TAP Vol 6 Issue 20 by Harborside Press LLC

Prostate Cancer

9, 14, 15

| Adolescent and Young Adult Oncology

48–49

| Geriatrics for the Oncologist

VOLUME 6, ISSUE 20

53–54

NOVEMBER 10, 2015

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

Is Health Care in the United States a Basic Human Right or an Entitlement?

ASTRO Annual Meeting

Intensity-Modulated Radiotherapy Gains Ground for Treatment of Stage III Non–Small Cell Lung Cancer

By Gregory H. Jones, BS, and Hagop Kantarjian, MD

By Alice Goodman

ntensity-modulated radiation therapy appears to be preferable to three-dimensional (3D) conformal radiation therapy as part of treatment for patients with locally advanced (stage III) non–small cell lung cancer (NSCLC). Compared with 3D conformal radiotherapy, intensity-modulated radiotherapy reduced the incidence of severe pneumonitis and allowed more consolidation chemotherapy to be given. Moreover, the low-dose bath with intensity-modulated radiotherapy was not associated with any severe toxicity. These findings of a secondary analysis of the large randomized NRG Oncology/RTOG 0617 trial, presented at the 2015 American Society for Radiation Oncology (ASTRO) Annual Meeting in San Antonio, Texas, suggest that intensity-modulated radiotherapy should gain a larger role in the treatment of stage III lung cancer.1 “We would advocate that [intensity-modulated radiotherapy] should be routinely considered for stage III

lung cancer patients. This study can potentially change practice patterns for locally advanced lung cancer,” said lead author S tephen Chun, MD, Fellow in the Department of Radiation Oncology at The University of Texas MD Anderson Cancer Center, Houston.

Stephen Chun, MD

Barriers to Adoption Current National Comprehensive Cancer Network (NCCN®) Clinical Practice Guidelines in Oncology® list both 3D conformal radiotherapy and intensity-modulated radiotherapy techniques as options for management of stage III lung cancers. Intencontinued on page 4

Issues in Oncology

Debate Over Physician-Assisted Suicide Continues, State by State n 1997, after surviving a storm of high-court legal challenges, Oregon’s Death With Dignity Act went into effect, making Oregon the first American state to legalize physician-assisted suicide. The Supreme Court ruled that there was no right to assisted suicide in the Constitution but implied that states have the right to decide whether to permit or prohibit the practice. To date, five states have legalized physician-assisted

suicide: Oregon, Vermont, Washington, California, and Montana (via court ruling). California was the most recent state to join in legalizing physician-assisted suicide, with the End of Life Option Act passing through the California Assembly and State Senate in September and Governor Jerry Brown signing the bill into law in early October. (The California law will not take effect until 2016.) A proposed bill in New York also seeks to legalize physician-assisted death.

The aim should be the alleviation of suffering, not the administration of medications that provide a ‘quick fix’ to complicated medical and social situations.

—Baron Lerner, MD, PhD

(see page 113)

continued on page 111

Mr. Jones is a first-year medical student at The University of Texas Health Sciences Center, and Dr. Kantarjian is Chairman of the Leukemia Department at The University of Texas MD Anderson Cancer Center, Houston. Disclaimer: This commentary represents the views of the author and may not necessarily reflect the views of ASCO.

MORE IN THIS ISSUE

By Ronald Piana

ercy Killers is a one-man show that details the consequences of a medical healthcare catastrophe (breast cancer) in a family.1 This disturbing fictional account is actually a daily event in cancer centers: losing insurance for technicalities, losing a home because of an inability to pay the mortgage, bankruptcy, humiliation and loss of dignity, divorcing spouses or quitting jobs to become eligible for indigent care, compromising on morality to save one’s life, and often dying of lack of care when treatments exist but are not accessible or affordable. “Mercy killers” in the play refers to assisting the

Revitalized Debate The vast majority of those requesting physician-assisted suicide are advanced cancer patients with a life expectancy of less than 6 months. Physician-assisted suicide has

Oncology Meetings Coverage ASTRO Annual Meeting �� 1–5 European Cancer Congress �� 9–26 Breast Cancer Symposium ��27 Ovarian Cancer Endpoints Workshop �� 31 PD-1/PD-L1 Inhibitors ��20 Diana J. Mason, RN, PhD, on End-of-Life Clinical Decisions ��33 Global Cancer Burden ��62 Direct From ASCO ��76–79 Hematology Quiz for the Oncologist �� 91–100 Postoperative Radiation for Endometrial Cancer �� 105–106

continued on page 113

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

A Harborside Press® Publication

The ASCO Post | NOVEMBER 10, 2015

PAGE 2

Harborside Press® Publishing Staff

Editorial Board

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

Bishoy Morris Faltas, MD Weill Cornell Medical College

George W. Sledge, MD Stanford University School of Medicine

Cara H. Glynn, Director of Editorial Cara@harborsidepress.com

Elizabeth Reed, MD Deputy Editor University of Nebraska Medical Center

John A. Fracchia, MD New York Urological Associates

Thomas J. Smith, MD Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Andrew Nash, Associate Director of Editorial Andrew@harborsidepress.com

Associate Editors

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Jame Abraham, MD Cleveland Clinic

Louis B. Harrison, MD Moffitt Cancer Center

Syed A. Abutalib, MD Cancer Treatment Centers of America

Jimmie C. Holland, MD Memorial Sloan Kettering Cancer Center

Manmeet Ahluwalia, MD, FACP Cleveland Clinic

Clifford A. Hudis, MD, FACP Memorial Sloan Kettering Cancer Center

Chandrakanth Are, MD University of Nebraska Medical Center

Nora Janjan, MD, MPSA, MBA National Center for Policy Analysis

Joseph S. Bailes, MD Texas Oncology

Hagop M. Kantarjian, MD MD Anderson Cancer Center

Laurence H. Baker, DO University of Michigan Health System

Mario E. Lacouture, MD Memorial Sloan Kettering Cancer Center

Richard R. Barakat, MD Memorial Sloan Kettering Cancer Center

Theodore S. Lawrence, MD, PhD University of Michigan Comprehensive Cancer Center

Charles L. Bennett, MD, PhD, MPP University of South Carolina, Columbia Douglas W. Blayney, MD Stanford University Medical Center Philip D. Bonomi, MD Rush University Medical Center

John Cox, DO Texas Oncology E. David Crawford, MD University of Colorado Nancy E. Davidson, MD University of Pittsburgh Cancer Institute George D. Demetri, MD Dana-Farber Cancer Institute Paul F. Engstrom, MD Fox Chase Cancer Center David S. Ettinger, MD Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

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Disclaimer: The ideas and opinions expressed in The ASCO Post™ do not necessarily reflect those of Harborside Press®, LLC, HSP News Service, LLC, or the American Society of Clinical Oncology, Inc. (ASCO®). The mention of any product, service, or therapy in this publication should not be construed as an endorsement of the products mentioned. It is the responsibility of the treating physician or other health-care provider, relying on independent experience and knowledge of the patient, to determine the appropriate treatment for the patient. Readers are advised to check the appropriate medical literature and the product information currently provided by the manufacturer of each product or therapy to be administered to verify the dosage, method, and duration of administration, or contraindications. Readers are also encouraged to contact the manufacturer with questions about the features or limitations of any products. Harborside Press®, HSP News Service, LLC, and ASCO® assume no responsibility for any injury or damage to persons or property arising out of or related to any use of material contained in this publication or to any errors or omissions.

ASCOPost.com | NOVEMBER 10, 2015

PAGE 3

ASTRO Annual Meeting Palliative Care

Dexamethasone to Preempt Radiation-Induced Pain By Alice Goodman

one is a common site of metastasis for prostate, breast, and lung cancers, and palliative radiotherapy is often used to treat these metastases. Although it is an effective therapy, severe pain flare following radia-

all patients receiving radiotherapy for bone metastases,” stated a coauthor of this study, Alysa Fairchild, MD, a radiation oncologist at the Cross Cancer Institute and University of Alberta, Edmonton, Canada.

Dexamethasone can help avoid debilitating pain due to radiation therapy and should now be recommended as standard of care for all patients receiving radiotherapy for bone metastasis.

EXPERT POINT OF VIEW

“Y

ou don’t need high-tech interventions to prove value. Sometimes we can use a medication that has been around a long time,” declared press conference moderator Brian D. Kavanagh, MD, MPH, FASTRO, of the University of Colorado, Anschutz Medical Campus, Denver. “It is better to prevent the problem of pain flare than to play catch up with pain medications down the road. This study showed that a few doses of an

It is better to prevent the problem of pain flare than to play catch up with pain medications down the road.

—Alysa Fairchild, MD

—Brian D. Kavanagh, MD, MPH, FASTRO

tion occurs in about one-third of patients. It usually resolves within 10 days, but during that time, it can be quite debilitating. Use of dexamethasone can significantly reduce the occurrence of pain flare, according to results of a randomized controlled phase III trial presented at the 2015 ASTRO Annual Meeting.1 “Pain flare should no longer be considered a barrier to radiation of bone metastasis. Dexamethasone, an inexpensive treatment, can help avoid debilitating pain due to radiation therapy and should now be recommended as standard of care for

Study Details and Results The study enrolled 298 patients from 23 centers in Canada. All patients had one to two bone metastases and were randomized to receive oral dexamethasone (8 mg) or placebo for 5 days beginning on day 1 of radiotherapy. All patients were treated with single-dose radiotherapy of 8 Gy in 1 fraction directed at the bone metastasis. Patients were asked to complete a pain diary on days 1–10 and were followed up on day 42. Pain flare was defined as at least a continued on page 4

Reducing Pain From Palliative Radiotherapy ■■ Pain flare occurs in about one-third of patients following palliative radiotherapy for bone metastases. ■■ Given 1 hour prior to radiation and daily for 4 days afterward (total 5 doses), dexamethasone reduced the incidence of pain flare and its severity. ■■ Results of this study are practice-changing, and this inexpensive oral medication should be offered to patients undergoing palliative radiotherapy for bone metastasis.

inexpensive, oral, well-tolerated medication can reduce the incidence of pain flare as well as severity and should change the standard of care,” he continued. Zain A. Husain, MD, Assistant Professor of Therapeutic Radiology at Yale University School of Medicine, New Haven, Connecticut, also commented on this paper. “Dexamethasone is a relatively easy to use, well-tolerated, inexpensive drug to give. About one-third of patients have significant pain flare, and there is something you can do about it,” he said. At Yale, pain premedication is reserved for paZain A. Husain, MD tients undergoing stereotactic body radiation therapy, who have a high rate of pain flare. Dr. Husain and his colleagues have started using dexamethasone in this setting in a similar regimen as that used by Dr. Fairchild’s group. “We haven’t prophylaxed patients receiving conventional dose radiotherapy yet,” he said. Dr. Husain pointed out that the percentage of patients who experience pain flare is still a minority. “It would be good to identify factors associated with risk of pain flare. The study includes about 300 patients, so hopefully the investigators will analyze the data to identify those who have pain flare vs those who do not,” he commented. n Disclosure: Drs. Kavanagh and Husain reported no potential conflicts of interest.

Don’t Miss These Important Reports in This Issue of The ASCO Post

Demytra Mitsis, MD, on the Increase of Melanoma Rates in Adolescents see page 48

Etienne Brain, MD, PhD, on Geriatric Oncology in Europe see page 53

Visit The ASCO Post online at ASCOPost.com

Chandrakanth Are, MBBS, MBA, FRCS, FACS, on Cancer Incidence and Mortality in Algeria see page 62

The ASCO Post | NOVEMBER 10, 2015

PAGE 4

ASTRO Annual Meeting Thoracic Oncology

Radiotherapy for Lung Cancer continued from page 1

sity-modulated radiotherapy is a more advanced and expensive technique and takes more time for physicians and patients. Planning for this approach is time-intensive, Dr. Chun explained, but it targets radiation to tumor tissue while minimizing exposure to surrounding tissue.

“Our hope is that this study will move along the more widespread adoption of [intensity-modulated radiotherapy] for stage III lung cancer. Perhaps our results might motivate a change in NCCN Guidelines to make [intensitymodulated radiotherapy] the preferred therapy,” Dr. Chun said. “Cost of hospitalizations for these toxicities is high. If you factor in an

These findings may fundamentally change the way we deliver radiation therapy for locally advanced lung cancer. —Stephen Chun, MD

Getting reimbursement for intensity-modulated radiotherapy is a barrier to more widespread adoption. Insurers prefer to reimburse for 3D conformal radiotherapy because it is less expensive. These new data suggest that intensity-modulated radiotherapy can lower the overall costs of treatment by reducing the incidence of severe pneumonitis, which is expensive to treat.

absolute 4.5% reduction in grade 3 or higher pneumonitis and multiply that by 70,000 patients per year with stage III NSCLC, the cost savings [with intensity-modulated radiotherapy] could run into billions of dollars,” Dr. Chun told The ASCO Post.

Study Details NRG Oncology/RTOG 0617 was a

Radiotherapy Techniques for Lung Cancer Compared ■■ Although more expensive and time-intensive compared with threedimensional (3D) conformal radiotherapy, intensity-modulated radiotherapy reduces the incidence of severe pneumonitis and allows more chemotherapy to be given to patients with stage III non–small cell lung cancer. ■■ Intensity-modulated radiotherapy was associated with a 44% relative risk reduction in severe pneumonitis and was more cardioprotective compared with 3D conformal radiotherapy. ■■ These data may pave the way for better reimbursement for intensitymodulated radiotherapy.

large, multi-institutional phase III randomized clinical trial conducted from 2007 to 2011 in patients with locally advanced NSCLC. The original study compared a high dose of radiation (74 Gy) to a standard dose (60 Gy). Patients received concurrent chemotherapy with carboplatin/paclitaxel with or without cetuximab (Erbitux). The secondary analysis that Dr. Chun presented at the ASTRO Annual Meeting focused on the comparison

of intensity-modulated radiotherapy vs 3D conformal radiotherapy. Physicians were allowed to choose radiation technique; of the 482 patients treated with radiotherapy, 47% received intensity-modulated radiotherapy and 53% received 3D conformal radiotherapy, which mirrors practice patterns in the United States, he said. The original trial did not randomize for radiation technique, so the incontinued on page 5

EXPERT POINT OF VIEW

t a press conference held during the ASTRO Annual Meeting, ASTRO President-Elect Brian D. Kavanagh, MD, MPH, FASTRO, interim Chair of Radiation Oncology at the University of Colorado, Anschutz Medical Campus, Denver, said, “This study provides an important lesson for the field. We are lucky to have a lot of good technology. We need to find out the best use of these technologies.” He continued, “The study points out a need for careful attention to the dose of radiation to surrounding tissue. I do think this is a great illustration of how sophisticated technology can be implemented across the country in a broad range of practice environments.”

Convincing Data Also commenting on this paper, Mark A. Hallman, MD, PhD, Assistant Professor of Radiation Oncology at Fox Chase Cancer Center, Philadel-

Radiation-Induced Pain continued from page 3

2-point increase in patient-rated worst pain on a scale of 0–10 with no decrease in analgesic intake, or a 25% or greater increase in analgesic intake with no decrease in worst pain score from days 0–10. Pain flare was reported in 17.6% of patients in the dexamethasone arm vs

phia, said, “These data are convincing. Although we have dosimetric and retrospective studies in favor of [intensity-modulated radiotherapy], clinical data from this prospective trial (RTOG 0617) are very informative and highly supportive of [intensitymodulated radiotherapy] in this patient subset.” A barrier to greater uptake of intensity-modulated radiotherapy has been lack of reimbursement. One argument was the uncertainty of the effects of the low-dose bath. “An important finding of this trial is that the low-dose bath did not increase pneumonitis and, in fact, [intensity-modulated radiotherapy] reduced the incidence of grade 3 or higher pneumonitis despite increased low-dose volumes,” Dr. Hallman said. “The fact that the patients who received [intensity-modulated radiotherapy] in this trial had worse prog-

29.3% in the placebo arm in those for whom complete patient diary data are available (P = .01). When pain flare occurred, it was less severe in the dexamethasone-treated arm than in the placebo arm. The median increase in pain score during days 6–10 of pain flare was 2.5 out of 10 for the dexamethasone arm vs 4

I hope these data will help convince physicians to utilize and insurance companies to reimburse for [intensitymodulated radiotherapy]. The reduced risk of pneumonitis would likely balance a significant portion of the increased cost… —Mark A. Hallman, MD, PhD

nostic factors, including larger tumor volumes, supports an even more widespread role for [intensity-modulated radiotherapy] in treating large lung tumors,” Dr. Hallman continued. “I hope these data will help convince physicians to utilize and insurance companies to reimburse for [intensity-modulated radiotherapy]. The reduced risk of pneumonitis would

out of 10 for the placebo arm. On day 10, dexamethasone resulted in significantly less functional interference, nausea, and vomiting compared with placebo (P = .02, P = .04, and P = .02, respectively). n Disclosure: The study was supported by a grant from the National Cancer Institute of Canada Clinical Trials Group. Dr. Fairchild reported no potential conflicts of interest.

likely balance a significant portion of the increased cost…. This may result in lowering the overall long-term costs of care, including treatment and hospitalization required for management of severe pneumonitis,” he stated. n Disclosure: Dr. Kavanagh reported no potential conflicts of interest. Dr. Hallman is on the scientific advisory board for New Century Health.

Reference 1. Chow E, Meyer R, Ding K, et al: Dexamethasone versus placebo in the prophylaxis of radiation-induced pain flare following palliative radiotherapy for bone metastases: A double-blind randomized, controlled, superiority trial. 2015 ASTRO Annual Meeting. Abstract LBA1. Presented October 18, 2015.

ASCOPost.com | NOVEMBER 10, 2015

PAGE 5

ASTRO Annual Meeting Neuro-oncology

Cooperative Group Study Finds Radiation May Benefit Patients With Atypical Meningiomas By Alice Goodman

anagement of the vast majority of meningiomas is straightforward, but treatment of atypical meningiomas has been controversial. Should radiation be part of therapy or not has been the question. The first analysis of Radiation Therapy Oncology Group (RTOG) 0539 suggested that patients will have improved outcomes with the addition of radiation therapy to surgery.1 Results of the trial showed that patients with atypical meningiomas treated with radiation had a 3-year progression-free survival of 96%, the 3-year local control rate was 98%, and 3-year survival was 96%. The treatment was safe and well tolerated.

meningioma trial. It is very difficult to run trials on meningiomas, so there has been trepidation about whether we could make a study work. After 15 years, this study has come to fruition. It gives us [in NRG Oncology/RTOG] clinical direction for the future and proves that we can accrue patients to a trial.”

Study Details and Results The study enrolled three groups of patients after surgery (gross total resection) for meningiomas: Group 1 included low-risk patients managed by observation alone; group 2 were intermediate-risk atypical meningiomas (recurrent grade 1 meningioma or newly

The study is notable because it is the first completed cooperative group meningioma trial. It is very difficult to run trials on meningiomas, so there has been trepidation about whether we could make a study work. After 15 years, this study has come to fruition.

EXPERT POINT OF VIEW

nita Mahajan, MD, a radiation oncologist at the University of Texas MD Anderson Cancer Center, Houston, moderated the press conference where these findings were discussed. “Use of radiation for atypical meningiomas has been controversial. It has been difficult to put a study together, because we thought we had a good handle on how to manage these tumors. But we managed to pull this off in a cooperative group setAnita Mahajan, MD ting, and now a randomized phase III trial is being proposed,” Dr. Mahajan remarked. “One of the most important things to emphasize is that management of brain tumors is multidisciplinary and involves collaboration between surgeons and radiation oncologists. In general, modern cancer care requires a multidisciplinary approach. You need your partners,” she stated. n Disclosure: Dr. Mahajan reported no potential conflicts of interest.

“Meningiomas are commonly treated with surgery. Radiation is less commonly used,” explained first author Leland Rogers, MD, Professor of Radiation Oncology at Virginia Commonwealth University, Richmond, to listeners at the 2015 Annual Meeting of the American Society for Radiation Oncology (ASTRO). “The study is notable because it is the first completed cooperative group

diagnosed grade 2) who received either three-dimensional conformal radiotherapy or intensity-modulated radiotherapy at 54 Gy in 30 fractions; group 3 were high-risk patients treated with intensity-modulated radiotherapy at 60 Gy in 30 fractions. Dr. Rogers presented results for group 2 only (56 patients, 52 evaluable). About 70% were grade 2 with surgery and about 30% were recurrent grade 1.

About 85% were treated with intensity-modulated radiotherapy, and 15% received three-dimensional conformal radiotherapy. He said that there was initial skepticism about grouping together recurrent grade 1 and newly diagnosed grade 2 meningiomas, but the results were the same in both subgroups. For group 2 patients treated with radiation after surgery, 3-year progression-free survival was 96%; 3-year local control was 98%; and 3-year survival was 96%. The treatment was safe and well tolerated. Side effects were limited to grades 1 and 2, added Dr. Rogers. No grade 3 events were reported. Among 44 patients treated with intensity-modulated radiotherapy, 4 (9%) developed grade 2 acute adverse events, and 11 (25%) developed grade 2 late events.

Radiotherapy for Lung Cancer

protective effect of intensity-modulated radiotherapy was seen in a multivariate analysis and was particularly pronounced in larger tumors, Dr. Chun said. Although the low-dose bath with intensity-modulated radiotherapy was a concern originally, it was not associated with severe pneumonitis or any other severe toxicity, Dr. Chun pointed out. Use of intensity-modulated radiotherapy allowed lower doses of radiation to be delivered to the heart, which was associated with improved survival, he said. Intensity-modulated radiotherapy also allowed more consolidative chemotherapy to be administered com-

pared with 3D conformal radiotherapy (37.3% of the intensity-modulated radiotherapy group received full consolidative therapy vs 29.1% of the 3D conformal radiotherapy group). “We looked at one of the largest clinical trials ever done for NSCLC and found that the most important predictors of severe pneumonitis were intensity-modulated radiotherapy technique and lung V20 [the percentage of lung volume (subtracting the volume involved by lung cancer) that receives radiation doses of 20 Gy or more]. The low-dose bath created by intensity-modulated radiotherapy was

—Leland Rogers, MD

continued from page 4

tensity-modulated radiotherapy group had patients with larger and more advanced-stage tumors considered more difficult to treat; in fact, 38.6% of the intensity-modulated radiotherapy group had stage IIIB tumors vs 30.3% of the 3D conformal radiotherapy group.

Reduced Toxicity Despite having more advanced tumors, intensity-modulated radiotherapy–treated patients had a lower incidence of grade 3 or higher pneumonitis: 3.5% vs 8% with 3D conformal radiotherapy (P = .046). The

After 3 years, two additional recurrences have been reported. Both patients have been treated and are alive, Dr. Rogers added. To put these findings into context, Dr. Rogers showed a slide summarizing the historical trials that used surgery alone or surgery plus external-beam radiotherapy to treat atypical meningiomas. Compared with historical controls, 3-year progression-free survival appears approximately 20% to 30% higher when radiation was part of therapy. “Radiation is used less commonly because of concerns about safety,” Dr. Rogers commented.

Randomized Phase III Trial Based on the successful accrual and promising results of the phase II trial continued on page 6

not associated with any survival or toxicity outcome. These findings may fundamentally change the way we deliver radiation therapy for locally advanced lung cancer,” Dr. Chun stated. n

Disclosures: Dr. Chun reported no potential conflicts of interest.

Reference 1. Chun SG, Hu C, Choy H, et al: Comparison of 3-D conformal and intensity modulated radiation therapy outcomes for locally advanced non-small cell lung cancer in NRG Oncology/RTOG 0617. 2015 ASTRO Annual Meeting. Abstract 2. Presented October 18, 2015.

The ASCO Post | NOVEMBER 10, 2015

PAGE 6

FDA Update

FDA Approves Trabectedin for Advanced Liposarcoma and Leiomyosarcoma

he U.S. Food and Drug Administration has approved the novel chemotherapy drug trabectedin (Yondelis) for the treatment of specific soft-tissue sarcomas—liposarcoma and leiomyosarcoma—that are

unresectable or metastatic. Trabectedin is a novel marine antineoplastic alkaloid with a unique mechanism of action. The active substance is a tetrahydroisoquinoline alkaloid, originally discovered in the Caribbean sea squirt,

Atypical Meningiomas continued from page 5

in atypical meningiomas, NRG Oncology/RTOG is planning a randomized phase III trial in patients with newly diagnosed atypical meningiomas. After gross total resection, patients will be randomized to observation vs radiation therapy with intensity-modulated radiotherapy or proton-beam therapy. n Disclosure: Dr. Rogers reported no potential conflicts of interest.

Reference 1. Rogers L, Zhang P, Vogelbaum MA, et al: Intermediate-risk meningioma: Initial outcomes from NRG Oncology/RTOG0539. 2015 ASTRO Annual Meeting. Abstract 317. Presented October 21, 2015.

Radiation Therapy for Atypical Meningiomas ■■ Despite the hurdles, a cooperative group study successfully accrued patients with meningiomas for a clinical trial. ■■ Radiation therapy improved outcomes over historical controls in patients with atypical meningiomas (recurrent grade 1 or newly diagnosed grade 2). ■■ Progression-free survival, local tumor control, and overall survival were in the high 90th percentiles when radiation was part of treatment. ■■ A phase III cooperative group trial is now being planned to compare radiation vs observation after surgery for atypical meningiomas.

Ecteinascidia turbinata. The agent is now manufactured by total synthesis and is approved for patients who previously received chemotherapy that contained anthracycline. “The treatment of advanced or metastatic soft-tissue sarcoma represents

a difficult challenge with few effective therapeutic choices available for patients,” said Richard Pazdur, MD, Director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “[This recent] approval of [tra-

bectedin] provides a treatment option for advanced or metastatic liposarcoma and leiomyosarcoma.”

Clinical Trial Results The effectiveness and safety of trabectedin were demonstrated in 518

ASCOPost.com | NOVEMBER 10, 2015

PAGE 7

FDA Update

clinical trial participants with metastatic or recurrent leiomyosarcoma or liposarcoma.1 Participants were randomly assigned to receive either trabectedin (n = 345) or dacarbazine (n = 173). Participants who received trabectedin experienced a 4.2-month improvement in median progressionfree survival, compared to participants

assigned to dacarbazine, whose disease progressed an average of 1.5 months after starting treatment.

Safety and Toxicity The most common side effects among participants who received trabectedin were nausea, fatigue, vomiting, diarrhea, constipation, decreased

appetite, dyspnea, headache, peripheral edema, neutropenia, thrombocytopenia, anemia, elevated liver enzymes, and decreases in albumin. Trabectedin carries a warning label alerting health-care providers to the risk of neutropenic sepsis, rhabdomyolysis, hepatotoxicity, extravasation, tissue necrosis, and cardiomyopathy. n

Reference 1. Demetri GD, von Mehren M, Jones RL, et al: Efficacy and safety of trabectedin or dacarbazine for metastatic liposarcoma or leiomyosarcoma after failure of conventional chemotherapy: Results of a phase III randomized multicenter clinical trial. J Clin Oncol. September 14, 2015 (early release online).

The ASCO Postâ&#x20AC;&#x201A; | â&#x20AC;&#x201A; NOVEMBER 10, 2015

PAGE 8

FDA Update

FDA Approves Liposomal Irinotecan for Advanced Pancreatic Cancer

he U.S. Food and Drug Administration has approved irinotecan liposome injection (Onivyde), in combination with fluorouracil (5-FU) and leucovorin, to treat patients with metastatic pancreatic cancer who have been previously treated with gemcitabine-based chemotherapy.

The effectiveness of liposomal irinotecan was demonstrated in a three-arm, randomized, open-label study of 417 patients with metastatic pancreatic adenocarcinoma whose cancer had grown after receiving the chemotherapeutic drug gemcitabine or a gemcitabine-based

therapy.1 The study was designed to determine whether patients receiving liposomal irinotecan plus 5-FU/leucovorin or liposomal irinotecan alone lived longer than those receiving 5-FU/leucovorin. Patients treated with liposomal irinotecan plus 5-FU/leucovorin lived an

average of 6.1 months, compared to 4.2 months for those treated with only 5-FU/ leucovorin. There was no survival improvement for those who received only liposomal irinotecan compared to those who received 5-FU/leucovorin.

In addition, patients receiving liposomal irinotecan plus 5-FU/leucovorin had a delay in the amount of time to tumor growth compared to those who received 5-FU/leucovorin. The average time for those receiving liposomal irinotecan plus 5-FU/leucovorin was 3.1 months compared to 1.5 months for those receiving 5-FU/leucovorin.

Safety and Toxicity The safety of liposomal irinotecan was evaluated in 398 patients who received either liposomal irinotecan with 5-FU/ leucovorin, liposomal irinotecan alone, or 5-FU/leucovorin. The most common side effects of treatment with liposomal irinotecan included diarrhea, fatigue, vomiting, nausea, decreased appetite, stomatitis, and pyrexia. Liposomal irinotecan was also found to result in lymphopenia and neutropenia. Death due to sepsis following neutropenia has been reported in patients treated with liposomal irinotecan. The labeling for liposomal irinotecan includes a boxed warning to alert healthcare professionals about the risks of severe neutropenia and diarrhea. The drug is not approved for use as a single agent for the treatment of patients with metastatic pancreatic cancer.Â According to the National Cancer Institute, there will be 48,960 new cases of pancreatic cancer diagnosed in the United States in 2015 and nearly the same number of deaths caused by the disease (40,560). Pancreatic cancer can be difficult to diagnose early and treatment options are limited, especially when the disease has become metastatic and surgery to remove the tumor is not possible. n Reference 1. Chen L-T, Von Hoff DD, Li C-P, et al: Expanded analyses of Napoli-1: Phase 3 study of MM-398 (nal-IRI), with or without 5-fluorouracil and leucovorin, versus 5-fluorouracil and leucovorin in metastatic pancreatic cancer previously treated with gemcitabine-based therapy. 2015 Gastrointestinal Cancers Symposium. Abstract 234. Presented January 15, 2015.

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PAGE 9

European Cancer Congress Genitourinary Oncology

Meta-Analysis Evaluates Benefit of Docetaxel and Bisphosphonates in Hormone-Sensitive Prostate Cancer By Caroline Helwick

he results of a meta-analysis conducted in the United Kingdom may guide clinicians in the use of docetaxel and bisphosphonates in patients with hormone-sensitive prostate cancer.1 Claire L. Vale, PhD, Senior Research Scientist at the Medical Research Council Clinical Trials Unit at University College London, and colleagues conducted a metaanalysis that examined the overall survival and failure-free survival benefit of both docetaxel and bisphosphonates, added to standard of care, among men with metastatic and nonmetastatic hormone-sensitive disease. She presented the findings at the 2015 European Cancer Congress. “Results are emerging from randomized controlled trials about adding systemic treatments to standard of care for metastatic and nonmetastatic hormonesensitive prostate cancer. There is a need to evaluate the accumulating evidence through systematic review, which can guide clinical practice, inform clinical trials, and assess the need for further syn-

theses of the evidence,” Dr. Vale said. The aim of the meta-analysis, she said, was to “build a clear picture of all the evidence” pertaining to the addition of docetaxel and bisphosphonates, an area of “immediate interest.” Outcomes were separately assessed for metastatic and nonmetastatic disease, with the endpoints being overall survival and failure-free survival at 4 years (the time point with most consistent follow-up). Most patients received docetaxel at 75 mg/m2 every 3 weeks for 6 or 9 cycles. Trials had to have sufficient data on these endpoints and reasonable power to show a 5% to 10% benefit.

Docetaxel in the Metastatic Setting For men with metastatic disease, the addition of docetaxel to standard of care was shown to convey an overall survival benefit, when the results from three trials— CHAARTED, GETUG-15, and STAMPEDE were pooled in a meta-analysis.

In the metastatic setting, reported trials have given us substantial and reliable evidence that adding docetaxel in men with metastatic disease improves both overall survival and failure-free survival and should become the new standard of care for these men…. —Claire L. Vale, PhD

The hazard ratio for overall survival was 0.77 (P < .0001), favoring the addition of docetaxel to standard of care. This finding translated into a 10% absolute improvement in survival (from 40% to 50%) at 4 years. Docetaxel also improved failure-free survival, with a hazard ratio of 0.64 (P < .0001), which translated into a 15% absolute reduction in failure (from 80% to 65%).

EXPERT POINT OF VIEW

onald de Wit, MD, PhD, of Erasmus Medical Center, Rotterdam, Netherlands, called the use of docetaxel in addition to androgen-deprivation therapy “the latest paradigm shift” in the treatment of prostate cancer. The data showing a 10% absolute improvement in survival in the metastatic setting “are pretty convincing,” he said. The greater benefit of docetaxel in hormone-sensitive as compared with castration-resistant disease may be the result of resistant clones or perhaps better exposure to the drug in the hormone-sensitive setting. Docetaxel clearance appears to be greatly increased in castrated men, noted Dr. de Wit. “We may have underdosed docetaxel in the setting of metastatic castrate-resistant prostate cancer,” he said, adding that he recommends using prednisone with the drug to increase efficacy.

The Lingering Question According to Dr. de Wit, the “lingering question” is how to optimize the use of the contemporary treatment options in this malignancy,

including (along with docetaxel) abiraterone [Zytiga], enzalutamide [Xtandi], and cabazitaxel [ Jevtana]. “Learning the optimal sequence of these compounds is important, since

ued Dr. de Wit. “The use of docetaxel in the castrate-sensitive setting, prior to the use of androgen receptor–targeted therapies, might produce a new opportunity.”

Men presenting with metastatic prostate cancer who are fit to receive chemotherapy should be offered six cycles of docetaxel plus androgen-deprivation therapy. —Ronald de Wit, MD, PhD

the potential overall survival benefit will be smaller with every subsequent line of treatment,” he indicated. One consideration is the crossresistance between androgen receptor–targeted agents and by taxanes. Taxanes work, in part, inhibiting androgen receptor nuclear transport and signaling, and their efficacy is affected by prior abiraterone and enzalutamide use, he said. “The most concern is with the use of these agents pre-docetaxel,” contin-

“My conclusion is that men presenting with metastatic prostate cancer who are fit to receive chemotherapy should be offered six cycles of docetaxel plus androgen-deprivation therapy. There is no distinction between high- and low-volume disease. Any metastatic disease by TNM criteria will do,” he said. n Disclosure: Dr. de Wit has served as a consultant or advisor for and has received honoraria from Sanofi, Janssen, Astellas, Roche, and Millennium.

Docetaxel in Nonmetastatic Disease In men with nonmetastatic disease, the evidence was insufficient for finding a survival benefit with docetaxel; however, failure-free survival was improved when the findings of four trials—GETUG-12, RTOG 0521, STAMPEDE, and TAX3501 were pooled. The hazard ratio for survival was 0.87 (P = .218), translating into a 5% potential improvement in survival (from 80% to 85%) at 4 years. For failure-free survival, the effect was statistically significant, with a hazard ratio of 0.70 (P < .0001), yielding an 8% absolute reduction in failure (from 70% to 62%). “The hazard ratio of 0.87 for overall survival was not statistically significant, but it suggests a trend toward a survival benefit,” Dr. Vale noted, adding that more data from unreported trials and additional follow-up from the trials included would be vital to obtain a more reliable estimate of the effect of docetaxel on survival in these men.

Bisphosphonates in the Metastatic Setting “In men with metastatic disease, we found some evidence that adding bisphosphonates to standard of care improves overall survival, but any potential benefit of zoledronic acid is small and not clinically meaningful,” Dr. Vale said. The findings were based on three trials—CALGB 90202, PR05, and STAMPEDE. Two trials evaluated zoledronic acid at 4 mg every 3 or 4 weeks, whereas one evaluated sodium clodronate at 2,080 mg/d plus standard of care. The hazard ratio for overall survival when all three trials were pooled in a meta-analysis was 0.88 (P = .025), translating continued on page 14

SELECTED IMPORTANT SAFETY INFORMATION WARNING: (A) PREMATURE DISCONTINUATION OF ELIQUIS INCREASES THE RISK OF THROMBOTIC EVENTS, (B) SPINAL/ EPIDURAL HEMATOMA (A) Premature discontinuation of any oral anticoagulant, including ELIQUIS, increases the risk of thrombotic events. If anticoagulation with ELIQUIS is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant. (B) Epidural or spinal hematomas may occur in patients treated with ELIQUIS who are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal procedures. Factors that can increase the risk of developing epidural or spinal hematomas in these patients include: • use of indwelling epidural catheters • concomitant use of other drugs that affect hemostasis, such as nonsteroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants • a history of traumatic or repeated epidural or spinal punctures • a history of spinal deformity or spinal surgery • optimal timing between the administration of ELIQUIS and neuraxial procedures is not known Monitor patients frequently for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary. Consider the benefits and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated.

• Spinal/Epidural Anesthesia or Puncture: Patients treated with ELIQUIS undergoing spinal/epidural anesthesia or puncture may develop an epidural or spinal hematoma which can result in long-term or permanent paralysis. The risk of these events may be increased by the postoperative use of indwelling epidural catheters or the concomitant use of medicinal products affecting hemostasis. Indwelling epidural or intrathecal catheters should not be removed earlier than 24 hours after the last administration of ELIQUIS. The next dose of ELIQUIS should not be administered earlier than 5 hours after the removal of the catheter. The risk may also be increased by traumatic or repeated epidural or spinal puncture. If traumatic puncture occurs, delay the administration of ELIQUIS for 48 hours. Monitor patients frequently and if neurological compromise is noted, urgent diagnosis and treatment is necessary. Physicians should consider the potential benefit versus the risk of neuraxial intervention in ELIQUIS patients. • Prosthetic Heart Valves: The safety and efficacy of ELIQUIS have not been studied in patients with prosthetic heart valves and is not recommended in these patients. • Acute PE in Hemodynamically Unstable Patients or Patients who Require Thrombolysis or Pulmonary Embolectomy: Initiation of ELIQUIS is not recommended as an alternative to unfractionated heparin for the initial treatment of patients with PE who present with hemodynamic instability or who may receive thrombolysis or pulmonary embolectomy. ADVERSE REACTIONS • The most common and most serious adverse reactions reported with ELIQUIS were related to bleeding. TEMPORARY INTERRUPTION FOR SURGERY AND OTHER INTERVENTIONS • ELIQUIS should be discontinued at least 48 hours prior to elective CONTRAINDICATIONS surgery or invasive procedures with a moderate or high risk of unacceptable or clinically significant bleeding. ELIQUIS should be • Active pathological bleeding discontinued at least 24 hours prior to elective surgery or invasive • Severe hypersensitivity reaction to ELIQUIS (e.g., anaphylactic reactions) procedures with a low risk of bleeding or where the bleeding would be WARNINGS AND PRECAUTIONS noncritical in location and easily controlled. Bridging anticoagulation • Increased Risk of Thrombotic Events After Premature Discontinuation: during the 24 to 48 hours after stopping ELIQUIS and prior to the Premature discontinuation of any oral anticoagulant, including ELIQUIS, intervention is not generally required. ELIQUIS should be restarted after in the absence of adequate alternative anticoagulation increases the the surgical or other procedures as soon as adequate hemostasis has risk of thrombotic events. An increased rate of stroke was observed been established. during the transition from ELIQUIS to warfarin in clinical trials in atrial DRUG INTERACTIONS fibrillation patients. If ELIQUIS is discontinued for a reason other than • Strong Dual Inhibitors of CYP3A4 and P-gp: Inhibitors of cytochrome pathological bleeding or completion of a course of therapy, consider P450 3A4 (CYP3A4) and P-glycoprotein (P-gp) increase exposure to apixaban coverage with another anticoagulant. and increase the risk of bleeding. For patients receiving ELIQUIS doses of • Bleeding Risk: ELIQUIS increases the risk of bleeding and can cause 5 mg or 10 mg twice daily, reduce the dose of ELIQUIS by 50% when serious, potentially fatal, bleeding. ELIQUIS is coadministered with drugs that are strong dual inhibitors of – Concomitant use of drugs affecting hemostasis increases the risk of CYP3A4 and P-gp (e.g., ketoconazole, itraconazole, ritonavir, or bleeding, including aspirin and other antiplatelet agents, other clarithromycin). In patients already taking 2.5 mg twice daily, avoid anticoagulants, heparin, thrombolytic agents, SSRIs, SNRIs, and coadministration of ELIQUIS with strong dual inhibitors of CYP3A4 and P-gp. NSAIDs. • Strong Dual Inducers of CYP3A4 and P-gp: Avoid concomitant use of – Advise patients of signs and symptoms of blood loss and to report ELIQUIS with strong dual inducers of CYP3A4 and P-gp (e.g., rifampin, them immediately or go to an emergency room. Discontinue ELIQUIS carbamazepine, phenytoin, St. John’s wort) because such drugs will in patients with active pathological hemorrhage. decrease exposure to apixaban and increase the risk of stroke and other thromboembolic events. – There is no established way to reverse the anticoagulant effect of apixaban, which can be expected to persist for at least 24 hours after the last dose (i.e., about two half-lives). A specific antidote for ELIQUIS is not available.

Please see Brief Summary of Full Prescribing Information, including Boxed WARNINGS, on the adjacent pages. ELIQUIS® and the ELIQUIS logo are trademarks of Bristol-Myers Squibb Company. © 2015 Bristol-Myers Squibb Company. All rights reserved. 432US15BR01135-02-01 10/15

Approved for 6 indications

Treatment of DVT

Treatment of PE

Reduction in the risk of recurrent DVT and PE following initial therapy

Reduction in risk of stroke/systemic embolism in NVAF

Prophylaxis of DVT, which may lead to PE, after hip replacement surgery

Prophylaxis of DVT, which may lead to PE, after knee replacement surgery

Learn more about ELIQUIS for the treatment of DVT/PE and access reprints of our clinical studies. hcp.eliquis.com

NVAF=nonvalvular atrial fibrillation; DVT=deep vein thrombosis; PE=pulmonary embolism.

SELECTED IMPORTANT SAFETY INFORMATION (CONT’D) DRUG INTERACTIONS (CONT’D) • Anticoagulants and Antiplatelet Agents: Coadministration of antiplatelet agents, fibrinolytics, heparin, aspirin, and chronic NSAID use increases the risk of bleeding. APPRAISE-2, a placebo-controlled clinical trial of apixaban in high-risk post-acute coronary syndrome patients treated with aspirin or the combination of aspirin and clopidogrel, was terminated early due to a higher rate of bleeding with apixaban compared to placebo. PREGNANCY CATEGORY B • There are no adequate and well-controlled studies of ELIQUIS in pregnant women. Treatment is likely to increase the risk of hemorrhage during pregnancy and delivery. ELIQUIS should be used during pregnancy only if the potential benefit outweighs the potential risk to the mother and fetus.

