patients with NSCLC, based on limited data, there did not appear to be a difference in the mean exposure of either carboplatin or paclitaxel when each was administered alone or in combination with Avastin. However, 3 of the 8 patients receiving Avastin plus paclitaxel/carboplatin had substantially lower paclitaxel exposure after four cycles of treatment (at Day 63) than those at Day 0, while patients receiving paclitaxel/carboplatin without Avastin had a greater paclitaxel exposure at Day 63 than at Day 0. In Study 8, there was no difference in the mean exposure of interferon alfa administered in combination with Avastin when compared to interferon alfa alone. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Avastin may cause fetal harm based on findings from animal studies and the drug’s mechanism of action [See Clinical Pharmacology (12.1).] Limited postmarketing reports describe cases of fetal malformations with use of Avastin in pregnancy; however, these reports are insufficient to determine drug associated risks. In animal reproduction studies, intravenous administration of bevacizumab to pregnant rabbits every 3 days during organogenesis at doses approximately 1 to 10 times the clinical dose of 10 mg/kg produced fetal resorptions, decreased maternal and fetal weight gain and multiple congenital malformations including corneal opacities and abnormal ossification of the skull and skeleton including limb and phalangeal defects [see Data]. Furthermore, animal models link angiogenesis and 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. The background risk of major birth defects and miscarriage for the indicated population is 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. Data Animal Data Pregnant rabbits dosed with 10 to 100 mg/kg bevacizumab (approximately 1 to 10 times the clinical dose of 10 mg/kg) every three days during the period of organogenesis (gestation day 6‑18) exhibited decreases in maternal and fetal body weights and increased number of fetal resorptions. There were dose‑related increases in the number of litters containing fetuses with any type of malformation (42.1% for the 0 mg/kg dose, 76.5% for the 30 mg/kg dose, and 95% for the 100 mg/kg dose ) or fetal alterations