Please see Brief Summary of Full Prescribing Information, including Boxed WARNINGS, on the adjacent pages.

ELIQUIS® (apixaban) tablets, for oral use Brief Summary of Prescribing Information. For complete prescribing information consult official package insert. WARNING: (A) PREMATURE DISCONTINUATION OF ELIQUIS INCREASES THE RISK OF THROMBOTIC EVENTS (B) SPINAL/EPIDURAL HEMATOMA (A) PREMATURE DISCONTINUATION OF ELIQUIS INCREASES THE RISK OF THROMBOTIC EVENTS Premature discontinuation of any oral anticoagulant, including ELIQUIS, increases the risk of thrombotic events. If anticoagulation with ELIQUIS is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant [see Dosage and Administration, Warnings and Precautions, and Clinical Studies (14.1) in full Prescribing Information]. (B) SPINAL/EPIDURAL HEMATOMA Epidural or spinal hematomas may occur in patients treated with ELIQUIS who are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal procedures. Factors that can increase the risk of developing epidural or spinal hematomas in these patients include: • use of indwelling epidural catheters • concomitant use of other drugs that affect hemostasis, such as nonsteroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants • a history of traumatic or repeated epidural or spinal punctures • a history of spinal deformity or spinal surgery • optimal timing between the administration of ELIQUIS and neuraxial procedures is not known [see Warnings and Precautions] Monitor patients frequently for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary [see Warnings and Precautions]. Consider the benefits and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated [see Warnings and Precautions]. INDICATIONS AND USAGE Reduction of Risk of Stroke and Systemic Embolism in Nonvalvular Atrial Fibrillation— ELIQUIS® (apixaban) is indicated to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery—ELIQUIS is indicated for the prophylaxis of deep vein thrombosis (DVT), which may lead to pulmonary embolism (PE), in patients who have undergone hip or knee replacement surgery. Treatment of Deep Vein Thrombosis—ELIQUIS is indicated for the treatment of DVT. Treatment of Pulmonary Embolism—ELIQUIS is indicated for the treatment of PE. Reduction in the Risk of Recurrence of DVT and PE—ELIQUIS is indicated to reduce the risk of recurrent DVT and PE following initial therapy. DOSAGE AND ADMINISTRATION (Selected information) Temporary Interruption for Surgery and Other Interventions ELIQUIS should be discontinued at least 48 hours prior to elective surgery or invasive procedures with a moderate or high risk of unacceptable or clinically significant bleeding. ELIQUIS should be discontinued at least 24 hours prior to elective surgery or invasive procedures with a low risk of bleeding or where the bleeding would be non-critical in location and easily controlled. Bridging anticoagulation during the 24 to 48 hours after stopping ELIQUIS and prior to the intervention is not generally required. ELIQUIS should be restarted after the surgical or other procedures as soon as adequate hemostasis has been established. (For complete Dosage and Administration section, see full Prescribing Information.) CONTRAINDICATIONS ELIQUIS is contraindicated in patients with the following conditions: • Active pathological bleeding [see Warnings and Precautions and Adverse Reactions] • Severe hypersensitivity reaction to ELIQUIS (e.g., anaphylactic reactions) [see Adverse Reactions] WARNINGS AND PRECAUTIONS Increased Risk of Thrombotic Events after Premature Discontinuation Premature discontinuation of any oral anticoagulant, including ELIQUIS, in the absence of adequate alternative anticoagulation increases the risk of thrombotic events. An increased rate of stroke was observed during the transition from ELIQUIS to warfarin in clinical trials in atrial fibrillation patients. If ELIQUIS is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant [see Dosage and Administration (2.4) and Clinical Studies (14.1) in full Prescribing Information]. Bleeding ELIQUIS increases the risk of bleeding and can cause serious, potentially fatal, bleeding [see Dosage and Administration (2.1) in full Prescribing Information and Adverse Reactions]. Concomitant use of drugs affecting hemostasis increases the risk of bleeding. These include aspirin and other antiplatelet agents, other anticoagulants, heparin, thrombolytic agents, selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, and nonsteroidal anti-inflammatory drugs (NSAIDs) [see Drug Interactions]. Advise patients of signs and symptoms of blood loss and to report them immediately or go to an emergency room. Discontinue ELIQUIS in patients with active pathological hemorrhage. There is no established way to reverse the anticoagulant effect of apixaban, which can be expected to persist for at least 24 hours after the last dose, i.e., for about two drug half-lives. A specific antidote for ELIQUIS is not available. Hemodialysis does not appear to have a substantial impact on apixaban exposure [see Clinical Pharmacology (12.3) in full Prescribing Information]. Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of apixaban. There is no experience with antifibrinolytic agents (tranexamic acid, aminocaproic acid) in individuals receiving apixaban. There is neither scientific rationale for reversal nor experience with systemic hemostatics (desmopressin and aprotinin) in individuals receiving apixaban. Use of procoagulant reversal agents such as prothrombin

complex concentrate, activated prothrombin complex concentrate, or recombinant factor VIIa may be considered but has not been evaluated in clinical studies. Activated oral charcoal reduces absorption of apixaban, thereby lowering apixaban plasma concentration [see Overdosage]. Spinal/Epidural Anesthesia or Puncture When neuraxial anesthesia (spinal/epidural anesthesia) or spinal/epidural puncture is employed, patients treated with antithrombotic agents for prevention of thromboembolic complications are at risk of developing an epidural or spinal hematoma which can result in long-term or permanent paralysis. The risk of these events may be increased by the postoperative use of indwelling epidural catheters or the concomitant use of medicinal products affecting hemostasis. Indwelling epidural or intrathecal catheters should not be removed earlier than 24 hours after the last administration of ELIQUIS (apixaban). The next dose of ELIQUIS should not be administered earlier than 5 hours after the removal of the catheter. The risk may also be increased by traumatic or repeated epidural or spinal puncture. If traumatic puncture occurs, delay the administration of ELIQUIS for 48 hours. Monitor patients frequently for signs and symptoms of neurological impairment (e.g., numbness or weakness of the legs, bowel, or bladder dysfunction). If neurological compromise is noted, urgent diagnosis and treatment is necessary. Prior to neuraxial intervention the physician should consider the potential benefit versus the risk in anticoagulated patients or in patients to be anticoagulated for thromboprophylaxis. Patients with Prosthetic Heart Valves The safety and efficacy of ELIQUIS have not been studied in patients with prosthetic heart valves. Therefore, use of ELIQUIS is not recommended in these patients. Acute PE in Hemodynamically Unstable Patients or Patients who Require Thrombolysis or Pulmonary Embolectomy Initiation of ELIQUIS is not recommended as an alternative to unfractionated heparin for the initial treatment of patients with PE who present with hemodynamic instability or who may receive thrombolysis or pulmonary embolectomy. ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the prescribing information. • Increased risk of thrombotic events after premature discontinuation [see Warnings and Precautions] • Bleeding [see Warnings and Precautions] • Spinal/epidural anesthesia or puncture [see Warnings and Precautions] Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Reduction of Risk of Stroke and Systemic Embolism in Patients with Nonvalvular Atrial Fibrillation The safety of ELIQUIS was evaluated in the ARISTOTLE and AVERROES studies [see Clinical Studies (14) in full Prescribing Information], including 11,284 patients exposed to ELIQUIS 5 mg twice daily and 602 patients exposed to ELIQUIS 2.5 mg twice daily. The duration of ELIQUIS exposure was ≥12 months for 9375 patients and ≥24 months for 3369 patients in the two studies. In ARISTOTLE, the mean duration of exposure was 89 weeks (>15,000 patient-years). In AVERROES, the mean duration of exposure was approximately 59 weeks (>3000 patient-years). The most common reason for treatment discontinuation in both studies was for bleeding-related adverse reactions; in ARISTOTLE this occurred in 1.7% and 2.5% of patients treated with ELIQUIS and warfarin, respectively, and in AVERROES, in 1.5% and 1.3% on ELIQUIS and aspirin, respectively. Bleeding in Patients with Nonvalvular Atrial Fibrillation in ARISTOTLE and AVERROES Tables 1 and 2 show the number of patients experiencing major bleeding during the treatment period and the bleeding rate (percentage of subjects with at least one bleeding event per 100 patient-years) in ARISTOTLE and AVERROES. Table 1:

Bleeding Events in Patients with Nonvalvular Atrial Fibrillation in ARISTOTLE*

ELIQUIS Warfarin Hazard Ratio P-value N=9088 N=9052 (95% CI) n (per n (per 100 pt-year) 100 pt-year) Major† 327 (2.13) 462 (3.09) 0.69 (0.60, 0.80) <0.0001 52 (0.33) 125 (0.82) 0.41 (0.30, 0.57) Intracranial (ICH)‡ 38 (0.24) 74 (0.49) 0.51 (0.34, 0.75) Hemorrhagic stroke§ Other ICH 15 (0.10) 51 (0.34) 0.29 (0.16, 0.51) 128 (0.83) 141 (0.93) 0.89 (0.70, 1.14) Gastrointestinal (GI)¶ 10 (0.06) 37 (0.24) 0.27 (0.13, 0.53) Fatal** Intracranial 4 (0.03) 30 (0.20) 0.13 (0.05, 0.37) Non-intracranial 6 (0.04) 7 (0.05) 0.84 (0.28, 2.15) * Bleeding events within each subcategory were counted once per subject, but subjects may have contributed events to multiple endpoints. Bleeding events were counted during treatment or within 2 days of stopping study treatment (on-treatment period). † Defined as clinically overt bleeding accompanied by one or more of the following: a decrease in hemoglobin of ≥2 g/dL, a transfusion of 2 or more units of packed red blood cells, bleeding at a critical site: intracranial, intraspinal, intraocular, pericardial, intra-articular, intramuscular with compartment syndrome, retroperitoneal or with fatal outcome. ‡ Intracranial bleed includes intracerebral, intraventricular, subdural, and subarachnoid bleeding. Any type of hemorrhagic stroke was adjudicated and counted as an intracranial major bleed. § On-treatment analysis based on the safety population, compared to ITT analysis presented in Section 14. ¶ GI bleed includes upper GI, lower GI, and rectal bleeding. ** Fatal bleeding is an adjudicated death with the primary cause of death as intracranial bleeding or non-intracranial bleeding during the on-treatment period. In ARISTOTLE, the results for major bleeding were generally consistent across most major subgroups including age, weight, CHADS2 score (a scale from 0 to 6 used to estimate risk of stroke, with higher scores predicting greater risk), prior warfarin use, geographic region, and aspirin use at randomization (Figure 1). Subjects treated with apixaban with diabetes bled more (3.0% per year) than did subjects without diabetes (1.9% per year).

Adverse reactions occurring in ≥1% of patients undergoing hip or knee replacement surgery in the 1 Phase II study and the 3 Phase III studies are listed in Table 4. Table 4:

Table 7:

Bleeding Results in the AMPLIFY-EXT Study ELIQUIS (apixaban) 2.5 mg bid N=840 n (%)

Adverse Reactions Occurring in ≥1% of Patients in Either Group Undergoing Hip or Knee Replacement Surgery ELIQUIS (apixaban), Enoxaparin, n (%) n (%) 2.5 mg po bid 40 mg sc qd or 30 mg sc q12h N=5924 N=5904

Nausea

153 (2.6)

ELIQUIS 5 mg bid N=811 n (%)

N=826 n (%)

Treatment of pregnant rats from implantation (gestation Day 7) to weaning (lactation Day 21) with apixaban at a dose of 1000 mg/kg (about 5 times the human exposure based on unbound apixaban) did not result in death of offspring or death of mother rats during labor in association with uterine bleeding. However, increased incidence of maternal bleeding, primarily during gestation, occurred at apixaban doses of ≥25 mg/kg, a dose corresponding to ≥1.3 times the human exposure. Nursing Mothers

Placebo

Major

2 (0.2)

1 (0.1)

4 (0.5)

CRNM*

25 (3.0)

34 (4.2)

19 (2.3)

Major + CRNM

27 (3.2)

35 (4.3)

22 (2.7)

159 (2.7)

Minor

75 (8.9)

98 (12.1)

58 (7.0)

94 (11.2)

121 (14.9)

74 (9.0)

Anemia (including postoperative and hemorrhagic anemia, and respective laboratory parameters)

153 (2.6)

178 (3.0)

All

Contusion

83 (1.4)

115 (1.9)

* CRNM = clinically relevant nonmajor bleeding. Events associated with each endpoint were counted once per subject, but subjects may have contributed events to multiple endpoints.

Hemorrhage (including hematoma, and vaginal and urethral hemorrhage)

67 (1.1)

81 (1.4)

Postprocedural hemorrhage (including postprocedural hematoma, wound hemorrhage, vessel puncture site hematoma and catheter site hemorrhage)

54 (0.9)

60 (1.0)

Transaminases increased (including alanine aminotransferase increased and alanine aminotransferase abnormal)

50 (0.8)

71 (1.2)

Aspartate aminotransferase increased

47 (0.8)

69 (1.2)

Gamma-glutamyltransferase increased

38 (0.6)

65 (1.1)

Less common adverse reactions in apixaban-treated patients undergoing hip or knee replacement surgery occurring at a frequency of ≥0.1% to <1%: Blood and lymphatic system disorders: thrombocytopenia (including platelet count decreases) Vascular disorders: hypotension (including procedural hypotension)

Adverse reactions occurring in ≥1% of patients in the AMPLIFY-EXT study are listed in Table 8. Table 8:

Adverse Reactions Occurring in ≥1% of Patients Undergoing Extended Treatment for DVT and PE in the AMPLIFY-EXT Study ELIQUIS 2.5 mg bid N=840 n (%)

ELIQUIS 5 mg bid N=811 n (%)

Placebo

13 (1.5)

29 (3.6)

9 (1.1)

N=826 n (%)

Pediatric Use Safety and effectiveness in pediatric patients have not been established. Geriatric Use Of the total subjects in the ARISTOTLE and AVERROES clinical studies, >69% were 65 and older, and >31% were 75 and older. In the ADVANCE-1, ADVANCE-2, and ADVANCE-3 clinical studies, 50% of subjects were 65 and older, while 16% were 75 and older. In the AMPLIFY and AMPLIFY-EXT clinical studies, >32% of subjects were 65 and older and >13% were 75 and older. No clinically significant differences in safety or effectiveness were observed when comparing subjects in different age groups. Renal Impairment

Hematuria

12 (1.4)

17 (2.1)

9 (1.1)

Hematoma

13 (1.5)

16 (2.0)

10 (1.2)

Contusion

18 (2.1)

18 (2.2)

Gingival bleeding

12 (1.4)

9 (1.1)

3 (0.4)

Hepatic Impairment

Other Adverse Reactions

Gastrointestinal disorders: gastrointestinal hemorrhage (including hematemesis and melena), hematochezia

Less common adverse reactions in ELIQUIS-treated patients in the AMPLIFY or AMPLIFY-EXT studies occurring at a frequency of ≥0.1% to <1%:

Hepatobiliary disorders: liver function test abnormal, blood alkaline phosphatase increased, blood bilirubin increased

Blood and lymphatic system disorders: hemorrhagic anemia

Renal and urinary disorders: hematuria (including respective laboratory parameters)

Gastrointestinal disorders: hematochezia, hemorrhoidal hemorrhage, gastrointestinal hemorrhage, hematemesis, melena, anal hemorrhage

Less common adverse reactions in apixaban-treated patients undergoing hip or knee replacement surgery occurring at a frequency of <0.1%:

Women should be instructed either to discontinue breastfeeding or to discontinue ELIQUIS (apixaban) therapy, taking into account the importance of the drug to the mother.

No dose adjustment is recommended for patients with renal impairment alone, including those with end-stage renal disease (ESRD) maintained on hemodialysis, except nonvalvular atrial fibrillation patients who meet the criteria for dosage adjustment [see Dosage and Administration (2.1) in full Prescribing Information]. Patients with ESRD (CrCl <15 mL/min) receiving or not receiving hemodialysis were not studied in clinical efficacy and safety studies with ELIQUIS; therefore, the dosing recommendations are based on pharmacokinetic and pharmacodynamic (anti-Factor Xa activity) data in subjects with ESRD maintained on dialysis [see Clinical Pharmacology (12.3) in full Prescribing Information].

Epistaxis

Respiratory, thoracic, and mediastinal disorders: epistaxis

Injury, poisoning, and procedural complications: wound secretion, incision-site hemorrhage (including incision-site hematoma), operative hemorrhage

It is unknown whether apixaban or its metabolites are excreted in human milk. Rats excrete apixaban in milk (12% of the maternal dose).

Injury, poisoning, and procedural complications: wound hemorrhage, postprocedural hemorrhage, traumatic hematoma, periorbital hematoma Musculoskeletal and connective tissue disorders: muscle hemorrhage

PATIENT COUNSELING INFORMATION

Common adverse reactions (≥1%) were gingival bleeding, epistaxis, contusion, hematuria, rectal hemorrhage, hematoma, menorrhagia, and hemoptysis.

Investigations: blood urine present, occult blood positive, occult blood, red blood cells urine positive

See FDA-approved patient labeling (Medication Guide).

AMPLIFY Study

General disorders and administration-site conditions: injection-site hematoma, vessel puncture-site hematoma

B:14.25”

Eye disorders: conjunctival hemorrhage, retinal hemorrhage, eye hemorrhage

T:13”

Skin and subcutaneous tissue disorders: ecchymosis, skin hemorrhage, petechiae

S:12”

Vascular disorders: hemorrhage

The safety of ELIQUIS has been evaluated in the AMPLIFY and AMPLIFY-EXT studies, including 2676 patients exposed to ELIQUIS 10 mg twice daily, 3359 patients exposed to ELIQUIS 5 mg twice daily, and 840 patients exposed to ELIQUIS 2.5 mg twice daily.

Table 5:

Bleeding Results in the AMPLIFY Study

Major

ELIQUIS N=2676 n (%)

Enoxaparin/Warfarin N=2689 n (%)

Relative Risk (95% CI)

15 (0.6)

49 (1.8)

0.31 (0.17, 0.55) p<0.0001

CRNM*

103 (3.9)

215 (8.0)

Major + CRNM

115 (4.3)

261 (9.7)

Minor

313 (11.7)

505 (18.8)

All

402 (15.0)

676 (25.1)

DRUG INTERACTIONS Apixaban is a substrate of both CYP3A4 and P-gp. Inhibitors of CYP3A4 and P-gp increase exposure to apixaban and increase the risk of bleeding. Inducers of CYP3A4 and P-gp decrease exposure to apixaban and increase the risk of stroke and other thromboembolic events. Strong Dual Inhibitors of CYP3A4 and P-gp For patients receiving ELIQUIS 5 mg or 10 mg twice daily, the dose of ELIQUIS should be decreased by 50% when it is coadministered with drugs that are strong dual inhibitors of CYP3A4 and P-gp (e.g., ketoconazole, itraconazole, ritonavir, or clarithromycin) [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3) in full Prescribing Information]. For patients receiving ELIQUIS at a dose of 2.5 mg twice daily, avoid coadministration with strong dual inhibitors of CYP3A4 and P-gp [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3) in full Prescribing Information].

In healthy subjects, administration of activated charcoal 2 and 6 hours after ingestion of a 20-mg dose of apixaban reduced mean apixaban AUC by 50% and 27%, respectively. Thus, administration of activated charcoal may be useful in the management of apixaban overdose or accidental ingestion.

Advise patients of the following: • They should not discontinue ELIQUIS without talking to their physician first. • They should be informed that it might take longer than usual for bleeding to stop, and they may bruise or bleed more easily when treated with ELIQUIS. Advise patients about how to recognize bleeding or symptoms of hypovolemia and of the urgent need to report any unusual bleeding to their physician. • They should tell their physicians and dentists they are taking ELIQUIS, and/or any other product known to affect bleeding (including nonprescription products, such as aspirin or NSAIDs), before any surgery or medical or dental procedure is scheduled and before any new drug is taken. • If the patient is having neuraxial anesthesia or spinal puncture, inform the patient to watch for signs and symptoms of spinal or epidural hematomas, such as numbness or weakness of the legs, or bowel or bladder dysfunction [see Warnings and Precautions]. If any of these symptoms occur, the patient should contact his or her physician immediately.

Strong Dual Inducers of CYP3A4 and P-gp

• They should tell their physicians if they are pregnant or plan to become pregnant or are breastfeeding or intend to breastfeed during treatment with ELIQUIS [see Use in Specific Populations].

Avoid concomitant use of ELIQUIS with strong dual inducers of CYP3A4 and P-gp (e.g., rifampin, carbamazepine, phenytoin, St. John’s wort) because such drugs will decrease exposure to apixaban [see Clinical Pharmacology (12.3) in full Prescribing Information].

• If a dose is missed, the dose should be taken as soon as possible on the same day and twice-daily administration should be resumed. The dose should not be doubled to make up for a missed dose.

Anticoagulants and Antiplatelet Agents

* CRNM = clinically relevant nonmajor bleeding. Events associated with each endpoint were counted once per subject, but subjects may have contributed events to multiple endpoints. Adverse reactions occurring in ≥1% of patients in the AMPLIFY study are listed in Table 6. Table 6:

metrorrhagia,

In controlled clinical trials, orally administered apixaban in healthy subjects at doses up to 50 mg daily for 3 to 7 days (25 mg twice daily for 7 days or 50 mg once daily for 3 days) had no clinically relevant adverse effects.

Treatment of DVT and PE and Reduction in the Risk of Recurrence of DVT or PE

Bleeding results from the AMPLIFY study are summarized in Table 5.

hemorrhage,

There is no antidote to ELIQUIS. Overdose of ELIQUIS increases the risk of bleeding [see Warnings and Precautions].

Reproductive system and breast menometrorrhagia, genital hemorrhage

In the AMPLIFY study, ELIQUIS was statistically superior to enoxaparin/warfarin in the primary safety endpoint of major bleeding (relative risk 0.31, 95% CI [0.17, 0.55], P-value <0.0001).

vaginal

OVERDOSAGE

Gingival bleeding, hemoptysis, hypersensitivity, muscle hemorrhage, ocular hemorrhage (including conjunctival hemorrhage), rectal hemorrhage

The mean duration of exposure to ELIQUIS was 154 days and to enoxaparin/warfarin was 152 days in the AMPLIFY study. Adverse reactions related to bleeding occurred in 417 (15.6%) ELIQUIS-treated patients compared to 661 (24.6%) enoxaparin/warfarin-treated patients. The discontinuation rate due to bleeding events was 0.7% in the ELIQUIS-treated patients compared to 1.7% in enoxaparin/warfarin-treated patients in the AMPLIFY study.

disorders:

No dose adjustment is required in patients with mild hepatic impairment (Child-Pugh class A). Because patients with moderate hepatic impairment (Child-Pugh class B) may have intrinsic coagulation abnormalities and there is limited clinical experience with ELIQUIS in these patients, dosing recommendations cannot be provided [see Clinical Pharmacology (12.2) in full Prescribing Information]. ELIQUIS is not recommended in patients with severe hepatic impairment (Child-Pugh class C) [see Clinical Pharmacology (12.2) in full Prescribing Information].

Adverse Reactions Occurring in ≥1% of Patients Treated for DVT and PE in the AMPLIFY Study ELIQUIS N=2676 n (%)

Enoxaparin/Warfarin N=2689 n (%)

Epistaxis

77 (2.9)

146 (5.4)

Contusion

49 (1.8)

97 (3.6)

Hematuria

46 (1.7)

102 (3.8)

Menorrhagia

38 (1.4)

30 (1.1)

Hematoma

35 (1.3)

76 (2.8)

Hemoptysis

32 (1.2)

31 (1.2)

Rectal hemorrhage

26 (1.0)

39 (1.5)

Gingival bleeding

26 (1.0)

50 (1.9)

AMPLIFY-EXT Study The mean duration of exposure to ELIQUIS was approximately 330 days and to placebo was 312 days in the AMPLIFY-EXT study. Adverse reactions related to bleeding occurred in 219 (13.3%) ELIQUIS-treated patients compared to 72 (8.7%) placebo-treated patients. The discontinuation rate due to bleeding events was approximately 1% in the ELIQUIS-treated patients compared to 0.4% in those patients in the placebo group in the AMPLIFY-EXT study. Bleeding results from the AMPLIFY-EXT study are summarized in Table 7.

Coadministration of antiplatelet agents, fibrinolytics, heparin, aspirin, and chronic NSAID use increases the risk of bleeding. APPRAISE-2, a placebo-controlled clinical trial of apixaban in high-risk, post-acute coronary syndrome patients treated with aspirin or the combination of aspirin and clopidogrel, was terminated early due to a higher rate of bleeding with apixaban compared to placebo. The rate of ISTH major bleeding was 2.8% per year with apixaban versus 0.6% per year with placebo in patients receiving single antiplatelet therapy and was 5.9% per year with apixaban versus 2.5% per year with placebo in those receiving dual antiplatelet therapy. In ARISTOTLE, concomitant use of aspirin increased the bleeding risk on ELIQUIS from 1.8% per year to 3.4% per year and concomitant use of aspirin and warfarin increased the bleeding risk from 2.7% per year to 4.6% per year. In this clinical trial, there was limited (2.3%) use of dual antiplatelet therapy with ELIQUIS. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category B There are no adequate and well-controlled studies of ELIQUIS in pregnant women. Treatment is likely to increase the risk of hemorrhage during pregnancy and delivery. ELIQUIS should be used during pregnancy only if the potential benefit outweighs the potential risk to the mother and fetus. Treatment of pregnant rats, rabbits, and mice after implantation until the end of gestation resulted in fetal exposure to apixaban, but was not associated with increased risk for fetal malformations or toxicity. No maternal or fetal deaths were attributed to bleeding. Increased incidence of maternal bleeding was observed in mice, rats, and rabbits at maternal exposures that were 19, 4, and 1 times, respectively, the human exposure of unbound drug, based on area under plasma-concentration time curve (AUC) comparisons at the maximum recommended human dose (MRHD) of 10 mg (5 mg twice daily). Labor and Delivery Safety and effectiveness of ELIQUIS during labor and delivery have not been studied in clinical trials. Consider the risks of bleeding and of stroke in using ELIQUIS in this setting [see Warnings and Precautions].

Marketed by: Bristol-Myers Squibb Company Princeton, New Jersey 08543 USA and Pfizer Inc New York, New York 10017 USA 1356615A0 / 1356514A0

Rev September 2015 432US1501679-06-01

The ASCO Post | NOVEMBER 10, 2015

PAGE 14

European Cancer Congress Genitourinary Oncology

Update on Clinical Trials in Metastatic Prostate Cancer By Alice Goodman

espite the proliferation of new drugs to treat prostate cancer, further progress is proving somewhat elusive, according to three trials presented at the 2015 European Cancer Congress. One study had positive results with orteronel maintenance therapy in patients with metastatic castration-resistant prostate cancer stabilized on docetaxel, but that drug has been abandoned.1 A second trial showed lackluster results for neoadjuvant therapy with enzalutamide (Xtandi) earlier in the course of disease.2 A third trial provided a glimmer of hope improving hormonal therapy with TAK-385, an oral antagonist under development.3

Orteronel: Not an Option Orteronel, a drug that was developed to be a more selective nonsteroidal androgen synthesis inhibitor, was studied in a phase III trial as maintenance therapy. “Maintenance therapy has proven effective in other malignancies,” explained senior author Silke Gillessen, MD, of Kantonsspital St. Gallen, St Gallen, Winterthur, Switzerland, providing a rationale for the trial. “In this trial, orteronel significantly improved event-free survival and radiographic progression-free survival as switch maintenance therapy. It was generally well tolerated in patients with disease stabilization after docetaxel. Although there was

Docetaxel and Bisphosphonates continued from page 9

into a 5% absolute improvement in survival (from 40% to 45%) at 4 years. When zoledronic acid was evaluated separately, the hazard ratio was 0.94 (P = .323), translating into a 2.5% potential improvement in survival (from 40% to 42.5%). “The analysis of the zoledronic acid trials lost some power, and we see a hazard ratio that, while not statistically significant, shows a slight trend favoring zoledronic acid,” noted Dr. Vale, adding that the survival benefit was unlikely to be clinically relevant.

Bisphosphonates in Nonmetastatic Disease In nonmetastatic disease, no overall survival benefit was observed with the addition of bisphosphonates, based on the pooled analysis of four studies—PR04, RADAR, STAMPEDE, and ZEUS.

Silke Gillessen, MD

increased toxicity in the orteronel arm, it was manageable. To our knowledge, this is the first trial using a novel androgen receptor pathway inhibitor as switch maintenance therapy in prostate cancer.” The study was initiated before development of orteronel was discontinued in June 2014, when it failed to prolong survival compared with prednisone

not progressed after first-line docetaxel had been enrolled. Patients continued on androgen-deprivation therapy and were randomized 1:1 to receive orteronel plus best supportive care or placebo plus best supportive care. The primary endpoint was eventfree survival. Prostate-specific antigen (PSA) rise alone (biochemical failure) was not considered an event. The trial was stopped prematurely, with only 47 patients enrolled. Median follow-up is 17 months for patients on orteronel and 18.4 months for patients on placebo. Median event-free survival was significantly better for orteronel: 8.5 months vs 2.9 months for placebo, which was shorter than anticipated (P = .001), Dr. Gillessen said.

Important Issues in Metastatic Prostate Cancer ■■ The concepts of maintenance therapy for metastatic castration-resistant prostate cancer and first-line neoadjuvant therapy for intermediate- and high-risk prostate cancer could theoretically benefit patients. ■■ However, two separate trials—one with orteronel and the other with enzalutamide— did not advance either of these concepts. ■■ A third trial showed promise for TAK-385, an investigational oral GnRH antagonist, as an alternative to injectable GnRH agonists.

from baseline vs 4% of the placebo group. Time to PSA progression was 6.5 months vs 1.8 months (P = .004). “This study suggests that the concept of maintenance should be further investigated,” Dr. Gillessen told listeners.

John Yarnold, MD

“Although orteronel is no longer being developed, the results show that pathway receptor inhibitors could have therapeutic potential in this setting and, as such, deserve further investigation,” wrote John Yarnold, MD, in the daily newspaper at the 2015 European Cancer Congress. He is Professor at the Institute of Cancer Research and Royal Marsden Hospital, NHS Foundation Trust, London, and was not involved in this study.

Enzalutamide Evaluated as Neoadjuvant Therapy

alone in chemotherapy-naive metastatic castration-resistant prostate cancer. At time of premature termination of the trial, 47 patients with metastatic castration-resistant prostate cancer who had

Radiographic progression-free survival was 8.5 months with orteronel vs 2.8 months with placebo (P = .02). In the orteronel group, 57% of patients had at least a 50% decline in PSA

Neoadjuvant therapy improves pathologic complete response rates and overall survival in other solid tumors, such as breast, lung, colorectal, and bladder can-

The hazard ratio for survival was when the findings of all four trials were pooled was 1.02 (P = .724). With zoledronic acid, the hazard ratio was 0.97 (P = .782), “suggesting no treatment effect in these men,” she said.

with metastatic disease, the potential benefit of zoledronic acid is small and is unlikely to have an impact. In metastatic disease, there is no evidence of a survival improvement with the addition of bisphosphonates; the investigators have not yet assessed their impact on other outcomes. n

Reference 1. Vale C, Rydzewska LH, Tierney JF, et al: What is the current evidence for adding docetaxel or bisphosphonates to androgen deprivation therapy in men with hormone sensitive prostate cancer? A systematic review and meta-analyses. 2015 European Cancer Congress. Abstract 20LBA. Presented September 27, 2015.

Concluding Thoughts “We think that the reported trials have given us substantial and reliable evidence that adding docetaxel in men with metastatic disease improves both overall survival and failure-free survival and should become the new standard of care for these men, where they are fit and able to take docetaxel,” Dr. Vale said. In the nonmetastatic setting, the evidence showed that adding docetaxel improves failure-free survival, “but we need more evidence to properly assess overall survival,” she added. For bisphosphonates, although there is a small survival benefit overall in men

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

continued on page 15

Key Prostate Cancer Trials in Hormone-Sensitive Disease ■■ A meta-analysis of key prostate cancer trials in hormone-sensitive disease shows that in metastatic disease, the addition of docetaxel to androgendeprivation therapy reduced deaths by 23% (P < .0001), translating into a 10% absolute improvement in survival at 4 years. Docetaxel also improved failure-free survival. ■■ In nonmetastatic disease, evidence was insufficient to show a survival benefit, but failure-free survival events were reduced by 30% (P < .0001) with docetaxel. ■■ Bisphosphonates provided a small benefit in terms of overall survival in metastatic disease but not in nonmetastatic disease.

ASCOPost.com | NOVEMBER 10, 2015

PAGE 15

European Cancer Congress Prostate Cancer Trials

EXPERT POINT OF VIEW

continued from page 14

cers. A randomized phase II study evaluated the role of neoadjuvant therapy with enzalutamide given 6 months before radical prostatectomy in 52 patients with intermediate- and high-risk, node-negative, localized prostate cancer. Patients were randomized to receive triple therapy with enzalutamide/leuprolide/dutasteride or enzalutamide alone, in an attempt to destroy micrometastasis that may persist after surgery for prostate cancer.

“W Richard Cathomas, MD

Richard Cathomas, MD, of Kantonsspital Graubünden, Switzerland, said, “With neoadjuvant enzalutamide monotherapy, we do not see many pathlogic complete responses despite high PSA responses. Outside of clinical trials, there is no role for neoadjuvant therapy. At this juncture, radiation and androgen-deprivation therapy are considered standard salvage therapy options.”

TAK-385, Oral GnRH Antagonist Bruce Montgomery, MD

“On the one hand, the glass is half full: We replicated results of the abiraterone study. On the other hand, the glass is half empty: We did not see pathologic complete responses in the 20%–25% range, which would justify going on to phase III trials in this population,” said lead author Bruce Montgomery, MD, of the University of Washington, Seattle. Pathologic complete response was achieved in two patients (9%) in the tripletherapy arm and none in the monotherapy arm. At prostatectomy, 26% of the tripletherapy arm and 4% of the monotherapy arm were found to be node-positive.

First results of a randomized phase II trial in patients with biologically confirmed prostate cancer who were candidates for first-line androgen-deprivation therapy were encouraging for TAK-385 vs leuprolide. TAK-385 is an oral gonadotropinreleasing hormone (GnRH) antagonist with the potential to improve cardiovascular safety and convenience compared with injectable GnRH androgen-deprivation therapy, which is widely used to treat locally advanced metastatic castration-resistant prostate cancer. “TAK-385 is potentially the first-inclass oral medication to achieve rapid reduction of testosterone. PSA respons-

This is the first demonstration in an oral formulation of a GnRH antagonist, and it is a nice demonstration of efficacy. —Neal Shore, MD

Dr. Montgomery said that the rates of node positivity in these patients requires further molecular study, and he is in favor of continued efforts to identify optimal neoadjuvant combination therapy with higher pathologic complete response rates to justify randomized phase III trials. “The short answer is that we did not ablate the androgen receptor signal,” Dr. Montgomery added. “We have hope that we have room to move to further suppress androgen receptor signaling with other combinations and novel agents,” he told listeners. Proffered Paper Session Co-Chair,

es were rapid and occurred during the first 4 weeks. Compliance was high, and efficacy was achieved. The interim analysis of the phase II trial revealed no new safety signals. TAK-385 is more convenient than an injectable GnRH agonist,” said lead author Neal Shore, MD, of Carolina Urologic Research Center, Myrtle Beach, South Carolina. Final results are awaited, and further phase II studies will guide future development, he said. “We did not get to a maximal tolerated dose in terms of toxicity, and the drug was well tolerated in young men and the elderly. We saw

e have made major progress by moving docetaxel forward, and now the largest pool of patients who become hormone resistant have received local therapy and then progressed. We have a lot of drugs for castration-resistant prostate cancer, and we are studying them earlier in the course of disease, but we have created a lot of confusion and don’t really know the best way to use them,” said formal discussant Bertrand Tombal, MD, PhD, Chairman of the Division of Urology and Associate Professor of Physiology at Université Catholique de Louvain, Brussels.

We have a lot of drugs for castration-resistant prostate cancer, and we are studying them earlier in the course of disease, but we have created a lot of confusion and don’t really know the best way to use them. —Bertrand Tombal, MD, PhD

“Regarding the orteronel study, results show maintenance therapy has the potential to delay progression. Unfortunately, the drug has been abandoned. The study shows that maintenance is feasible but not better. Clearly, we have to move forward,” said Dr. Tombal. Turning to the enzalutamide study, he said, “We don’t have the ability to eradicate micrometastasis. Three drugs appear to be better than one, but only in a subset of patients. Enzalutamide alone is weaker than the three-drug arm, but it may be enough for selected patients. It is worth investigating enzalutamide/dutasteride to act on the testosterone surge seen with GnRH agonists.” Dr. Tombal was encouraged by the TAK-385 results. “On paper, at the end of phase II, TAK-385 appears to be an extremely attractive way to overcome disadvantages of degarelix [Firmagon; another GnRH antagonist that has been studied]. The drug is promising.” Dr. Tombal continued: “We need to know long-term genitourinary tolerance and adherence. TAK-385 appears to solve most of the problems with depot GnRH agonists. The question is if antagonists had been developed first, would we have ever used an agonist?” n Disclosure: Dr. Tombal is a paid advisor or investigator for Amgen, Astellas, Bayer, Medivation, Ferring Pharmaceuticals, Janssen, and Sanofi-Aventis.

excellent testosterone suppression at 24 weeks. We await data in a radiation therapy cohort, and then we will decide on the dose for phase III,” he told listeners. The study randomized patients who were candidates for first-line androgendeprivation therapy to TAK-385 80 mg/d (n = 50), TAK-385 100 mg/d (n = 50), or leuprolide subcutaneously every 12 weeks (n = 25). No visceral or lung metastases were allowed. The primary endpoint of the trial was testosterone suppression. TAK385 achieved consistent testosterone suppression rapidly, with a reduction to castrate levels seen by day 7 that was sustained out to 6 months. No testosterone surge was observed with TAK385, whereas a surge in testosterone was observed with leuprolide over the first week, followed by eventual testos-

terone suppression. “This is the first demonstration in an oral formulation of a GnRH antagonist, and it is a nice demonstration of efficacy,” Dr. Shore told listeners. Drug-related adverse events were similar in all three arms. No treatment discontinuations were needed due to hepatic toxicity. n Disclosure: Dr. Gillessen is on the advisory board of Curevac, Dendreon, Janssen Cilag, Janssen Diagnostics, Novartis, Orion Pharma, Pfizer, Millennium Pharmaceuticals, Astellas, Sanofi Aventis, and Bayer (compensated), ProteoMediX and ESSA Pharmaceuticals Corp. (uncompensated); is on the speakers bureau of Amgen, Bayer, Janssen Cilag, and Sanofi Aventis (without honorarium); and has a patent application for a method for biomarker WO 2009138392 A1. Dr. Montgomery disclosed financial relationships continued on page 18

i am proof of extended survival in newly diagnosed GBM

Actor portrayal

Optuneâ&#x201E;˘ is intended as a treatment for adult patients (22 years of age or older) with histologically-confirmed glioblastoma multiforme (GBM). Optune with temozolomide is indicated for the treatment of adult patients with newly diagnosed, supratentorial glioblastoma following maximal debulking surgery, and completion of radiation therapy together with concomitant standard of care chemotherapy. Optune was studied in the EF-14 trial, a prospective, international, multicenter, open-label, randomized, controlled, phase 3 trial in newly diagnosed GBM patients comparing Optune + TMZ with TMZ alone (N=700). The prespecified interim analysis occurred when the first 315 patients completed 18 months of follow-up. The primary endpoint was PFS (ITT); OS (per protocol) was a powered secondary endpoint; 1- and 2-year survival rates, PFS6, QoL, and radiological response rates, along with safety, were also secondary endpoints. The final analysis included all patients randomized to EF-14 who had CRF information available at the database cutoff of December 3, 2014. This included 695 of the 700 patients randomized at that time: 466 patients in the Optune + TMZ arm and 229 patients in the TMZ-alone arm.1,2

Please see the following Summary of Important Safety Information for Optune and visit www.Optune.com/IFU for Optune Instructions for Use for complete information regarding the deviceâ&#x20AC;&#x2122;s indication, contraindications, warnings and precautions. CI, confidence interval; CRF, case report form; GBM, glioblastoma; HR, hazard ratio; ITT, intent to treat; OS, overall survival; PFS, progression-free survival; PFS6, progression-free survival at 6 months; QoL, quality of life; TMZ, temozolomide. References: 1. Optune Instructions for Use. Novocure 2015. 2. Novocure Data on File. OPT-103.

Optune + TMZ significantly extended median overall survival by 4.9 months and median PFS by 3.2 months 1 20.5 months median OS with Optune + TMZ1

Fraction Survival

Overall Survival (interim analysis)1 1.0

Median OS from randomization (months)1

0.9

Log-rank P-value1

0.0042

HR (95% CI)1

0.666 (0.495-0.898)

0.8

Optune + TMZ

0.7

20.5 MONTHS

0.6 0.5

20.5

Median OS from diagnosis (months)2

Median OS

24.4

15.6

19.4

Per Protocol population

0.4

TMZ alone

Optune + TMZ (n=196)

0.3

15.6

TMZ alone (n=84)

MONTHS

0.2 0.1 + Censored

0.0 0

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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European Cancer Congress 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.

Dermatologic Oncology

Survival Benefit in Metastatic Melanoma Grows Larger in COMBI-v Update By Caroline Helwick

ombined BRAF and MEK inhibition was superior to BRAF inhibition alone in unresectable metastatic melanoma, according to the updated survival analysis of the large randomized COMBI-v trial.1 These findings were reported at the 2015 European Cancer Congress recently held in Vienna, Austria.

agent vemurafenib treatment. The updated analysis showed the advantage of combination therapy increases over time. The difference in overall survival has grown from 9% at 1 year, to 10% at 18 months, and to 13% at the 2-year mark, she noted. COMBI-v is the second trial to show superiority for the combination

The longest benefit was in patients with an LDH less than or equal to the upper limit of normal, who had a 2-year overall survival rate of 66% and a median progression-free survival of 17.5 months. —Caroline Robert, MD

“Dabrafenib [Tafinlar] plus trametinib [Mekinist] has demonstrated superiority over BRAF inhibitor monotherapy now in two phase III trials, supporting its use as a standardof-care therapy in patients with BRAF V600–mutant melanoma,” said lead author Caroline Robert, MD, of Institut Gustave Roussy in Paris. COMBI-v, which enrolled 704 patients with advanced, treatment-naive BRAF-mutant melanoma, evaluated the BRAF inhibitor dabrafenib plus the MEK inhibitor trametinib and compared it with the single-agent treatment with the first-approved BRAF inhibitor vemurafenib (Zelboraf). Patients treated with dabrafenib plus trametinib had a 2-year overall survival of 51%, compared with 38% for single-

vs monotherapy in advanced melanoma. It was initiated at the same time as COMBI-d, which showed that overall survival at 2 years was 51%, compared with 42% for single-agent dabrafenib. These consistent results, Dr. Robert said in a press briefing, “confirm that the combination is superior to BRAFinhibitor monotherapy…. We can use this treatment as the standard of care for patients with BRAF-mutant melanoma.”