AVASTIN® (bevacizumab) (9.1% for the 0 mg/kg dose, 14.8% for the 30 mg/kg dose, and 61.2% for the 100 mg/kg dose ). Skeletal deformities were observed at all dose levels, with some abnormalities including meningocele observed only at the 100 mg/kg dose level. Teratogenic effects included: reduced or irregular ossification in the skull, jaw, spine, ribs, tibia and bones of the paws; fontanel, rib and hindlimb deformities; corneal opacity; and absent hindlimb phalanges. 8.2 Lactation No data are available regarding the presence of bevacizumab 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 for serious adverse reactions in breastfed infants from bevacizumab, advise a nursing woman that breastfeeding is not recommended during treatment with Avastin. 8.3 Females and Males of Reproductive Potential Contraception Females Avastin may cause fetal harm when administered to a pregnant woman. Advise female patients of reproductive potential to use effective contraception during treatment with Avastin and for 6 months following the last dose of Avastin. [See Use in Specific Populations (8.1).] Infertility Females Avastin increases the risk of ovarian failure and may impair fertility. Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin. Long term effects of Avastin exposure on fertility are unknown. In a prospectively designed substudy of 179 premenopausal women randomized to receive chemotherapy with or without Avastin, the incidence of ovarian failure was higher in the Avastin arm (34%) compared to the control arm (2%). After discontinuation of Avastin and chemotherapy, recovery of ovarian function occurred in 22% (7/32) of these Avastin‑treated patients. [See Warnings and Precautions (5.12), Adverse Reactions (6.1).] 8.4 Pediatric Use The safety, effectiveness and pharmacokinetic profile of Avastin in pediatric patients have not been established. In published literature reports, cases of non‑mandibular osteonecrosis have been observed in patients under the age of 18 years who have received Avastin. Avastin is not approved for use in patients under the age of 18 years. Antitumor activity was not observed among eight children with relapsed glioblastoma treated with bevacizumab and irinotecan. There is insufficient information to determine the safety and efficacy of Avastin in children with glioblastoma. Animal Data Juvenile cynomolgus monkeys with open growth plates exhibited physeal dysplasia following 4 to 26 weeks exposure at 0.4 to 20 times the recommended human dose (based on mg/kg and exposure). The incidence and severity of physeal dysplasia were dose‑related and were partially reversible upon cessation of treatment. 8.5 Geriatric Use In Study 1, severe adverse events that occurred at a higher incidence ( ≥ 2%) in patients aged ≥ 65 years as compared to younger patients were asthenia, sepsis, deep thrombophlebitis, hypertension, hypotension, myocardial infarction, congestive heart failure, diarrhea, constipation, anorexia, leukopenia, anemia, dehydration, hypokalemia, and hyponatremia. The effect of Avastin on overall survival was similar in elderly patients as compared to younger patients. In Study 2, patients aged ≥ 65 years receiving Avastin plus FOLFOX4 had a greater relative risk as compared to younger patients for the following adverse events: nausea, emesis, ileus, and fatigue. In Study 5, patients aged ≥ 65 years receiving carboplatin, paclitaxel, and Avastin had a greater relative risk for proteinuria as compared to younger patients. [See Warnings and Precautions (5.9).] Of the 742 patients enrolled in Genentech‑sponsored clinical studies in which all adverse events were captured, 212 (29%) were age 65 or older and 43 (6%) were age 75 or older. Adverse events of any severity that occurred at a higher incidence in the elderly as compared to younger patients, in addition to those described above, were dyspepsia, gastrointestinal hemorrhage, edema, epistaxis, increased cough, and voice alteration. In an exploratory, pooled analysis of 1745 patients treated in five randomized, controlled studies, there were 618 (35%) patients aged ≥ 65 years and 1127 patients < 65 years of age. The overall incidence of arterial thromboembolic events was increased in all patients receiving Avastin with chemotherapy as compared to those receiving chemotherapy alone, regardless of age. However, the increase in arterial thromboembolic events incidence was greater in patients aged ≥ 65 years (8.5% vs. 2.9%) as compared to those < 65 years (2.1% vs. 1.4%). [See Warnings and Precautions (5.5).] 10 OVERDOSAGE The highest dose tested in humans (20 mg/kg IV) was associated with headache in nine of 16 patients and with severe headache in three of 16 patients. 17 PATIENT COUNSELING INFORMATION Advise patients: • To undergo routine blood pressure monitoring and to contact their health care provider if blood pressure is elevated. • To immediately contact their health care provider for unusual bleeding, high fever, rigors, sudden onset of worsening neurological function, or persistent or severe abdominal pain, severe constipation, or vomiting. • Of increased risk of wound healing complications during and following Avastin. • Of increased risk of an arterial thromboembolic event. • Of the increased risk for ovarian failure following Avastin treatment. Embryo‑fetal Toxicity • Advise female patients that Avastin may cause fetal harm and to inform their healthcare provider with a known or suspected pregnancy. [See Warnings and Precautions (5.11), Use in Specific Populations (8.1).] • Advise females of reproductive potential to use effective contraception during treatment with Avastin and for 6 months after the last dose of Avastin. [See Use in Specific Populations (8.3).] Lactation • Advise nursing women that breastfeeding is not recommended during treatment with Avastin. [See Use in Specific Populations (8.2).]

Avastin® (bevacizumab) Manufactured by: Genentech, Inc. A Member of the Roche Group 1 DNA Way South San Francisco, CA 94080‑4990

S:12.5"

NCI‑CTC Grade 3‑4 Events Body as a Whole Asthenia Abdominal Pain Pain Cardiovascular Hypertension Deep Vein Thrombosis Intra‑Abdominal Thrombosis Syncope Digestive Diarrhea Constipation Hemic/Lymphatic Leukopenia Neutropeniaa

AVASTIN® (bevacizumab) Unresectable Non-Squamous Non-Small Cell Lung Cancer (NSCLC) Only Grade 3‑5 non‑hematologic and Grade 4‑5 hematologic adverse events were collected in Study 5. Grade 3–5 non‑hematologic and Grade 4–5 hematologic adverse events (occurring at a higher incidence (≥ 2%) in 427 patients receiving PC plus Avastin compared with 441 patients receiving PC alone were neutropenia (27% vs. 17%), fatigue (16% vs. 13%), hypertension (8% vs. 0.7%), infection without neutropenia (7% vs. 3%), venous thrombus/ embolism (5% vs. 3%), febrile neutropenia (5% vs. 2%), pneumonitis/pulmonary infiltrates (5% vs. 3%), infection with Grade 3 or 4 neutropenia (4% vs. 2%), hyponatremia (4% vs. 1%), headache (3% vs. 1%) and proteinuria (3% vs. 0%). Glioblastoma All adverse events were collected in 163 patients enrolled in Study 6 who either received Avastin alone or Avastin plus irinotecan. All patients received prior radiotherapy and temozolomide. Avastin was administered at 10 mg/kg every 2 weeks alone or in combination with irinotecan. Avastin was discontinued due to adverse events in 4.8% of patients treated with Avastin alone. In patients receiving Avastin alone (N = 84), the most frequently reported adverse events of any grade were infection (55%), fatigue (45%), headache (37%), hypertension (30%), epistaxis (19%) and diarrhea (21%). Of these, the incidence of Grade ≥ 3 adverse events was infection (10%), fatigue (4%), headache (4%), hypertension (8%) and diarrhea (1%). Two deaths on study were possibly related to Avastin: one retroperitoneal hemorrhage and one neutropenic infection. In patients receiving Avastin alone or Avastin plus irinotecan (N = 163), the incidence of Avastin‑related adverse events (Grade 1–4) were bleeding/ hemorrhage (40%), epistaxis (26%), CNS hemorrhage (5%), hypertension (32%), venous thromboembolic event (8%), arterial thromboembolic event (6%), wound‑healing complications (6%), proteinuria (4%), gastrointestinal perforation (2%), and PRES (1%). The incidence of Grade 3–5 events in these 163 patients were bleeding/hemorrhage (2%), CNS hemorrhage (1%), hypertension (5%), venous thromboembolic event (7%), arterial thromboembolic event (3%), wound‑healing complications (3%), proteinuria (1%), and gastrointestinal perforation (2%). Metastatic Renal Cell Carcinoma (mRCC) All grade adverse events were collected in Study 8. Grade 3–5 adverse events occurring at a higher incidence ( ≥ 2%) in 337 patients receiving interferon alfa (IFN‑α) plus Avastin compared to 304 patients receiving IFN‑α plus placebo arm were fatigue (13% vs. 8%), asthenia (10% vs. 7%), proteinuria (7% vs. 0%), hypertension (6% vs. 1%; including hypertension and hypertensive crisis), and hemorrhage (3% vs. 0.3%; including epistaxis, small intestinal hemorrhage, aneurysm ruptured, gastric ulcer hemorrhage, gingival bleeding, haemoptysis, hemorrhage intracranial, large intestinal hemorrhage, respiratory tract hemorrhage, and traumatic hematoma). Grade 1–5 adverse events occurring at a higher incidence ( ≥ 5%) in patients receiving IFN‑α plus Avastin compared to the IFN‑α plus placebo arm are presented in Table 3. Table 3 NCI‑CTC Grades 1−5 Adverse Events in Study 8 (Occurring at Higher Incidence [≥ 5%] in IFN‑α + Avastin vs. IFN‑α + Placebo)

Because Overall Survival Matters Avastin plus chemotherapy in advanced cervical cancer demonstrated a statistically significant increase in median OS vs chemotherapy alone in the GOG 240 study (16.8 vs 12.9 months)1

3.9-month increase

1.0

in median OS (HR=0.74 [95% CI, 0.58–0.94], P=0.0132)

Proportion Surviving

0.8 0.6

Avastin + chemotherapy (n=227) Chemotherapy alone (n=225)

0.4

16.8

months

(vs 12.9 months with chemotherapy alone) (HR=0.74 [95% CI, 0.58–0.94], P=0.0132)

ORR

45%

0.2 0

Median OS

(95% CI, 39–52)

(vs 34% with chemotherapy alone) (95% CI, 28–40)

Months

Chemotherapy included either cisplatin/paclitaxel or topotecan/paclitaxel. OS=overall survival; GOG=Gynecologic Oncology Group; HR=hazard ratio; CI=confidence interval; ORR=objective response rate.

Indication

Avastin in combination with paclitaxel and cisplatin or paclitaxel and topotecan is indicated for the treatment of persistent, recurrent, or metastatic carcinoma of the cervix.