Prostate Cancer Trials

2015 European Cancer Congress. Abstract 2500. Presented September 26, 2015. 2. Montgomery B, Joshua A, Gleave M, et al: A randomized, open-label, phase 2 study of enzalutamide as neoadjuvant therapy for patients undergoing prostatectomy for localized prostate cancer. 2015 European Cancer Congress. Abstract 2501. Presented September 26, 2015. 3. Shore N, Bailen J, Pieczonka C, et al: TAK-385, an oral GnRH antagonist: Efficacy and safety results from a randomized phase 2 trial in prostate cancer patients. 2015 European Cancer Congress. Abstract 2502. Presented September 26, 2015.

continued from page 15 with Medivation, Janssen, Tokai, and ESSA Pharma. Dr. Shore has received financial support from Millennium Pharmaceuticals. Drs. Yarnold and Cathomas reported no potential conflicts of interest.

References 1. Cathomas R, Crabb S, Kenner H, et al: Orteronel maintenance therapy in patients with metastatic castration resistant prostate cancer and non-progressive disease after first-line docetaxel therapy: Results of a multicenter randomized double-blind placebocontrolled phase III trial (SAKK 08/11).

A Closer Look at COMBI-v In COMBI-v, 704 patients with unresectable, BRAF-mutant, stage III/IV melanoma were randomized to receive the combination of dabrafenib at 150 mg twice daily plus trametinib at 2 mg every day (n = 352) or a standard dose continued on page 19

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European Cancer Congress Metastatic Melanoma continued from page 18

of vemurafenib at 960 mg twice daily (n = 352). The trial had a primary endpoint of overall survival. Earlier reports showed a statistically significant improvement in survival at 18 months, from 50% with vemurafenib to 60% with the combination. In the current 2-year analysis, whose data cutoff was March 2015, the absolute difference increased to 13%. Median overall survival was 25.6 months with combination therapy and 18.0 months with single-agent vemurafenib, a 34% reduction in the hazard ratio (HR = 0.66; P < .001). Median progression-free survival was 12.6 months and 7.3 months, respectively (HR = 0.61; P < .001). The combination produced more responses (66% vs 53%; P = .0008), including complete responses in 17% of the combination group vs 10% with vemurafenib. Dr. Robert noted that 98 patients of the combination arm are censored and still on treatment, vs 33 of the vemurafenib arm, which leaves a lot of hope for the follow-up benefit of the combination.

Robust Benefit in Lower LDH Group Approximately two-thirds of the population had baseline levels of lactate dehydrogenase (LDH)equal to or less than the upper limit of normal. This subset fared particularly well on the combination. “The longest benefit was in patients with an LDH less than or equal to the upper limit of normal, who had a 2-year overall survival rate of 66% and a me-

dian progression-free survival of 17.5 months,” reported Dr. Robert. In the subgroup of patients with an LDH less than or equal to the upper limit of normal, the median overall survival was not yet reached with the combination and was 21.5 months with vemurafenib (HR = 0.56). Median progression-free survival was 17.5 vs 9.2 months with the combination and monotherapy, respectively, in the low LDH subset (HR = 0.55). In contrast, patients with an LDH above the upper limit of normal had a median overall survival of 10.6 months with the combination, vs 8.9 months with monotherapy (HR = 0.81), and a median progression-free survival of 5.5 months vs 4.0 months, respectively (HR = 0.70). These differences were a focus of discussion after her presentation. “Patients with high LDH, whatever treatment we use, remain a big medical need,” Dr. Robert indicated. “They derive a small benefit each time we evaluate a new, effective therapy. The benefit is always less in this population.” Dr. Robert maintained that high LDH indicates more than tumor burden, rather “something biologic underlies it,” but this remains unclear. “These are interesting hypotheses to explore.” In contrast, those with low LDH respond extremely well to targeted treatment, she added. “Targeted treatment is very convincing in this group,” she noted. The combination had a manageable adverse event profile, with no new safety signals with additional 6-month median follow-up. Virtually all patients in each arm experienced an adverse event, but those leading to treatment discon-

Dabrafenib/Trametinib in Advanced Melanoma ■■ Updated survival analysis of the COMBI-v study showed that BRAF plus MEK inhibition improved survival in advanced BRAF-mutated melanoma, vs single-agent trametinib therapy. ■■ Patients receiving the combination had a 2-year overall survival of 51%, compared with 38% with single-agent therapy. ■■ Patients with an LDH equal to or less than the upper limit of normal derived the most benefit, showing a 66% survival rate at 2 years.

tinuation were observed in 16% of the combination arm and in 14% of the vemurafenib arm. Dr. Robert added that the combination also proved superior in terms of quality of life at all time points, even at progression. n

Disclosure: Dr. Robert disclosed relevant relationships with Amgen, Bristol-Myers Squibb, GlaxoSmithKline, Merck, Novartis, and Roche. The study was supported by GlaxoSmithKline and Novartis.

Reference 1. Robert C, Karaszewska B, Schachter J, et al: Two year estimate of overall survival in COMBI-v, a randomized, open-label, phase III study comparing the combination of dabrafenib and trametinib vs vemurafenib as firstline therapy in patients with unresectable or metastatic BRAF V600E/K mutation-positive cutaneous melanoma. 2015 European Cancer Congress. Abstract 3301. Presented September 28, 2015.

EXPERT POINT OF VIEW

hristian Blank, MD, Group Leader of Immunology at the Netherlands Cancer Institute, Amsterdam, formally discussed the COMBI-v findings. He first credited targeted therapy and immunotherapy for almost tripling the chance of patients with metastatic melanoma living beyond 1 year; however, he noted that 80% of patients still do not achieve long-term survival. COMBI-v and COMBI-d have confirmed the advantage of inhibiting both BRAF and MEK, since monotherapy with a BRAF inhibitor alone affords little that chemotherapy cannot provide, he said. Although the data are still not mature enough “to draw high-end conclusions,” he said, “they suggest we can achieve real benefit beyond 1.5 years, and as expected, the combination of BRAF and MEK inhibition is superior to BRAF inhibition only…. We now have several trials supporting the superiority of the combination.”

What worries me is that only 47% of patients treated with the combination in COMBI-v got subsequent treatment. We should offer our patients at least two treatment options: one a targeted treatment and one an immunotherapy. —Christian Blank, MD

Regarding the LDH subgroup analysis, Dr. Blank found the results somewhat surprising and disappointing but maintained these patients should still be offered the targeted combination. “LDH is a marker for outcome upon targeted therapy, but to a lesser extent than with immunotherapy,” he observed. “What worries me is that only 47% of patients treated with the combination in COMBI-v got subsequent treatment,” he continued. “Now, with the array of treatment options, we should offer our patients at least two treatment options: one a targeted treatment and one an immunotherapy. When patients do not receive at least a second chance—that is a bad result.” n Disclosure: Dr. Blank reported financial relationships with Bristol-Myers Squibb, Merck, Novartis, Roche, GlaxoSmithKline, and Pfizer.

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

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European Cancer Congress Novel Agents

PD-1/PD-L1 Inhibitors Show Promise in Additional Tumor Types By Caroline Helwick

hile inhibitors of programmed cell death protein 1 (PD-1) or its ligand (PD-L1) are becoming established in melanoma, non–small cell lung cancer, and renal cell carcinoma, their efficacy is also being evaluated in numerous other tumor types, with promising results, according to studies presented at the 2015 European Cancer Congress in Vienna.

Urothelial Cancer “Atezolizumab [formerly known as MPDL3280A] has the potential to change the standard of care in metastatic urothelial carcinoma,” according to Jonathan E. Rosenberg, MD, of Memorial Sloan Kettering Cancer Center, New York, who led the global phase II IMvigor 210 trial of the anti–PD-L1 drug in this malignancy.1 Patients with advanced bladder cancer have limited survival time, and no single agent has proven effective in extending lives, he noted. IMvigor 210 included 311 patients, 78% of whom had received treatment for metastatic disease. The study enrolled “all comers,” but their PD-L1 expression was evaluated by immunohistochemistry, showing that two-thirds of patients had some degree of ligand expression. “IMvigor 210 met its co–primary endpoints in [immune cell (IC) status] 2/3 (≥ 5% staining), IC1/2/3 (≥ 1%), and all-comer subgroups, demonstrating significant improvement over a historical 10% objective response rate,” Dr. Rosenberg announced. “Durable responses were seen in a heavily pretreated population with metastatic urothelial carcinoma that progressed on platinum-based chemotherapy. Median duration of response was not reached in any [immune cell] or prognostic subgroup, including patients with liver metastases at baseline,” he said.

High PD-L1 status was associated with higher objective response rates. The highest, 27%, was seen in the IC2/3 subgroup (8% complete responses), 60% of whom had some decrease in target lesion size. Responses were observed in 18% of the IC1/2/3 group (5% complete responses) and 15% in all comers (4% complete responses). Altogether, 43% of patients with tumor assessments had notable tumor shrinkage.

to be associated with [immunohistochemistry] positivity on immune cells. Unfortunately, high positivity accounts for only one-third of the patients,” he pointed out. “But we have encouraging data,” he said, not only with [atezolizumab] but also with pembrolizumab [Keytruda] and ramucirumab [Cyramza], in heavily pretreated patients. At the 2015 European Cancer Congress, other investigators reported a 24% response rate to ramucirumab plus

Atezolizumab [formerly known as MPDL3280A] has the potential to change the standard of care in metastatic urothelial carcinoma. —Jonathan E. Rosenberg, MD

While the data remain immature at a median follow-up of 7 months, median overall survival was 7.9 months in all comers and was not reached in the IC2/3 subgroup. Median progression-free survival was 2.1 months in all groups. “Atezolizumab was well tolerated, with no treatment-related deaths. The adverse event profile was consistent across IC2/3, IC1/2/3, and all-comer populations,” he added. Grade 3/4 toxicities were observed in 15% of patients, and 4% had a grade 3/4 immune-related event. No treatment-related renal toxicity was seen. Ronald de Wit, MD, PhD, of Erasmus Medical Center, Rotterdam, the Netherlands, discussed the IMvigor 210 study. He noted that the initial results “show promising response rates and a survival benefit that seems promising vs historical controls.” “We have to realize, though, that the high response rate to atezolizumab seems

New Data on Immune Checkpoint Inhibitors ■■ Atezolimumab produced responses in 27% of patients with heavily pretreated, advanced urothelial cancer who had high expression of the PD-L1 ligand. After a median follow-up of 7 months, median overall survival was not reached in this group. ■■ Pembrolizumab produced responses in 71% of patients with advanced Merkel cell carcinoma. ■■ Pembrolizumab produced responses in 20% of heavily pretreated advanced anal cancer; at 12 months, 20% of patients remained progression-free.

docetaxel and a median overall survival of 10.4 months.2 At the 2015 ASCO Annual Meeting, Plimack et al reported a 28% response rate and 13-month median overall survival with pembrolizumab.3 “These responses may be quite durable. There are promising overall survival data, and we have seen responses in patients with visceral metastases. So the data are promising, but we have to wait for the phase III results in an ongoing trial,” Dr. de Wit concluded.

Paul Nghiem, MD, PhD

patients have progressed and gone off treatment.” Many patients, he added, “have demonstrated profound shrinkage of tumor that has not rebounded.”

Anal Cancer Pembrolizumab also demonstrated “promising, durable antitumor activity” in a heavily pretreated population of patients with PD-L1–positive squamous cell carcinoma of the anal canal, reported Patrick A. Ott, MD, PhD, of Dana-Farber Cancer Institute, Boston.5 In the phase Ib KEYNOTE-028 study, 25 pretreated patients received pembrolizumab. Responses to the anti– PD-1 agent were observed in 20% of patients (all partial), while 44% achieved stable disease. Median response duration has not been reached, Dr. Ott reported.

Merkel Cell Carcinoma Advanced Merkel cell carcinoma is typically a rapidly lethal tumor, associated with a median overall survival of less than 10 months. Anti–PD-1 agents may change the dire prognosis, based on the high response rates and durability of response observed in an open-label phase II study reported at the meeting by Paul Nghiem, MD, PhD, of the University of Washington in Seattle.4 The study included 24 patients who received pembrolizumab at 2 mg/kg for up to 2 years. Of the 14 patients with at least one post-treatment scan, 10 patients (71%) responded, 2 with complete responses. One patient had stable disease, and three had disease progression on treatment. “Responses were rapid and appear more durable than we see with chemotherapy,” Dr. Nghiem said. “Pembrolizumab looks to be very favorable in terms of durability of response. With chemotherapy, at 90 days, half of our

Patrick A. Ott, MD, PhD

Median progression-free survival was 3.0 months. At 6 months, 31.6% were free of progression, and at 12 months, almost 20% still had not shown disease progression. n

Disclosures: Dr. Rosenberg has received consulting fees from Bristol-Myers Squibb, Boehringer Ingelheim, Janssen, Oncogenex, Eli Lilly, Merck, and Agensys and owns stock in Merck. Dr. de Wit disclosed relationships with Merck and Eli Lilly. Dr. Nghiem reported no potential conflicts of interest. Dr. Ott is a consultant to Amgen and Bristol-Myers Squibb and has received research funding from ARMO Biosciences, Bristol-Myers Squibb, and Merck.

References 1. Rosenberg J, Petrylak D, Abidoye O, et al: Atezolizumab in patients (pts) with locally-advanced or metastatic urothelial carcinoma (mUC): Results from a pivotal continued on page 21

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FDA Update

FDA Approves Ipilimumab in Adjuvant Treatment of Stage III Melanoma

n October 28, 2015, the U.S. Food and Drug Administration (FDA) approved the monoclonal antibody ipilimumab (Yervoy) for the adjuvant treatment of patients with cutaneous melanoma with pathologic involvement of regional lymph nodes of more than 1 mm who have undergone complete resection, including total lymphadenectomy. The CTLA-4 antibody–blocking drug, ipilimumab, was approved previously for treatment of unresectable or metastatic melanoma. The recent approval was based on improvement in recurrence-free survival in a randomized, double-blind, placebo-controlled trial in 951 patients with resected stage IIIA (lymph node

in the ipilimumab (n = 475) and placebo (n = 476) arms, respectively (hazard ratio [HR] = 0.75, 95% confidence interval [CI] = 0.64–0.90, P < .002). Safety data were evaluated in 945 patients (median age = 51 years, 62% male), who received ipilimumab at 10 mg/kg

(n = 471) or placebo (n = 474) given as an intravenous infusion for four doses every 3 weeks, followed by 10 mg/ kg every 12 weeks beginning at week 24, up to a maximum of 3 years. Ipilimumab-treated patients received a median of four doses, and 36% of patients received ipi-

limumab for longer than 6 months. Ipilimumab was discontinued for adverse reactions in 52% of patients. n Reference 1. Eggermont AM, et al: Lancet Oncol 16:522-530, 2015.

> 1 mm), IIIB, and IIIC (with no intransit metastases) histologically confirmed cutaneous melanoma.1 The primary efficacy endpoint was recurrence-free survival. The median recurrence-free survival was 26 and 17 months

PD-1/PD-L1 Inhibitors continued from page 20

multicenter phase II study (IMvigor 210). 2015 European Cancer Congress. Abstract 21LBA. Presented September 27, 2015. 2. Petrylak DP, Tagawa T, Kohl M, et al: Three-arm phase II randomized trial of docetaxel monotherapy or combined with ramucirumab or icrucumab in second-line locally advanced or metastatic urothelial carcinoma. 2015 European Cancer Congress. Abstract 2508. Presented September 27, 2015. 3. Plimack ER, Bellmunt J, Gupta S, et al: Pembrolizumab for advanced urothelial cancer: Updated results and biomarker analysis from KEYNOTE-012. 2015 ASCO Annual Meeting. Abstract 4502. Presented June 1, 2015. 4. Nghiem P, Bhatia S, Daud A, et al: Activity of PD-1 blockade with pembrolizumab as first systemic therapy in patients with advanced Merkel cell carcinoma. 2015 European Cancer Congress. Abstract 22LBA. Presented September 27, 2015. 5. Ott PA, Piha-Paul SA, Munster P, et al: Pembrolizumab (MK-3475) for PD-L1positive squamous cell carcinoma (SCC) of the anal canal: Preliminary safety and efficacy results from KEYNOTE-028. 2015 European Cancer Congress. Abstract 500. Presented September 27, 2015.

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European Cancer Congress Breast Cancer

Primary vs Metastatic Breast Cancer: The Genetic Landscape Varies By Caroline Helwick

reast tumors that recur appear to have a different genetic profile than those that do not, and they often demonstrate targetable mutations, according to the largest study of genetic sequencing of breast cancer tissue to date.1 This finding was presented at the 2015 European Cancer Congress.

The investigators found 11 genes that were significantly enriched in the relapsed cohort compared with the primary tumor cohort. At metastasis, the most heavily enriched genes were TP53 and ARID1A (P < .001). In the estrogen receptor–signaling pathway, ESR1 and FOXA1, but not GATA3, were enriched.

We identified stark differences between the ‘average’ primary breast cancer and relapsed cancers. This probably reflects a combination of predisposition to relapse and differences in the mutations acquired during the relapse and metastasis phase. —Lucy Yates, MD

EXPERT POINT OF VIEW

n discussing the findings of this study on genetic sequencing of breast cancer tissue, Fabrice André, MD, PhD, of the Gustave Roussy Institute, in Villejuif, France, questioned whether all the genes that were found to be enriched in the relapsed samples were driving the relapse and whether any could be considered markers of recurrence. Dr. André also indicated that research from his own laboratory does not substantiate the findings. Fabrice André, MD, PhD Although Dr. Yates’ study identified 11 genes that were highly enriched in the relapsed tissue samples, his examination of 183 samples in SAFIR 01/02 found only 1 of these genes (ESR1) to be highly enriched. Dr. André also wondered whether the late mutations that were identified are clinically relevant and whether they may explain the development of resistance to therapy, as has been seen in some other tumor types. He also questioned the mandate to re-biopsy, since “liquid biopsy” with circulating tumor cells and cell-free DNA are emerging as possible—and easier—alternatives.

Additional Comments “We identified stark differences between the ‘average’ primary breast cancer and relapsed cancers,” said Lucy Yates, MD, a clinical research oncologist at the Wellcome Trust Sanger Institute in Cambridge, United Kingdom. “This probably reflects a combination of predisposition to relapse and differences in the mutations acquired during the relapse and metastasis phase.” Thus, patients at high risk for relapse might be identified upon diagnosis and targeted for more aggressive interventions aimed at preventing these relapses, she added.

Study Details This study compared the genetic profiles of breast cancer from 839 tissue samples taken from women upon diagnosis with 161 samples obtained from recurrent or metastatic tumors. According to the investigators, it is the largest and most comprehensive to date in terms of the number of samples from relapsed tumors and the breadth of the genetic sequencing, which examined 365 genes involved in cancer-related pathways. “For each of the 365 genes, we compared the proportion of cancers in each cohort that contained a driver mutation in that gene,” explained Dr. Yates. Multiple samples were available for 66 patients, which allowed the researchers to trace the evolution of mutations.

In the PI3K-AKT pathway, AKT1 and PIK3RI were enriched—but all to a lesser degree than TP53 and ARID1A. “We have found that some of the genetic mutations that drive breast cancers that relapse are relatively uncommon amongst cancers that do not relapse at the point of primary diagnosis,” Dr. Yates said. A wide range of rare or unexpected cancer genes were also implicated at relapse, and immunohistochemical subtype–specific gene patterns were also altered. “We found even greater inter- and intratumoral heterogeneity than anticipated,” Dr. Yates offered. “The catalogue of likely cancer genes in breast cancer may be even greater than previously anticipated.” In primary tumors, TP53 dominated in the triple-negative cancers, whereas PIK3CA dominated in estro-

Also commenting on the study was Peter Naredi, MD, PhD, Professor of Surgery at Sahlgrenska University Hospital in Gothenburg, Sweden. Dr. Naredi, who served as the European Cancer Organization scientific co-chair of the 2015 European Cancer Congress, stated that the study provides important information for “the era of precision medicine.” “This study underlines the fact that we should consider a recurrence of a cancer as a new event and Peter Naredi, MD, PhD carefully select the right treatment for the recurrent tumor as opposed to just relying on information from the first occurrence,” Dr. Naredi suggested. n Disclosure: Dr. André has received research grants from Novartis, AstraZeneca, Lilly, Eisai, and has received honorarium from Celgene. Dr. Naredi reported no potential conflicts of interest.

gen receptor–positive cancers. “We believe that the differences we have seen reflect genetic differences that can predispose a cancer to return, combined with mutations acquired throughout the period from first diagnosis to the subsequent relapse,” Dr.

Genetic Sequencing of Breast Cancer ■■ In the largest study of genetic sequencing of breast cancer to date, researchers identified 11 genes that were enriched in the relapsed samples but were not present in the primary tissue sample. ■■ At metastasis, the most heavily enriched genes were TP53 and ARID1A (P < .001). ■■ The finding suggests that patients at high risk for relapse may be identified upon diagnosis and targeted for more aggressive interventions aimed at preventing these relapses.

Yates said. Since many cancers acquire new mutations after the primary diagnosis, it is important to resample the tumor over time, she added. “The data reveal extreme heterogeneity and indicate that genomic analysis of primary, relapse, and matched normal samples needs to be performed on a large scale. We need to bank more tissue!” she concluded. n

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

Reference 1. Yates L, Knappskog S, Martincorena I, et al: The driver landscape of breast cancer metastasis and relapse. 2015 European Cancer Congress. Abstract 1804. Presented September 26, 2015.

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European Cancer Congress Thoracic Oncology

Combined EGFR and VEGF Inhibition Ameliorates the Impact of the EGFR T790M Mutation in NSCLC By Caroline Helwick

reatment with erlotinib and bevacizumab (Avastin) may help overcome the poor prognosis associated with T790M mutations present at diagnosis in advanced non–small cell lung cancer (NSCLC), according to the results of the phase II BELIEF trial.1

not very active but with the addition of an antiangiogenic agent, tumors seem to shrink. BELIEF is exploring whether firstline erlotinib (150 mg daily) plus bevacizumab (15 mg/kg on day 1) improves progression-free survival in 109

Our target was ambitious. We wanted to reach a 12-month progression-free survival rate of 63% in the subpopulation of T790M mutation–positive patients at diagnosis. We reached our endpoint. —Rolf A. Stahel, MD

At the 2015 European Cancer Congress, Rolf A. Stahel, MD, of University Hospital Zurich in Switzerland, presented the findings of the phase II open-label single-arm BELIEF trial, which was conducted by the Spanish Lung Cancer Group and the European Thoracic Oncology Platform. The study evaluated combined inhibition of the epidermal growth factor receptor (EGFR) and the vascular endothelial growth factor (VEGF) in patients with advanced NSCLC with activating EGFR mutations, with and without T790M mutations at diagnosis.

Pretreatment T790M Mutations The T790M EGFR gatekeeper mutation has been described as the main mechanism of acquired resistance to EGFR tyrosine kinase inhibitors. Pretreatment T790M mutations can be identified before exposure to an EGFR tyrosine kinase inhibitor and is related to shorter progression-free survival in patients receiving EGFR tyrosine kinase inhibitors, Dr. Stahel explained. In preclinical models of such tumors, he said, gefitinib and erlotinib are

patients with EGFR-mutant advanced NSCLC. Two cohorts are being evaluated: those with the T790M mutation at diagnosis and those without. Pretreatment T790M was centrally determined by a sensitive method based on laser microdissection and peptide nucleic acid–clamping polymerase chain reaction. Of the 109 patients, 37 were determined to be T790M-positive, and 72 were found to be T790Mnegative. “The presence of the T790M mutation at diagnosis was documented in 34% of patients who also had classical EGFR mutations, using our sensitive assay,” said Dr. Stahel. This percentage is much higher than what is usually detected with conventional DNA sequencing (1%–8%). The groups were similar in terms of baseline characteristics. The T790M-positive cohort was followed for a median of 16 months, whereas the T790M-negative group was followed for 18.6 months. The median time of treatment was 13.1 and 8.7 months, respectively. Approximately half the mutation-positive group dis-

T790M Mutations in Advanced NSCLC ■■ In the phase II BELIEF trial, one-third of patients with advanced NSCLC had T790M mutations at presentation. ■■ After treatment with erlotinib plus bevacizumab, among the T790Mpositive cohort, median progression-free survival was 16 months, and 1-year progression-free survival rate was 72.4%. ■■ For all 109 patients, median progression-free survival was 13.8 months, and 1-year progression-free survival was 56%, whereas for the T790M-negative cohort, these numbers were 10.5 months and 49%, respectively.

continued treatment due to progressive disease, whereas 73% of the negative group did so.

‘Ambitious’ Target Was Met “Our target was ambitious,” Dr. Stahel indicated. “We wanted to reach a 12-month progression-free survival rate of 63% in the subpopulation of T790M mutation-positive patients at diagnosis. We reached our endpoint.” Among the T790M-positive cohort, median progression-free survival was 16

months, and 1-year progression-free survival rate was 72.4%. For all 109 patients, median progression-free survival was 13.8 months, and 1-year progressionfree survival was 56%. For the T790Mnegative cohort, these numbers were 10.5 months and 49%, respectively. “With the exception of just one patient, all patients with measurable disease had some documented tumor shrinkage,” he reported. Response rates were 70.3% for the continued on page 24

EXPERT POINT OF VIEW

artin Reck, MD, PhD, Head of the Department of Thoracic Oncology at the Lung Clinic Grosshansdorf in Germany, discussed the study at the Presidential Session, calling it “very important work.” This study shows that, with more sensitive assays, T790M mutations are much more frequent than previously believed. “Even in treatment-naive patients, we see incidence rates up to 38%,” said Dr. Reck. “So it’s clear that the difference is related to the testing method. The deeper you dive, the more you find.”

Even in treatment-naive patients, we see incidence rates up to 38%. So it’s clear that the difference is related to the testing method. The deeper you dive, the more you find. —Martin Reck, MD, PhD

“The clinical impact of these high-sensitivity results needs to be determined; however, we have very good preclinical data showing that VEGF inhibition may delay the resistance toward EGFR tyrosine kinase inhibitors, related to the T790M mutation,” he added. “The response rates [to erlotinib plus bevacizumab] are on the upper boundary that we have seen in EGFR-mutated NSCLC,” he noted. “The progression-free survival is nearly 14 months, with an interesting signal of 16 months in patients determined to have T790M-positive tumors.” “Will the findings change clinical practice? Not directly,” he maintained Dr. Reck. “We have introduced oral compounds to the patients’ convenience, and this convenience would be afflicted by giving bevacizumab [intravenously] every 3 weeks. We also still see some adverse events. And this was a nonrandomized phase II trial.” Dr. Reck would be interested in seeing how these benefits compare with those of a single-agent third-generation EGFR tyrosine kinase inhibitor, such as AZD9291, and in knowing the molecular patterns of resistance after treatment with erlotinib/bevacizumab. The phase III RELAY trial could provide validation for combined EGFR and VEGF inhibition. It is comparing erlotinib plus ramucirumab (Cyramza) vs erlotinib alone in patients with EGFR-mutated NSCLC. n Disclosure: Dr. Reck has been a member of advisory boards for Hoffmann-La Roche, Lilly, Bristol-Myers Squibb, AstraZeneca, Merck, Boehringer-Ingelheim, Pfizer, and Novartis and has received honoraria from all but Novartis.

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European Cancer Congress EGFR and VEGF Inhibition continued from page 23

T790M-positive patients (8.1% complete responses) and 79.2% in the T790M-negative cohort (5.6% complete responses). Median duration of response for the whole population was 14.8 months; it was not reached for the mutation-positive cohort and was 12 months in the mutation-negative group. The T790M-positive patients treated with erlotinib and bevacizumab had longer progression-free survival than the mutation-negative cohort, in virtually all subgroups examined, he said. Dr. Stahel put the findings into context with previous studies, highlighting the potential benefit of combining an EGFR tyrosine kinase inhibitor with an antiangiogenic agent in treating T790M-positive patients. In the EURTAC trial of erlotinib alone, he noted, patients with T790M mutations

at presentation had a median progression-free survival of 9.7 months, compared with 16.0 months in the current study.2 n Disclosure: Dr. Stahel reported financial relationships with Abbott, Astellas, AstraZeneca, Bayer, Bristol-Myers Squibb, Boehringer Ingelheim, Clovis, Eli Lilly, Genentech, Merck, Novartis, Pfizer, Puma Biotechnology, and Roche.

References 1. Stahel RA, Dafni U, Gautschi O, et al: A phase II trial of erlotinib and bevacizu mab in patients with advanced non-smallcell lung cancer with activating epidermal growth factor receptor mutations with and without T790M mutation. The Spanish Lung Cancer Group and the European Thoracic Oncology Platform BELIEF trial.

2015 European Cancer Congress. Abstract 3BA. Presented September 28, 2015. 2. Costa C, Molina MA, Drozdowskyj, A et al: The impact of EGFR T790M mutations and BIM mRNA expression on outcome in patients with EGFR-mutant NSCLC treated with erlotinib or chemotherapy in the randomized phase III EURTAC trial. Clin Cancer Res 20:2001-2010, 2014.

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

Rights & Permissions e-mail: Permissions@harborsidepress.com

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

Editorial Office Harborside Press 37 Main Street Cold Spring Harbor, NY 11724 Phone: 631.692.0800 Fax: 631.692.0805 ASCOPost.com HarborsidePress.com

ASCOPost.com | NOVEMBER 10, 2015

PAGE 25

Announcements

Sandra L. Wong, MD, MS, Named Chair of Surgery at Geisel School of Medicine and Dartmouth-Hitchcock

andra L. Wong, MD, MS, the William W. Coon Professor of Surgical Oncology and Associate Chair of Clinical Affairs at the University of Michigan Health System, has been named Chair

of Surgery at Dartmouth-Hitchcock and the Geisel School of Medicine at Dartmouth and Senior Vice President of the Surgical Service Line at Dartmouth-Hitchcock. She joined the Dart-

mouth faculty officially on October 26. Dr. Wong will oversee 13 specialty sections within the Department of Surgery at Dartmouth-Hitchcock Medical Center. Dr. Wong is a nationally recognized

Sandra L. Wong, MD, MS

IN ONCOLOGY, HAVE WE

MAXIMIZED THE POTENTIAL OF TARGETING THE MAPK PATHWAY?

Research has found that abnormal MAPK signaling may lead to increased or uncontrolled cell proliferation and resistance to apoptosis. Studies have shown that the MAPK pathway plays an important role in some cancers.1 Based on these findings, Genentech is investigating further ways to target the MAPK pathway.

Learn more at TargetMAPK.com.

REFERENCE: 1. Santarpia L, Lippman SM, El-Naggar AK. Targeting the MAPK-RAS-RAF signaling pathway in cancer therapy. Expert Opin Ther Targets. 2012;16:103-119.

authority in the management of softtissue sarcomas, melanoma, Merkel cell carcinoma, and gastrointestinal cancers. Reflecting her skills and commitment as an educator, she received medical student teaching awards (2009, 2011) and the resident teaching award (2011) from the University of Michigan. With current funding from the Agency for Healthcare Research and Quality and the American Cancer Society, her current work is examining variation in treatment intensity for poor-prognosis cancers. She also studies prognostic modeling for melanoma, socioeconomic disparities, and factors related to the quality of cancer care. Dr. Wong has expertise in the development and implementation of clinical practice guidelines and advises on health policy and technology evaluation nationally. Dr. Wong serves on the editorial boards of Annals of Surgical Oncology and Journal of Surgical Oncology and is an Associate Editor for the Journal of Oncology Practice. She holds or has held leadership positions in several national professional societies, including ASCO, the Association for Academic Surgery, and the Society of Surgical Oncology. Dr. Wong served as Associate Chief of Staff for the University of Michigan Health System. She received her medical degree from Northwestern University. Dr. Wong completed her general surgery residency at the University of Louisville and a clinical fellowship in surgical oncology at Memorial Sloan Kettering Cancer Center, where she served as the Chief Administrative Fellow. n

Send Us Your NEWS Write to editor@ASCOPost.com. All submissions will be considered for publication

The ASCO Post | NOVEMBER 10, 2015

PAGE 26

European Cancer Congress Thoracic Oncology

Antibody-Drug Conjugate Makes Strong Showing in Small Cell Lung Cancer By Caroline Helwick

he antibody-drug conjugate rovalpituzumab tesirine has shown strong clinical activity as second- and third-line treatment for small cell lung cancer in a phase I/Ib multicenter study,1 especially in the subset with high expression of the delta-like protein 3 (DLL3), which the drug targets. This finding also may point to the discovery of the first predictive biomarker associated with drug efficacy in this malignancy. “[Rovalpituzumab tesirine] has manageable toxicity and demonstrates substantial single-agent antitumor activity and durability in patients with relapsed or refractory DLL3-positive small cell lung cancer (SCLC),” reported M. Catherine Pietanza, MD, of Memorial Sloan Kettering Cancer Center, New York. “The response rate is similar whether patients receive the drug second or third line.” Dr. Pietanza reported these emerging results from this first-in-human phase I trial of rovalpituzumab tesirine in recurrent SCLC at the 2015 European Cancer Congress. Rovalpituzumab tesirine consists of a humanized monoclonal antibody, a dipeptide linker, and a pyrrolobenzodiazepine dimer toxin. It targets DLL3, a Notch ligand that is overexpressed in SCLC tumor–initiating cells but not in normal tissue. In DLL3-expressing patient-derived xenograft tumor models of

[Rovalpituzumab tesirine] has manageable toxicity and demonstrates substantial single-agent antitumor activity and durability in patients with relapsed or refractory DLL3-positive small cell lung cancer. —M. Catherine Pietanza, MD

SCLC, rovalpituzumab tesirine induced tumor regression and prolonged the time to progression, outperforming cisplatin/ etoposide, investigators of a related preclinical publication noted.2 The 73 previously treated patients with progressive SCLC received rovalpituzumab tesirine as a single agent once every 3 or 6 weeks, in dose-escalating cohorts (0.05–0.8 mg/kg). Of these patients, 47% had primary refractory or resistant disease, and 45% had progressed after second-line therapy. Dose-limiting thrombocytopenia and/or serosal effusions were observed at 0.8 and 0.4 mg/kg once every 3 weeks, respectively; therefore, these schedules were not pursued further. Pharmacokinetic data revealed a longer-than-expected half-life, encouraging a schedule of once every 6 weeks. The phase Ib expansion cohorts

EXPERT POINT OF VIEW

“T

hese are interesting results,” said Martin Reck, MD, PhD, Head of the Department of Thoracic Oncology at the Lung Clinic Grosshansdorf in Germany, who discussed the study at the Presidential Session of the 2015 European Cancer Congress. Responses to rovalpituzumab tesirine, he noted, “are superior to topotecan,” the only approved agent in the second-line setting (with none approved in the third-line setting). “So far, the median duration of response and overall survival seem to be quite encouraging. If we compare data to our conventional data for second-line chemotherapy, which is with topotecan, these data are quite attractive.” Dr. Reck added: “But more clinical data are needed,” including information on the optimal setting for using this drug and data regarding its relative benefit compared with emerging immunotherapies. “Are we seeing a new chapter in [small cell lung cancer]?” he asked. “Perhaps this will be the first targeted therapy in this disease.” n Disclosure: Dr. Reck reported no potential conflicts of interest.

received doses of 0.2 mg/kg once every 3 weeks or 0.3 mg/kg once every 6 weeks. A DLL3 antibody was developed and utilized to assess antigen expression in archived tumor specimens. DLL3-high tumors were defined by immunohistochemistry membrane– associated H scores ≥ 180; within the study, 70% of the patients were DLL3high, 11% had intermediate expression of DLL3, and 19% had low expression of DLL3.

Strong Activity in DLL3-Positive Patients Among all evaluable patients in the dose-expansion cohorts, the objective response rate was 23%, and the clinical benefit rate was 68%. All responses were observed among DLL3-high patients; patients with stable disease had variable expression of DLL3. Among the DLL3-high population, the response rate rose sharply to 44%, and 78% of patients achieved a clinical benefit. In this group, response rates were similar in the second- and thirdline settings, and they exceeded 20%, even among patients who were refractory or resistant to their first line of treatment. “Responses were durable,” Dr.

ietanza noted. At the 0.3 mg/kg P schedule once every 6 weeks, there were seven responders, six of whom remained progression-free at a postresponse follow-up of a mean of 189 days or longer. The mean overall survival for this cohort was 236 days, with some patients surviving up to 1 year to date. “For these reasons, 0.3 mg/kg once every 6 weeks is the recommended, phase II dose,” she added.

Unique Toxicities “Safety was manageable,” reported Dr. Pietanza, although she described a “unique” toxicity profile for rovalpituzumab tesirine. The profile primarily includes serosal effusions (pleural, pericardial, peritoneal) and rash/photosensitivity, in addition to fatigue and thrombocytopenia. “Effusions range from asymptomatic to those requiring drainage, and sometimes are recurrent,” she said. “Photosensitivity reactions occur in sun-exposed skin and may be most problematic during summer months.” n

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

References 1. Pietanza MC, Spigel D, Bauer TM, et al: Safety, activity, and response durability assessment of single agent rovalpituzumab tesirine, a delta-like protein 3 (DLL3)targeted antibody drug conjugate, in small cell lung cancer. 2015 European Cancer Congress. Abstract 7LBA. Presented September 28, 2015. 2. Saunders LR, Bankovich AJ, Anderson WG, et al: A DLL3-targeted antibodydrug conjugate eradicated high-grade pulmonary neuroendocrine tumor-initiating cells in vivo. Sci Transl Med 7:302ra136, 2015.

Rovalpituzumab Tesirine in Small Cell Lung Cancer ■■ Rovalpituzumab tesirine showed strong single-agent clinical activity in patients with small cell lung cancer as second- or third-line treatment. ■■ In patients who were high expressers of the DLL3 protein, which the drug targets, the response rate was 44%, and the clinical benefit rate was 78%. ■■ Responses were durable, with some patients alive without progression at 1 year.

November is Lung Cancer Awareness Month

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Breast Cancer Symposium Breast Cancer

Functional Subtyping With 80-Gene Assay Identifies Distinct Triple-Positive Subtypes in Breast Cancer Patients By Chase Doyle

olecular categorization of tumors with immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) has become a critical component in the diagnosis and treatment of breast cancer, improving outcomes by assigning the most appropriate therapy to specific tumor pathways. According to a study presented at the 2015 Breast Cancer Symposium, a new functional molecular subtyping reclassifies approximately 23% of tumors compared to conventional immunostaining, with potential therapeutic and prognostic implications.1

ever pertuzumab [Perjeta] overcame resistance to chemotherapy/trastuzu mab in a substantial portion of the triple-positive/80-gene luminal subtype.”

Neoadjuvant Breast Symphony Trial As Dr. Beitsch noted, classification into molecular subtypes is important for the selection of therapy for patients with breast cancer, as previous analyses have demonstrated that these subtypes have distinct clinical outcomes. The primary aim of the Neoadjuvant Breast Symphony Trial (NBRST)

The 80-gene subtyping divided triple-positive [HER2-positive/hormone receptor–positive] cancers into two groups of almost equal size: one being luminal-driven and one being HER2/neu-driven. —Peter D. Beitsch, MD

“BluePrint 80-gene subtyping yielded significantly better correlation with both neoadjuvant chemotherapy responsiveness in the HER2-positive group and basal group, as well as resistance—putting more people into the luminal group, which is fairly resistant to chemotherapy,” said Peter D. Beitsch, MD, Director of the Dallas Breast Center. “The 80-gene subtyping divided triple-positive [HER2-positive/hormone receptor–positive] cancers into two groups of almost equal size: one being luminal-driven and one being HER2/ neu-driven.” He added, “This triple-positive/80gene luminal subtype is relatively resistant to neoadjuvant chemotherapy with trastuzumab [Herceptin] alone, how-

was to compare a multigene classifier to conventional IHC/FISH subtyping to predict chemosensitivity as defined by pathologic complete response. Researchers enrolled 1.000 patients from 62 U.S. institutions and reported on 889 who have completed all therapy. The median age of the cohort was 52. Over 90% of the patients had stage II or III disease. Two-thirds of patients had hormone receptor–positive breast cancer, 23% had triple-negative disease, and 29% were HER2-positive. The 80-gene assay split tumors into luminal-type, HER2/neu-type, and basal-type. The 70-gene assay further divided luminal type into luminal A and luminal B. All of the assays were completed on a core biopsy upfront.

Table 1: Treatment in the Neoadjuvant Breast Symphony Trial (N = 889) Treatment (at discretion of physician)

Number of Patients

Neoadjuvant chemotherapy

575 (65%)

Neoadjuvant chemotherapy with trastuzumab

175 (20%)

Neoadjuvant chemotherapy with trastuzumab and pertuzumab

89 (10%)

Neoadjuvant endocrine therapy

44 (5%)

Neoadjuvant chemotherapy and neoadjuvant endocrine therapy

6 (< 1%)

Courtesy of Whitworth et al.1

EXPERT POINT OF VIEW

iscussant of the Neoadjuvant Breast Symphony Trial data, William J. Gradishar, MD, FASCO, Betsy Bramsen Professor of Breast Oncology at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University in Chicago, underscored the importance of identifying patients in a more precise and refined way in order to apply the most appropriate therapy to a given patient. William J. Gradishar, MD, FASCO “Using this particular molecular platform may indeed allow us to better categorize patients over what [immunohistochemistry] alone is able to do. By extension, the therapies that we choose, particularly in individuals where there may be some underlying resistance, may be even more potent,” said Dr. Gradishar. “In the end,” he concluded, “the only way that we’re going to be able to definitively address this issue is by rigorously looking at this in a prospective manner.” n Disclosure: Dr. Gradishar reported no potential conflicts of interest.

“Patients received neoadjuvant chemotherapy or systemic endocrine therapy based on [National Comprehensive Cancer Network] guidelines. Patients then came to surgery. Pathology was reported as either complete or partial response to neoadjuvant chemotherapy . “A few patients received neoadjuvant endocrine therapy, but that was only 5% of the whole group,” he observed, “but we are reporting only on the neoadjuvant chemotherapy patients [see Table 1].” Patients who were classified as HER2positive received HER2-directed therapy, which changed from trastuzumab alone to trastuzumab plus pertuzumab, as standard of care in the middle of the trial.