Pregnancy warning

Boxed WARNINGS

Gastrointestinal (GI) perforation — Serious and sometimes fatal GI perforation occurs at a higher incidence in Avastin-treated patients compared to controls — The incidences of GI perforation ranged from 0.3% to 3.2% across clinical studies — Discontinue Avastin in patients with GI perforation Surgery and wound healing complications — The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Avastin-treated patients — Do not initiate Avastin for at least 28 days after surgery and until the surgical wound is fully healed. The appropriate interval between termination of Avastin and subsequent elective surgery required to reduce the risks of impaired wound healing/wound dehiscence has not been determined — Discontinue Avastin at least 28 days prior to elective surgery and in patients with wound healing complications requiring medical intervention Hemorrhage — Severe or fatal hemorrhage, including hemoptysis, GI bleeding, hematemesis, central nervous system hemorrhage, epistaxis, and vaginal bleeding, occurred up to 5-fold more frequently in patients receiving Avastin. Across indications, the incidence of grade ≥3 hemorrhagic events among patients receiving Avastin ranged from 0.4% to 6.9% — Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis (≥1/2 tsp of red blood) — Discontinue Avastin in patients with serious hemorrhage (ie, requiring medical intervention)

Additional serious adverse events

Additional serious and sometimes fatal adverse events with increased incidence in the Avastin-treated arm vs control included — GI fistulae (up to 2% in metastatic colorectal cancer and ovarian cancer patients) — Non-GI fistulae (<1% in trials across various indications; 1.8% in a cervical cancer trial) — Arterial thromboembolic events (grade ≥3, 2.6%) — Proteinuria (nephrotic syndrome, <1%) Additional serious adverse events with increased incidence in the Avastin-treated arm vs control included — GI-vaginal fistulae occurred in 8.3% of patients in a cervical cancer trial — Venous thromboembolism (grade 3–4, up to 10.6%) in patients with persistent, recurrent, or metastatic cervical cancer treated with Avastin — Hypertension (grade 3–4, 5%–18%) — Posterior reversible encephalopathy syndrome (PRES) (<0.5%)

Infusion reactions with the first dose of Avastin were uncommon (<3%), and severe reactions occurred in 0.2% of patients Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin

AVY/101215/0064

Printed in USA.

(11/15)

Based on the mechanism of action and animal studies, Avastin may cause fetal harm Advise female patients that Avastin may cause fetal harm, and to inform their healthcare provider of a known or suspected pregnancy Advise females of reproductive potential to use effective contraception during treatment with Avastin and for 6 months after the last dose of Avastin Advise nursing women that breastfeeding is not recommended during treatment with Avastin Avastin may impair fertility

Most common adverse events

Across indications, the most common adverse reactions observed in Avastin patients at a rate >10% and at least twice the control arm rate were — Epistaxis — Proteinuria — Lacrimation disorder — Headache — Taste alteration — Back pain — Hypertension — Dry skin — Exfoliative dermatitis — Rhinitis — Rectal hemorrhage Across all studies, Avastin was discontinued in 8.4% to 21% of patients because of adverse reactions

Indication-specific adverse events

In CC, grade 3 or 4 adverse reactions in Study GOG 240, occurring at a higher incidence (≥2%) in 218 patients receiving chemotherapy plus Avastin compared to 222 patients receiving chemotherapy alone, were abdominal pain (11.9% vs 9.9%), diarrhea (5.5% vs 2.7%), anal fistula (3.7% vs 0%), proctalgia (2.8% vs 0%), urinary tract infection (8.3% vs 6.3%), cellulitis (3.2% vs 0.5%), fatigue (14.2% vs 9.9%), hypertension (11.5% vs 0.5%), thrombosis (8.3% vs 2.7%), hypokalemia (7.3% vs 4.5%), hyponatremia (3.7% vs 1.4%), dehydration (4.1% vs 0.5%), neutropenia (7.8% vs 4.1%), lymphopenia (6.0% vs 3.2%), back pain (5.5% vs 3.2%), and pelvic pain (5.5% vs 1.4%). There were no grade 5 adverse reactions occurring at a higher incidence (≥2%) in patients receiving chemotherapy plus Avastin compared to patients receiving chemotherapy alone You may report side effects to the FDA at (800) FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Genentech at (888) 835-2555. Please see accompanying brief summary of Prescribing Information, including Boxed WARNINGS, for additional important safety information. CC=persistent, recurrent, or metastatic cervical cancer. Reference: 1. Avastin Prescribing Information. Genentech, Inc. September 2015.