Key Results Compared to conventional IHC and FISH subtyping, the 80-gene functional subtyping reclassified more than 1 in 5 tumors. Approximately 20% of the original luminal group were reclassified into the basal group. These were all estrogen receptor–positive tumors with > 50% having > 10% positivity. “We increased the basal group by 50% with molecular subtyping compared to immunostaining, but we maintained [pathologic complete response] rates in that group,” said Dr. Beitsch. The original basal group and the HER2-positive/hormone receptor–negative group basically remained the same, he noted. The group with the biggest change, however, was the triple-positive group

(estrogen receptor–positive, progesterone receptor–positive, and HER2-positive), where half the patients had HER2driven disease and the HER2 subtype and half had the luminal subtype. “When we reclassified patients into ‘proper subtypes,’” said Dr. Beitsch, “the number of patients [with HER2-driven disease] went down from 258 to 141, but the [pathologic complete response] rate actually increased considerably and was statistically significant compared to surrogate immunohistochemical subtyping.”

Problem Solved As Dr. Beitsch explained, the conundrum of patients with triple-positive disease having less responsiveness to trastuzumab and chemotherapy has been well documented for years. When reclassified by functional subtyping, however, the group that was classified as HER2-driven had nearly a 50% pathologic complete response rate. Conversely, patients with triple-positive disease who were molecularly subtyped into the luminal group were basically non responsive to neoadjuvant chemotherapy plus trastuzumab alone. “We solved the problem with triple-positive patients,” said Dr. Beitsch. “They’re actually two subtypes of equal numbers in the groups, but their response rates are remarkably different.” However, during the course of the trial, Dr. Beitsch observed a marked increase in pathologic complete recontinued on page 28

The ASCO Post | NOVEMBER 10, 2015

PAGE 28

Announcements

Beth Israel Deaconess Medical Center Names Manuel Hidalgo, MD, PhD, Clinical Director of the Cancer Center and Chief of Hematology-Oncology

anuel Hidalgo, MD, PhD, an oncologist whose work in experimental cancer therapy and tumor model development has led to key advances in the treatment of pancreatic cancer, has been named Director of the Leon V. & Marilyn L. Rosenberg Clinical Cancer Center and Chief of the Division of Hematology-Oncology at Beth Israel Deaconess Medical Center (BIDMC). Dr. Hidalgo will oversee all BIDMC clinical cancer programs when he joins the medical center in the coming months. A native of Spain, Dr. Hidalgo comes to BIDMC from the Centro Nacional de Investigaciones Oncologicas (Spanish National Cancer Center), where he currently serves as

Manuel Hidalgo, MD, PhD

Director of the Clinical Research Program and Vice Director of Translational Research. He holds faculty positions at University CEU San Pablo and Johns Hopkins University. “I am honored to join BIDMC, which is a global leader in bringing together clinicians and scientists to promote excellence in cancer care,” said Dr.

Hidalgo. “I share BIDMC’s philosophy that research and patient care inform and complement one another and that the skill and expertise of both disciplines will be required to win the fight against all types of cancer.” Dr. Hidalgo is a founder of the Pancreatic Cancer Research Team, a private nonprofit cooperative group dedicated to rapid drug development in pancreatic cancer. Dr. Hidalgo received his medical degree from the University of Navarra and his doctorate from the University Autonoma of Madrid. He completed a fellowship in anticancer drug development at the University of Texas Health Science Center in San Antonio. In 2001, Dr. Hidalgo joined Johns

Hopkins as an Associate Professor and in 2003 became Codirector of its Gastrointestinal Cancer Program. Dr. Hidalgo joined the Spanish National Cancer Center in 2009. “Dr. Hidalgo succeeds Lowell Schnipper, MD, an international leader in cancer care, who built and led from its inception BIDMC’s Hematology-Oncology Division,” said Mark Zeidel, MD, PhD, Chair of BIDMC’s Department of Medicine. “Through both his direct care of patients and his tireless advocacy for national patient-care initiatives, as well as his influential mentoring of BIDMC faculty, Dr. Schnipper has markedly improved the lives of thousands of cancer patients.” n

NYU Langone Appoints Alec Kimmelman, MD, PhD, as Chair of Radiation Oncology

enowned clinician-scientist Alec Kimmelman, MD, PhD, has been named Chair of the Department of Radiation Oncology at NYU Langone Medical Center. His appointment is effective February 1, 2016.

Alec Kimmelman, MD, PhD

Dr. Kimmelman joins the Laura and Isaac Perlmutter Cancer Center at NYU Langone following a distinguished career as Associate Professor

80-Gene Assay in Breast Cancer continued from page 27

sponse in this previously unresponsive group. When we looked at this group of triple-positive luminal patients, their [pathologic complete response] rate went from 3% to 18%. We then noticed that standard of care changed in the middle of the trial, when we went from chemotherapy plus trastuzumab

in the Department of Radiation Oncology at Harvard Medical School and its major teaching affiliates, the DanaFarber Cancer Institute and Brigham and Women’s Hospital. His laboratory has made seminal contributions to the biological underpinnings of pancreatic cancer. Dr. Kimmelman also is a practicing radiation oncologist specializing in the treatment of gastrointestinal cancers. For more than 15 years, Dr. Kimmelman’s research has focused on RAS oncogenes, one of the most commonly mutated families of cancercausing genes. His research team has made seminal contributions to the understanding of the biology of pancreatic cancer, which is driven by “activating” mutations in the KRAS oncogene. Dr. Kimmelman and his colleagues to chemotherapy plus trastuzumab plus pertuzumab. This change corresponded exactly with the increase in pathologic complete response, which in fact had increased 10-fold! n Disclosure: Dr. Beitsch is a member of the speakers bureau for and has received research funding from Agendia.

Reference 1. Whitworth PW, Beitsch PD, Rotkis MC, et al: Functional subtyping with

used sophisticated mouse and cellular models to provide one of the first demonstrations that KRAS was required for the continued growth of pancreatic tumors through its role in rewiring cellular metabolism. His laboratory continues to be at the forefront of studies identifying metabolic adaptations in pancreatic cancer and exploiting them for the development of novel therapeutics. Recent work from his laboratory on a form of metabolic process called “autophagy” has shown that pancreatic cancers depend on this “self-eating” pathway for proper growth. Based on these studies, multiple clinical trials targeting auto phagy are underway worldwide. Dr. Kimmelman is a National Institutes of Health (NIH)-funded investigator. He has served as an editor for

journals such as Oncogene and PLOS ONE and on several grant review committees, including those for the NIH. Dr. Kimmelman has been the recipient of many prestigious awards, including the Ruth Leff Siegel Award from Columbia University for excellence in pancreatic cancer research, and was recently inducted into the American Society for Clinical Investigation. Dr. Kimmelman earned a dual MD/PhD degree from the Medical Scientist Training Program at Icahn School of Medicine at Mount Sinai. He completed his residency in radiation oncology at the Harvard Medical School Combined Program, as well as a postdoctoral fellowship in the laboratory of Ronald A. DePinho, MD, current President of The University of Texas MD Anderson Cancer Center. n

Subtyping Breast Cancer ■■ Compared to conventional immunohistochemistry and fluorescence in situ hybridization subtyping, the BluePrint 80-gene functional subtyping reclassified 1 in 5 tumors. ■■ 80-Gene subtyping yields significantly better correlation with both neoadjuvant chemotherapy responsiveness and resistance. BluePrint 80-gene profile to identify distinct triple-positive subtypes with and without trastuzumab/chemosensi-

tivity. 2015 Breast Cancer Symposium. Abstract 114. Presented September 25, 2015.

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Announcements

National Coalition for Cancer Survivorship Honors Richard Pazdur, MD, and Ellen Goodman er in clinical trial design and drug development in advanced colorectal cancer, Dr. Pazdur is the Director of the Office of Hematology and Oncology Products in the Center for Drug Evaluation and Research at the FDA.

Jessie Gruman Award for Patient Engagement

n October 21 in Washington, DC, the National Coalition for Cancer Survivorship (NCCS) hosted a reception to honor Richard P azdur, MD, and Ellen Goodman. NCCS Chief Executive Officer, Shelly Fuld Nasso (pictured above), welcomed attendees to the special awards reception.

The inaugural Jessie Gruman Award for Patient Engagement was presented to Ms. Goodman, a Pulitzer Prize–winning columnist, author, and founder of The Conversation Project, a widely celebrated national public health campaign that works to change the way people talk about and prepare for end-of-life care. The award was established with a grant from the Center for Advancing Health to honor the legacy of Dr. Gruman, a tireless advocate and leader in patient e mpowerment.

NCCS Public Service Leadership Award

NCCS: Quality of Care and Quality of Life After Diagnosis

The NCCS Public Service Leadership Award is given to an individual whose efforts have advanced cancer survivorship in the public sector. Robert M. Califf, MD, Deputy Commissioner for Medical Products and Tobacco at the U.S. Food and Drug Administration (FDA), and a special guest, presented the 2015 NCCS Public Service Leadership Award to Dr. Pazdur. A distinguished researcher and lead-

The NCCS advocates for quality cancer care for all individuals touched by cancer. Founded by and for cancer survivors, NCCS is a leader in advocating for policy changes to promote quality of care and quality of life after diagnosis. The organization strongly believes in evidence-based advocacy that reflects the needs of cancer patients to effect policy change at the national level. n

Dr. Robert Califf (right) presented the NCCS Public Service Leadership Award to Dr. Richard Pazdur, Director of the Office of Hematology and Oncology Products in the Center for Drug Evaluation and Research at the FDA. Photo by Leslie E. Kossoff.

Shelly Fuld Nasso (left), Chief Executive Officer of NCCS, presented the Jessie Gruman Award for Patient Engagement to Ellen Goodman, a Pulitzer Prize–winning columnist, author and founder of The Conversation Project. To learn more, visit http://theconversationproject.org/. Photo by Leslie E. Kossoff.

Dr. Richard Pazdur and his wife, Mary Pazdur, MSN, CRNP (pictured above), spoke to NCCS prior to the reception, and the conversation is available to the public at https://www.youtube.com/ watch?v=jRotg2oRIeM. The Pazdur’s spoke about the future of oncology research and treatment and how their experiences with cancer—both personal and professional—have impacted how they view the patient experience. Photo by Leslie E. Kossoff.

The ASCO Post | NOVEMBER 10, 2015

PAGE 30

Ovarian Cancer Endpoints Workshop Gynecologic Oncology

Ovarian Cancer Trialists Forming Work Group to Standardize Definition of Pathologic Complete Response By Kirsten Boyd Goldberg

varian cancer clinical trialists are forming a working group to develop a standard definition of pathologic complete response in ovarian cancer treated with neoadjuvant chemotherapy. Such agreement within the field potentially would enable the U.S. Food and Drug Administration (FDA) to consider accepting pathologic complete response as an endpoint to support accelerated approval of new therapies. The effort is an outgrowth of a September 3 workshop on ovarian cancer endpoints sponsored by the FDA, ASCO, the American Association for Cancer Research, and the Society of Gynecologic Oncology.1

2014 as an endpoint to support accelerated approval for neoadjuvant therapies for high-risk, early-stage breast cancer. In an October 2014 Guidance for Industry, the agency provided two acceptable definitions of pathologic complete response in early-stage breast cancer. A new therapy for ovarian cancer wouldn’t have to improve pathologic complete response much to demonstrate an increase in activity. Most studies that have tracked it reported a pathologic complete response of less than 10%, Geoffrey Kim, MD, Director of the Division of Oncology Products 1 in the FDA Office of Hematol-

A big part of this is agreeing on definitions and standardization of procedures so we can speak among different institutions and countries to compare trial outcomes. —Thomas Herzog, MD

“A big part of this is agreeing on definitions and standardization of procedures so we can speak among different institutions and countries to compare trial outcomes,” Thomas Herzog, MD, Clinical Director of the University of Cincinnati Cancer Institute and one of the workshop organizers, said in an interview. The field also has yet to define which ovarian cancer patients are most likely to benefit from neoadjuvant chemotherapy, rather than initial surgery followed by chemotherapy, Dr. Herzog said. “That determination would be best answered in a clinical trial, but a working group could formulate recommendations based on current evidence,” he said. The working group would be led by some of the organizations involved in the workshop and would be open to participation by investigators, therapeutics sponsors, and patient advocates, Dr. Herzog said.

Low Bar to Overcome The interest in standardizing pathologic complete response as an endpoint for ovarian cancer studies stems from its acceptance by the FDA in

ogy and Oncology Products, said in an interview. “Due to the apparently low rates of [pathologic complete response] with standard regimens, it is a potentially low bar to overcome at this time in terms

Susanna I. Lee, MD, PhD

David M. Gershenson, MD

Recommendations for Development Gwynn Ison, MD, Clinical Reviewer in gynecologic malignancies in the FDA Office of Hematology and Oncology Products, said a link between pathologic complete response in neoadjuvant treatment and long-term outcome in ovarian cancer has yet to be definitively established. She noted that a 2010 randomized trial in Europe suggested that neoadjuvant chemotherapy isn’t inferior to primary debulking surgery in ovarian cancer.2 Dr. Ison’s advice to sponsors: “Talk to the FDA early and often during the development process.” The FDA doesn’t accept the CA125 test as a sole independent endpoint for approval, Dr. Kim said. He recommended that trials collect and report both CA125 and radiographic information. Other workshop participants suggested that every ovarian cancer trial collect data on a variety of potential biomarkers.

The immune checkpoints are really not a home run in ovarian cancer, based on some of these early results, suggesting that we’re going to need combinations, and we’re going to need to define patients who are [most likely] to benefit. —Kunle Odunsi, MD, PhD

of assessing activity,” Dr. Kim said. “It was accepted at the workshop that in patients for whom neoadjuvant chemotherapy is indicated—and it would be very important to understand exactly who that population would be—this would be a potential platform to assess drug activity. Whether this activity (or how much of an increase in activity) is needed to predict long-term outcome is the key question.”

Susanna I. Lee, MD, PhD, Chief of Women’s Imaging at Massachusetts General Hospital and Associate Professor of Radiology at Harvard Medical School, Boston, described the extensive development of imaging biomarkers to predict response or patient outcome response in some ovarian cancer trials. David M. Gershenson, MD, Professor, Department of Gynecologic Oncology & Reproductive Medicine,

Mary L. (Nora) Disis, MD

The University of Texas MD Anderson Cancer Center, Houston, advocated for trials of low-grade serous and clear cell ovarian cancer—a notoriously hard-totreat form of the disease. Rare tumors present an opportunity to achieve larger benefits in smaller sample sizes of patients, he said.

Phenotypes Will Point the Way for Immunotherapy Ovarian cancer can be stratified by the presence or absence of tumorinfiltrating lymphocytes and expression of programmed cell death ligand (PD-L1), said Kunle Odunsi, MD, PhD, Cancer Center Deputy Director, Chair of the Department of Gynecologic Oncology, and Executive Director of the Center for Immunotherapy at Roswell Park Cancer Institute, Buffalo, New York. “Going forward with immunotherapy trials, it’s going to be important to stratify patients based on some of these phenotypes,” Dr. Odunsi said. “For example, if your patient has a tumor that is rich in tumor-infiltrating lymphocytes, the type of immunotherapy that you will select for that patient is likely to be a checkpoint blockade, because you want to rescue these T cells that are probably dysfunctional. So by using simple immunohistochemistry, you can begin to select patients and tailor therapy.” Most studies exploring blockade of programmed cell death protein 1 (PD‑1) and PD-L1 in ovarian cancer have been very small, Dr. Odunsi said. The largest so far was a phase Ib study of avelumab in 75 patients, presented at the 2015 ASCO Annual Meeting by Mary L. (Nora) Disis, MD, medical oncologist at the Fred Hutchinson Cancer Research Center and the Seattle Cancer Care Alliance.3 PD-L1 positivity was not required for entry into the study. The objective response rate was 10.7% (95% confi-

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Ovarian Cancer Endpoints Workshop dence interval = 4.7%–19.9%) after a median follow-up duration of 5 months. The stable disease rate was 44%, and the disease control rate was 54.7%. The median duration of response was 21 weeks, with 62.5% of responses ongoing at the time data were reported. “The immune checkpoints are really not a home run in ovarian cancer, based on some of these early results, suggesting that we’re going to need combinations, and we’re going to need to define patients who are [most likely] to benefit,” Dr. Odunsi said. However, Sanjeeve Bala, MD, MPH, Medical Officer in the FDA

Sanjeeve Bala, MD, MPH

Office of Hematology and Oncology Products, noted that in immunotherapy approvals in other cancers, the FDA considered the prolonged duration of response an important hallmark of clinical benefit.

Dr. Kim said a similar scenario is likely to play out in ovarian cancer. “People focus on how high that response rate number is, but with the immune checkpoint inhibitors, it’s really the duration of the response that’s impressive,” he said. “When patients respond, they respond for a long time. That’s what makes immunotherapy an exciting modality of treatment right now.” n Disclosure: Drs. Herzog, Kim, Ison, Lee, Gershenson, Odunsi, and Bala reported no potential conflicts of interest. Dr. Disis has received grant funding from EMD Serono, VentiRx, and Seattle Genetics and has stock in VentiRx ad Epithany.

References 1. FDA Public Workshop: Ovarian Cancer Endpoints Workshop. Presentations available at http://www.fda.gov/ Drugs/NewsEvents/ucm463933.htm. Accessed October 15, 2015. 2. Vergote I, Trope CG, Amant F, et al: Neoadjuvant chemotherapy or primary surgery in stage IIIC or IV ovarian cancer. N Engl J Med 363:943-953, 2010. 3. Disis ML, Patel MR, Pant S, et al: Avelumab (MSB0010718C), an anti-PDL1 antibody, in patients with previously treated, recurrent or refractory ovarian cancer. 2015 ASCO Annual Meeting. Abstract 5509. Presented June 1, 2015.

News

Study Finds Quality of Physician Recommendation to Parents Key to Encourage/Discourage HPV Vaccination of Adolescents By Jo Cavallo

nationwide online survey of 776 pediatricians and family physicians assessing the quality of their human papillomavirus (HPV) vaccine recommendations to parents has found that approximately 27% of respondents said they do not strongly endorse HPV vaccination; further, 26% and 39% of respondents reported that they do not provide timely recommendations for vaccinating girls and boys, respectively. The survey also found that recommendation quality was lower among physicians who were uncomfortable talking about the HPV vaccine or who believed that parents did not value the vaccine. These practices, according to the study, likely contribute to underimmunization among adolescents and may convey ambivalence to parents. Recommendation quality was higher among physicians who began discussions by saying the child was due for HPV vaccine vs giving information or eliciting questions. The study by Gilkey et al is published in Cancer Epidemiology, Biomarkers & Prevention.1

Study Details The Physician and Communication About HPV Vaccination Study was an online survey of pediatricians and family physicians in the United States conducted from April to June 2014. The survey was emailed to

2,368 primary care physicians who indicated that they provide preventive care, including vaccinations, to adolescent patients aged 11 to 12 years, the ages specified to receive routine HPV vaccination. A total of 776 physicians completed the survey. About two-thirds of respondents were male, and over half had 20 or more years of experience in practice. The vast majority of physicians (83%) saw 10 or more adolescent patients per week.

assessed the respondents’ strength of endorsement, or saying that the vaccine is “very” or “extremely” important vs less so.

Study Findings The researchers found that a sizable minority of physicians reported that they do not strongly endorse HPV vaccine (27%) or deliver timely recommendations for girls (26%) or boys (39%). Many physicians (59%) used a risk-

Helping providers communicate about the HPV vaccine effectively is a promising strategy for getting more adolescents vaccinated. —Melissa B. Gilkey, PhD

The researchers assessed the quality of the respondents’ HPV vaccine recommendations based on strength of endorsement, such as saying the vaccine is important; timeliness, recommending it by ages 11 to 12; consistency, recommending it routinely vs using a risk-based approach; and urgency, recommending same-day vaccination. Because some physicians characterize the HPV vaccine as an optional vaccine, the researchers also

based approach to recommending the HPV vaccine, and only half (51%) usually recommended same-day vaccination. Overall recommendation quality was lower among physicians who were uncomfortable talking about HPV vaccine or who believed parents did not value it. Quality was higher among physicians who began discussions by saying the child was due for HPV vaccine vs giving information or eliciting questions.

“We were surprised that physicians so often reported recommending HPV vaccination inconsistently, behind schedule, or without urgency,” said Melissa B. Gilkey, PhD, Assistant Professor of Population Medicine at Harvard Medical School and Harvard Pilgrim Health Care Institute in Boston, and lead author of the study, in a statement. “Of the five communication practices we assessed, about half of physicians reported two or more practices that likely discourage timely HPV vaccination. We are currently missing many opportunities to protect today’s young people from future HPV-related cancers. Helping providers communicate about the HPV vaccine effectively is a promising strategy for getting more adolescents vaccinated.” n

Disclosure: Funding for the study was provided by the Cancer Control Education Program at UNC Lineberger Comprehensive Cancer Center, the National Cancer Institute, and an unrestricted educational grant from Pfizer. Noel T. Brewer, PhD, received HPV vaccine-related grants from or has been on advisory boards for GlaxoSmithKline PLC, Merck, and Pfizer. The other study authors reported no conflicts of interest.

Reference 1. Gilkey MB, Malo TL, Shah PD, et al: Quality of physician communication about human papillomavirus vaccine: Findings from a national survey. Cancer Epidemiol Biomarkers Prev 24(11):1–7, 2015.

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NCCN Congress: Hematologic Malignancies Guidelines

NCCN Unveils Graphic Evidence Blocks to Guide Decision-Making By Caroline Helwick

reatment decision-making for oncologists and their patients may become simpler through the use of graphic NCCN Evidence Blocks™, which were unveiled at the NCCN 10th Annual Congress: Hematologic Malignancies™ sponsored by the National Comprehensive Cancer Network® (NCCN®). The first of the NCCN Evidence Blocks are published within new versions of the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Chronic Myelogenous Leukemia and Multiple Myeloma. “In an age of visual information, the NCCN Evidence Blocks are a timesaving tool for efficient scanning and interpretation of multiple therapy options in an efficient format,” said Robert W. Carlson, MD, Chief Executive Officer of the NCCN. The NCCN Evidence Blocks are part of NCCN’s decision to include “value” in its Guidelines and to enhance shared decision-making. According to Dr. Carlson, clinicians have wanted more rationale for NCCN Guidelines’ recommendations. Patients have requested information to enhance their decision-making. And, in response to the rising cost of cancer care, payers have wanted affordability to be added to the standard criteria of efficacy, toxicity, and level of evidence. “To address these issues, NCCN developed a novel system,” he said.

Customizing Treatment Decisions The NCCN Evidence Blocks, he noted, will enhance treatment choices based on individual perspectives of value. Physician and patient together can consider the attributes and drawbacks of possible therapies and select the most acceptable treatment for that patient. “A 35-year-old breast cancer patient with young children, for example, will almost exclusively focus on effectiveness and be less concerned about toxic-

ity and affordability,” said Dr. Carlson, a breast cancer specialist. “In contrast, an 80-year-old with identical breast cancer is more likely to focus on quality of life, and perhaps affordability.” “We believe both perspectives are important and valid. We needed a system that will accommodate both those and others,” he added. “The NCCN Evidence Blocks provide information so the patient can create her own value equation and apply this framework in selecting treatment.”

Demystifying the Cost of Care The new component of this list is affordability, which has never been a factor in NCCN recommendations of specific treatments. It is time, Dr. Carlson said, to “demystify” the cost of care and,

In an age of visual information, the NCCN Evidence BlocksTM are a time-saving tool for efficient scanning and interpretation of multiple therapy options in an efficient format. —Robert W. Carlson, MD

Dr. Carlson emphasized that the graphics will be “merely a starting point for discussion” and should not be perceived as directives. “They do not replace the categories of evidence that we use.”

Specifics of the Blocks The NCCN Evidence Blocks are published in new versions of the NCCN Guidelines (at this point, only for chronic myelogenous leukemia and multiple myeloma) and are a visual representation of five key value measures that are part of specific NCCN Guidelines’ recommendations: efficacy of the regimen, safety of the regimen, quality and quantity of evidence in support of the regimen, consistency of evidence, and affordability of the regimen. The scoring system is simple: Shading of only one block indicates “least favorable,” whereas five shaded blocks indicate “most favorable.” The more

NCCN EVIDENCE BLOCKS CATEGORIES AND DEFINITIONS 5 4 3 2 1

shading the block has, the better the regimen in all components. With such a graphic, NCCN figured clinicians and patients alike could quickly appreciate the relative merits of the treatment options.

E = Efficacy of Regimen/Agent S = Safety of Regimen/Agent Q = Quality of Evidence C = Consistency of Evidence A = Affordability of Regimen/Agent E S Q C A

at the very least, enhance the financial discussion. “There’s been a conspiracy of silence” on this issue, he said. “Patients are embarrassed to bring up cost. Physicians hesitate to bring it up, because there’s the implication that maybe if you can’t afford it, you won’t get the most effective treatment. The result is that patients leave with a prescription they won’t fill, because they can’t pay for it.” By being an equal factor in the NCCN Evidence Blocks, affordability enters the discussion. “If patients are concerned about expense, and they see a therapy listed as very expensive, this is a signal to the patients and providers that it’s time to understand the magnitude of the financial risk,” he said. The affordability measurement represents an estimate of overall total cost to society of a therapy, including but not limited to acquisition, administration, in-patient and out-patient care, supportive care (antiemetics, growth factors, etc), infusions, toxicity monitoring, and so forth.

The Development Process To develop the graphics, NCCN panel members were asked to score each of the five key measures for each systemic treatment recommendation. The scores from all members were averaged and rounded to the nearest integer. NCCN staff developed a survey instrument that included the five key

measures for each treatment recommendation with the Guidelines. Individual panel members, in isolation (not collaboration), then scored each of the regimens. Responses were collated, and an average was generated and rounded to the nearest integer. Results were translated into the graphic and placed within the Guidelines. Dr. Carlson predicted that, for some panels, this will be “a mammoth task.” For example, there are about a dozen regimens for metastatic non–small cell lung cancer, used across five lines of treatment. For the affordability estimates, panelists were not provided specific dollar amounts for each regimen, since cost figures can be unreliable and vary by institution, insurance coverage, and other factors. Instead, they used their expertise as “subsubspecialists” in a disease state to rank regimens (total cost of care) on a 5-point affordability scale, from “very inexpensive” to “very expensive,” Dr. Carlson explained. “Panelists may not be able to give you the exact cost of a regimen, but they can tell you whether it is hundreds of thousands of dollars a year, $50,000, or $10,000. The estimate will not be what the patient will pay, but it will signal, ‘This is very expensive, and if the price tag is important, you need additional information,’” he said. “There was remarkable agreement in terms of which buckets this ‘affordability’ fell into.”

Moving Forward By the end of 2015, NCCN expects to publish NCCN Evidence Blocks for systemic therapies (not surgery or radiation therapy) for breast, colon, non–small cell lung, and rectal cancers. NCCN Evidence Blocks for systemic therapies are expected to be contained within the complete library of NCCN Guidelines by the end of 2016. In the near term, NCCN will continue to publish two sets of NCCN Guidelines: those including NCCN Evidence Blocks and those published without them. The NCCN Evidence Blocks are not currently published in the NCCN Guidelines for Patients® and are intended for use in the United States only. For more information on the NCCN Evidence Blocks, visit www.nccn.org/ EvidenceBlocks/. n Disclosure: Dr. Carlson reported no potential conflicts of interest.

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Expert’s Corner End-of-Life Care

End-of-Life Clinical Decisions Still Need Conversations About Improving Care A Conversation With Diana J. Mason, RN, PhD, FAAN By Ronald Piana

Diana J. Mason, RN, PhD, FAAN

n 2014, the Institute of Medicine report Dying in America: Improving Quality and Honoring Individual Preferences Near the End of Life called for more conversations about improving care for those who are dying. Improving the care of the imminently dying is an important issue in the oncology community. To that end, the maturation of palliative care and geriatric oncology disciplines has markedly advanced the quality of outcomes for patients with late-stage cancer. However, end-of-life care, from ethics to costs, remains a thorny topic in the ongoing health-care debate. To bring added perspective to this issue, The ASCO Post spoke with Diana J. Mason, RN, PhD, FAAN, former Editor-in-Chief of the American Journal of Nursing. Dr. Mason is also the co-editor of the award-winning book Policy and Politics in Nursing and Health Care. She writes and speaks about health policy and politics for national and international audiences.

ing, which has had a profound effect on me. However, it was a more personal story that accelerated my interest in endof-life issues. In the 1970s, I cared for my father for the last month of his life, and the experiences we had with the healthcare system were pretty awful, and it had a lasting effect on me. The providers did not take into account my father’s wishes and goals. And they certainly didn’t ask or take into account our family’s well-being and wishes for my father’s end-of-life care. When I was Editor-in-Chief of the American Journal of Nursing in the early 2000s, we were given a grant from the Robert Wood Johnson Foundation to

As we approach the next national election cycle, health care will certainly be a hot topic of debate. To that end, one of the most controversial parts of the Affordable Care Act was the Independent Payment Advisory Board (IPAB), which was infamously coined the “death panel.” What are your thoughts about the IPAB? First off, the public, for the most part, does not have a clue about the IPAB, so scare tactics have an effect. I believe that

—Diana J. Mason, RN, PhD, FAAN

do a series of papers on end-of-life care. I’m very proud of that series; recently, I spoke with a nurse who works in hospice care, and he told me that the articles had a profound effect on him. Moreover, he shared the pieces with his colleagues, and they essentially made changes in the way they practiced end-of-life care. Here we are in 2015, and end-of-life care is still a vital issue that needs constructive discussion that will lead to better care.

Breaking the Silence

Please tell the readers a bit about your background and your current work. I am a registered nurse. Over my career, I’ve been a clinician, researcher, administrator, educator, and a policy wonk. So I’ve worn numerous hats. I’m currently the Rudin Professor of Nursing and Co-Director of the Center for Health, Media, and Policy at Hunter College in New York. I’m also President of the American Academy of Nursing. My background has given me a broad-based perspective on the American health-care system.

The seminal 2014 Institute of Medicine report Dying in America: Improving Quality and Honoring Individual Preferences Near the End of Life stirred controversy in certain sectors that felt it was yet one more step in reducing expensive care for the dying for budgetary reasons. What is your reaction to the report? The report doesn’t advocate that people with terminal conditions opt out of aggressive treatment. Rather, it calls for health professionals to ascertain the values, preferences, and goals of people with advanced illness and support them in making informed choices. However, it will take all sectors of our communities to move our nation from silence about dying to exploring the full range of emotions and issues that are associated with this last transition in our lives. That said, improving end-of-life care

You’ve written extensively and spoken in the media about raising awareness for endof-life care. What experiences or influences got you involved in this work? I’ve cared for patients who were dy-

Making Forward Progress

It will take all sectors of our communities to move our nation from silence about dying to exploring the full range of emotions and issues that are associated with this last transition in our lives.

Worn Many Hats

Personal Motivation

for patients and families can also reduce costs, which the report makes clear, as patients opt for fewer aggressive treatments and avail themselves of palliative and hospice care.

during the past election, the death panel rhetoric was so harmful to the movement of providing choices and alternative-care options for those in end-of-life care that even those who opposed the IPAB and other like issues in the Affordable Care Act came to realize that in the end, it’s all about delivering high-quality care. So I believe that if that counterproductive rhetoric rears its head again, there will be considerable pushback by some conservatives. Moreover, I think that there’s a consensus from both sides of the political spectrum that building conversations and educated decision-making into

end-of-life care align with best medical practice. After all, that’s what everyone ultimately wants. We’ve come a long way, but there’s still much to do. An example of our forward progress is the Choosing Wisely® campaign, which covers more than 70 specialty society partners, including the American Academy of Nursing. It is another example of the health-care community leading the way in promoting conversations between providers and patients informed by evidence-based recommendation that foster wise decisions about the most appropriate care based on a patient’s individual situation.

The Need for Honest Dialogue Aside from the basic medical issues involved in treating patients with late-stage cancer, there are a host of other issues that affect quality of life for the patient and caregivers that often get overlooked. Any thoughts? That’s correct. In fact, nurses in the field have shared such examples. For instance, patients who are dying of cancer are often urged by their families to undergo further experimental chemotherapies, even though their oncologists have said there is very little chance of extending their lives, irrespective of quality of life. As mentioned, this is where the hard discussions come in. And in the end, honest dialogue produces better care. I would like to return to your other point about the complicated global issues surrounding end-of-life care. An advanced practice registered nurse associate of mine, whose husband has cancer, recently spoke with a lawyer who is an estate planner. At first, she was taken continued on page 34

The Independent Payment Advisory Board in a Nutshell

he Affordable Care Act established a 15-member Independent Payment Advisory Board (IPAB) to reduce Medicare spending growth using a target system and fast-track legislative approval process. By April 30 of each year, the Centers for Medicare & Medicaid Services will project whether Medicare’s per-capita spending growth rate in the following 2 years will exceed a target rate. Initially, the targeted rate of spending growth will be based on the projected 5-year average percentage increase in the Consumer Price Index for all urban consumers. Beginning in 2019, the target will be set at the nominal gross domestic product per capita plus 1.0%. If future Medicare spending is projected to exceed the targets, the IPAB will propose recommendations to reduce the growth rate. n

The ASCO Post | NOVEMBER 10, 2015

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Announcements

The Breast Cancer Research Foundation Names Marc Hurlbert, PhD, as Chief Mission Officer

he Breast Cancer Research Foundation (BCRF) announced that it has appointed Marc Hurlbert, PhD, as its new Chief Mission Officer (CMO). Formerly the Executive Director of the Avon Breast Cancer Crusade, Dr. Hurlbert succeeds Margaret (Peg) Mastrianni, who will retire in January 2016 after serving as BCRF’s Deputy Director and Chief Program Officer for the past 14-plus years. Dr. Hurlbert will oversee the Foundation’s global research grants program and a nearly $50 million annual research-granting budget. BCRF will also serve as the new home of the Metastatic Breast Cancer Alliance, where Dr. Hurlbert has served as Chair since it was founded in 2013 and which he will continue to lead at BCRF.

est privately funded project exclusively focused on metastasis in the world. BCRF’s focus on metastatic breast cancer research makes it the ideal new headquarters for the Metastatic Breast

Cancer Alliance. The Alliance comprises organizations and individuals with the mission of accelerating research and developing new treatments for metastatic breast cancer by encouraging col-

laboration. In his ongoing role with the Alliance, Dr. Hurlbert will continue to work toward improving the prognosis of women and men living with metastatic breast cancer. n

Marc Hurlbert, PhD

In 2015, BCRF’s annual grants program has committed more than $14.5 million to metastatic breast cancer research. BCRF-funded studies focus on understanding the biology of why and how cancer cells spread, the development of new treatments for advanced disease, clinical trials for new drug or drug combinations, and correlative research to discover biomarkers that can predict which breast cancers are more likely to spread. In 2013, BCRF established the Evelyn H. Lauder Founder’s Fund, a multiyear international program that is the first large-scale global effort to unravel the biology of metastasis. With $31 million raised to date, it is the larg-

End-of-Life Clinical Decisions continued from page 33

aback by the sheer volume of the forms related to end-of-life preferences. But it was a relief, because he brought up issues she never would have thought about. The point is that dealing with the issues around cancer and end-of-life preparations is more than medical decisionmaking; it takes a thorough, well-trained support system. And that is part of the overall discussion. n Disclosure: Dr. Mason reported no potential conflicts of interest.

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ASCOPost.com | NOVEMBER 10, 2015

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Announcements

Nancy A. Speck, PhD, Named Chair, Cell and Developmental Biology, Perelman School of Medicine/University of Pennsylvania

ancy A. Speck, PhD, has been named Chair of the Department of Cell and Developmental Biology in the Perelman School of Medicine at the University of Pennsylvania. She is also

the Associate Director of Penn’s Institute for Regenerative Medicine, Co-Leader of the Hematologic Malignancies Program at the Abramson Cancer Center, and an Investigator in the Abramson Family Can-

cer Research Institute. Dr. Speck is credited with many important contributions to a better understanding of developmental hematopoiesis and translating these findings to

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managing leukemia. She joined the Penn faculty in 2008. Dr. Speck succeeds Jon Epstein, MD, who has assumed the role of Executive Vice Dean and Chief Scientific Officer of Penn Medicine. n

The ASCO Post | NOVEMBER 10, 2015

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Announcements

Victoria Seewaldt, MD, Joins City of Hope

reast cancer and ovarian cancer specialist, Victoria L. Seewaldt, MD, has joined City of Hope as the Ruth Ziegler Chair in Population Sciences. Dr. Seewaldt, who is a specialist in developing risk models for aggressive cancers, will also serve as the Associate

Director of the Comprehensive Cancer Center in Duarte, California. She assumed these roles on October 1. Dr. Seewaldt will also lead the Breast Cancer Early Detection and Health Disparities Program at City of Hope, operating a clinic for women at

high risk for breast and ovarian cancers and working to better understand which cancers can be predicted and thus prevented. She will also work with City of Hope’s community sites to gather information on the areas’ Victoria Seewaldt, MD

continued on page 37

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ASCOPost.com | NOVEMBER 10, 2015

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Announcements

Maciej Lesniak, MD, Named Chair of Neurological Surgery at Northwestern

aciej (Matt) Lesniak, MD, has been named the Michael J. Marchese Professor and Chair of the Departments of Neurological Surgery at Feinberg School of Medicine and Northwestern Memorial Hospital in Chicago. Prior to joining Northwest-

ern, Dr. Lesniak was a Professor of Neurosurgery, Neurology, and Cancer Biology, as well as Director of Neurosurgical Oncology and Neuro-Oncology Research, at the University of Chicago Pritzker School of Medicine. Dr. Lesniak’s laboratory work ex-

plores a diverse range of brain cancer therapies, focusing on genetics, stem cell therapy, immunotherapy, and nanotechnology. He is currently the principal investigator of six multimilliondollar grants funded by the National Institutes of Health (NIH). Maciej Lesniak, MD

Dr. Lesniak is the recipient of a number of honors and awards, notably the American Society of Gene and Cell Therapy Outstanding Investigator Award and the National Cancer Institute Outstanding Investigator Award for exceptional and transformative cancer research. He is a member of ASCO, the American Association for Cancer Research, the American Academy of Neurological Surgeons, and the Society of Neurological Surgeons. Dr. L esniak earned his medical degree from the Johns Hopkins University School of Medicine and completed both his residency in neurosurgery and fellowship in neurosurgical oncology at the Johns Hopkins Hospital. In 2003, he joined the University of Chicago. n

Victoria Seewaldt, MD continued from page 36

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diverse population in order to gain a more thorough understanding of risk and disease progression. Prior to joining City of Hope, Dr. Seewaldt was Professor of Medicine and Leader of the Comprehensive Cancer Breast and Ovarian Cancer Program at Duke University. She also founded the institution’s community outreach program for underserved women. Dr. Seewaldt earned her medical degree from the University of California, Davis, completed her residency and clinical fellowship in medical oncology under the ABIM Clinical Investigator Pathway at the University of Washington, and was a postdoctoral fellow at Fred Hutchinson Cancer Research Center. n

Send Us Your NEWS Write to editor@ASCOPost.com. All submissions will be considered for publication

The ASCO Post | NOVEMBER 10, 2015

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JCO Spotlight Guidelines

ASCO Clinical Practice Guideline Update: Recommendations for the Use of White Blood Cell Growth Factors By Matthew Stenger

SCO has issued a clinical practice guideline update on use of hematopoietic colony-stimulating factors, as reported in the Journal of Clinical Oncology by Thomas J. Smith, MD, FACP, FASCO, FAAHMP, and colleagues.1 This update to the ASCO 2006 guideline was based on a systematic review of randomized clinical trials, meta-analyses, and systematic reviews from October 2005 through September 2014 by an ASCO update committee. The committee was cochaired by Dr. Smith, of Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, and James O. A rmitage, MD, FASCO, of the University of Nebraska Medical Center. Changes to prior recommendations include the addition of tbo-filgrastim and the biosimilar filgrastim-sndz (Zarxio), moderation of the recommendation regarding routine use of colony-stimulating factors in older patients with diffuse aggressive lymphoma, and the addition of recommendations against routine dose-dense chemotherapy in lymphoma and in favor of high dose-intensity chemotherapy in urothelial cancer. The updated guideline does not address recommendations on the use of colony-stimulating factors in acute myeloid leukemia or myelodysplastic syndromes in adults. A summary of the updated recommendations is reproduced below. Type of recommendation, evidence quality, and strength of recommendation are shown in parentheses.

Recommendations Primary prophylaxis with a colonystimulating factor starting with the first cycle and continuing through subsequent cycles of chemotherapy is recommended in patients with an approximately 20% or higher risk for febrile neutropenia based on patient-, disease-, and treatment-related factors. Primary colony-stimulating factor prophylaxis should also be administered in patients receiving dose-dense chemotherapy when considered appropriate. Consideration should be given to alternative, equally effective, and safe chemotherapy regimens not requiring colony-stimulating factor support when available. (type = evidence based, benefits outweigh harms; evidence quality = high; strength of recommendation = strong)

Secondary prophylaxis with a colony-stimulating factor is recommended for patients who experienced a neutropenic complication from a prior cycle of chemotherapy (for which primary prophylaxis was not received), in which a reduced dose or treatment delay may compromise disease-free or overall survival or treatment outcome. In many clinical situations, dose reduction or delay may be a reasonable alternative. (type = evidence based, benefits outweigh harms; evidence quality = high; strength of recommendation = strong) Colony-stimulating factors should not be routinely used for patients with neutropenia who are afebrile. (type = evidence based, benefits outweigh harms; evidence quality = high; strength of recommendation = strong) Colony-stimulating factors should not be routinely used as adjunctive treatment with antibiotic therapy for

recommended at this time. (type = evidence based, benefits outweigh harms; evidence quality = high for breast cancer and lymphoma, intermediate for urothelial cancer; strength of recommendation = strong for breast cancer and lymphoma, modThomas J. Smith, MD, FACP, James O. A rmitage, MD, erate for urothelial cancer) FASCO, FAAHMP FASCO Colony-stimulating factors may be used alone, after chemother- adults, the use of colony-stimulating facapy, or in combination with plerixafor tors is reasonable as primary prophylaxis (Mozobil) to mobilize peripheral-blood for pediatric patients with a high likeliprogenitor cells. Choice of mobilization hood of febrile neutropenia. Similarly, strategy depends in part on the type of the use of colony-stimulating factors for cancer and the type of transplantation. secondary prophylaxis or for therapy (type = evidence based, benefits out- should be limited to high-risk patients. weigh harms; evidence quality = strong; (type = evidence based, benefits outstrength of recommendation = high) weigh harms; evidence quality = high; Colony-stimulating factors should strength of recommendation = strong) be administered after autologous stem For pediatric indications in which cell transplantation to reduce the dura- dose-intense chemotherapy is known to have a survival benefit, such as Ewing sarcoma, colony-stimulating Primary prophylaxis with a colony-stimulating factor factors should be used to enable the starting with the first cycle and continuing through administration of these regimens. (type = evidence based, benefits outsubsequent cycles of chemotherapy is recommended weigh harms; evidence quality = high; in patients with an approximately 20% or higher risk strength of recommendation = strong) Colony-stimulating factors should for febrile neutropenia based on patient-, disease-, and not be used in pediatric patients with treatment-related factors. nonrelapsed acute lymphoblastic leu—Thomas J. Smith, MD, FACP, FASCO, FAAHMP, and colleagues kemia or nonrelapsed acute myeloid leukemia who do not have an infecpatients with fever and neutropenia. tion of severe neutropenia. (type = evi- tion. (type = informal consensus; eviHowever, colony-stimulating factors dence based, benefits outweigh harms; dence quality = intermediate; strength should be considered in patients with evidence quality = high; strength of of recommendation = moderate) fever and neutropenia who are at high recommendation = strong) Pegfilgrastim (Neulasta), filgrasrisk for infection-associated complicaColony-stimulating factors may be tim (Neupogen), tbo-filgrastim, tions or who have prognostic factors administered after allogeneic stem cell and filgrastim-sndz (and other biopredictive of poor clinical outcomes. transplantation to reduce the duration similars, as they become available) (type = evidence based, benefits out- of severe neutropenia. (type = evi- can be used for the prevention of weigh harms; evidence quality = high; dence based; evidence quality = low; treatment-related febrile neutropestrength of recommendation = strong) strength of recommendation = weak) nia. The choice of agent depends on Dose-dense regimens with colonyProphylactic colony-stimulating convenience, cost, and clinical situastimulating factor support should only factors for patients aged ≥ 65 years tion. There have been no additional be used if supported by convincing ef- with diffuse aggressive lymphoma data comparing granulocyte colonyficacy data or within an appropriately treated with curative chemotherapy stimulating factors and granulocytedesigned clinical trial. Efficacy data (cyclophosphamide, doxorubicin, vin- macrophage colony-stimulating facsupport the use of dose-dense chemo- cristine, prednisone, and rituximab tors since the 2006 update; therefore, therapy in the adjuvant treatment of [Rituxan]) should be considered, par- there is no change in the recommenhigh-risk breast cancer and the use of ticularly in the presence of comorbidi- dation regarding their therapeutic high-dose intensity methotrexate, vin- ties. (type = evidence based, benefits equivalency. (type = evidence based, blastine, doxorubicin, and cisplatin in outweigh harms; evidence quality = benefits outweigh harms; evidence urothelial cancer. There are limited and intermediate; strength of recommen- quality = high; strength of recomconflicting data on the value of dose- dation = moderate) mendation = strong) dense regimens with colony-stimuThe use of colony-stimulating factors Current recommendations for the lating factor support in non-Hodgkin in pediatric patients will almost always management of patients exposed to lecontinued on page 39 lymphoma, and it cannot routinely be be guided by clinical protocols. As in

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Perspective

ASCO Recommendations for Use of White Blood Cell Growth Factors: What Remains the Same and What Has Been Modified By Gary H. Lyman, MD, MPH

eutropenic complications remain the main dose-limiting toxicity of cancer chemotherapy treatment and are associated with considerable morbidity, mortality, and costs.1 Although patients who have experienced a prior neutropenic event are at increased risk of subsequent events, several studies have shown that the risk of the initial neutropenic event is greatest in the first

date based on a comprehensive and systematic review of the medical literature since 2005 was published in the Journal of Clinical Oncology.9 A complete summary of the recommendations appears in this issue of The ASCO Post. These recommendations include a restatement of previous recommendations as well as several important modifications and additions to the previous guide-

These recommendations include a restatement of previous recommendations as well as several important modifications and additions to the previous guidelines based on several additional clinical trials and newly introduced agents. —Gary H. Lyman, MD, MPH

cycle, when most patients are receiving full-dose chemotherapy.2-4 Recombinant white blood cell growth factors or colony-stimulating factors have been demonstrated to reduce the risk and consequences of neutropenic complications and enable safe delivery of myelosuppressive chemotherapy at full dose on schedule in multiple randomized controlled trials.5 ASCO published its first clinical practice guideline on the use of hematopoietic colony-stimulating factors in 1994. These guidelines have been updated periodically, including in 1996, 1997, 2000, and 2006.6 In the interim, several additional guidelines on the use of colony-stimulating factors were updated.7,8 In July 2015, another guideline upDr. Lyman is Co-Director of the Hutchinson Institute for Cancer Outcomes Research, Divisions of Public Health Sciences and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle.

Clinical Practice Guideline continued from page 38

thal doses of total-body radiotherapy, but not doses high enough to lead to certain death resulting from injury to other organs, include the prompt administration of colony-stimulating

lines based on several additional clinical trials and newly introduced agents. The recommendations are applicable to patients with a broad range of adult and pediatric malignancies including solid tumors and lymphoma.

Restatement of Previous Recommendations Recommendations with little or no modification based on the updated review include primary prophylaxis, starting shortly after completion of the initial and subsequent cycles of chemotherapy in patients with an approximately ≥ 20% risk of febrile neutropenia based on treatment-, disease-, and patient-specific risk factors for febrile neutropenia, as well as in patients receiving dose-dense chemotherapy regimens. This recommendation is supported by well-designed clinical trials. Although evidence has shown that colony-stimulating factor prophylaxis may reduce early treatment-related as well as long-term factors or pegylated granulocyte colony-stimulating factors. (type = formal consensus [by others], benefits outweigh harms; evidence quality = intermediate; strength of recommendation = moderate) n Disclosure: Dr. Smith owns stock in United

mortality, this recommendation was based on the reduction in risk of febrile neutropenia as a clinically meaningful outcome in patients receiving cancer chemotherapy.5,10 While encouraging the further development and validation of risk prediction models, the guidelines updated a list of recognized patient risk factors for the development of febrile neutropenia, as well as those predictive of a poor clinical outcome resulting from febrile neutropenia or infection.9,11,12 Specifically, the update panel recommended the use of prophylactic colony-stimulating factors in patients aged ≥ 65 years receiving potentially curative chemotherapy for diffuse aggressive non-Hodgkin lymphoma (NHL), especially in the presence of comorbidities.13,14 Secondary prophylaxis in subsequent cycles is again recommended in patients who experience febrile neutropenia in a prior cycle of the same chemotherapy when a reduction in dose, delay in treatment, or an alternative less-myelosuppressive regimen might adversely impact important patient outcomes. The panel again recommended against the routine use of colony-stimulating factors in patients with afebrile neutropenia, as well as in most patients with existing febrile neutropenia receiving antibiotics, unless there is high risk for infectious complications. The use of colony-stimulating factors continues to be recommended for peripheral blood cell mobilization, as well as to support patients undergoing stem cell transplantation. The panel presented similar recommendations for appropriate use of these agents in pediatric patients with cancer but specifically recommended against their use in children with nonrelapsed acute lymphoblastic leukemia or acute myeloid leukemia. The guidelines do not address the use of colony-stimulating factors in adults Healthcare. Dr. Armitage has a leadership position with Tesaro Bio and a consulting or advisory role with GlaxoSmithKline, Roche, Spectrum Pharmaceuticals, Ziopharm Oncology, Conatus IDMC, and Celgene. For full disclosures of the other authors, visit jco. ascopubs.org.

with acute myeloid leukemia or myelodysplastic syndromes. On the basis of formal consensus, use of the colony-stimulating factors is recommended in patients exposed to potentially lethal doses of total-body radiation.9

Modifications or Additions At the same time, the updated white blood cell growth factor guidelines have modified or added to previous guideline recommendations. After a review of the limited and conflicting available evidence, the panel concluded that the value of dosedense regimens with colony-stimulating factor support has been demonstrated in patients receiving adjuvant systemic chemotherapy for earlystage breast cancer but not in patients with NHL, and, therefore, cannot be routinely recommended in the latter.15,16 However, evidence supporting colony-stimulating factor support of patients receiving high-dose intensity methotrexate, vinblastine, doxorubicin, and cisplatin for urothelial cancer was considered sufficient for recommendation.17 Finally, although the data are rapidly evolving and variable, the panel concluded that filgrastim, pegfilgrastim, tbo-filgrastim, and filgrastim-sndz could all be used for the prevention of treatment-related febrile neutropenia. The panel concluded that in addition to filgrastim and pegfilgrastim, newly introduced agents, either through a conventional approval mechanism (tbo-filgrastim) or through a new approval process for biosimilars (filgrastim-sndz), can be used to reduce the risk of febrile neutropenia. Limited data have suggested that pegfilgrastim may be more effective than filgrastim in reducing the risk of febrile neutropenia.18,19 The choice of agent will depend upon clinical experience, patient convenience, and cost. continued on page 40

Reference 1. Smith TJ, Bohlke K, Lyman GH, et al: Recommendations for the use of WBC growth factors: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol 33:31993212, 2015.

The ASCO Post | NOVEMBER 10, 2015

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Announcements

ASH Elects New Leadership to Its Executive Committee

he American Society of Hematology (ASH) has announced the election of three new members to its Executive Committee, the governing body of the organization, for terms beginning after the 2015 ASH Annual Meeting, taking place December 5–8 in Orlando. Alexis A. Thompson, MD, MPH, will serve a 1-year term as Vice President, followed by successive terms as PresidentElect and President. Jane N. Winter, MD, and Steven L. Allen, MD, will each serve a 4-year term as Councillor.

Alexis A. Thompson, MD, MPH Dr. Thompson is Head of the Hematology Section of the Division of Hematology Oncology Transplantation and Director of the Comprehensive Thalassemia Program at Ann and Robert H. Lurie Children’s Hospital of Chicago, where she also serves as the A. Watson and Sarah Armour Endowed Chair for Childhood Cancer and Blood Disorders. Dr. Thompson is also Associate Director of Equity and Minority Health at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.

Gary H. Lyman, MD, MPH continued from page 39

The panel reiterated recommendations for administration of the colonystimulating factors to start within 1 to 3 days after administration of chemotherapy.9 n

Disclosure: Dr. Lyman is a member of the ASCO Guideline Panel on the Use of White Blood Cell Growth Factors and principal investigator on a research grant to the Fred Hutchinson Cancer Research Center from Amgen.

References 1. Kuderer NM, Dale DC, Crawford J, et al: Mortality, morbidity, and cost associated with febrile neutropenia in adult cancer patients. Cancer 106:2258-2266, 2006. 2. Crawford J, Dale DC, Kuderer NM, et al: Risk and timing of neutropenic events in adult cancer patients receiving chemotherapy: The results of a prospective nationwide study of oncology practice. J Natl Compr Canc Netw 6:109-118, 2008. 3. Lyman GH, Delgado DJ: Risk and timing of hospitalization for febrile neutropenia in patients receiving CHOP, CHOP-R, or CNOP chemotherapy for intermediate-grade non-Hodgkin lymphoma. Cancer 98:2402-2409, 2003. 4. Lyman GH, Morrison VA, Dale DC, et al: Risk of febrile neutropenia

Dr. Thompson’s major fields of interest include sickle cell disease, thalassemia, transfusional iron overload, and stem cell transplantation for pediatric patients. In her position as Vice President, Dr. Thompson aims to enhance training programs to attract the next generation of scientists to hematology, as well as increase collaboration between ASH and global partners to improve hematology care and capacity around the world. Dr. Thompson served as an ASH Councillor from 2010–2013 and is a member of the ASH Sickle Cell Task Force. She has served as a mentor for the Minority Medical Student Award Program for more than 10 years and is currently a reviewer for ASH’s journal, Blood.

Jane N. Winter, MD Dr. Winter is Professor of Medicine in the Division of Hematology/ Oncology at the Feinberg School of Medicine of Northwestern University in Chicago. She also serves as a member of the Robert H. Lurie Comprehensive Cancer Center.

among patients with intermediate-grade non-Hodgkin’s lymphoma receiving CHOP chemotherapy. Leuk Lymphoma 44:2069-2076, 2003. 5. Kuderer NM, Dale DC, Crawford J, Lyman GH: Impact of primary prophylaxis with granulocyte colony-stimulating factor on febrile neutropenia and mortality in adult cancer patients receiving chemotherapy: A systematic review. J Clin Oncol 25:3158-3167, 2007. 6. Smith TJ, Khatcheressian J, Lyman GH, et al: 2006 update of recommendations for the use of white blood cell growth factors: an evidence-based clinical practice guideline. J Clin Oncol 24:3187-3205, 2006. 7. Aapro MS, Bohlius J, Cameron DA, et al: 2010 update of EORTC guidelines for the use of granulocyte-colony stimulating factor to reduce the incidence of chemotherapy-induced febrile neutropenia in adult patients with lymphoproliferative disorders and solid tumours. Eur J Cancer 47:8-32, 2011. 8. Crawford J, Armitage J, Balducci L, et al: Myeloid growth factors. J Natl Compr Canc Netw 11:1266-1290, 2013. 9. Smith TJ, Bohlke K, Lyman GH, et al: Recommendations for the use of WBC growth factors: American Society of Clinical Oncology clinical practice

Alexis A. Thompson, MD, MPH

Jane N. Winter, MD

Dr. Winter’s research interests include the clinical and biologic markers of prognosis in diffuse large B-cell lymphoma and clinical trials with novel agents in lymphoma. An ASH member for more than 30 years, Dr. Winter has recently served as Chair of the Committee on Educational Affairs, as well as faculty for the ASH Clinical Research Training Institute and the ASH/European Hematology Association Translational Research Training in Hematology.

Steven L. Allen, MD Dr. Allen is Associate Chief of Hematology at the Monter Cancer Cen-

guideline update. J Clin Oncol 33:31993212, 2015. 10. Lyman GH, Dale DC, Wolff DA, et al: Acute myeloid leukemia or myelodysplastic syndrome in randomized controlled clinical trials of cancer chemotherapy with granulocyte colony-stimulating factor: A systematic review. J Clin Oncol 28:2914-2924, 2010. 11. Lyman GH, Kuderer NM, Crawford J, et al: Predicting individual risk of neutropenic complications in patients receiving cancer chemotherapy. Cancer 117:1917-1927, 2011. 12. Lyman GH, Abella E, Pettengell R: Risk factors for febrile neutropenia among patients with cancer receiving chemotherapy: A systematic review. Crit Rev Oncol Hematol 90:190-199, 2014. 13. Balducci L, Al-Halawani H, Charu V, et al: Elderly cancer patients receiving chemotherapy benefit from first-cycle pegfilgrastim. Oncologist 12:1416-1424, 2007. 14. Shayne M, Culakova E, Poniewierski MS, et al: Risk factors for in-hospital mortality and prolonged length of stay in older patients with solid tumor malignancies. J Geriatr Oncol 4:310-318, 2013. 15. Cunningham D, Hawkes EA, Jack A, et al: Rituximab plus cyclophosphamide, doxorubicin, vincristine, and

Steven L. Allen, MD,

ter, North Shore-Long Island Jewish Health System in New Hyde Park, New York, and Professor of Medicine at Hofstra North Shore-Long Island Jewish School of Medicine in Hempstead, New York. Dr. Allen has maintained an active clinical practice and has been highly involved in the Society’s practice initiatives for more than 30 years. He currently serves as Chair of the Committee on Practice and is a participant in the ASH Practice Partnership program. Dr. Allen received the ASH Outstanding Service Award in 2006 for his leadership on the ASH Pay-for-Performance Task Force. n

prednisolone in patients with newly diagnosed diffuse large B-cell non-Hodgkin lymphoma: A phase 3 comparison of dose intensification with 14-day versus 21-day cycles. Lancet 381:1817-1826, 2013. 16. Delarue R, Tilly H, Mounier N, et al: Dose-dense rituximab-CHOP compared with standard rituximab-CHOP in elderly patients with diffuse large B-cell lymphoma (the LNH03-6B study): A randomised phase 3 trial. Lancet Oncol 14:525-533, 2013. 17. Sternberg CN, de Mulder P, Schornagel JH, et al: Seven year update of an EORTC phase III trial of high-dose intensity M-VAC chemotherapy and GCSF versus classic M-VAC in advanced urothelial tract tumours. Eur J Cancer 42:50-54, 2006. 18. Cooper KL, Madan J, Whyte S, et al: Granulocyte colony-stimulating factors for febrile neutropenia prophylaxis following chemotherapy: Systematic review and meta-analysis. BMC Cancer 11:404, 2011. 19. Pinto L, Liu Z, Doan Q, et al: Comparison of pegfilgrastim with filgrastim on febrile neutropenia, grade IV neutropenia and bone pain: A meta-analysis of randomized controlled trials. Curr Med Res Opin 23:2283-2295, 2007.

ASCOPost.com | NOVEMBER 10, 2015

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Journal Spotlight Breast Cancer

Improved Overall Survival With Neoadjuvant Plus Adjuvant Bevacizumab in Early HER2-Negative Breast Cancer By Matthew Stenger

he phase III National Surgical Adjuvant Breast and Bowel Project (NSABP) B-40 (NRG Oncology) trial showed that the addition of bevacizumab (Avastin) to docetaxel + anthracycline-based neoadjuvant chemotherapy improved pathologic complete response rate, the primary endpoint,

weeks for 4 cycles. In addition, all patients were randomized to receive or not receive neoadjuvant bevacizumab (15 mg/kg every 3 weeks for the first 6 neoadjuvant cycles) and postoperative bevacizumab for 10 doses. Disease-free survival was a prespecified secondary endpoint; although

The improved overall survival with bevacizumab contradicts the findings of other studies of bevacizumab in breast cancer and may indicate the need for additional investigation of this agent. —Harry D. Bear, MD, PhD, and colleagues

in patients with early HER2-negative breast cancer; the effect appeared to be greatest in women with hormone receptor–positive tumors.1 In a report of secondary outcomes in The Lancet Oncology, Harry D. Bear, MD, PhD, of Virginia Commonwealth University School of Medicine and the Massey Cancer Center, Richmond, Virginia, and colleagues found a nonsignificant increase in disease-free survival and a significant increase in overall survival with the addition of neoadjuvant plus adjuvant bevacizumab, with some evidence of greater benefit in hormone receptor–positive disease.2 The addition of capecitabine or gemcitabine to neoadjuvant chemotherapy did not improve disease-free or overall survival.

Study Details In the 3 × 2 factorial trial, 1,206 patients with clinical stage T1c–3, cN0, cN1, or cN2a disease without distant metastases were randomized between January 2007 and June 2010 to receive 4 cycles of neoadjuvant docetaxel alone (100 mg/m²), with capecitabine (825 mg/m² orally twice daily on days 1–14, docetaxel 75 mg/m²) or with gemcitabine (1,000 mg/m² on days 1 and 8, docetaxel 75 mg/m²). All patients then were given neoadjuvant doxorubicin and cyclophosphamide (60 mg/m² and 600 mg/m²) every 3

overall survival was not, it was prospectively followed. Follow-up data were collected between October 2007 and March 2014 and were available for overall survival in 1,186 patients and for disease-free survival in 1,184 patients (591 with and 593 without bevacizumab).

Disease-Free and Overall Survival Median follow-up was 4.7 years. No significant differences between docetaxel alone vs with capecitabine or gemcitabine were observed in 5-year disease-free survival (hazard ratios [HRs = 1.01, 95% confidence interval [CI] = 0.77–1.33, and 0.90, 95% CI = 0.67–1.19) or 5-year overall survival (HRs = 0.95, 95% CI = 0.68–1.32, and 0.73, 95% CI = 0.51–1.04). The addition of bevacizumab was associated with a borderline increase in

disease-free survival (HR = 0.80, 95% CI = 0.63–1.01, P = .06) and a significant increase in overall survival (HR = 0.65, 95% CI = 0.49–0.88, P = .004). Kaplan-Meier analysis showed increasing separation of the curves between bevacizumab and no bevacizumab starting at 2 years for both disease-free and overall survival. An exploratory analysis suggested a somewhat greater benefit of bevacizumab among patients with hormone receptor–positive tumors (HR = 0.73, P = .05, for disease-free survival; HR = 0.63, P = .03 for overall survival), but the interaction between hormone receptor status and bevacizumab effect was not significant for either outcome. An exploratory analysis of distant recurrence-free interval also showed that the addition of bevacizumab significantly decreased the risk of distant metastasis overall (HR = 0.70, P = .01) and among patients with hormone receptor–positive disease (HR = 0.68, P = .03). The effect of bevacizumab was greater in the groups in which patients received gemcitabine or capecitabine with docetaxel. The interaction between the effect of bevacizumab and the treatment group was significant for distant recurrence-free interval but not for disease-free survival or overall survival.

Toxicity The most common grade 3 or 4 adverse events in the bevacizumab group were neutropenia (17% grade 3, 6% grade 4), hand-foot syndrome (11% grade 3), and hypertension (10% grade 3, < 1% grade 4). The most com-

Revisiting Bevacizumab in Breast Cancer ■■ The addition of capecitabine or gemcitabine to neoadjuvant docetaxelbased chemotherapy did not improve disease-free or overall survival in patients with operable HER2-negative breast cancer, according to the findings of the NSABP B-40 trial. ■■ The addition of neoadjuvant and adjuvant bevacizumab was associated with a nonsignificant increase in disease-free survival and a significant increase in overall survival. ■■ There was some evidence of a greater benefit with bevacizumab in hormone receptor–positive disease.

mon grade 3 or 4 adverse events in the no-bevacizumab group were neutropenia (16% grade 3, 6% grade 4), fatigue (9% grade 3), and hand-foot syndrome (7% grade 3). Four deaths occurred during treatment, due to vascular disorder (docetaxel-capecitabine group), sudden death (docetaxelcapecitabine group), infective endocarditis (docetaxel plus bevacizumab group), and visceral arterial ischemia (docetaxel group). The investigators concluded: “The addition of gemcitabine or capecitabine to neoadjuvant docetaxel plus doxorubicin plus cyclophosphamide does not seem to provide any benefit to patients with operable breast cancer and should not change clinical practice in the short term. The improved overall survival with bevacizumab contradicts the findings of other studies of bevacizumab in breast cancer and may indicate the need for additional investigation of this agent.” They noted: “The pattern of the bevacizumab effect seen here, with the greatest effect being on distant metastases and being proportionately greater beyond 2 years of follow-up, also suggests a predominant effect on occult micrometastases present at the time of diagnosis. This also fits with the preferential effect of bevacizumab in women with hormone-receptor-positive cancers, whose recurrences tend to be later than for patients with triple-negative breast cancer.” n

Disclosure: The study was funded by the National Institutes of Health, Genentech, Roche Laboratories, Lilly Research Laboratories, and Precision Therapeutics. For full disclosures of the study authors, visit www.thelancet.com.

References 1. Bear HD, Tang G, Rastogi P, et al: Bevacizumab added to neoadjuvant chemotherapy for breast cancer. N Engl J Med 366:310-320, 2012. 2. Bear HD, Tang G, Rastogi P, et al: Neoadjuvant plus adjuvant bevacizumab in early breast cancer (NSABP B-40 [NRG Oncology]): Secondary outcomes of a phase 3, randomised controlled trial. Lancet Oncol 16:10371048, 2015.

Survival and Bevacizumab in Early Breast Cancer: Time to Reconsider? See page 46 for a commentary on NSABP B-40 by Jens Huober, MD, PhD, and Beat Thürlimann, MD.

XTANDI (enzalutamide) capsules is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC).

ion s s e r g o r p isease d t a atients I p D r u N o A y T r X o Start RPC f1 C c i t a t s a t to me erapy* h t H R n G on

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*Or af

chie eral or r bilat

Important Safety Information Contraindications XTANDI is not indicated for women and

is contraindicated in women who are or may become pregnant. XTANDI can cause fetal harm when administered to a pregnant woman.

Warnings and Precautions

Seizure In Study 1, conducted in patients with metastatic castrationresistant prostate cancer (CRPC) who previously received docetaxel, seizure occurred in 0.9% of XTANDI patients and 0% of placebo patients. In Study 2, conducted in patients with chemotherapy-naive metastatic CRPC, seizure occurred in 0.1% of XTANDI patients and 0.1% of placebo patients. There is no clinical trial experience readministering XTANDI to patients who experienced a seizure, and limited safety data are available in patients with predisposing factors for seizure. Study 1 excluded the use of concomitant medications that may lower threshold; Study 2 permitted the use of these medications. Because of the risk of seizure associated with XTANDI use, patients should be advised of the risk of engaging in any activity during which sudden loss of consciousness could cause serious harm to themselves or others. Permanently discontinue XTANDI in patients who develop a seizure during treatment.

Posterior Reversible Encephalopathy Syndrome (PRES) In post approval use, there have been reports of PRES in patients receiving XTANDI. PRES is a neurological disorder which can present with rapidly evolving symptoms including seizure, headache, lethargy, confusion, blindness, and other visual and neurological disturbances, with or without associated hypertension. A diagnosis of PRES

requires confirmation by brain imaging, preferably MRI. Discontinue XTANDI in patients who develop PRES.

Adverse Reactions

The most common adverse reactions (≥ 10%) reported from two combined clinical studies that occurred more commonly (≥ 2% over placebo) in XTANDI patients were asthenia/fatigue, back pain, decreased appetite, constipation, arthralgia, diarrhea, hot flush, upper respiratory tract infection, peripheral edema, dyspnea, musculoskeletal pain, weight decreased, headache, hypertension, and dizziness/vertigo. In Study 1, Grade 3 and higher adverse reactions were reported among 47% of XTANDI patients and 53% of placebo patients. Discontinuations due to adverse events were reported for 16% of XTANDI patients and 18% of placebo patients. In Study 2, Grade 3-4 adverse reactions were reported in 44% of XTANDI patients and 37% of placebo patients. Discontinuations due to adverse events were reported for 6% of both study groups. • Lab Abnormalities: Grade 1-4 neutropenia occurred in 15% of XTANDI patients (1% Grade 3-4) and 6% of placebo patients (0.5% Grade 3-4). Grade 1-4 thrombocytopenia occurred in 6% of XTANDI patients (0.3% Grade 3-4) and 5% of placebo patients (0.5% Grade 3-4). Grade 1-4 elevations in ALT occurred in 10% of XTANDI patients (0.2% Grade 3-4) and 16% of placebo patients (0.2% Grade 3-4). Grade 1-4 elevations in bilirubin occurred in 3% of XTANDI patients (0.1% Grade 3-4) and 2% of placebo patients (no Grade 3-4).

Significantly improved radiographic progression-free survival†1

Significantly improved overall survival†‡§1 Updated overall survival analysis: • 23% reduction in risk of death with XTANDI + GnRH therapy* vs placebo + GnRH therapy* (co-primary endpoint: HR = 0.77 [95% CI, 0.67-0.88])

• 83% reduction in risk of radiographic disease progression or death with XTANDI + GnRH therapy* vs placebo + GnRH therapy* (co-primary endpoint: HR = 0.17 [95% CI, 0.14-0.21]; P < 0.0001)

• Median overall survival was 35.3 months with XTANDI + GnRH therapy* (95% CI, 32.2-not reached) vs 31.3 months with placebo + GnRH therapy* (95% CI, 28.8-34.2)

• Median radiographic progression-free survival was not reached (95% CI, 13.8-not reached) for XTANDI + GnRH therapy* and was 3.7 months (95% CI, 3.6-4.6) for placebo + GnRH therapy*

‡At a prespecified interim analysis for overall survival (co-primary endpoint): HR = 0.71 (95% CI, 0.600.84); P < 0.00011

Significantly delayed the time to chemotherapy initiation†1 • Delayed time to chemotherapy initiation by a median of 28.0 months with XTANDI + GnRH therapy* vs 10.8 months with placebo + GnRH therapy* (HR = 0.35 [95% CI, 0.30-0.40]; P < 0.0001)

Oral, once-daily dosing with no required steroid coadministration1 • Dosage: XTANDI 160 mg (four 40 mg capsules) is administered orally, once daily • Steroids were allowed but not required||

patient lives 94% ofareinsured covered for XTANDI

¶3

¶As of February 2015. A product’s placement on a plan formulary involves a variety of factors known only to the plan and is subject to eligibility.

To learn more, please visit XtandiHCP.com

• Infections: In Study 1, 1% of XTANDI patients compared to 0.3% of placebo patients died from infections or sepsis. In Study 2, 1 patient in each treatment group (0.1%) had an infection resulting in death. • Falls (including fall-related injuries), occurred in 9% of XTANDI patients and 4% of placebo patients. Falls were not associated with loss of consciousness or seizure. Fall-related injuries were more severe in XTANDI patients, and included non-pathologic fractures, joint injuries, and hematomas. • Hypertension occurred in 11% of XTANDI patients and 4% of placebo patients. No patients experienced hypertensive crisis. Medical history of hypertension was balanced between arms. Hypertension led to study discontinuation in < 1% of all patients.

Drug Interactions

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

Effect of XTANDI on Other Drugs Avoid CYP3A4, CYP2C9, and CYP2C19 substrates with a narrow therapeutic index, as XTANDI may decrease the plasma exposures of these drugs. If XTANDI is co-administered with warfarin (CYP2C9 substrate), conduct additional INR monitoring. Please see adjacent pages for Brief Summary of Full Prescribing Information. †As seen in the PREVAIL trial (Study 2): a multinational, double-blind, randomized, phase 3 trial that enrolled 1717 patients with metastatic CRPC that progressed on GnRH therapy or after bilateral orchiectomy, and who had not received prior cytotoxic chemotherapy. All patients continued on GnRH therapy.1,2 §Results from this analysis were consistent with those from the prespecified interim analysis. ||In the PREVAIL trial, 27% of patients in the XTANDI arm and 30% of patients in the placebo arm received glucocorticoids for varying reasons. In the AFFIRM trial (Study 1), 48% of patients in the XTANDI arm and 46% of patients in the placebo arm received glucocorticoids. AFFIRM was a phase 3, multicenter, placebo-controlled, randomized trial that enrolled 1199 patients with metastatic CRPC who had previously received docetaxel.1 References: 1. XTANDI [package insert]. Northbrook, IL: Astellas Pharma US, Inc. 2. Beer TM, Armstrong AJ, Rathkopf DE, et al, for the PREVAIL Investigators. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med. 2014;371:424-433. 3. Data on file, Medivation, Inc.

The ASCO Post | NOVEMBER 10, 2015

PAGE 44

Announcements

UCLA and VA Launch Program to Enhance Cancer Care for Veterans

new collaboration between the University of California, Los Angeles (UCLA) and the Veterans Affairs (VA) Greater Los Angeles Healthcare System will provide access to the latest therapeutic cancer clinical trials and state-of-the-art care for men and women

who have served in the armed forces. The Operation Mend Project to Enhance Cancer Care for Veterans will involve three UCLA entities: the Jonsson Comprehensive Cancer Center, the Ronald A. Katz Center for Collaborative Military Medicine, and Operation Mend.

XTANDI® (enzalutamide) capsules for oral use Initial U.S. Approval: 2012 BRIEF SUMMARY OF PRESCRIBING INFORMATION The following is a brief summary. Please see the package insert for full prescribing information. INDICATIONS AND USAGE XTANDI is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC). CONTRAINDICATIONS Pregnancy XTANDI can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. XTANDI is not indicated for use in women. XTANDI is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss. WARNINGS AND PRECAUTIONS Seizure In Study 1, which enrolled patients who previously received docetaxel, 7 of 800 (0.9%) patients treated with XTANDI experienced a seizure and no patients treated with placebo experienced a seizure. Seizure occurred from 31 to 603 days after initiation of XTANDI. In Study 2, 1 of 871 (0.1%) chemotherapy-naive patients treated with XTANDI and 1 of 844 (0.1%) patients treated with placebo experienced a seizure. Patients experiencing seizure were permanently discontinued from therapy and all seizure events resolved. There is no clinical trial experience re-administering XTANDI to patients who experienced seizure. Limited safety data are available in patients with predisposing factors for seizure because these patients were generally excluded from the trials. These exclusion criteria included a history of seizure, underlying brain injury with loss of consciousness, transient ischemic attack within the past 12 months, cerebral vascular accident, brain metastases, and brain arteriovenous malformation. Study 1 excluded the use of concomitant medications that may lower the seizure threshold, whereas Study 2 permitted the use of these medications. Because of the risk of seizure associated with XTANDI use, patients should be advised of the risk of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others. Permanently discontinue XTANDI in patients who develop a seizure during treatment. Posterior Reversible Encephalopathy Syndrome (PRES) There have been reports of posterior reversible encephalopathy syndrome (PRES) in patients receiving XTANDI [see Adverse Reactions (6.2)]. PRES is a neurological disorder which can present with rapidly evolving symptoms including seizure, headache, lethargy, confusion, blindness, and other visual and neurological disturbances, with or without associated hypertension. A diagnosis of PRES requires confirmation by brain imaging, preferably magnetic resonance imaging (MRI). Discontinue XTANDI in patients who develop PRES. ADVERSE REACTIONS Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Two randomized clinical trials enrolled patients with metastatic prostate cancer that has progressed on androgen deprivation therapy (GnRH therapy or bilateral orchiectomy), a disease setting that is also defined as metastatic CRPC. In both studies, patients received XTANDI 160 mg orally once daily in the active treatment arm or placebo in the control arm. All patients continued androgen deprivation therapy. Patients were allowed, but not required, to take glucocorticoids. The most common adverse reactions (≥ 10%) that occurred more commonly (≥ 2% over placebo) in the

Veterans have a higher-than-normal risk for many types of cancer, but administrative and financial hurdles often prevent them from having access to clinical trials outside of the VA health-care system where promising new cancer treatments are beXTANDI-treated patients from the two randomized clinical trials were asthenia/fatigue, back pain, decreased appetite, constipation, arthralgia, diarrhea, hot flush, upper respiratory tract infection, peripheral edema, dyspnea, musculoskeletal pain, weight decreased, headache, hypertension, and dizziness/vertigo. Study 1: Metastatic Castration-Resistant Prostate Cancer Following Chemotherapy Study 1 enrolled 1199 patients with metastatic CRPC who had previously received docetaxel. The median duration of treatment was 8.3 months with XTANDI and 3.0 months with placebo. During the trial, 48% of patients on the XTANDI arm and 46% of patients on the placebo arm received glucocorticoids. Grade 3 and higher adverse reactions were reported among 47% of XTANDI-treated patients and 53% of placebo-treated patients. Discontinuations due to adverse events were reported for 16% of XTANDI-treated patients and 18% of placebo-treated patients. The most common adverse reaction leading to treatment discontinuation was seizure, which occurred in 0.9% of the XTANDI-treated patients compared to none (0%) of the placebo-treated patients. Table 1 shows adverse reactions reported in Study 1 that occurred at a ≥ 2% higher frequency in the XTANDI arm compared to the placebo arm. Table 1. Adverse Reactions in Study 1 XTANDI Placebo N = 800 N = 399 Grade Grade Grade Grade a 3-4 1-4 3-4 1-4 (%) (%) (%) (%) General Disorders Asthenic 50.6 9.0 44.4 9.3 Conditionsb Peripheral 15.4 1.0 13.3 0.8 Edema Musculoskeletal And Connective Tissue Disorders Back Pain 26.4 5.3 24.3 4.0 Arthralgia 20.5 2.5 17.3 1.8 Musculoskeletal 15.0 1.3 11.5 0.3 Pain Muscular 9.8 1.5 6.8 1.8 Weakness Musculoskeletal 2.6 0.3 0.3 0.0 Stiffness Gastrointestinal Disorders Diarrhea 21.8 1.1 17.5 0.3 Vascular Disorders Hot Flush 20.3 0.0 10.3 0.0 Hypertension 6.4 2.1 2.8 1.3 Nervous System Disorders Headache 12.1 0.9 5.5 0.0 Dizzinessc 9.5 0.5 7.5 0.5 Spinal Cord Compression and Cauda 7.4 6.6 4.5 3.8 Equina Syndrome Paresthesia 6.6 0.0 4.5 0.0 Mental Impairment 4.3 0.3 1.8 0.0 Disordersd Hypoesthesia 4.0 0.3 1.8 0.0 Infections And Infestations Upper Respiratory 10.9 0.0 6.5 0.3 Tract Infectione Lower Respiratory 8.5 2.4 4.8 1.3 Tract And Lung Infectionf Psychiatric Disorders Insomnia 8.8 0.0 6.0 0.5 Anxiety 6.5 0.3 4.0 0.0 Renal And Urinary Disorders Hematuria 6.9 1.8 4.5 1.0 Pollakiuria 4.8 0.0 2.5 0.0 Injury, Poisoning And Procedural Complications Fall 4.6 0.3 1.3 0.0 Non-pathologic 4.0 1.4 0.8 0.3 Fractures Skin And Subcutaneous Tissue Disorders Pruritus 3.8 0.0 1.3 0.0 Dry Skin 3.5 0.0 1.3 0.0

ing tested, said F airooz Kabbinavar, MD, FACP, Professor of Hematology and Oncology at UCLA and a coleader of the new program. The 2-year project will provide a streamlined and patient-friendly system that will allow Los Angeles–area Table 1. Adverse Reactions in Study 1 (cont.) Respiratory Disorders Epistaxis 3.3 0.1 1.3

0.3

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

Study 2: Chemotherapy-naive Metastatic CastrationResistant Prostate Cancer Study 2 enrolled 1717 patients with metastatic CRPC who had not received prior cytotoxic chemotherapy, of whom 1715 received at least one dose of study drug. The median duration of treatment was 17.5 months with XTANDI and 4.6 months with placebo. Grade 3-4 adverse reactions were reported in 44% of XTANDI-treated patients and 37% of placebo-treated patients. Discontinuations due to adverse events were reported for 6% of XTANDI-treated patients and 6% of placebo-treated patients. The most common adverse reaction leading to treatment discontinuation was fatigue/asthenia, which occurred in 1% of patients on each treatment arm. Table 2 includes adverse reactions reported in Study 2 that occurred at a ≥ 2% higher frequency in the XTANDI arm compared to the placebo arm. Table 2. Adverse Reactions in Study 2 Placebo XTANDI N = 844 N = 871 Grade Grade Grade Grade 1-4 3-4 3-4 1-4a (%) (%) (%) (%) General Disorders Asthenic 33.0 46.9 3.4 2.8 Conditionsb Peripheral 8.2 11.5 0.2 0.4 Edema Musculoskeletal And Connective Tissue Disorders 22.4 Back Pain 28.6 2.5 3.0 16.1 Arthralgia 21.4 1.6 1.1 Gastrointestinal Disorders 17.3 Constipation 23.2 0.7 0.4 14.3 Diarrhea 16.8 0.3 0.4 Vascular Disorders 7.8 Hot Flush 18.0 0.1 0.0 4.1 Hypertension 14.2 7.2 2.3 Nervous System Disorders 7.1 11.3 0.3 0.0 Dizzinessc 7.0 Headache 11.0 0.2 0.4 3.7 Dysgeusia 7.6 0.1 0.0 Mental 1.3 5.7 0.0 0.1 Impairment Disordersd Restless Legs 0.4 2.1 0.1 0.0 Syndrome Respiratory Disorders 8.5 11.0 0.6 0.6 Dyspneae Infections And Infestations Upper 10.5 0.0 0.0 Respiratory Tract 16.4 Infectionf Lower Respiratory 4.7 7.9 1.5 1.1 Tract And Lung Infectiong Psychiatric Disorders 5.7 Insomnia 8.2 0.1 0.0 Renal And Urinary Disorders 5.8 Hematuria 8.8 1.3 1.3 Injury, Poisoning And Procedural Complications 5.3 Fall 12.7 1.6 0.7 Non-Pathological 3.0 8.8 2.1 1.1 Fracture Metabolism and Nutrition Disorders Decreased 16.4 18.9 0.3 0.7 Appetite Investigations Weight 8.5 12.4 0.8 0.2 Decreased Reproductive System and Breast Disorders 1.4 Gynecomastia 3.4 0.0 0.0

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veterans to enroll in early-phase cancer treatment trials being led by UCLA scientists. It is the first time that Southern California veterans will have access to these clinical trials directly through the local VA, and it is the nation’s first program to bring experimental cancerrelated treatments to veterans. “We are gratified and excited that we Table 2. Adverse Reactions in Study 2 (cont.)

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

Laboratory Abnormalities In the two randomized clinical trials, Grade 1-4 neutropenia occurred in 15% of patients treated with XTANDI (1% Grade 3-4) and in 6% of patients treated with placebo (0.5% Grade 3-4). The incidence of Grade 1-4 thrombocytopenia was 6% of patients treated with XTANDI (0.3% Grade 3-4) and 5% of patients treated with placebo (0.5% Grade 3-4). Grade 1-4 elevations in ALT occurred in 10% of patients treated with XTANDI (0.2% Grade 3-4) and 16% of patients treated with placebo (0.2% Grade 3-4). Grade 1-4 elevations in bilirubin occurred in 3% of patients treated with XTANDI (0.1% Grade 3-4) and 2% of patients treated with placebo (no Grade 3-4). Infections In Study 1, 1% of patients treated with XTANDI compared to 0.3% of patients treated with placebo died from infections or sepsis. In Study 2, 1 patient in each treatment group (0.1%) had an infection resulting in death. Falls and Fall-related Injuries In the two randomized clinical trials, falls including fallrelated injuries, occurred in 9% of patients treated with XTANDI compared to 4% of patients treated with placebo. Falls were not associated with loss of consciousness or seizure. Fall-related injuries were more severe in patients treated with XTANDI and included non-pathologic fractures, joint injuries, and hematomas. Hypertension In the two randomized trials, hypertension was reported in 11% of patients receiving XTANDI and 4% of patients receiving placebo. No patients experienced hypertensive crisis. Medical history of hypertension was balanced between arms. Hypertension led to study discontinuation in < 1% of patients in each arm. Post-Marketing Experience The following additional adverse reactions have been identified during post approval use of XTANDI. Because these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure. Neurological Disorders: posterior reversible encephalopathy syndrome (PRES) DRUG INTERACTIONS Drugs that Inhibit or Induce CYP2C8 Co-administration of a strong CYP2C8 inhibitor (gemfibrozil) increased the composite area under the plasma concentration-time curve (AUC) of enzalutamide plus N-desmethyl enzalutamide by 2.2-fold in healthy volunteers. Co-administration of XTANDI with strong CYP2C8 inhibitors should be avoided if possible. If co-administration of XTANDI with a strong CYP2C8 inhibitor cannot be avoided, reduce the dose of XTANDI. The effects of CYP2C8 inducers on the pharmacokinetics of enzalutamide have not been evaluated in vivo. Coadministration of XTANDI with strong or moderate CYP2C8 inducers (e.g., rifampin) may alter the plasma exposure of XTANDI and should be avoided if possible. Selection of a concomitant medication with no or minimal CYP2C8 induction potential is recommended. Drugs that Inhibit or Induce CYP3A4 Co-administration of a strong CYP3A4 inhibitor (itraconazole) increased the composite AUC of enzalutamide plus N-desmethyl enzalutamide by 1.3-fold in healthy volunteers. The effects of CYP3A4 inducers on the pharmacokinetics of enzalutamide have not been evaluated in vivo. Coadministration of XTANDI with strong CYP3A4 inducers (e.g., carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine) may decrease the plasma exposure of XTANDI and should be avoided if possible. Selection of a concomitant medication with no or minimal CYP3A4 induction potential is recommended. Moderate CYP3A4 inducers (e.g., bosentan, efavirenz, etravirine, modafinil, nafcillin) and St. John’s Wort may also reduce the plasma

will be able to extend novel and innovative cancer treatments to our veterans for many of the common cancers that they face, such as lung, kidney, and prostate cancers,” said Dennis Slamon, MD, PhD, Director of Clinical and Translational Research at the Jonsson Cancer Center and the program’s other coleader. To facilitate these efforts for veter-

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

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

USE IN SPECIFIC POPULATIONS

OVERDOSAGE

Pregnancy- Pregnancy Category X. Risk Summary XTANDI can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. While there are no human data on the use of XTANDI in pregnancy and XTANDI is not indicated for use in women, it is important to know that maternal use of an androgen receptor inhibitor could affect development of the fetus. Enzalutamide caused embryo-fetal toxicity in mice at exposures that were lower than in patients receiving the recommended dose. XTANDI is contraindicated in women who are or may become pregnant while receiving the drug. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss. Advise females of reproductive potential to avoid becoming pregnant during treatment with XTANDI. Animal Data In an embryo-fetal developmental toxicity study in mice, enzalutamide caused developmental toxicity when administered at oral doses of 10 or 30 mg/kg/day throughout the period of organogenesis (gestational days 6-15). Findings included embryo-fetal lethality (increased post-implantation loss and resorptions) and decreased anogenital distance at ≥ 10 mg/kg/day, and cleft palate and absent palatine bone at 30 mg/kg/day. Doses of 30 mg/kg/day caused maternal toxicity. The doses tested in mice (1, 10 and 30 mg/kg/day) resulted in systemic exposures (AUC) approximately 0.04, 0.4 and 1.1 times, respectively, the exposures in patients. Enzalutamide did not cause developmental toxicity in rabbits when administered throughout the period of organogenesis (gestational days 6-18) at dose levels up to 10 mg/kg/ day (approximately 0.4 times the exposures in patients based on AUC). Nursing Mothers XTANDI is not indicated for use in women. It is not known if enzalutamide is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from XTANDI, a decision should be made to either discontinue nursing, or discontinue the drug taking into account the importance of the drug to the mother. Pediatric Use Safety and effectiveness of XTANDI in pediatric patients have not been established. Geriatric Use Of 1671 patients who received XTANDI in the two randomized clinical trials, 75% were 65 and over, while 31% were 75 and over. No overall differences in safety or effectiveness were observed between these patients and younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Patients with Renal Impairment A dedicated renal impairment trial for XTANDI has not been conducted. Based on the population pharmacokinetic analysis using data from clinical trials in patients with metastatic CRPC and healthy volunteers, no significant difference in enzalutamide clearance was observed in patients with pre-existing mild to moderate renal impairment (30 mL/min ≤ creatinine clearance [CrCL] ≤ 89 mL/min) compared to patients and volunteers with baseline normal renal function (CrCL ≥ 90 mL/min). No initial dosage adjustment is necessary for patients with mild to moderate renal impairment. Severe renal impairment (CrCL < 30 mL/min) and end-stage renal

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

Dennis Slamon, MD, PhD

ans, the VA Greater Los Angeles Healthcare System and the Jonsson Cancer Center will provide doctors with stateof-the-art patient clinics, diagnostic procedures, and laboratories. Matthew Rettig, MD, its Chief of Hematology and Oncology, who also is a member of the Jonsson Cancer Center, is directing the VA system’s participation.

NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal studies have not been conducted to evaluate the carcinogenic potential of enzalutamide. Enzalutamide did not induce mutations in the bacterial reverse mutation (Ames) assay and was not genotoxic in either the in vitro mouse lymphoma thymidine kinase (Tk) gene mutation assay or the in vivo mouse micronucleus assay. Based on nonclinical findings in repeat-dose toxicology studies, which were consistent with the pharmacological activity of enzalutamide, male fertility may be impaired by treatment with XTANDI. In a 26-week study in rats, atrophy of the prostate and seminal vesicles was observed at ≥ 30 mg/kg/day (equal to the human exposure based on AUC). In 4-, 13-, and 39-week studies in dogs, hypospermatogenesis and atrophy of the prostate and epididymides were observed at ≥ 4 mg/kg/day (0.3 times the human exposure based on AUC). Manufactured by: Catalent Pharma Solutions, LLC, St. Petersburg, FL 33716 Manufactured for and Distributed by: Astellas Pharma US, Inc., Northbrook, IL 60062 Marketed by: Astellas Pharma US, Inc., Northbrook, IL 60062 Medivation, Inc., San Francisco, CA 94105 Revised: August 2015 14L082-XTA

Matthew Rettig, MD

Funding and staffing for the project are provided thanks to a generous donation through the Ronald A. Katz Center for Collaborative Military Medicine and Operation Mend, which provide reconstructive surgery and medical care to members of the military who have been wounded in battle or training. Founded in 2007 by philanthropist Ronald A. Katz and his late wife, Maddie, UCLA’s Operation Mend is a part of the Katz Center, which serves as a nexus for the university’s many research projects and support programs designed to help America’s service members and their families.

076-1119-PM

Ronald A. Katz

“We are delighted to support this innovative effort,” Mr. Katz said. “There are more than 21 million veterans living in the United States today, and nearly half of them are 65 years of age or older. However, there is no effective system currently available to provide them access to therapeutic cancer clinical trials, even when they have exhausted all forms of conventional therapy.” n

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Continued from page 41

Survival and Bevacizumab in Early Breast Cancer: Time to Reconsider? By Jens Huober, MD, and Beat Thürlimann, MD

n metastatic HER2-negative breast cancer, several trials have shown that the addition of the anti–vascular endothelial growth factor (VEGF) monoclonal antibody bevacizumab (Avastin) to different chemotherapy regimens significantly improved response rates and progression-free survival by various magnitudes compared to chemotherapy alone.1 Even though these trials failed to show an increase in overall survival with the addition of bevacizumab in metastatic disease, there has been considerable interest in evaluating bevacizumab in both the neoadjuvant and adjuvant settings.

HER2-negative disease and both hormone receptor–positive and hormone receptor–negative disease. In both trials, bevacizumab was added to chemotherapy, and after completing chemotherapy, patients were randomly assigned to receive or not receive single-agent bevacizumab for a

Dr. Huober is Professor and Head of the Breast Center, Department of Gynecology and Obstetrics, University of Ulm, Germany, and Dr. Thürlimann is Professor and Head of the Breast Center, Cantonal Hospital St. Gallen, Switzerland.

Since bevacizumab is a targeted antiangiogenic agent, it is potentially less likely to eradicate micrometastatic disease—eg, in the bone marrow—whereas a manifest tumor in the breast, which is angiogenesisdependent, may be more effectively treated by additional antiangiogenic therapy. This activity is reflected by the increased pathologic complete response rate with the use of bevacizumab in all neoadjuvant trials. Once the relatively short neoadjuvant treatment is completed, there might be a rebound of tumor cell growth. Thus, continuous bevacizumab treatment after surgery might be a better strategy to prevent this phenomenon. However, the negative results of the adjuvant trials do not fully support this hypothesis. If the effect of bevacizumab in terms of overall survival in the NSABP B-40 is real, we may speculate that it is the combination of neoadjuvant and adjuvant application that is achieving this outcome.

Other Study Differences

Disappointing Findings

Further differences among trials are that all trials used different chemo-

The so far contradictory or overall negative results of bevacizumab

[S]o far, there is still no role for bevacizumab in the adjuvant or neoadjuvant setting in patients with HER2-negative breast cancer outside of clinical trials.

Four Trials So far, we have data from four randomized phase III trials investigating bevacizumab in the neoadjuvant setting.2-5 All used pathologic complete response rate as the primary endpoint, albeit with different definitions of pathologic complete response (see Table 1). The common observation in all four trials (GeparQuinto, National Surgical Adjuvant Breast and Bowel Project [NSABP] B-40, ARTemis, and Cancer and Leukemia Group B [CALGB] 40603) was that the pathologic complete response rate could be modestly but significantly increased with the addition of bevacizumab to anthracycline/taxane–based chemotherapy, with statistical significance being reached probably due to the high numbers of enrolled patients. Until now, survival outcome data were only available for the GeparQuinto trial, which showed no significant improvement in disease-free survival or overall survival with the addition of neoadjuvant bevacizumab among all patients or those with triple-negative disease.6 The role of bevacizumab in HER2negative disease was also investigated in two big randomized phase III adjuvant trials7,8: The BEATRICE trial enrolled 2,591 patients with only triple-negative disease, and the E5103 study recruited 4,994 patients with

therapy backbones and that both the NSABP B-40 and CALGB 40603 trials had factorial designs in which modifications of the chemotherapy regimens were tested in parallel with the addition of bevacizumab. In the GeparQuinto trial, patients with no clinical response after the first four cycles of epirubicin and cyclophosphamide were removed from the study, potentially introducing bias. Moreover, the cutoff point for estrogen receptor–positive disease was different in the various trials. In addition, there are some major caveats in the interpretation of the NSABP B-40 trial. The endpoints of distant diseasefree survival and overall survival were not prespecified, and thus there were no preplanned statistical calculations for these outcomes. Further, disease-free survival was not significantly different in the B-40 trial between the bevacizumab and no-bevacizumab group (HR = 0.80, 95% CI = 0.63–1.01, P = .06). Since in almost all adjuvant trials, an improvement in overall survival is accompanied by an improvement in diseasefree survival, this observation in the B-40 trial is difficult to explain. Moreover, in the GeparQuinto and ARTemis trials, improved pathologic complete response rates were mainly observed in triple-negative patients but not in the hormone receptor–positive population. This finding is supported by the results of CALGB 40603 (which enrolled patients with triple-negative disease only). Contrary to these three studies, in the B-40 trial, the addition of bevacizumab increased the pathologic complete response rates in patients with hormone receptor–positive breast cancers but not in triple-negative disease. An exploratory analysis suggested somewhat greater benefit of bevacizumab among patients with hormone receptor–positive tumors, even though the interaction was not significant. No such difference regarding hormone-receptor status could be seen in the adjuvant E5103 trial, which included patients with both hormone receptor–positive and hormone receptor–negative disease.

in the other trials, bevacizumab was given purely as either adjuvant or neoadjuvant treatment, patients in the NSABP B-40 trial received both neoadjuvant bevacizumab (for the first six cycles of chemotherapy) and adjuvant bevacizumab, for 10 additional doses every 3 weeks postoperatively.

—Jens Huober, MD (top), and Beat Thürlimann, MD

total duration of 1 year. Neither trial showed improvement in disease-free survival or overall survival with the addition of 1 year of bevacizumab to adjuvant chemotherapy. In contrast to the GeparQuinto study and the two big adjuvant trials, the recently published secondary outcome data of the neoadjuvant NSABP B-40 trial surprisingly reported a significant increase in overall survival (hazard ratio [HR] = 0.65, 95% confidence interval [CI] = 0.49–0.88, P = .004) with the addition of neoadjuvant plus adjuvant bevacizumab, with some evidence of greater benefit in hormone receptor–positive disease.9 The trial, reported by Bear and colleagues in the Lancet Oncology, is summarized in this issue of The ASCO Post.

Explaining the Different Results Different trial designs and methodologic issues may explain the difference in the trial results. A major difference between the NSABP B-40 trial and the other neoadjuvant and adjuvant trials is the use of bevacizumab pre- and postoperatively. Whereas

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trials may come as a disappointment for many. Trials that investigate targeting drugs in populations without identified targets have been a large part of clinical research in the past 2 decades and have proven to be unsuccessful in most cases. Meta-analysis of such trials can identify the effects of bevacizumab in similar subgroups of the patient populations in the abovementioned studies, but the heterogeneity of other patient characteristics, treatment regimens, and treatment durations in these trials will limit the validity and value of the findings. Neoadjuvant trials offer a unique opportunity to investigate activity of different treatment regimens and, in conjunction, to harvest pre- and posttreatment tumor samples and to collect liquid biopsy samples. Translational studies allow us to look for predictors of efficacy (eg, with bevacizumab) and to gain further insight into the molecular mechanisms of action and resistance. Predictors of efficacy of bevacizumab identified in translational studies may foster new trials of this drug in defined subgroups. However, so far, there is still no role for bevacizumab in the adjuvant or neoadjuvant setting in patients with HER2-negative breast cancer outside of clinical trials. n Disclosure: Dr. Huober has received consultation fees from Roche and GlaxoSmithKline, research funding from GlaxoSmithKline, and travel support from Roche. Dr. Thürlimann holds stock in Roche and has received consultation honoraria and travel support from Roche.

References 1. Miles DW, Dieras V, Cortes J, et al: First-line bevacizumab in combination with chemotherapy for HER2-negative metastatic breast cancer: Pooled and

Table 1: Outcomes in Neoadjuvant Bevacizumab Trials in Breast Cancer Trial (definition of pCR)

pCR in all patients

pCR in ER/PR–positive patients

pCR in ER– and PR–negative patients

GeparQuinto (ypT0, ypN0)

Disease-free survival

Overall survival

3 yr

Bevacizumab

18.4%

7.7%

39.9%

80.8%

90.7%

No bevacizumab

14.9%

7.8%

27.9%

81.5%

88.7%

Bevacizumab

34.5%

23.2%

51.1%

HR = 0.8, P = .06

HR = 0.65, P = .004

No bevacizumab

28.2%

15.1%

47.1% Not reported

Not reported

NSABP B-40 (ypT0, any pN)

ARTemis (ypT0, ypTis, ypN0) Bevacizumab

22.0%

6.0%

45.0%

No bevacizumab

17.0%

7.0%

31.0%

All patients triple-negative

Not applicable

CALGB 40603 (ypT0, any pN) Bevacizumab

59%

No bevacizumab

48%

ER = estrogen receptor, HR = hazard ratio, pCR = pathologic complete response, PR = progesterone receptor.

subgroup analyses of data from 2447 patients. Ann Oncol 24:2773-2280, 2013. 2. von Minckwitz G, Eidtmann H, Rezai M, et al: Neoadjuvant chemotherapy and bevacizumab for HER2negative breast cancer. N Engl J Med 366: 299-309, 2012. 3. Bear HD, Tang G, Rastogi P, et al: Bevacizumab added to neoadjuvant chemotherapy for breast cancer. N Engl J Med 366:310-320, 2012. 4. Earl HM, Hiller L, Dunn JA, et al: Efficacy of neoadjuvant bevacizumab added to docetaxel followed by fluorouracil, epirubicin, and cyclophosphamide, for women with HER2-negative early breast cancer (ARTemis): An open-label, randomised, phase 3 trial.

Lancet Oncol 16:656-666, 2015. 5. Sikov WM, Berry DA, Perou CM, et al: Impact of the addition of carboplatin and/or bevacizumab to neoadjuvant once-per-week paclitaxel followed by dose-dense doxorubicin and cyclophosphamide on pathologic complete response rates in stage II to III triplenegative breast cancer: CALGB 40603 (Alliance). J Clin Oncol 33:13-21, 2015. 6. von Minckwitz G, Loibl S, Untch M, et al: Survival after neoadjuvant chemotherapy with or without bevacizumab or everolimus for HER2-negative primary breast cancer (GBG 44-GeparQuinto). Ann Oncol 25:2363-2372, 2014. 7. Cameron D, Brown J, Dent R, et

al: Adjuvant bevacizumab-containing therapy in triple-negative breast cancer (BEATRICE): Primary results of a randomised, phase 3 trial. Lancet Oncol 14:933-942, 2013. 8. Miller K, O`Neill AM, Dang CT, et al: Bevacizumab in the adjuvant treatment of HER2 negative breast cancer: Final results from Eastern Cooperative Oncology Group E5103. 2014 ASCO Annual Meeting. Abstract 500. 9. Bear HD, Tang G, Rastogi P, et al: Neoadjuvant plus adjuvant bevacizumab in early breast cancer (NSABP B-40 [NRG Oncology]): Secondary outcomes of a phase 3, randomised controlled trial. Lancet Oncol 16:10371048, 2015.

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The ASCO Post | NOVEMBER 10, 2015

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Adolescent and Young Adult Oncology Melanoma

Why Melanoma Rates Are Increasing in Adolescents and Young Adults, Especially Among Females

A Conversation With Demytra Mitsis, MD, and Nikhil I. Khushalani, MD By Jo Cavallo

he incidence of melanoma among children, adolescents, and young adults has reached epidemic proportions, increasing more than 250% over the past 4 decades, with young females at highest risk for the deadly cancer, according to a study1 by researchers at Roswell Park Cancer Institute in Buffalo, New York. According to the Skin Cancer Foundation, melanoma is the most common cancer for young adults aged 25 to 29 and the second most common form of cancer for people aged 15 to 29.2

risk for developing the cancer? Dr. Mitsis: We initially did the study because we had noticed an increasing proportion of young patients in their 20s and 30s diagnosed with melanoma establishing care in our clinic at Roswell Park Cancer Institute. We wanted to investigate the incidence and survival trends in this age group over the past few decades. Our results were staggering, not just in the increasing number of cases of melanoma during this time frame, but in the rapid rise specifically in young females.

We want to raise awareness among oncology practitioners and the general public that there has been a rapid rise in the incidence of melanoma in [adolescents and young adults] and that the ratio of incidence in females to males is increasing…. —Demytra Mitsis, MD

While excessive unprotected sun exposure and the use of commercial tanning beds are two of the major culprits in the increasing rates of melanoma in this age group, other factors may be at play, including genetics, according to two of the study’s authors, Demytra Mitsis, MD, Fellow in the Department of Medical Oncology at Roswell Park Cancer Institute, and Nikhil I. Khushalani, MD, Associate Member of the Cutaneous Oncology Program at Moffitt Cancer Center in Tampa, Florida. The ASCO Post talked with Drs. Mitsis and Khushalani about the results of this important study, which was recognized with an ASCO Merit Award during the 2015 ASCO Annual Meeting. The authors also discussed the need for better prevention and screening strategies for melanoma in the adolescent and young adult population as well as for more research in the biology of melanoma in this age group.

Tanning Bed Connection? Your study found that a disproportionate number—over 60%—of adolescents and young adults diagnosed with melanoma are female. Do you know why young women are at greater

We know that the use of commercial tanning beds has become popular over the past few decades, and this is likely a contributing factor to the increase in melanoma incidence that we saw. Over 70% of tanning salon patrons in 2013 were Caucasian girls and women primarily aged 15 to 29.3 Looking at our data, the median age range in our female adolescent/young adult group diagnosed with melanoma was 32, so it is definitely a concerning finding. Recently, a number of states, including California, Delaware, District of Columbia, Illinois, Louisiana, Minnesota, Nevada, New Hampshire, North Carolina, Oregon, Texas, and Vermont have banned the use of tanning beds for minors under age 18, and it will be interesting to see if the incidence of melanoma in this age group changes over the next decades.

Other Factors Is ultraviolet (UV) radiation from excessive sun exposure and tanning bed use, while not taking enough sun protection measures, the main reason for the high incidence of melanoma in this population? Dr. Mitsis: It is, but other factors may also be at play. Large studies have

been done in Australia, which has one of the highest rates of melanoma in young people, and they found that nevi, facial freckling, family history, and eye color were also associated with an increased risk of developing melanoma. So, genetic predisposition may also be a primary determinant. It is important to reinforce that the risk of developing melanoma in younger patients is likely the result of an interaction between genetic and environmental factors. Our study was not a case-control analysis, but there are definitely data showing that in the adolescent and young adult group, an individual with a susceptible pigmentary trait or a family history of melanoma may be more susceptible to developing melanoma.

Biologic Differences Are melanomas in adolescents and young adults biologically different from these tumors in older adults? Dr. Khushalani: The question really is: Is there an inherent difference in the biology among children, young adults, and older adults? And the simple answer is we do not know yet. Part of the reason for that lack of knowledge is because we don’t traditionally consider melanoma to be a common disease in young children or young adults. A study4 by researchers at Moffitt Cancer Center, which looked at data on about 120 patients aged 29 and younger, found that melanomas in children are deeper and thicker and are associated with a higher incidence of lymph node metastases—almost double the rate you would see in adults. In adults, the incidence of lymph node metastases is roughly between 12% and 15%, whereas in children, it was about 30%, which biologically makes sense because deeper melanomas do have a higher preponderance of spreading to lymph nodes. What I infer from that study is that we are not diagnosing these patients at an early enough stage, so we need better screening and prevention strategies in this age group. That will take more public education about the risk of skin cancer in young people. The good news is that despite the study results showing a higher incidence of lymph node metastases in

Brandon Hayes-Lattin, MD, FACP

GUEST EDITOR

dolescent and Young Adult Oncology explores the unique physical, psychosocial, social, emotional, sexual, and financial challenges adolescents and young adults with cancer face. The column is guest edited by Brandon Hayes-Lattin, MD, FACP, Associate Professor of Medicine and Medical Director of the Adolescent and Young Adult Oncology Program at the Knight Cancer Institute at Oregon Health and Science University in Portland; Senior Medical Advisor to the LIVESTRONG Foundation; and Chief Medical Officer of Critical Mass: The Young Cancer Alliance.

those children, their survivorship rate was actually very good, even better than for adults. So the researchers’ conclusions were that you should treat adolescents and young adults with melanoma as you would an adult, and you should treat the cancer aggressively. What we are learning about melanoma in this population is that the incidence is definitely increasing, and you have to ask why. Is it that more children and young adults are getting melanoma, or is it that we are getting better at diagnosing this cancer and picking it up earlier? This is clearly an area that has to be explored.

Research and Treatment Please talk about the need for more research in this age group and for better skin cancer prevention and treatment strategies. Dr. Mitsis: Looking at the design of future studies, we definitely need continued translational and molecu-

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Adolescent and Young Adult Oncology lar research to investigate the specific differences in melanoma in young and older adults. Some very preliminary microRNA profiling data have been used in attempts to answer this very question, with the ultimate goal of finding useful biomarkers that predict outcome in the adolescent and young adult age group. We are not quite there yet, but this is an exciting time for melanoma research in this population. Dr. Khushalani: There is no question that this is a public health problem that needs to be tackled. At least in a good majority of patients, this is such a preventable disease. We all like to be out in the sun, but we need to protect ourselves and our children from the sun’s UV rays and to know the signs of a mole or skin lesion changing to melanoma, because this is a disease where an increase in depth of even just 1 mm can be a matter of life and death. People always wonder how a mole that is only 2 or 3 mm deep can cause so much havoc. But that is the unfortunate truth about the biology of melanoma.

Screening Guidelines Are there screening guidelines for melanoma and other skin cancers? Dr. Mitsis: Currently, the U.S. Preventive Services Task Force has no official screening guidelines for

skin cancer in adolescents and young adults. People should be aware of skin changes. Examining skin regularly and seeking medical attention with evidence of changing moles or new moles with abnormal features are important.

lic that there has been a rapid rise in the incidence of melanoma in this age group and that the ratio of incidence in females to males is increasing, so young Caucasian females especially need to do whatever they can to reduce their risk factors for this cancer. It is wonder-

People always wonder how a mole that is only 2 or 3 mm deep can cause so much havoc. But that is the unfortunate truth about the biology of melanoma. —Nikhil I. Khushalani, MD

Preventing these cancers from occurring in the first place is the goal. Teaching sun safety education to children and adolescents so they develop effective prevention strategies is key. Avoiding commercial tanning beds as described earlier is also a message we need to send to young people.

Closing Thoughts Is there anything else you would like oncologists to know about the prevalence of melanoma in the adolescent and young adult population? Dr. Mitsis: Most importantly, we want to raise awareness among oncology practitioners and the general pub-

ful that survival rates in adolescents and young adults have improved, but we would really like to see fewer cases of this cancer. There is a need for more research investigating the specific biologic differences in melanoma between this age group and adults, because the treatment regimens and guidelines we are using were developed based on data from older adults. We want to increase adolescent and young adult participation rates in clinical trials so we have data specifically for this age group in terms of tumor characteristics, biology, and treatment response rates.

Dr. Khushalani: Unfortunately, cancer is a disease that affects individuals spanning from the youngest to the oldest, but, encouragingly, we have the ability to potentially prevent melanoma. We also have the potential to treat these patients very aggressively with very good outcomes. So all is not bad here. The key really is in raising awareness. n

Disclosure: Drs. Khushalani and Mitsis reported no potential conflicts of interest.

References 1. Mitsis DKL, Groman A, Beaupin LM, et al: Trends in demographics, incidence, and survival in children, adolescents, and young adults (AYA) with melanoma: A Surveillance, Epidemiology, and End Results (SEER) population-based analysis. 2015 ASCO Annual Meeting. Abstract 9058. Presented June 1, 2015. 2. Skin Cancer Foundation: Skin cancer facts: Melanoma. Available at skincancer.org/skin-cancer-information/ skin-cancer-facts#melanoma. Accessed October 19, 2015. 3. American Academy of Dermatology: Dangers of indoor tanning. Available at aad.org/media-resources/stats-andfacts/prevention-and-care/indoor-tanning#.uyxakrvvhqm. Accessed October 19, 2015. 4. Han D, Zager JS, Han G, et al: The unique clinical characteristics of melanoma diagnosed in children. Ann Surg Oncol 19:3888-3895, 2012.

Don’t Miss These Important Reports in This Issue of The ASCO Post Stephen Chun, MD, on IMRT in Stage III NSCLC see page 1

Hagop Kantarjian, MD, on American Health Care as a Right or Entitlement see page 1

Baron Lerner, MD, PhD, on Physician-Assisted Suicide see page 1

Alysa Fairchild, MD, on Dexamethasone in Radiation-Induced Pain see page 3

Leland Rogers, MD, on Radiation in Atypical Meningiomas see page 5

Claire L. Vale, PhD, on Docetaxel and Bisphosphonates in Hormone-Sensitive Prostate Cancer see page 9

Caroline Robert, MD, on Metastatic Melanoma and COMBI-v see page 18

Lucy Yates, MD, on the Genetic Landscapes on Primary and Metastatic Breast Cancer see page 22

M. Catherine Pietanza, MD, on Rovalpitzumab in SCLC see page 26

Visit The ASCO Post online at ASCOPost.com

When multiple myeloma relapses

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

IMPORTANT SAFETY INFORMATION Cardiac Toxicities: New onset or worsening of pre-existing cardiac

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

until resolved or returned to baseline and consider whether to restart Kyprolis based on a benefit/risk assessment.

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

Hypertension: Hypertension, including hypertensive crisis and

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

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

Acute Renal Failure: Cases of acute renal failure and renal

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

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

Thrombocytopenia: Kyprolis causes thrombocytopenia with

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

Pulmonary Toxicity: Acute Respiratory Distress Syndrome (ARDS),

acute respiratory failure, and acute diffuse infiltrative pulmonary disease such as pneumonitis and interstitial lung disease have occurred in patients receiving Kyprolis. Some events have been fatal. In the event of drug-induced pulmonary toxicity, discontinue Kyprolis.

Pulmonary Hypertension: Pulmonary arterial hypertension (PAH) was reported in patients treated with Kyprolis. Evaluate with cardiac imaging and/or other tests as indicated. Withhold Kyprolis for PAH

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

Hepatic Toxicity and Hepatic Failure: Cases of hepatic failure,

including fatal cases, have been reported during treatment with Kyprolis. Kyprolis can cause increased serum transaminases. Monitor liver enzymes regularly. Reduce or withhold dose as appropriate.

Thrombotic Thrombocytopenic Purpura/Hemolytic Uremic Syndrome (TTP/HUS): Cases of TTP/HUS including fatal outcome

have occurred in patients receiving Kyprolis. Monitor for signs and symptoms of TTP/HUS. Discontinue Kyprolis if diagnosis is suspected. If the diagnosis of TTP/HUS is excluded, Kyprolis may be restarted. The safety of reinitiating Kyprolis therapy in patients previously experiencing TTP/HUS is not known.

Onyx, Onyx Pharmaceuticals, Onyx Pharmaceuticals logo, KYPROLIS, and KYPROLIS logo are all trademarks of Onyx Pharmaceuticals, Inc. ©2015 Onyx Pharmaceuticals, Inc., an Amgen Inc. subsidiary, Thousand Oaks, CA TROPIC-KYPR-103559 August 2015 Printed in USA

Ne w

RESPOND

In dic at

ion

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

Posterior Reversible Encephalopathy Syndrome (PRES):

Cases of PRES have occurred in patients receiving Kyprolis. PRES was formerly known as Reversible Posterior Leukoencephalopathy Syndrome. Consider a neuro-radiological imaging (MRI) for onset of visual or neurological symptoms. Discontinue Kyprolis if PRES is suspected and evaluate. The safety of reinitiating Kyprolis therapy in patients previously experiencing PRES is not known.

The KYPROLIS regimen significantly improved PFS in patients with relapsed multiple myeloma1

Embryo-fetal Toxicity: Kyprolis can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals.

In the ASPIRE study of KYPROLIS + lenalidomide + low-dose dexamethasone (KRd) vs lenalidomide + low-dose dexamethasone (Rd), the KYPROLIS regimen delivered improved efficacy with a safety profile comparable to Rd.1,2*

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

26.3 months median progression-free

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

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

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

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

The ASCO Post | NOVEMBER 10, 2015

PAGE 52

Announcements

Lewis Cantley, PhD, Receives 2015 AACI Distinguished Scientist Award

he Association of American Cancer Institutes (AACI) presented the AACI Distinguished Scientist Award to Lewis Cantley, PhD, on October 26, during the 2015 AACI/Cancer Center Administrators Forum Annual Meeting, in Washington, DC.

A cell biologist and biochemist who serves as The Margaret and Herman Sokol Professor in Oncology Research and Director of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medical College, Dr. Cantley’s pioneering research has resulted in revolution-

ary treatments for cancer, diabetes, and autoimmune diseases. Dr. Cantley is a fellow of the American Academy of Arts and Sciences and a member of the National Academy of Sciences USA. He received his doctorate in biophysical chemistry from Cornell University. n

B:16.75” T:16.25” S:14.625”

Lewis Cantley, PhD

(carfilzomib) forintravenous injection, foruse intravenous use Brief of Hepatic ToxicityFailure and Hepatic Failure KYPROLIS® KYPROLIS (carfilzomib)® for injection, for Brief Summary of Summary Hepatic Toxicity and Hepatic Prescribing Information. Prescribing Information. Cases of hepatic failure, fatal cases, have(< been (< 1%) in patients Cases of hepatic failure, including fatal including cases, have been reported 1%)reported in patients see thepackage KYPROLIS insert for full prescribing information. Please see the Please KYPROLIS insertpackage for full prescribing information. receiving Kyprolis. Kyprolis can cause increased serum transaminases. receiving Kyprolis. Kyprolis can cause increased serum transaminases. Monitor liver Monitor liver INDICATIONS enzymes regularly. Reduce or as withhold dose as appropriate. INDICATIONS enzymes regularly. Reduce or withhold dose appropriate.

Kyprolis inwith combination withand lenalidomide and dexamethasone indicated for theThrombotic Thrombocytopenic Thrombotic Thrombocytopenic Purpura/Hemolytic Uremic Syndrome (TTP/HUS) Kyprolis in combination lenalidomide dexamethasone is indicated foristhe Purpura/Hemolytic Uremic Syndrome (TTP/HUS) treatment patientsmultiple with relapsed multiple who one havetoreceived treatment of patients withofrelapsed myeloma who myeloma have received three one to three Cases of TTP/HUS, including fatal outcome, have been reported inreceived patients who received Cases of TTP/HUS, including fatal outcome, have been reported in patients who prior lines of therapy. prior lines of therapy. Kyprolis. Monitor for signs and symptoms Discontinue of TTP/HUS.Kyprolis Discontinue Kyprolis if TTP/ Kyprolis. Monitor for signs and symptoms of TTP/HUS. if TTP/ WARNINGS AND PRECAUTIONS HUS is evaluate. suspected Ifand diagnosisisofexcluded, TTP/HUS is excluded, WARNINGS AND PRECAUTIONS HUS is suspected and theevaluate. diagnosisIfofthe TTP/HUS Kyprolis may Kyprolis may be restarted. The safetyKyprolis of reinitiating Kyprolis therapy in patients previously experiencing be restarted. The safety of reinitiating therapy in patients previously experiencing Cardiac Toxicities Cardiac Toxicities TTP/HUS TTP/HUS is not known. is not known. New onsetoforpre-existing worsening of pre-existing failure (e.g., congestive New onset or worsening cardiac failure cardiac (e.g., congestive heart failure, heart failure, Posterior Reversible Encephalopathy Syndrome (PRES) Posterior Reversible Encephalopathy Syndrome (PRES) pulmonary edema, decreased ejection fraction), restrictive cardiomyopathy, pulmonary edema, decreased ejection fraction), restrictive cardiomyopathy, myocardial myocardial ischemia, and myocardial infarction including a day in patients receiving of PRES havein been reported in patients receiving Kyprolis. formally known ischemia, and myocardial infarction including fatalities withinfatalities a day inwithin patients receiving Cases of PRESCases have been reported patients receiving Kyprolis. PRES, formallyPRES, known Kyprolis. Withhold Kyprolis Gradeadverse 3 or 4 cardiac events until recovery, as Reversible Posterior Leukoencephalopathy Syndrome (RPLS), can present with seizure, Kyprolis. Withhold Kyprolis for Grade 3 or for 4 cardiac events adverse until recovery, as Reversible Posterior Leukoencephalopathy Syndrome (RPLS), can present with seizure, and consider whether to restart Kyprolis 1 dose level based on a benefit/risk headache, lethargy, confusion, blindness, altered consciousness, and consider whether to restart Kyprolis at 1 dose level at reduction basedreduction on a benefit/risk headache, lethargy, confusion, blindness, altered consciousness, and other visualand andother visual and assessment. Adequately hydrate alltopatients prior to receiving Kyprolis. neurologicalalong disturbances, along with Perform hypertension. Perform diagnostic neuroradiological assessment. Adequately hydrate all patients prior receiving Kyprolis. neurological disturbances, with hypertension. diagnostic neuroradiological (MRI) at the onset of visual orsymptoms. neurological symptoms.Kyprolis Discontinue Kyprolis if imaging (MRI)imaging at the onset of visual or neurological Discontinue if Monitor patientsoffor evidence of volume overload, especially at risk for cardiac Monitor all patients for all evidence volume overload, especially patients at risk patients for cardiac PRES is evaluate. suspected The and safety evaluate. The safetyKyprolis of reinitiating Kyprolis therapy in patients PRES is suspected and of reinitiating therapy in patients failure. Adjust total fluid intake as clinically appropriate. Patients ≥ 75 years, with New failure. Adjust total fluid intake as clinically appropriate. Patients ≥ 75 years, with New previouslyPRES experiencing PRES is not known. previously experiencing is not known. York Heart Association and IVrecent heart myocardial failure, recent myocardial York Heart Association Class III and IVClass heartIIIfailure, infarction, and infarction, and conduction abnormalities may be at greater risk for cardiac complications. Embryo-fetal Toxicity conduction abnormalities may be at greater risk for cardiac complications. Embryo-fetal Toxicity Acute Renal Failure Acute Renal Failure

Kyprolis cause fetal harm whentoadministered to a pregnant woman Kyprolis can cause fetal can harm when administered a pregnant woman based on its based on its mechanism of action findings in animals. There are nowell-controlled adequate and well-controlled mechanism of action and findings inand animals. There are no adequate and of acute renal failure in have occurred in patients receiving Kyprolis. Renal Cases of acute Cases renal failure have occurred patients receiving Kyprolis. Renal studies in pregnant women using Kyprolis. studies in pregnant women using Kyprolis. insufficiency events (renal impairment, acuterenal renalfailure) failure,occurred renal failure) occurred insufficiency adverse events adverse (renal impairment, acute renal failure, in approximately patients incontrolled a randomized trial. Acute renal failureFemales was Females ofpotential reproductive should be potential advised ofhazard the potential hazard in approximately 8% patients in 8% a randomized trial.controlled Acute renal failure was of reproductive shouldpotential be advised of the to the fetus andto the fetus and reported more frequently patients with advanced relapsed multiple and refractory multiple to avoid becoming whilewith being treated with Kyprolis. If this drug is used during reported more frequently in patients withinadvanced relapsed and refractory to avoid becoming pregnant whilepregnant being treated Kyprolis. If this drug is used during who received Kyprolis monotherapy. This risk was greater if the patient becomes while taking Kyprolis, advise myeloma who myeloma received Kyprolis monotherapy. This risk was greater in patients within patients with pregnancy, or ifpregnancy, the patientorbecomes pregnant whilepregnant taking Kyprolis, advise the patient of the patient of a baseline reduced estimated creatinine clearance. Monitor with renalregular function with regular the potential hazard to the fetus. a baseline reduced estimated creatinine clearance. Monitor renal function the potential hazard to the fetus. of the serum creatinine and/or estimated creatinine clearance. Reduce or measurement ofmeasurement the serum creatinine and/or estimated creatinine clearance. Reduce or ADVERSE REACTIONS ADVERSE REACTIONS withhold Kyprolis dose as appropriate. withhold Kyprolis dose as appropriate. The following adverse have been discussed andthe canWarning be found the WarningK The following adverse reactions have reactions been discussed above and can above be found Tumor Lysis Syndrome (TLS) Tumor Lysis Syndrome (TLS) de Precautions section of the package insert. cardiac They include cardiac and Precautionsand section of the package insert. They include toxicities, acutetoxicities, kidney acute kidney a of TLS, havein been reported patients who received injury, TLS, Pulmonary toxicity, pulmonarydyspnea, hypertension, dyspnea,venous hypertension, venous Cases of TLS, Cases including fatal including outcomes,fatal haveoutcomes, been reported patients whoinreceived injury, TLS, Pulmonary toxicity, pulmonary hypertension, hypertension, b Kyprolis. Patientsmyeloma with multiple andburden a highare tumor burdenrisk are at greater thromboses, risk thromboses, infusion reactions, thrombocytopenia, toxicity and hepatic failure, c Kyprolis. Patients with multiple and amyeloma high tumor at greater infusion reactions, thrombocytopenia, hepatic toxicityhepatic and hepatic failure, forpatients TLS. Ensure patients arebefore well hydrated before administration of Kyprolis. Consider and PRES. for TLS. Ensure are well hydrated administration of Kyprolis. Consider TTP/HUS and TTP/HUS PRES. d uricdrugs acid lowering drugs in patients risk for TLS. Monitoroffor evidence uric acid lowering in patients at risk for TLS.atMonitor for evidence TLS during of TLS during Trials Safety Experience Clinical Trials Clinical Safety Experience treatment and manage promptly. Withold Kyprolis until TLS is resolved. treatment and manage promptly. Withold Kyprolis until TLS is resolved. e Because clinical trials under are conducted under widely varying conditions, adverse reaction Because clinical trials are conducted widely varying conditions, adverse reaction Pulmonary Toxicity Pulmonary Toxicity in theofclinical ofbe a drug cannot be directly rates observed rates in theobserved clinical trials a drug trials cannot directly compared withcompared rates in thewith rates in the N another and may not reflect the rates observed in medical practice. p Acute Respiratory Distress Syndrome acute respiratory failure, and acuteclinical diffusetrials ofclinical anothertrials drug,ofand may drug, not reflect the rates observed in medical practice. Acute Respiratory Distress Syndrome (ARDS), acute(ARDS), respiratory failure, and acute diffuse infiltrative pulmonary such asand pneumonitis lung of disease, some of infiltrative pulmonary disease such asdisease pneumonitis interstitial and lunginterstitial disease, some The safety of Kyprolis inwith combination withand lenalidomide and dexamethasone (KRd) was G The safety of Kyprolis in combination lenalidomide dexamethasone (KRd) was which fatal, in have than 1% of patients receiving Kyprolis. In the which were fatal, havewere occurred lessoccurred than 1%inofless patients receiving Kyprolis. In the inrandomized an open-label randomized study patientsmultiple with relapsed multiple myeloma. d evaluated in anevaluated open-label study in patients withinrelapsed myeloma. event ofpulmonary drug-induced pulmonary toxicity, discontinue Kyprolis. event of drug-induced toxicity, discontinue Kyprolis. The median number of cycles wasthe 22KRd cycles forand the14 KRd armfor and 14 cycles for h The median number of cycles initiated was 22initiated cycles for arm cycles Pulmonary Hypertension (PAH) the Rd arm. the Rd arm. Pulmonary Hypertension (PAH) L Deaths due to adverse events 30 days dose of therapy Cases of PAH(~1%) was reported (~1%) in patients treated with KYPROLIS , <1% experiencing Deaths due to adverse events within 30 dayswithin of the last doseof ofthe anylast therapy in any the KRd armin the KRd arm Cases of PAH was reported in patients treated with KYPROLIS , <1% experiencing vs. Rd arm was 27/392 (7%) patients vs. 27/389 (7%) patients in the Rd arm. The most Grade 3 or greater PAH.. Evaluate with cardiac imaging and/or other tests as indicated. In vs. Rd arm was 27/392 (7%) patients vs. 27/389 (7%) patients in the Rd arm. The most Grade 3 or greater PAH.. Evaluate with cardiac imaging and/or other tests as indicated. In of deaths occurring patients 10 (3%) vs. 7 (2%), infection 9 the discontinue event of PAH, discontinue Kyprolisor until resolved or returned to baseline. Perform a causecommon common of deathscause occurring in patients (%) in cardiac 10(%) (3%)cardiac vs. 7 (2%), infection 9 the event of PAH, Kyprolis until resolved returned to baseline. Perform a (2%) vs. 10 (3%),vs.renal (0%)and vs. other 1 (< 1%), andevents other adverse events 9 (2%) vs. 10 (3%). benefit/risk assessment when considering restarting Kyprolis. (2%) vs. 10 (3%), renal 0 (0%) 1 (<01%), adverse 9 (2%) vs. 10 (3%). benefit/risk assessment when considering restarting Kyprolis. events in were reported vs. 54% of KRd patients theRd KRd arm vs. Rd Serious adverseSerious events adverse were reported 60% vs. 54%inof60% patients in the arminvs. Dyspnea Dyspnea The most common the KRd arm. The mostarm. common serious adverseserious events adverse reportedevents in the reported KRd arminverses the arm Rd verses the Rd arm were pneumonia vs. 11%), tractvs. infection vs. 1.5%), pyrexia arm were pneumonia (14% vs. 11%),(14% respiratory tractrespiratory infection (4% 1.5%),(4% pyrexia Dyspnea(28%) was reported (28%) in patients treated with Kyprolis, with 4% of cases being Dyspnea was reported in patients treated with Kyprolis, 4% of cases being (4%pulmonary vs. 2%), and pulmonary (3% vs. 2%). Discontinuation due to any adverse (4% vs. 2%), and embolism (3% embolism vs. 2%). Discontinuation due to any adverse GradeEvaluate 3 or greater. Evaluate dyspnea to exclude cardiopulmonary conditions including Grade 3 or greater. dyspnea to exclude cardiopulmonary conditions including occurred in 26% the25% KRdinarm the Rd events arm. Adverse leading to in 26% in the KRd arminvs. the vs. Rd 25% arm. in Adverse leading events to failure and pulmonary syndromes. Stop Kyprolis Grade 3until or 4 dyspneaevent untiloccurredevent cardiac failure cardiac and pulmonary syndromes. Stop Kyprolis for Grade 3 or for 4 dyspnea of Kyprolis occurred in 12% of patients. discontinuationdiscontinuation of Kyprolis occurred in 12% of patients. resolved or returned to baseline. Performassessment a benefit/risk assessment when considering resolved or returned to baseline. Perform a benefit/risk when considering restarting Kyprolis. restarting Kyprolis. Common Adverse (≥ 10% the KRd Arm) Occurring Common Adverse Events (≥ 10% inEvents the KRd Arm)inOccurring in Cycles 1–12 in Cycles 1–12 (Combination Therapy) (Combination Therapy)

Hypertension Hypertension

KRd Arm Rd Arm KRd Arm Rd Arm Hypertension, includingcrisis hypertensive crisis andemergency, hypertensive emergency, Hypertension, including hypertensive and hypertensive some of whichsome of which System Organ Class (N = 392) (N = 392) (N = 389) System Organ Class (N = 389) has been observed with Kyprolis. pressure were fatal, has were been fatal, observed with Kyprolis. Monitor blood Monitor pressure blood regularly in all regularly in all patients. Ifcannot hypertension cannot controlled, be adequately controlled, withhold Kyprolis and evaluate. Preferred Term Preferred Term patients. If hypertension be adequately withhold Kyprolis and evaluate. Grade Grade ≥ Grade ≥ Grade 3 Any Grade Any Grade3 ≥Any Grade 3 ≥Any Grade 3 Performassessment a benefit/risk assessment when considering restarting Kyprolis. Perform a benefit/risk when considering restarting Kyprolis.

Venous Thrombosis Venous Thrombosis

Blood System and Lymphatic System Disorders Blood and Lymphatic Disorders

138 (35%) 53 (14%)

53 (33%) (14%) 127

127(12%) (33%) 47

47 (12%)

124(27%) (32%) 104

104(30%) (27%) 115

115(23%) (30%) 89

89 (23%)

100 (26%) 58 (15%)

58(19%) (15%) 75

75(10%) (19%) 39

39 (10%)

115 (29%) 7 (2%)

(2%) 1057 (27%)

105 (27%) 12 (3%)

680(17%)

0 53 (14%)

53 (14%) 1 (0%)

1 (0%)

Infusion reactions, including life-threatening have occurred in patients receiving Infusion reactions, including life-threatening reactions, havereactions, occurred in patients receiving Nausea (15%) (0%) Nausea 60 (15%) 160(0%) 391(10%) Kyprolis. Symptoms include fever, chills, arthralgia, Kyprolis. Symptoms include fever, chills, arthralgia, myalgia, facialmyalgia, flushing,facial facialflushing, edema, facial edema, General Disorders and Administration Site Conditions General Disorders and Administration Site Conditions vomiting, weakness, shortness of breath, hypotension, syncope, chest tightness, or angina. vomiting, weakness, shortness of breath, hypotension, syncope, chest tightness, or angina. reactions can occurfollowing immediately or up to administration 24 hours after administration These reactionsThese can occur immediately or upfollowing to 24 hours after Fatigue 109(5%) (28%) 21(27%) (5%) Fatigue 109 (28%) 21 104 of Kyprolis. with Pre-medicate with dexamethasone to reduceand the severity incidence of Kyprolis. Pre-medicate dexamethasone to reduce the incidence ofand severity of Pyrexia 93 (24%) 5 (1%) Pyrexia 93 (24%) 5 (1%) 64 (17%) infusion reactions Inform patients of the risk and symptoms of an infusion reaction and to infusion reactions Inform patients of the risk and symptoms of an infusion reaction and to contact a physicianif immediately of an infusion contact a physician immediately symptoms ofifansymptoms infusion reaction occur.reaction occur. (16%) (1%) Edema PeripheralEdema Peripheral 63 (16%) 263(1%) 572(15%)

39 (10%) 3 (1%)

3 (1%)

104 (27%) 20 (5%)

57 (15%) 2 (1%)

2 (1%)

Thrombocytopenia Thrombocytopenia

Anemia

138 (35%)

Venous thromboembolic events, deep venous Venous thromboembolic events, including deepincluding venous thrombosis andthrombosis pulmonaryand pulmonary Neutropenia 124 (32%) have been observed with Kyprolis. In thestudy, combination study, the incidenceNeutropenia embolism, haveembolism, been observed with Kyprolis. In the combination the incidence of venous thromboembolic events in the was first 13% 12 cycles was vs. 6% in the Kyprolis of venous thromboembolic events in the first 12 cycles vs. 6% in 13% the Kyprolis Thrombocytopenia Thrombocytopenia 100 (26%) combination control armWith respectively. Kyprolisthe monotherapy, combination arm and controlarm armand respectively. Kyprolis With monotherapy, incidence the incidence Disorders GastrointestinalGastrointestinal Disorders of venous thromboembolic was 2%. Thromboprophylaxis is recommended and of venous thromboembolic events was 2%.events Thromboprophylaxis is recommended and based onpatient an individual patient assessment. should be basedshould on anbe individual assessment. Diarrhea Diarrhea 115 (29%) Infusion Reactions Infusion Reactions

Constipation

64 (17%) 1 (0%)

T K si re 12 (3%) a

K a a 20 (5%) in 1 (0%)

53 (14%)

53(3%) (14%) 11

(3%) 4611(12%)

46 (12%) 7 (2%)

7 (2%)

Cases of thrombocytopenia caninoccur (40%) in patients receiving Cases of thrombocytopenia can occur (40%) patients receiving Kyprolis, with Kyprolis, platelet with platelet Infections and Infestations Infections and Infestations observed 8 and 15 of eachwith 28-day cycle, to with recovery to baseline nadirs observednadirs between Day 8between and DayDay 15 of eachDay 28-day cycle, recovery baseline Upper Infection Upper Respiratory TractRespiratory Infection Tract85 (22%) plateletoccurring count usually occurring by the of the next cycle. Monitor platelet count usually by the start of the nextstart cycle. Monitor platelet counts platelet counts frequently during Kyprolis. Reduce or as withhold dose as appropriate. Nasopharyngitis Nasopharyngitis frequently during treatment with treatment Kyprolis. with Reduce or withhold dose appropriate. 63 (16%)

(22%) 785(2%)

(2%) 527(13%)

52 (13%) 3 (1%)

3 (1%)

630(16%)

0 43 (11%)

43 0(11%)

Asthenia

68 (17%)

K de

K p

F b ri

ASCOPost.com | NOVEMBER 10, 2015

Geriatrics for the Oncologist

Geriatric Oncology in Europe: A Commitment to Improving Cancer Care for Older Patients By Etienne Brain, MD, PhD

B:16.75”

n Europe, the field of geriatric oncology has a long history of development, and its organization and implementation continue to improve

T:16.25” S:14.625”

Bronchitis

Pneumonia

every day. This would not have happened without the strong commitment of national authorities to health policies, a critical success factor.

54 (14%)

(14%) 554(1%)

(1%) 395(10%)

39 (10%) 2 (1%)

54 (14%)

54(9%) (14%) 35

(9%) 4335(11%)

43(7%) (11%) 27

and Nutrition Disorders Metabolism andMetabolism Nutrition Disorders Hypokalemia

Hypokalemia

78 (20%)

78(6%) (20%) 22

22(9%) (6%) 35

Hypocalcemia

55 (14%)

55(3%) (14%) 10

(3%) 3910(10%)

39 (10%) 5 (1%)

43 (11%)

43(5%) (11%) 18

18(9%) (5%) 33

33(4%) (9%) 15

(22%) 388(1%)

(1%) 733(19%)

73 (19%) 3 (1%)

(11%) 743(2%)

(2%) 377(10%)

37 (10%) 4 (1%)

(16%) 663(2%)

(2%) 506(13%)

50 (13%) 8 (2%)

Hyperglycemia Hyperglycemia

35(3%) (9%) 12

and Connective and Connective Tissue DisordersTissue Disorders gMusculoskeletalMusculoskeletal

PAGE 53

Muscle Spasms Muscle Spasms

88 (22%)

Psychiatric Disorders Psychiatric Disorders Insomnia

Insomnia

63 (16%)

Respiratory, Thoracic, and Mediastinal Disorders Respiratory, Thoracic, and Mediastinal Disorders Cough

Cough

85 (22%)

(22%) 185(0%)

(0%) 461(12%)

46 0(12%)

Dyspneac

70 (18%)

(18%) 970(2%)

(2%) 589(15%)

58 (15%) 6 (2%)

45 (12%)

(12%) 545(1%)

(1%) 535(14%)

53 (14%) 5 (1%)

EmbolicEvents, and Thrombotic49Events, (13%) Embolic and Thrombotic Venousd Venousd

49(4%) (13%) 16

16(6%) (4%) 22

(6%) 922(2%)

41(3%) (11%) 12

12(4%) (3%) 15

(4%) 415(1%)

Skin andTissue Subcutaneous Tissue Skin and Subcutaneous Disorders Disorders Rash

Rash

Vascular Disorders Vascular Disorders

Hypertensione

41 (11%)

In France, for example, this commitment has been repeatedly reflected in three successive Cancer Plans of the

during pregnancy, if the patient becomes while taking Kyprolis, advise the during pregnancy, or if the patientorbecomes pregnant whilepregnant taking Kyprolis, advise the 2 (1%) patient ofhazard the potential hazard to the fetus. patient of the potential to the fetus. 27 (7%)

Lactation

There is no information regardingofthe presence of Kyprolis human milk, the effects There is no information regarding the presence Kyprolis in human milk,inthe effects (3%) the breastfed infant,on ormilk the effects on milk production. The developmental and health on12the breastfedoninfant, or the effects production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for benefits 5 (1%) of breastfeeding should be considered along with the mother’s clinical need for Kyprolis andadverse any potential effects oninfant the breastfed infant from Kyprolis or from Kyprolis and any potential effectsadverse on the breastfed from Kyprolis or from (4%) the underlying maternal condition. the15underlying maternal condition. ContraceptionContraception

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

Four Missions

3 (1%) can cause Kyprolis cause fetal harm whentoadministered to pregnant Kyprolis fetal can harm when administered pregnant women Advisewomen femalesAdvise females reproductive use effectivemeasures contraception measures to prevent pregnancy of reproductiveofpotential to usepotential effectivetocontraception to prevent pregnancy during withfor Kyprolis for atfollowing least 2 weeks following completion of therapy. during treatment with treatment Kyprolis and at leastand 2 weeks completion of therapy. 4 (1%)

Pediatric Use Pediatric Use safety andofeffectiveness of Kyprolis in pediatric patients have not been established. The safety andThe effectiveness Kyprolis in pediatric patients have not been established. 8 (2%)

Geriatric Use Geriatric Use 392 patients treated in with Kyprolis inwith combination withand lenalidomide and Of 392 patientsOf treated with Kyprolis combination lenalidomide 0 dexamethasone, 185 patients (47%) ≥ 65 years of age and 43 patients dexamethasone, 185 patients (47%) were ≥ 65 yearswere of age and 43 patients (11%) were (11%) were ≥75No years of age. No overall differences inwere effectiveness observed ≥75 years of age. overall differences in effectiveness observed were between these between these 6 (2%) and younger patients. of The incidence of serious events was 50% and younger patients. The incidence serious adverse events adverse was 50% in patients ≤ 65in patients ≤ 65 years age, 70% patients 65age, to 74and years ofin age, and 74% patients ≥ 75 years of age. years of age, 70% in of patients 65 toin74 years of 74% patients ≥ 75inyears of age. Renal Impairment Renal Impairment 5 (1%)

Noadjustment starting dose adjustment is required patientsmild, with moderate, baseline mild, moderate, or severe No starting dose is required in patients withinbaseline or severe renal or patients on chronic dialysis based on a phase 2 pharmacokinetic and renal impairment or impairment patients on chronic dialysis based on a phase 2 pharmacokinetic and 9 (2%) safety trialThe of Kyprolis. The pharmacokinetics Kyprolis was not influenced by the safety trial of Kyprolis. pharmacokinetics of Kyprolis wasofnot influenced by the degree of impairment, baseline renal impairment, whenreceiving patients were receiving dialysis. degree of baseline renal including whenincluding patients were dialysis. Administer KYPROLIS after the dialysis procedure. Administer KYPROLIS after the dialysis procedure. 4 (1%)

Hepatic Impairment Hepatic Impairment = Kyprolis, and low-doseRd dexamethasone; Rdand = lenalidomide and low-dose KRd = Kyprolis, KRd lenalidomide, andlenalidomide, low-dose dexamethasone; = lenalidomide low-dose dexamethasone dexamethasone y The safety, efficacy and pharmacokinetics of not Kyprolis have not been evaluated in patients The safety, efficacy and pharmacokinetics of Kyprolis have been evaluated in patients a Pneumonia terms of pneumonia, bronchopneumonia Pneumonia includes preferredincludes terms ofpreferred pneumonia, bronchopneumonia with baseline hepaticPatients impairment. Patients withlaboratory the following laboratory with baseline hepatic impairment. with the following values were values were b Peripheral NEC includes preferred underneuropathies HLT peripheral Peripheral neuropathies NECneuropathies includes preferred terms under HLT terms peripheral NECneuropathies NEC fromclinical the Kyprolis clinical trials: ≥ 3of× normal upper limit of normal (ULN) excluded from excluded the Kyprolis trials: ALT/AST ≥ 3 ×ALT/AST upper limit (ULN) c Dyspnea of dyspnea, dyspnea exertional Dyspnea includes preferredincludes terms ofpreferred dyspnea,terms dyspnea exertional bilirubin ≥and 2 × bilirubin ULN. ≥ 2 × ULN. d Embolicevents, and thrombotic events,preferred venous include terms MedDRA SMQ narrowand scope Embolic and thrombotic venous include terms inpreferred MedDRA SMQinnarrow scope of embolicevents, and thrombotic search of embolicsearch and thrombotic venous. events, venous. Cardiac Impairment Cardiac Impairment e Hypertension terms hypertensive of hypertension, hypertensive crisis, hypertensive emergency Hypertension includes preferredincludes terms ofpreferred hypertension, crisis, hypertensive emergency

182 (46%)

182 (46%) 119 (31%)

withintravenous both oral and intravenous (IV) fluids.with Premedicate with dexamethasone prior to with both oral and (IV) fluids. Premedicate dexamethasone prior to 119 (31%)

Decreased Absolute Decreased Absolute Neutrophil CountNeutrophil Count152 (39%)

152 (39%) 140 (36%)

140 (36%) at baseline. Administer over 10-minuteDo IVnot infusion. Do not surface area at surface baseline.area Administer Kyprolis over aKyprolis 10-minute IVainfusion.

Decreased Lymphocytes Decreased Lymphocytes

administering Kyprolis. Calculatedose the using Kyprolis using the patient’s administering Kyprolis. Calculate the Kyprolis the dose patient’s acutal body acutal body

Decreased Phosphorus Decreased Phosphorus

122 (31%)

122 (31%) 106 (27%)

as athe bolus. Flush IV line withor normal saline orinjection 5% dextrose injection administer as aadminister bolus. Flush IV line withthe normal saline 5% dextrose 106 (27%)

Decreased Platelets Decreased Platelets

101 (26%)

101 (26%) 59 (15%)

59 (15%) administer as another infusion with other medicines. Thromboprophylaxis is recommend for administer as an infusion with medicines. Thromboprophylaxis is recommend for

immediately and administration. after Kyprolis administration. Do notwith mix or Kyprolis with or immediately before and afterbefore Kyprolis Do not mix Kyprolis

Decreased Total Decreased Total White Blood CellWhite CountBlood Cell Count 97 (25%)

97 (25%) 71 (18%)

patientswith being with theofcombination of Kyprolis,and lenalidomide and dexamethasone. patients being treated thetreated combination Kyprolis, lenalidomide dexamethasone. 71 (18%)

Decreased Hemoglobin Decreased Hemoglobin

58 (15%)

58 (15%) 68 (18%)

68 (18%)

Decreased Potassium Decreased Potassium

41 (11%)

41 (11%) 23 (6%)

23 (6%) product can be found at www.kyprolis.com or 1-877-669-9121. product labeling can belabeling found at www.kyprolis.com or 1-877-669-9121.

Consider antiviral in treated patientswith being treated with Kyprolis. Consider antiviral prophylaxis in prophylaxis patients being Kyprolis.

The riskprovided information here is not comprehensive. The FDA-approved The risk information hereprovided is not comprehensive. The FDA-approved

KRdlenalidomide, = KYPROLIS, and low-doseRd dexamethasone; Rdand = lenalidomide KRd = KYPROLIS, andlenalidomide, low-dose dexamethasone; = lenalidomide low-dose and low-dose This product, its production, and/or its use may be covered or more US Patents, This product, its production, and/or its use may be covered by one or moreby USone Patents, dexamethasone dexamethasone including Patent Nos. 7,232,818; 7,417,042; 7,491,704; 7,737,112; 8,129,346; including US Patent Nos.US 7,232,818; 7,417,042; 7,491,704; 7,737,112; 8,129,346;

Post-marketing Post-marketing Experience Experience

8,207,125; 8,207,126; andwell 8,207,297 well asorother patents or patents pending. 8,207,125; 8,207,126; 8,207,127; and8,207,127; 8,207,297 as as otheraspatents patents pending.

following adverse were in the post-marketing experience with The following The adverse reactions were reactions reported in thereported post-marketing experience with Kyprolis. Because these reactions are reported voluntarily fromofauncertain population of uncertain Kyprolis. Because these reactions are reported voluntarily from a population size, itpossible is not always possible to reliably estimate their frequency or establish a causal ize, it is not always to reliably estimate their frequency or establish a causal to drug exposure:TTP/HUS, dehydration, elationship to relationship drug exposure: dehydration, TLSTTP/HUS, including TLS fatal including outcomes,fatal outcomes, and PRES. and PRES.

DRUG INTERACTIONS DRUG INTERACTIONS

Kyprolis is primarily viaepoxide peptidase and epoxide hydrolase activities, and as Kyprolis is primarily metabolized viametabolized peptidase and hydrolase activities, and as a result, the pharmacokinetic profile of Kyprolis unlikelyby to concomitant be affected by concomitant a result, the pharmacokinetic profile of Kyprolis is unlikely to beis affected cytochrome inhibitors Kyprolis and inducers. administration administration of cytochrome of P450 inhibitorsP450 and inducers. is notKyprolis expectedistonot expected to influence exposure nfluence exposure of other drugs. of other drugs.

B:11.25”

DOSAGE AND ADMINISTRATION DOSAGE AND ADMINISTRATION

Rd (N = 389) Adequately hydrate alltopatients prior to the andadministration following the administration Adequately hydrate all patients prior and following of Kyprolis of Kyprolis

S:10”

KRd Rd (N = 392) (N = 389)

T:10.875”

Laboratory Abnormality Laboratory Abnormality

KRd (N = 392)

B:11.25”

(Combination Therapy) (Combination Therapy)

S:10”

difference 2%) between the two arms werethrombocytopenia, neutropenia, thrombocytopenia, difference (≥ 2%) between(≥the two arms were neutropenia, of chills,renal hypotension, renalthrombocytopenia insufficiency, thrombocytopenia and lymphopenia Acute onset of Acute chills, onset hypotension, insufficiency, and lymphopenia hypokalemia, and hypophosphatemia. hypokalemia, and hypophosphatemia. hasfollowing been reported following a dose of 200 mg of Kyprolis administed in error. has been reported a dose of 200 mg of Kyprolis administed in error. Laboratory Abnormalities Laboratory Abnormalities Thereantidote is no specific antidote for KyprolisInoverdosage. the event overdose, the patient There is no specific for Kyprolis overdosage. the event of In overdose, theofpatient m should specifically be monitored, the adverse in the adverse reaction section. should be monitored, forspecifically the adversefor reactions in thereactions adverse reaction section. Grade Abnormalities 3–4 Laboratory( Abnormalities ( ≥1-12 10%) in Cycles 1-12 Grade 3–4 Laboratory ≥ 10%) in Cycles

T:10.875”

Safety patients New York Heart Association and IV Safety of patients withofNew Yorkwith Heart Association Class III and IVClass heartIIIfailure orheart failure or No relevant new clinically relevantin ARs in the later treatment cycles in the 274recent (70%)myocardial No new clinically ARs emerged theemerged later treatment cycles in the 274 (70%) recent myocardial infarction (within 3has to not 6 months) has not been evaluated. infarction (within 3 to 6 months) been evaluated. patients the KRd armtreatment who received treatment beyond Cycle 12. patients in the KRd arminwho received beyond Cycle 12. OVERDOSE OVERDOSE Gradeadverse 3 and higher adverse reactionsduring that occurred during Cycles 1-12 with a substantial Grade 3 and higher reactions that occurred Cycles 1-12 with a substantial

Institut National du Cancer (INCa). These plans have allowed the development and funding of 28 coordination units in geriatric oncology (Unités de Coordination en Onco Gériatrie, or UCOG) to cover France, each one cochaired by an oncologist and a geriatrician to carry out four shared missions: 1. To disseminate the know-how of interaction between oncology and geriatrics teams 2. To make this expertise accessible to any elderly cancer patient 3. To stimulate specific clinical and translational research 4. To improve both information for the regular population and education of health-care providers So far, this territorial grid has been very successful, culminating in the joint effort to build an intergroup for clinical research dedicated to geriatric oncology. This intergroup encompasses the 28 UCOG units and the French cooperative group GERICO, which was created 15 years ago under the auspices of UNICANCER, a French network of comprehensive cancer centers similar to the National Comprehensive Cancer Network (NCCN). The newly launched GERICO/ UCOG Intergroup, as it was dubbed by INCa, has been renamed DIALOG. Its first primary task is to move the rate of elderly cancer patients enrolled on clinical trials from 1% (already improved from a previous rate of 0.2%, after an important effort conducted between 2005 and 2012) to 5%, getting closer to the 15% target rate for the overall adult population (which now has an enrollment rate of only 7.5%). To this end, a share of the budget in national grant applications has been reserved for specific programs addressing the elderly cancer population.

Cross-Border Collaborations Of course, the challenges remain high, but the DIALOG undertaking will benefit from cross-border collaborations. This will increase chances to identify the most relevant specific research questions and encourage the continued on page 54

USE IN SPECIFIC POPULATIONS USE IN SPECIFIC POPULATIONS

Pregnancy

Kyprolis cause fetalare harm. There areand nowell-controlled adequate and well-controlled studies in Kyprolis may cause fetalmay harm. There no adequate studies in pregnant women using Kyprolis. pregnant women using Kyprolis.

Females ofpotential reproductive potential should be advised to avoid becoming Females of reproductive should be advised to avoid becoming pregnant whilepregnant while being treated with Kyprolis. Consider benefits and risks Kyprolis and possible being treated with Kyprolis. Consider the benefits andtherisks of Kyprolis andofpossible risks to the fetus when prescribing Kyproliswoman. to a pregnant woman. If Kyprolis is used isks to the fetus when prescribing Kyprolis to a pregnant If Kyprolis is used

Dr. Brain is a medical oncologist at Institut Curie/Hôpital René Huguenin in SaintCloud, France, and President of the International Society of Geriatric Oncology (SIOG).

The ASCO Post | NOVEMBER 10, 2015

PAGE 54

Geriatrics for the Oncologist Geriatric Oncology in Europe continued from page 53

oncology community to “get out of its cave” and see other perspectives in the current world of clinical research. This should facilitate revisiting standard cancer research endpoints, conferring priority to areas considered secondary in younger adults (eg, quality of life, independence), questioning the

learning to teach) our closest colleagues from the worlds of oncology and geriatrics, developing and disseminating specific high-standard guidelines that advocate fine-tuned strategies in elderly cancer patients, and advancing geriatric oncology training in universities. All of these goals are part of the current strategy of the International Society of Geriatric Oncology (SIOG) that I

We live in a fast-evolving and aging world. Geriatric oncology is an area where young generations of health professionals need to be provocative and imaginative in order to step up the challenges posed by the age transition in our society. —Etienne Brain, MD, PhD

impact of cancer treatments on the aging process, breaking or disrupting the rules of the therapeutic decision process used for younger patients as a simplistic extrapolation for the elderly, and reaching out to patients with a more holistic approach, among other potential advances. One such example of this evolution is the multicenter phase III ASTER 70s trial investigating the role of adjuvant chemotherapy for women over age 70 with luminal B early-stage breast cancer. The trial is being led by GERICO in France, with active participation by centers in Belgium. That sort of international cooperation in geriatric oncology is also illustrated by the European Organisation for Research and Treatment of Cancer (EORTC) with its Cancer in the Elderly Task Force. The Task Force is a key actor in lobbying at the level of European regulatory mechanisms to stimulate collaborative research efforts.

Role of Education None of these activities could happen without physician education: In our aging society, education is the most important cornerstone of both building a better future and achieving tangible change today. This entails teaching (and

have the honor to chair. History shows that important trends occurred when there was a stimulating environment conducive to learning, enabling genuine revolutions, as during the Italian Renaissance, when “cenacoli” were well-intentioned and welcoming communities where elders and youths reciprocally nurtured, inspired, and educated each other. These communities made education the cement between generations, disseminating knowledge and eventually impacting on society and practice. This concept has paved the road to the development of the 4-day SIOG Treviso Advanced Post Graduate Course, held at the Study Centre Achille and Linda Lorenzon in Treviso, in the vicinity of Venice (Italy), with the support of the Università Cattolica del Sacro Cuore and the European School of Oncology, and under the auspices of ASCO. Thanks to Silvio Monfardini, MD, a most learned oncologist, Past President of SIOG, and 2015 ASCO B.J. Kennedy Award winner, and geriatrician Giuseppe Colloca, MD, SIOG has embraced the challenge of having an audience from the two worlds of oncology and geriatrics—20 to 30 young oncologists and geriatricians

coming from all around the world annually. For the 2014 and 2015 program, participants traveled from Italy, Spain, France, Poland, the United States, Costa Rica, Australia, and Brazil. July 2016 will see the third edition of the course, which is hopefully becoming a new cradle for geriatric oncology, resurrecting a longstanding Italian tradition. While the format may slightly change, the main goal will remain to introduce the audience to the general principles of both geriatrics and clinical oncology, under the supervision of an international faculty aiming to train students to understand how they can work together, in the hope that they will become the bridge between the oncology and geriatrics teams in their own institutions. We live in a fast-evolving and aging world. Geriatric oncology is an area where young generations of health professionals need to be provocative and imaginative in order to step up the challenges posed by the age transition in our society. Join us for the 2016 edition of the Treviso Advanced Post Graduate

GUEST EDITOR

Stuart M. Lichtman, MD

r. 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).

Course. For more information, visit www.siog.org. n Disclosure: Dr. Brain is President of the International Society of Geriatric Oncology (SIOG).

Prague Castle The Prague Castle is considered among the most significant of Czech monuments and one of the most important cultural institutions in the Czech Republic. It dates back to 880 and is considered the largest coherent castle complex in the world, with an area of almost 70,000 m². The 2015 International Society of Geriatric Oncology is taking place this month in Prague Czech Republic. Watch future issues of The ASCO Post for important coverage from this meeting. Photo courtesy of Andrew Nash.

For more on Geriatric Oncology, visit ASCOPost.com and search “Geriatrics for the Oncologist.”

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

NOW ENROLLING IN LUNG CANCER Genentech is committed to exploring the potential of cancer immunotherapy by investigating the safety and efficacy of atezolizumab (MPDL3280A) in non-small cell lung cancer (NSCLC). Seven clinical trials† are now recruiting patients.

NON-SQUAMOUS Atezolizumab + chemotherapy ± bevacizumab compared with bevacizumab + chemotherapy NCT02366143—“IMpower 150”

Ph III

Atezolizumab + chemotherapy compared with chemotherapy

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NCT02367781—“IMpower 130” Atezolizumab compared with chemotherapy

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NCT02409355—“IMpower 111”

PD-L1+

NON-SQUAMOUS/SQUAMOUS

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Atezolizumab compared with best supportive care following chemotherapy NCT02486718—“IMpower 010”

Atezolizumab (MPDL3280A)

Ph III 2L PD-L1+ Ph Ib

Atezolizumab + erlotinib‡

1L/2L

NCT02013219

EGFR+

Find out if your lung cancer patients are eligible for enrollment. For more information Visit:

Locate.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 July 2, 2015. ‡No limit to the number of prior therapies except for epidermal growth factor receptor tyrosine kinase inhibitors.

The ASCO Post | NOVEMBER 10, 2015

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Clinical Trials Resource Guide

Clinical Trials Actively Recruiting Patients With Lung Cancer By Liz Janetschek

he information contained in this Clinical Trials Resource Guide includes actively recruiting clinical studies for patients with lung cancer. The trials are investigating DNA, RNA, and protein changes contributing to carcinogenesis; new prevention strategies; combination therapies; radiation, stereotactic, and proton therapy; and surgical measures. All of the studies are listed on the National Institutes of Health website at ClinicalTrials.gov.

National Cancer Institute Purpose: To study the side effects and best dose of calcitriol in preventing lung cancer in current smokers and former smokers at high risk of lung cancer Primary Outcome Measures: Grade III-IV toxicities or any grade II toxicities lasting more than 2 weeks [time frame: 3 months] Principal Investigator: Alex A. Adjei, MD, PhD, Roswell Park Cancer Institute; contact 877-275-7724, AskRPCI@RoswellPark.org For More Information: Use ClinicalTrials.gov Identifier NCT00690924

OBSERVATIONAL

PHASE I/II

Study Type: Observational Study Title: Molecular Fingerprints in Lung Cancer: Predicting Tumor Response to Therapy Study Sponsor and Collaborators: Vanderbilt-Ingram Cancer Center, National Cancer Institute Purpose: To evaluate changes in DNA, RNA, and proteins with the goal of predicting response to treatment in patients with lung cancer Primary Outcome Measures: DNA, RNA, and protein expression patterns and mutational analysis [time frame: after lung tumor tissue and blood collection] Principal Investigator: Christine Lovly, MD, PhD, Vanderbilt-Ingram Cancer Center; 800-811-8480 For More Information: Use ClinicalTrials.gov Identifier NCT00897650

Study Type: Phase I/II/Interventional/Single-Group Assignment Study Title: Phase 1b/II Trial of Carfilzomib With Irinotecan in Irinotecan-Sensitive Malignancies (Phase Ib) and Small Cell Lung Cancer Patients (Phase II) Who Have Progressed on Prior Platinum-based Chemotherapy Study Sponsor and Collaborators: Cancer Research and Biostatistics Clinical Trials Consortium, Lucille P. Markey Cancer Center at University of Kentucky, Washington University School of Medicine Purpose: To determine a welltolerated dose of carfilzomib in combination with irinotecan in subjects with relapsed small and non–small cell lung cancer or other irinotecansensitive cancers, and to assess the 6-month survival of relapsed small cell lung cancer patients treated with this combination therapy Primary Outcome Measures: Phase 1b: Determine maximum tolerated dose of carfilzomib in combination with irinotecan in subjects with relapsed small and non–small cell lung cancer or other irinotecan-sensitive cancers [time frame: 28 days]

PHASE I Study Type: Phase I/Interventional/Single-Group Assignment Study Title: A Pilot Study of Oral Calcitriol in Patients at High Risk for Lung Cancer Study Sponsor and Collaborators: Roswell Park Cancer Institute,

Phase II: Assess 6-month survival of relapsed small cell lung cancer patients treated with carfilzomib in combination with irinotecan [time frame: up to 6 months] Principal Investigator: Susanne M. Arnold, MD, Lucille P. Markey Cancer Center; 859-323-8043, smarno0@uky.edu. For More Information: Use ClinicalTrials.gov Identifier NCT01941316

PHASE II Study Type: Phase II/Interventional/Parallel Assignment Study Title: Hypofractionated, Image-Guided Radiation Therapy With Proton Therapy for Stage I Non– Small Cell Lung Cancer Study Sponsor and Collaborators: University of Florida Purpose: To determine if hypofractionated image-guided radiation therapy (hypoIGRT) with proton therapy is a good way to treat earlystage lung tumors for patients who will not have surgery Primary Outcome Measures: Confirm grade III or higher toxicity rate of hypoIGRT proton therapy in patients with stage I non–small cell lung cancer [time frame: 1 year after the end of radiation therapy] Principal Investigator: Bradford S. Hoppe, MD, MPH, University of Florida Proton Therapy Institute; 877-686-6009 For More Information: Use ClinicalTrials.gov Identifier NCT00875901

PHASE II/III Study Type: Phase II/III/Interventional/Single Group Assignment Study Title: STARS Revised Clinical Trial Protocol: Stereotactic Ablative Radiotherapy (SABR) in Stage I Non–Small Cell Lung Cancer Patients Who Can Undergo Lobectomy

Study Sponsor and Collaborators: MD Anderson Cancer Center Purpose: To evaluate the outcome of a standard radiation treatment called stereotactic radiotherapy (SRT) for non–small cell lung cancer, specifically, to learn if standard SRT has as good of an outcome at 3 years after the procedure. Primary Outcome Measures: Overall survival for stage I non– small cell lung cancer patients treated with stereotactic body radiotherapy [time frame: 3 years] Principal Investigator: Jack Roth, MD, BA, MD Anderson Cancer Center; 713-563-9152 For More Information: Use ClinicalTrials.gov Identifier NCT02357992

PHASE III Study Type: Phase III/Interventional/Parallel Assignment Study Title: Phase III Comparison of Thoracic Radiotherapy Regimens in Patients With Limited Small Cell Lung Cancer Also Receiving Cisplatin and Etoposide Study Sponsor and Collaborators: Alliance for Clinical Trials in Oncology, National Cancer Institute Purpose: To compare different chest radiation therapy regimens to see how well they work in treating patients with limited-stage small cell lung cancer Primary Outcome Measures: Overall survival time between 3 treatment arms [time frame: up to 5 years] Principal Investigator: Jeffery A. Bogart, MD, SUNY Upstate Medical University; 315-464-5276 For More Information: Use ClinicalTrials.gov Identifier NCT00632853 n Editor’s Note: The clinical trials presented here do not represent all the trials listed on ClinicalTrials.gov. For the complete list, go to ClinicalTrials.gov.

November is Lung Cancer Awareness Month

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News European Cancer Congress

Telotristat Etiprate Added to Standard Therapy for Carcinoid Syndrome Shows Clinical Benefit in Patients With Metastatic Neuroendocrine Tumors

he investigational drug telotristat etiprate was shown to have clinical benefit when added to somatostatin analog therapy for carcinoid syndrome not adequately controlled by long-acting somatostatin analog therapy, the current standard of care, in patients with metastatic neuroendocrine tumors. Matthew H. Kulke, MD, primary investigator of the phase III TELESTAR study, presented these findings at the European Cancer Congress held recently in Vienna.1

syndrome that was not adequately controlled on somatostatin analog therapy. The three-arm study evaluated two doses of oral telotristat etiprate—250 mg and 500 mg—each taken three times per day vs placebo over a 12-week period. Investigators measured the reduction from baseline in the average number of daily bowel movements. Patients in both of the telotristat etiprate arms and in the placebo arm continued their somatostatin analog

Telotristat etiprate represents a novel approach by specifically inhibiting serotonin synthesis and, as such, is a promising potential new treatment for patients whose lives can be significantly impacted by this debilitating condition. —Matthew H. Kulke, MD

Dr. Kulke is Director, Program in Neuroendocrine and Carcinoid Tumors and Senior Physician, DanaFarber Cancer Institute, and Associate Professor of Medicine, Harvard Medical School. Carcinoid syndrome, characterized by debilitating diarrhea, facial flushing, abdominal pain, heart valve damage, and other serious consequences, is triggered by excess serotonin production within the cells of metastatic neuroendocrine tumors. Telotristat etiprate targets tryptophan hydroxylase, an enzyme that triggers this excess serotonin production, leading to carcinoid syndrome in patients with neuroendocrine tumors.

TELESTAR Study The double-blind phase III TELESTAR study enrolled 135 patients with metastatic neuroendocrine tumors and who had carcinoid

therapy throughout the study. Data showed that patients who received telotristat etiprate added to somatostatin analog therapy at both the 250-mg and 500-mg doses experienced a statistically significant reduction from baseline compared to placebo in the average number of daily bowel movements over the 12-week study period (P < .001), thus meeting the study’s primary endpoint. Patients who received 250 mg of telotristat etiprate experienced a reduction of 1.71 bowel movements (29%) in the average number of daily bowel movements during the final week of the study compared to baseline, and those in the 500-mg arm experienced a reduction of 2.11 bowel movements (35%); the placebo group showed a reduction of 0.87 bowel movements (17%).

Durable Responses A substantially greater proportion

of patients on telotristat etiprate/somatostatin analog therapy achieved a durable response (44% and 42% in the 250-mg and 500-mg arms, respectively), defined as at least a 30% reduction in daily bowel movements over at least half the days of the study period, as compared to 20% response in patients receiving the placebo plus somatostatin analog therapy (P < .02). The mean change in urinary 5-HIAA, the main metabolite of serotonin, from baseline to week 12 was a reduction of 40 mg/24 hours in the 250-mg arm and 58 mg/24 hours in the 500-mg arm. These changes compared with an increase in urinary 5-HIAA of 11 mg/24 hours in the placebo group (P < .001). Baseline urinary 5-HIAA levels were 93 mg/24 hours in the 250-mg arm, 90 mg/24 hours in the 500-mg arm, and 81 mg/24 hours in the placebo group.

Tolerability Treatment with telotristat etiprate was generally well tolerated during the double-blind treatment period. The proportions of patients with treatmentemergent adverse events were 82% in the 250-mg arm, 93% in the 500-mg arm, and 87% in the placebo group during the 12-week study period. The proportions of patients who discontinued treatment due to adverse events in both the 250mg and 500-mg arms were 7% as compared to 13% in the placebo group. Patients who received telotristat etiprate added to somatostatin analog therapy also experienced a lower frequency of flushing episodes and less intense abdominal pain compared to those receiving the placebo with somatostatin analog therapy. These differences did not reach statistical significance.

Efficacy and Safety Data “Telotristat etiprate represents a novel approach by specifically inhibiting serotonin synthesis and, as such, is a promising potential new treatment for patients whose lives can be significantly

impacted by this debilitating condition,” said Dr. Kulke. “These results are exciting from both an efficacy and safety perspective for [patients with] carcinoid syndrome.” The tolerability profile of the telotristat etiprate 250-mg dose appeared similar to placebo and somewhat better than the 500-mg dose in terms of gastrointestinal discomfort and mood. There were 6 events of patients experiencing mild to moderate nausea in the 250-mg arm, 13 in the 500-mg arm, and 5 in the placebo group. There were 2 events of depression or depressed mood in the 250-mg arm, 8 in the 500mg arm, and 3 in the placebo group. There were no discontinuations of treatment due to nausea, depression, or depressed mood in the 250-mg and 500-mg arms during the 12-week study period. “Carcinoid syndrome has a significant impact on the lives of patients who already have been battling metastatic cancer,” said Maryann Wahmann, Founder and President of the Neuroendocrine Cancer Awareness Network. “These patients can live for many years with their cancer, yet the symptoms of carcinoid syndrome are what frequently limit their lives and restrict their activities every single day. So there is a tremendous need for effective new treatment options.” Telotristat etiprate has received Fast Track and Orphan Drug designation from the U.S. Food and Drug Administration. n

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

Reference 1. Kulke M, Hörsch D, Caplin M, et al: Telotristat etiprate is effective in treating patients with carcinoid syndrome that is inadequately controlled by somatostatin analog therapy: The phase III TELESTAR clinical trial. 2015 European Cancer Congress. Abstract 37LBA. Presented September 29, 2015.

More From the European Cancer Congress For more reports from the European Cancer Congress, held recently in Vienna, see pages 9 through 26 in this issue of The ASCO Post. Plus, visit http://video.ascopost.com/ to view videos of interviews with experts filmed live during the annual congress.

The ASCO Post | NOVEMBER 10, 2015

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Announcements

Martine Extermann, MD, PhD, Recognized for Her Work in Geriatric Oncology at Assembly in Basel, Switzerland

artine Extermann, MD, PhD, senior member of Moffitt’s Senior Adult Oncology Program, has been honored with the Geriatric Oncology Lifetime Achievement Award, originally known as the “Preis geriatrische Onkologie für das Lebenswerk 2015,” at this year’s German, Austrian, and Swiss Congress of the Societies for Hematology and Oncology. She was recognized at a ceremony held October 10, during the conference, which took place October 9–13 in Basel, Switzerland.

cer’s behavior, which can be used to guide treatment choices. Among her many accomplishments, she has established an index to assess an individual’s risk of severe toxicity from

chemotherapy: the Chemotherapy Risk Assessment Scale for High-age patients, or CRASH, score. Dr. Extermann received her MD and PhD degrees in Geneva, Switzer-

land, and later came to the University of South Florida College of Medicine for a fellowship in medical oncology/ senior adult oncology. She has been at Moffitt since 1997. n

Martine Extermann, MD, PhD

“Receiving this award is quite an honor,” said Dr. Extermann. “I am grateful that I can contribute to such an important [field] that has global attention and support.” In July, the Kay Yow Cancer Fund, in partnership with The V Foundation for Cancer Research, awarded a $1.25 million ovarian cancer research grant to Dr. Extermann. The grant will support research focused on how to personalize care for aging women with ovarian cancer.

Other Awards and Achievements Dr. Extermann has received numerous awards for her work in geriatric oncology including the ASCO B.J. Kennedy Award for Scientific Excellence in Geriatric Oncology in 2009 and the Paul Calabresi Award in 2014 presented by the International Society of Geriatric Oncology. She has also served as President of the International Society of Geriatric Oncology, of which she is a founding board member. Along with receiving this Lifetime Achievement Award, Dr. Extermann also was among the 35 experts who presented at the Congress. She discussed the “Development of Geriatric Oncology in the USA” on October 11. Dr. Extermann’s main interests are to understand how the health of older patients affects their can-

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ASCOPost.com | NOVEMBER 10, 2015

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Announcements

Peter A. Kanetsky, PhD, MPH, Named Next President of ASPO

eter A. Kanetsky, PhD, MPH, Chair and Program Leader of Cancer Epidemiology at the Moffitt Cancer Center, has been elected as the new president for the American Society of Preventive Oncology (ASPO). He will serve as President-

Elect before taking the post in March 2017. ASPO is a multidisciplinary society that, through a variety of professional education activities, is committed to accelerating progress toward cancer prevention and control. Dr.

Kanetsky previously served on the executive committee of ASPO. A member of the Moffitt faculty since January 2014, Dr. Kanetsky’s research focuses on inherited genetics and the manner in which genes and Peter A. Kanetsky, PhD, MPH

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continued on page 60

The ASCO Post | NOVEMBER 10, 2015

PAGE 60

Announcements Peter A. Kanetsky, PhD, MPH continued from page 59

the environment interact to influence the development of melanoma and testicular germ cell tumors. He also has investigated how inherited genetics relate to and inform disease progression, including somatic genetics and metabolomics and longer-term

survival outcomes. He currently holds federal funding from the National Cancer Institute that supports, in part, the ongoing research of two large, international consortia: GenoMEL, an international melanoma genetics consortium, and TECAC, an international testicular cancer consortium. 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

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ASCOPost.com | NOVEMBER 10, 2015

PAGE 61

Announcements

LUNGevity Foundation and Celgene Collaborate to Create Resource for Lung Cancer Caregivers

he LUNGevity Foundation and the biopharmaceutical company Celgene have joined forces to launch a new resource for caregivers of people diagnosed with lung cancer. The pro-

gram, “Your Journey Together,” is a support tool focusing on the specific needs of this group and includes a series of videos, tip sheets, and other resources to assist caregivers in transitioning into

their new roles, take care of themselves, and connect with other caregivers. The joint effort enhances the online LUNGevity Caregiver Resource Center. In addition, each month a live

conversation will be held on Twitter using the hashtag #LCCaregiver, open to caregivers across the nation, and will allow questions to be asked and answered in real time. “Celgene is truly pleased to be working alongside LUNGevity to provide tools and resources for caregivers—a critical and essential member of a lung cancer survivor’s health-care team,” said Joel Beetsch, Vice President of Patient Advocacy at Celgene. “It is our hope that these resources provide important insights for the caregiver and the patient as they ‘Journey Together’ in the fight against lung cancer.”

Andrea Ferris

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“The ‘Your Journey Together’ program is a great addition to the online Caregiver Resource Center,” said Andrea Ferris, President of LUNGevity Foundation. “At LUNGevity, we are focused on supporting anyone affected by lung cancer, both survivors and the friends and family members who serve as their rock through diagnosis and treatment. We’re grateful to work with Celgene on addressing this unmet need in the lung cancer community.” The Caregiver Resource Center and new “Your Journey Together” materials can be found at www.LUNGevity.org/ caregiver. n

November is Lung Cancer Awareness Month

The ASCO Postâ&#x20AC;&#x201A; | â&#x20AC;&#x201A; NOVEMBER 10, 2015

PAGE 62

Global Cancer Burden World Health Organization Region: Africa Country: Algeria

Cancer on the Global Stage: Incidence and Cancer-Related Mortality in Algeria The ASCO Post is pleased to continue this special focus on the worldwide cancer burden. In this issue, we feature a close look at the cancer incidence and mortality rates in Algeria. 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 installment 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 by 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.

lgeria, a country of more than 39 million inhabitants, with a median age of 27 years, currently experiences a cancer incidence of more than 40,000 cases per year and a cancer mortality rate of approximately 25,000 per year (Table 1, Figs. 1 to 4). Like the worldwide rates of incidence of new cancer cases and cancer-related mortality, in Algeria rates of new cancer cases and mortality are predicted to increase significantly between 2015 and 2035 to approximately 75,000 and 46,000 per year, respectively. Cancer accounts for 10% of all deaths in Algeria. Although this is lower than that for cardiovascular diseases now (41% in 2014), the trends in age-standardized death rates have been gradually increasing for cancer. The incidence of cancer is rising in Algeria due to various factors including the adoption of western lifestyle habits. A review of the types of cancer reveals some differences when compared to western nations such as the United States. Breast cancer is the most common type of cancer and supersedes cancers of the other organs such as colorectum and lungs

ASCOPost.com | NOVEMBER 10, 2015

PAGE 63

Focus: Algeria by wider margins. Prostate cancer, the highest by incidence in the United States, does not feature in the top 10 cancers by incidence in Algeria. Breast cancer in Algeria also accounts for the largest number of cancer-related deaths. Breast cancer in Algeria surpasses cancer-related deaths attributable to other cancers such as lung and colorectum, which are the two leading contributors to cancer-related mortality in the United States. Most cancers in Algeria present in late stages, making curative-intent treatment difficult. Algeria is the largest country in Africa with some sparsely populated areas. Due to this geographic predicament, providing timely and comprehensive cancer care to all regions of the country can be difficult. It has been noted that sometimes patients have to wait for long periods to receive radiotherapy. Nonetheless, several efforts are underway to improve cancer care. One example of such efforts is the existence of several cancer registries that are procuring data, which will be beneficial. A recent publication of Cherif et al by using the Setif Cancer Registry documented a statistically significant increase in overall cancer incidence for both men and women (annual percentage increase of +2.5% and +3.7% respectively, P < .005). In addition, the recently proposed National Cancer Plan, with its eight main goals and the approval of the President of the Republic, Abdelaziz Bouteflika, has put the spotlight on cancer. It is hoped these efforts will go a long way in tackling the rising cancer burden in Algeria. n Table 1: Algeria: Demographics and General Facts

9,000 8,000 7,000 6,000 5,000 4,000 3,000 2,000 1,000 0 Breast

Lung

Brain, Nervous System

Stomach

Bladder

Leukemia

Thyroid

Non-Hodgkin Lymphoma

Cervix uteri

Bladder

Prostate

Fig. 1: Top 10 Cancers by Incidence—Current Rates in Algeria.

3,000 2,500 2,000 1,500 1,000

Population

39.5 million

Median age

27.3 years

500 0 Breast

Population growth rate

1.84% (2015)

Birth rate per 1,000 population

23.67 (2015)

Death rate per 1,000 population

4.31 (2015)

Life expectancy at birth

79.59 years

80,000

Health expenditure as % of gross domestic product

5.2% (2015)

60,000

Physicians per 1,000 population

1.21 (2007)

Lung

Colorectum

Stomach

Leukemia

Brain, Nervous System

NonGallbladder Hodgkin Lymphoma

Fig. 2: Top 10 Cancers by Mortality—Current Rates in Algeria.

90,000 70,000 50,000

Hospital bed density per 1,000 population Obesity prevalence rate

1.7 beds (2004) 23.6% (2014)

Mobile telephones

37.3 million (2014)

Land lines

3.1 million (2014)

40,000 30,000 20,000 10,000 0 2015

50,000

Additional Readings

40,000

http://www.cia.gov/library/publications/the-world-factbook/ http://globocan.iarc.frDefault.aspx 2012 http://www.who.int/nmh/countries/dza_en.pdf http://www.who.int/nmh/countries/dza_en.pdf

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.

2020

2025

2030

2035

Fig. 3: Trends in the Incidence of New Cancer Cases in Algeria: 2015–2035.

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

1. 2. 3. 4.

Colorectum

30,000 20,000 10,000 0 2015

2020

2025

2030

2035

Fig. 4: Trends in Cancer-Related Mortality in Algeria: 2015–2035.

GUEST EDITOR

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. Chandrakanth Are, MBBS, MBA, FRCS, FACS

The ASCO Post | NOVEMBER 10, 2015

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Issues in Oncology ASCO Statement

ASCO Calls for Comprehensive Payment Reform to Address Issue of Site Neutrality

SCO recently called for comprehensive physician payment reform to support the full scope of services required by patients with cancer, rather than jeopardizing patient outcomes by reducing the available resources in a par-

hospital outpatient setting (Hospital Outpatient Prospective Payment System), are based on different data sets for rate setting, explained the society in its “Policy Statement on Site-Neutral Payments in Oncology.”

Alternative payment models that shift the emphasis away from face-toface office visits and administration of intravenous anticancer drug regimens and toward providing patients with high-quality, high-value oncology care are needed in order to provide the full scope of oncology services to all Medicare beneficiaries, regardless of where they are treated. —Julie M. Vose, MD, MBA, FASCO

ticular cancer care setting in an effort to achieve “site neutrality” in reimbursement for oncology services. In a new policy statement on site-neutral payments in oncology, published in the Journal of Clinical Oncology (JCO), ASCO asserted that the traditional approach to physician payment under Medicare is flawed and reflects a narrow and outdated view of the needs of individuals with cancer and the best available options for delivering high-quality, high-value care.

Site Neutrality According to ASCO, current discussions on site neutrality—the concept of providing equal reimbursement for the same services delivered in any care setting—have centered on a flawed comparison between outpatient cancer treatment settings. ASCO contends that there is no basis to conclude that the reimbursement levels developed for oncology services under the two dominant Medicare reimbursement methodologies for outpatient oncology services—the Medicare Physician Fee Schedule and the Hospital Outpatient Prospective Payment System—should be substituted for one another. The two Medicare reimbursement systems, for the physician office setting (Medicare Physician Fee Schedule) and for the

The differences between Medicare Physician Fee Schedule and Hospital Outpatient Prospective Payment System are further exacerbated, in ASCO’s view, by separate conversion factors established by the Centers for Medicare & Medicaid Services under rules that are unique to each care setting. The conversion factors for the two settings are established in different ways that have little relationship to each other or to the actual cost of providing oncology care to Medicare beneficiaries, as they are based on the aggregate amount of Medicare funding allocated for each setting of care for a particular year. “Given these variables and challenges, there is no reasonable rationale for concluding that reductions are warranted in the payment levels for either setting of care on the basis of payment levels established for the other setting,” according to the statement authored by the ASCO Site-Neutrality Working Group. “The current systems for reimbursement of outpatient cancer care under Medicare are outdated,” said ASCO President Julie M. Vose, MD, MBA, FASCO. “Alternative payment models that shift the emphasis away from face-to-face office visits and administration of intravenous anticancer drug regimens and toward providing patients

with high-quality, high-value oncology care are needed in order to provide the full scope of oncology services to all Medicare beneficiaries, regardless of where they are treated.” A number of stakeholder groups are working to improve cancer care by developing alternative models for coding and reimbursing oncology services under Medicare. Models developed by ASCO, the Center for Medicare & Medicaid Innovation, and other groups are designed to transform the outdated Medicare oncology coding and reimbursement systems by establishing episode-based or bundled payments that include coverage and adequate reimbursement for the many critical cancer care services that are unrecognized, uncompensated, or undercompensated under the current system. An expanded set of professional services will promote efficiency and reduce unplanned hospitalizations and emergency room visits, noted ASCO. By providing adequate resources to oncology practices for the full scope of medically necessary services, these new models take a patient-centered approach to promoting value and improving patient outcomes, with the promise of lower aggregate Medicare expenditures.

Recommendations Given the move across medicine toward providing value-based care, ASCO recommends a transformative approach to Medicare reimbursement that embraces currently accepted best practices for delivering a patientcentered oncology payment model focused on providing high-quality, high-value cancer care, while also addressing disparities. ASCO’s specific recommendations include: 1. Creating value-based incentives that raise quality and lower cost rather than arbitrarily cutting payment levels based on the site of care. 2. Ensuring that payment levels for physician practices provide adequate support for the full scope of medical and ancillary services required to treat individuals with cancer. 3. Engaging in additional study of the full scope of services required by patients with cancer, including the specific needs of low-income individuals, before implementing any change in resources paid to oncology practices and hospitals. 4. Transforming Medicare coding and payment for outpatient cancer care

Private payer initiatives have demonstrated that even greater cost savings can be achieved by transforming and improving the oncology care delivery model compared with traditional siteneutrality initiatives. —Philip J. Stella, MD

“Private payer initiatives have demonstrated that even greater cost savings can be achieved by transforming and improving the oncology care delivery model compared with traditional siteneutrality initiatives,” said Philip J. Stella, MD, Chair of the ASCO Government Relations Committee. “Conversely, cutting reimbursement levels based on site-neutrality could limit the scope of services available to Medicare beneficiaries across treatment settings.”

by implementing policies that are consistent with proposals such as ASCO’s “Patient-Centered Oncology Payment: Payment Reform to Support Higher Quality, More Affordable Cancer Care” (PCOP) model. To read the full statement in JCO, go to http://jco.ascopubs.org/content/ early/2015/10/23/JCO.2015.64.0615? et_cid=36883959&et_rid=466246220 &linkid=here. n

DID YOU KNOW? FOR NEARLY 15 YEARS (1999-2014), NO FDAAPPROVED, SECOND-LINE REGIMEN EXTENDED OVERALL SURVIVAL VERSUS DOCETAXEL ACROSS A BROAD POPULATION OF PATIENTS WITH METASTATIC NSCLC1-4

NSCLC=non-small cell lung cancer.

Visit www.CYRAMZAHCP.com for more information CYRAMZA® (ramucirumab), in combination with docetaxel, is indicated for the treatment of patients with metastatic NSCLC with disease progression on or after platinum-based chemotherapy. Patients with epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving CYRAMZA.

ADVANCING THE SECOND-LINE TREATMENT OF METASTATIC NSCLC5 CYRAMZA is the first antiangiogenic agent FDA approved in combination with docetaxel for the second-line treatment of metastatic NSCLC, including nonsquamous and squamous histologies.5

IMPORTANT SAFETY INFORMATION FOR CYRAMZA WARNING: HEMORRHAGE, GASTROINTESTINAL PERFORATION, AND IMPAIRED WOUND HEALING Hemorrhage: CYRAMZA increased the risk of hemorrhage and gastrointestinal hemorrhage, including severe and sometimes fatal hemorrhagic events. Permanently discontinue CYRAMZA in patients who experience severe bleeding. Gastrointestinal Perforation: CYRAMZA can increase the risk of gastrointestinal perforation, a potentially fatal event. Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation. Impaired Wound Healing: Impaired wound healing can occur with antibodies inhibiting the VEGF pathway. Discontinue CYRAMZA therapy in patients with impaired wound healing. Withhold CYRAMZA prior to surgery and discontinue CYRAMZA if a patient develops wound healing complications.

Warnings and Precautions Hemorrhage • CYRAMZA increased the risk of hemorrhage and gastrointestinal hemorrhage, including severe and sometimes fatal hemorrhagic events. In study 3, which evaluated CYRAMZA plus docetaxel in metastatic non-small cell lung cancer (NSCLC), the incidence of severe bleeding was 2.4% for CYRAMZA plus docetaxel and 2.3% for placebo plus docetaxel. Patients with NSCLC receiving therapeutic anticoagulation or chronic therapy with NSAIDs or other antiplatelet therapy other than once-daily aspirin or with radiographic evidence of major airway or blood vessel invasion or intratumor cavitation were excluded from study 3; therefore, the risk of pulmonary hemorrhage in these groups of patients is unknown. Permanently discontinue CYRAMZA in patients who experience severe bleeding. Arterial Thromboembolic Events (ATEs)

• Serious, sometimes fatal, ATEs including myocardial infarction, cardiac

arrest, cerebrovascular accident, and cerebral ischemia occurred in clinical trials. Permanently discontinue CYRAMZA in patients who experience a severe ATE.

Hypertension

• An increased incidence of severe hypertension occurred in patients

receiving CYRAMZA plus docetaxel (6%) as compared to placebo plus docetaxel (2%). Control hypertension prior to initiating treatment with CYRAMZA. Monitor blood pressure every 2 weeks or more frequently as indicated during treatment. Temporarily suspend CYRAMZA for severe hypertension until medically controlled. Permanently discontinue

CYRAMZA if medically significant hypertension cannot be controlled with antihypertensive therapy or in patients with hypertensive crisis or hypertensive encephalopathy. Infusion-Related Reactions (IRRs) • Prior to the institution of premedication recommendations across clinical trials of CYRAMZA, IRRs occurred in 6 out of 37 patients (16%), including 2 severe events. The majority of IRRs across trials occurred during or following a first or second CYRAMZA infusion. Symptoms of IRRs included rigors/tremors, back pain/spasms, chest pain and/or tightness, chills, flushing, dyspnea, wheezing, hypoxia, and paresthesia. In severe cases, symptoms included bronchospasm, supraventricular tachycardia, and hypotension. Monitor patients during the infusion for signs and symptoms of IRRs in a setting with available resuscitation equipment. Immediately and permanently discontinue CYRAMZA for grade 3 or 4 IRRs. Gastrointestinal Perforations

• CYRAMZA is an antiangiogenic therapy that can increase the risk of

gastrointestinal perforation, a potentially fatal event. In study 3, the incidence of gastrointestinal perforation was 1% for CYRAMZA plus docetaxel versus 0.3% for placebo plus docetaxel. Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation.

Impaired Wound Healing

• Impaired wound healing can occur with antibodies inhibiting the VEGF

pathway. CYRAMZA has not been studied in patients with serious or nonhealing wounds. CYRAMZA, as an antiangiogenic therapy, has the potential to adversely affect wound healing. Withhold CYRAMZA prior to surgery. Resume CYRAMZA following the surgical intervention based on clinical judgment of adequate wound healing. If a patient develops wound healing complications during therapy, discontinue CYRAMZA until the wound is fully healed.

Clinical Deterioration in Child-Pugh B or C Cirrhosis

• Clinical deterioration, manifested by new onset or worsening

encephalopathy, ascites, or hepatorenal syndrome, was reported in patients with Child-Pugh B or C cirrhosis who received single-agent CYRAMZA. Use CYRAMZA in patients with Child-Pugh B or C cirrhosis only if the potential benefits of treatment are judged to outweigh the risks of clinical deterioration.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS)

• RPLS has been reported at a rate of <0.1% in clinical studies with

CYRAMZA. Confirm the diagnosis of RPLS with MRI and discontinue CYRAMZA in patients who develop RPLS. Symptoms may resolve or improve within days, although some patients with RPLS can experience ongoing neurologic sequelae or death.

Proteinuria Including Nephrotic Syndrome

• Monitor proteinuria by urine dipstick and/or urinary protein creatinine ratio

for the development of worsening of proteinuria during CYRAMZA therapy. Withhold CYRAMZA for urine protein levels that are ≥2 g over 24 hours.

CYRAMZA plus docetaxel demonstrated a statistically significant improvement in overall survival vs docetaxel5 OVERALL SURVIVAL: MEDIAN - MONTHS (95% CI) CYRAMZA + docetaxel (n=628)

1.0

OS PROBABILITY

0.8

MAJOR OUTCOME MEASURE

10.5

15% INCREASE IN MEDIAN OS

MONTHS

(9.5, 11.2) Hazard Ratio (95% CI)=0.86 (0.75, 0.98); P=0.024

0.6

CYRAMZA + docetaxel

0.4

Placebo + docetaxel

9.1

0.2

Placebo + docetaxel (n=625)

MONTHS (8.4, 10.0)

0.0 0

TIME FROM RANDOMIZATION (MONTHS)

Number at Risk

CYRAMZA + docetaxel 628 Placebo + docetaxel 625

527

415

329

231

156

103

501

386

306

197

129

• The percentage of deaths at the time of analysis was 68% (428 patients) and 73% (456 patients) in the CYRAMZA plus docetaxel and placebo plus docetaxel arms, respectively 5

Demonstrated improvements across all three efficacy outcomes (OS, PFS, ORR)5 • Median PFS with CYRAMZA plus docetaxel was 4.5 months (95% CI: 4.2, 5.4) vs 3.0 months (95% CI: 2.8, 3.9) with placebo plus docetaxel (hazard ratio 0.76 [95% CI: 0.68, 0.86]; P<0.001) — The percentage of events at the time of analysis was 89% (558 patients) and 93% (583 patients) in the CYRAMZA plus docetaxel and placebo plus docetaxel arms, respectively • ORR with CYRAMZA plus docetaxel was 23% (95% CI: 20, 26) vs 14% (95% CI: 11, 17) with placebo plus docetaxel (P<0.001)* CI=confidence interval; OS=overall survival; PFS=progression-free survival; ORR=objective response rate. *Intent-to-treat population. Disease progression and tumor response were assessed by investigators in accordance with Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.6 ORR is defined as complete plus partial response.

REVEL TRIAL DESIGN (N=1253) The phase III REVEL trial evaluated the efficacy and safety of CYRAMZA plus docetaxel vs placebo plus docetaxel in patients with metastatic NSCLC with disease progression on or after platinum-based chemotherapy. Major efficacy outcome measure was OS. Supportive efficacy outcome measures were PFS and ORR. All patients were required to have Eastern Cooperative Oncology Group performance status 0 or 1. Patients were randomized 1:1 (N=1253) to receive either CYRAMZA 10 mg/kg or placebo, in combination with docetaxel at 75 mg/m2 every 21 days.5 Reinitiate CYRAMZA at a reduced dose once the urine protein level returns to <2 g over 24 hours. Permanently discontinue CYRAMZA for urine protein levels >3 g over 24 hours or in the setting of nephrotic syndrome. Thyroid Dysfunction

• Monitor thyroid function during treatment with CYRAMZA.

Embryofetal Toxicity

• Based on its mechanism of action, CYRAMZA can cause fetal harm

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

Most Common Adverse Reactions

• The most commonly reported adverse reactions (all grades; grade 3/4)

occurring in ≥5% of patients receiving CYRAMZA plus docetaxel and ≥2% higher than placebo plus docetaxel in study 3 were neutropenia (55% vs 46%; 49% vs 40%), fatigue/asthenia (55% vs 50%; 14% vs 11%), stomatitis/ mucosal inflammation (37% vs 19%; 7% vs 2%), epistaxis (19% vs 7%; <1% vs <1%), febrile neutropenia (16% vs 10%; 16% vs 10%), peripheral edema (16% vs 9%; 0% vs <1%), thrombocytopenia (13% vs 5%; 3% vs <1%), lacrimation increased (13% vs 5%; <1% vs 0%), and hypertension (11% vs 5%; 6% vs 2%).

• The most common serious adverse events with CYRAMZA plus docetaxel

in study 3 were febrile neutropenia (14%), pneumonia (6%), and neutropenia (5%). The use of granulocyte colony-stimulating factors was 42% in CYRAMZA plus docetaxel-treated patients versus 37% in patients who received placebo plus docetaxel.

• In patients ≥65 years of age, there were 18 (8%) deaths on treatment

or within 30 days of discontinuation for CYRAMZA plus docetaxel and 9 (4%) deaths for placebo plus docetaxel. In patients <65 years of age, there were 13 (3%) deaths on treatment or within 30 days of discontinuation for CYRAMZA plus docetaxel and 26 (6%) deaths for placebo plus docetaxel.

• Treatment discontinuation due to adverse reactions occurred more

frequently in CYRAMZA plus docetaxel-treated patients (9%) than in placebo plus docetaxel-treated patients (5%). The most common adverse events leading to treatment discontinuation of CYRAMZA were infusion-related reaction (0.5%) and epistaxis (0.3%).

• For patients with nonsquamous histology, the overall incidence of

pulmonary hemorrhage was 7% and the incidence of grade ≥3 pulmonary hemorrhage was 1% for CYRAMZA plus docetaxel compared to 6% overall incidence and 1% for grade ≥3 pulmonary hemorrhage for placebo plus docetaxel. For patients with squamous histology, the overall incidence of pulmonary hemorrhage was 10% and

the incidence of grade ≥3 pulmonary hemorrhage was 2% for CYRAMZA plus docetaxel compared to 12% overall incidence and 2% for grade ≥3 pulmonary hemorrhage for placebo plus docetaxel. • Clinically relevant adverse reactions reported in ≥1% and <5% of

CYRAMZA plus docetaxel-treated patients in study 3 were hyponatremia (4.8% CYRAMZA plus docetaxel versus 2.4% for placebo plus docetaxel) and proteinuria (3.3% CYRAMZA plus docetaxel versus 0.8% placebo plus docetaxel).

Drug Interactions

• No pharmacokinetic interactions were observed between ramucirumab

and docetaxel.

Use in Specific Populations

• Pregnancy: Based on its mechanism of action, CYRAMZA can cause

fetal harm. Animal models link angiogenesis, VEGF, and VEGF Receptor 2 (VEGFR2) to critical aspects of female reproduction, embryofetal development, and postnatal development. There are no available data on CYRAMZA use in pregnant women to inform any drug-associated risks. No animal studies have been conducted to evaluate the effect of ramucirumab on reproduction and fetal development. Advise females of reproductive potential of the potential risk for maintaining pregnancy, risk to the fetus, and risk to newborn and infant development, and to use effective contraception during CYRAMZA therapy and for at least 3 months following the last dose of CYRAMZA.

• Lactation: Because of the potential risk for serious adverse reactions in

nursing infants from ramucirumab, advise women that breastfeeding is not recommended during treatment with CYRAMZA.

• Females of Reproductive Potential: Advise females of reproductive potential

that based on animal data CYRAMZA may impair fertility.

Please see Brief Summary of Prescribing Information for CYRAMZA, including Boxed Warnings for hemorrhage, gastrointestinal perforation, and impaired wound healing, on next page. RB-L HCP ISI 24APR2015 References: 1. Reck M, Kaiser R, Mellemgaard A, et al. Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1): a phase 3, double-blind, randomised controlled trial. Lancet Oncol. 2014;15:143-155. 2. Supplement to: Reck M, Kaiser R, Mellemgaard A, et al. Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1): a phase 3, double-blind, randomised controlled trial. Lancet Oncol. 2014;15:143-155. 3. National Cancer Institute. Cancer drug information. FDA approval for docetaxel. http://www.cancer.gov/cancertopics/druginfo/fda-docetaxel/print. Accessed August 26, 2014. 4. National Cancer Institute. Cancer drug information. FDA approval for ramucirumab. http://www.cancer.gov/ cancertopics/treatment/drugs/fda-ramucirumab#nsclc. Accessed May 4, 2015. 5. CYRAMZA (ramucirumab) [package insert]. Indianapolis, IN: Eli Lilly and Company; 2015. 6. Garon EB, Ciuleanu T-E, Arrieta O, et al. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial. Lancet. 2014;384(9944):665-673. RB96549 05/2015 PRINTED IN USA © Lilly USA, LLC 2015. All rights reserved. CYRAMZA is a trademark owned by or licensed to Eli Lilly and Company, its subsidiaries, or affiliates.

CYRAMZA® (ramucirumab) injection BRIEF SUMMARY: For complete safety, please consult the full Prescribing Information. WARNING: HEMORRHAGE, GASTROINTESTINAL PERFORATION, AND IMPAIRED WOUND HEALING Hemorrhage: CYRAMZA increased the risk of hemorrhage and gastrointestinal hemorrhage, including severe and sometimes fatal hemorrhagic events. Permanently discontinue CYRAMZA in patients who experience severe bleeding. Gastrointestinal Perforation: CYRAMZA can increase the risk of gastrointestinal perforation, a potentially fatal event. Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation. Impaired Wound Healing: Impaired wound healing can occur with antibodies inhibiting the VEGF pathway. Discontinue CYRAMZA therapy in patients with impaired wound healing. Withold CYRAMZA prior to surgery and discontinue CYRAMZA if a patient develops wound healing complications. INDICATIONS AND USAGE Non-Small Cell Lung Cancer: CYRAMZA, in combination with docetaxel, is indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with disease progression on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving CYRAMZA. CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS Hemorrhage CYRAMZA increased the risk of hemorrhage and gastrointestinal hemorrhage, including severe and sometimes fatal hemorrhagic events. In Study 1, the incidence of severe bleeding was 3.4% for CYRAMZA and 2.6% for placebo. In Study 2, the incidence of severe bleeding was 4.3% for CYRAMZA plus paclitaxel and 2.4% for placebo plus paclitaxel. Patients with gastric cancer receiving nonsteroid anti-inflammatory drugs (NSAIDs) were excluded from enrollment in Studies 1 and 2; therefore, the risk of gastric hemorrhage in CYRAMZA-treated patients with gastric tumors receiving NSAIDs is unknown. In Study 3, the incidence of severe bleeding was 2.4% for CYRAMZA plus docetaxel and 2.3% for placebo plus docetaxel. Patients with NSCLC receiving therapeutic anticoagulation or chronic therapy with NSAIDS or other antiplatelet therapy other than once daily aspirin or with radiographic evidence of major airway or blood vessel invasion or intratumor cavitation were excluded from Study 3; therefore the risk of pulmonary hemorrhage in these groups of patients is unknown. In Study 4, the incidence of severe bleeding was 2.5% for CYRAMZA plus FOLFIRI and 1.7% for placebo plus FOLFIRI. Permanently discontinue CYRAMZA in patients who experience severe bleeding. Arterial Thromboembolic Events Serious, sometimes fatal, arterial thromboembolic events (ATEs) including myocardial infarction, cardiac arrest, cerebrovascular accident, and cerebral ischemia occurred in clinical trials including 1.7% of 236 patients who received CYRAMZA as a single agent for gastric cancer in Study 1. Permanently discontinue CYRAMZA in patients who experience a severe ATE. Hypertension An increased incidence of severe hypertension occurred in patients receiving CYRAMZA as a single agent (8%) as compared to placebo (3%) and in patients receiving CYRAMZA plus paclitaxel (15%) as compared to placebo plus paclitaxel (3%), in patients receiving CYRAMZA plus docetaxel (6%) as compared to placebo plus docetaxel (2%), and in patients receiving CYRAMZA plus FOLFIRI (11%) as compared to placebo plus FOLFIRI (3%). Control hypertension prior to initiating treatment with CYRAMZA. Monitor blood pressure every two weeks or more frequently as indicated during treatment. Temporarily suspend CYRAMZA for severe hypertension until medically controlled. Permanently discontinue CYRAMZA if medically significant hypertension cannot be controlled with antihypertensive therapy or in patients with hypertensive crisis or hypertensive encephalopathy. Infusion-Related Reactions Prior to the institution of premedication recommendations across clinical trials of CYRAMZA, infusion-related reactions (IRRs) occurred in 6 out of 37 patients (16%), including two severe events. The majority of IRRs across trials occurred during or following a first or second CYRAMZA infusion. Symptoms of IRRs included rigors/tremors, back pain/spasms, chest pain and/or tightness, chills, flushing, dyspnea, wheezing, hypoxia, and paresthesia. In severe cases, symptoms included bronchospasm, supraventricular tachycardia, and hypotension. Monitor patients during the infusion for signs and symptoms of IRRs in a setting with available resuscitation equipment. Immediately and permanently discontinue CYRAMZA for Grade 3 or 4 IRRs. Gastrointestinal Perforations CYRAMZA is an antiangiogenic therapy that can increase the risk of gastrointestinal perforation, a potentially fatal event. Four of 570 patients (0.7%) who received CYRAMZA as a single agent in clinical trials experienced gastrointestinal perforation. In Study 2, the incidence of gastrointestinal perforations was also increased in patients that received CYRAMZA plus paclitaxel (1.2%) as compared to patients receiving placebo plus paclitaxel (0.3%). In Study 3, the incidence of gastrointestinal perforation was 1% for CYRAMZA plus docetaxel and 0.3% for placebo plus docetaxel. In Study 4, the incidence of gastrointestinal perforation was 1.7% for CYRAMZA plus FOLFIRI and 0.6% for placebo plus FOLFIRI. Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation. Impaired Wound Healing Impaired wound healing can occur with antibodies inhibiting the VEGF pathway. CYRAMZA has not been studied in patients with serious or non-healing wounds. CYRAMZA, as an antiangiogenic therapy, has the potential to adversely affect wound healing. Withhold CYRAMZA prior to surgery. Resume following the surgical intervention based on clinical judgment of adequate wound healing. If a patient develops wound healing complications during therapy, discontinue CYRAMZA until the wound is fully healed. Clinical Deterioration in Patients with Child-Pugh B or C Cirrhosis Clinical deterioration, manifested by new onset or worsening encephalopathy, ascites, or hepatorenal syndrome was reported in patients with Child-Pugh B or C cirrhosis who received single-agent CYRAMZA. Use CYRAMZA in patients with Child-Pugh B or C cirrhosis only if the potential benefits of treatment are judged to outweigh the risks of clinical deterioration. Reversible Posterior Leukoencephalopathy Syndrome (RPLS) RPLS has been reported with a rate of <0.1% in clinical studies with CYRAMZA. Confirm the diagnosis of RPLS with MRI and discontinue CYRAMZA in patients who develop RPLS. Symptoms may resolve or improve within days, although some patients with RPLS can experience ongoing neurologic sequelae or death. Proteinuria Including Nephrotic Syndrome In Study 4, severe proteinuria occurred more frequently in patients treated with CYRAMZA plus FOLFIRI compared to patients receiving placebo plus FOLFIRI. Severe proteinuria was reported in 3% of patients treated with CYRAMZA plus FOLFIRI (including 3 cases [0.6%] of nephrotic syndrome) compared to 0.2% of patients treated with placebo plus FOLFIRI. Monitor proteinuria by urine dipstick and/or urinary protein creatinine ratio for the development of worsening of proteinuria during CYRAMZA therapy. Withhold CYRAMZA for urine protein levels that are 2 or more grams over 24 hours. Reinitiate CYRAMZA at a reduced dose once the urine protein level returns to less than 2 grams over 24 hours. Permanently discontinue CYRAMZA for urine protein levels greater than 3 grams over 24 hours or in the setting of nephrotic syndrome. Thyroid Dysfunction Monitor thyroid function during treatment with CYRAMZA. In Study 4, the incidence of hypothyroidism reported as an adverse event was 2.6% in the CYRAMZA plus FOLFIRI treated patients and 0.9% in the placebo plus FOLFIRI treated patients. Embryofetal Toxicity Based on its mechanism of action, CYRAMZA can cause fetal harm when administered to pregnant women. Animal models link angiogenesis, VEGF and VEGF Receptor 2 (VEGFR2) to critical aspects of female reproduction, embryofetal development, and postnatal development. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with CYRAMZA and for at 3 least months after the last dose of CYRAMZA. ADVERSE REACTIONS Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. CYRAMZA® (ramucirumab) injection RB-L HCP BS 04MAY2015

CYRAMZA Administered in Combination with Docetaxel Study 3 was a multinational, randomized, double-blind study conducted in patients with NSCLC with disease progression on or after one platinum-based therapy for locally advanced or metastatic disease. Patients received either CYRAMZA 10 mg/kg intravenously plus docetaxel 75 mg/m2 intravenously every 3 weeks or placebo plus docetaxel 75 mg/m2 intravenously every 3 weeks. Due to an increased incidence of neutropenia and febrile neutropenia in patients enrolled in East Asian sites, Study 3 was amended and 24 patients (11 CYRAMZA plus docetaxel, 13 placebo plus docetaxel) at East Asian sites received a starting dose of docetaxel at 60 mg/m2 every 3 weeks. Study 3 excluded patients with an ECOG PS of 2 or greater, bilirubin greater than the upper limit of normal (ULN), uncontrolled hypertension, major surgery within 28 days, radiographic evidence of major airway or blood vessel invasion by cancer, radiographic evidence of intratumor cavitation, or gross hemoptysis within the preceding 2 months, and patients receiving therapeutic anticoagulation or chronic anti-platelet therapy other than once daily aspirin. The study also excluded patients whose only prior treatment for advanced NSCLC was a tyrosine kinase (epidermal growth factor receptor [EGFR] or anaplastic lymphoma kinase [ALK]) inhibitor. The data described below reflect exposure to CYRAMZA plus docetaxel in 627 patients in Study 3. Demographics and baseline characteristics were similar between treatment arms. Median age was 62 years; 67% of patients were men; 84% were White and 12% were Asian; 33% had ECOG PS 0; 74% had non-squamous histology and 25% had squamous histology. Patients received a median of 4.5 doses of CYRAMZA; the median duration of exposure was 3.5 months, and 195 (31% of 627) patients received CYRAMZA for at least six months. In Study 3, the most common adverse reactions (all grades) observed in CYRAMZA plus docetaxel-treated patients at a rate of ≥30% and ≥2% higher than placebo plus docetaxel were neutropenia, fatigue/asthenia, and stomatitis/mucosal inflammation. Treatment discontinuation due to adverse reactions occurred more frequently in CYRAMZA plus docetaxeltreated patients (9%) than in placebo plus docetaxel-treated patients (5%). The most common adverse events leading to treatment discontinuation of CYRAMZA were infusion-related reaction (0.5%) and epistaxis (0.3%). For patients with non-squamous histology, the overall incidence of pulmonary hemorrhage was 7% and the incidence of ≥Grade 3 pulmonary hemorrhage was 1% for CYRAMZA plus docetaxel compared to 6% overall incidence and 1% for ≥Grade 3 pulmonary hemorrhage for placebo plus docetaxel. For patients with squamous histology, the overall incidence of pulmonary hemorrhage was 10% and the incidence of ≥Grade 3 pulmonary hemorrhage was 2% for CYRAMZA plus docetaxel compared to 12% overall incidence and 2% for ≥Grade 3 pulmonary hemorrhage for placebo plus docetaxel. The most common serious adverse events with CYRAMZA plus docetaxel were febrile neutropenia (14%), pneumonia (6%), and neutropenia (5%). The use of granulocyte colony-stimulating factors was 42% in CYRAMZA plus docetaxel-treated patients versus 37% in patients who received placebo plus docetaxel. In patients ≥65 years, there were 18 (8%) deaths on treatment or within 30 days of discontinuation for CYRAMZA plus docetaxel and 9 (4%) deaths for placebo plus docetaxel. In patients <65 years, there were 13 (3%) deaths on treatment or within 30 days of discontinuation for CYRAMZA plus docetaxel and 26 (6%) deaths for placebo plus docetaxel. Table 4 provides the frequency and severity of adverse reactions in Study 3. Table 4: Adverse Reactions Occurring at Incidence Rate ≥5% and a ≥2% Difference Between Arms in Patients Receiving CYRAMZA in Study 3 CYRAMZA plus docetaxel Placebo plus docetaxel (N=627) (N=618) Adverse Reactions (MedDRA) System Organ Class All Grades Grade 3-4 All Grades Grade 3-4 (Frequency %) (Frequency %) (Frequency %) (Frequency %) Blood and Lymphatic System Disorders Febrile neutropenia 16 16 10 10 Neutropenia 55 49 46 40 Thrombocytopenia 13 3 5 <1 Gastrointestinal Disorders Stomatitis/Mucosal inflammation 37 7 19 2 Eye Disorders Lacrimation increased 13 <1 5 0 General Disorders and Administration Site Disorders Fatigue/Asthenia 55 14 50 11 Peripheral edema 16 0 9 <1 Respiratory, Thoracic, and Mediastinal Disorders Epistaxis 19 <1 7 <1 Vascular Disorders Hypertension 11 6 5 2 Clinically relevant adverse drug reactions reported in ≥1% and <5% of the CYRAMZA plus docetaxel-treated patients in Study 3 were hyponatremia (4.8% CYRAMZA plus docetaxel versus 2.4% for placebo plus docetaxel) and proteinuria (3.3% CYRAMZA plus docetaxel versus 0.8% placebo plus docetaxel). Immunogenicity As with all therapeutic proteins, there is the potential for immunogenicity. In 23 clinical trials, 86/2890 (3.0%) of CYRAMZA-treated patients tested positive for treatment-emergent anti-ramucirumab antibodies by an enzyme-linked immunosorbent assay (ELISA). Neutralizing antibodies were detected in 14 of the 86 patients who tested positive for treatment-emergent anti-ramucirumab antibodies. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to CYRAMZA with the incidences of antibodies to other products may be misleading. DRUG INTERACTIONS No pharmacokinetic (PK) interactions were observed between ramucirumab and docetaxel. USE IN SPECIFIC POPULATIONS Pregnancy Risk Summary Based on its mechanism of action, CYRAMZA can cause fetal harm. Animal models link angiogenesis, VEGF and VEGF Receptor 2 (VEGFR2) to critical aspects of female reproduction, embryofetal development, and postnatal development. There are no available data on CYRAMZA in pregnant women to inform any drug-associated risks. No animal studies have been conducted to evaluate the effect of ramucirumab on reproduction and fetal development. The background risk of major birth defects and miscarriage for the indicated populations are unknown. In the U.S. general population the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Advise pregnant women of the potential risk to a fetus. Animal Data No animal studies have been specifically conducted to evaluate the effect of ramucirumab on reproduction and fetal development. In mice, loss of the VEGFR2 gene resulted in embryofetal death and these fetuses lacked organized blood vessels and blood islands in the yolk sac. In other models, VEGFR2 signaling was associated with development and maintenance of endometrial and placental vascular function, successful blastocyst implantation, maternal and feto-placental vascular differentiation, and development during early pregnancy in rodents and non-human primates. Disruption of VEGF signaling has also been associated with developmental anomalies including poor development of the cranial region, forelimbs, forebrain, heart, and blood vessels. Lactation Risk Summary There is no information on the presence of ramucirumab in human milk, the effects on the breast-fed infant, or the effects on milk production. Human IgG is present in human milk, but published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because of the potential risk for serious adverse reactions in nursing infants from ramucirumab, advise women that breastfeeding is not recommended during treatment with CYRAMZA. CYRAMZA® (ramucirumab) injection RB-L HCP BS 04MAY2015

Females and Males of Reproductive Potential Contraception Females Based on its mechanism of action, CYRAMZA can cause fetal harm. Advise females of reproductive potential to use effective contraception while receiving CYRAMZA and for at least 3 months after the last dose of CYRAMZA. Infertility Females Advise females of reproductive potential that based on animal data CYRAMZA may impair fertility. Pediatric Use The safety and effectiveness of CYRAMZA in pediatric patients have not been established. In animal studies, effects on epiphyseal growth plates were identified. In cynomolgus monkeys, anatomical pathology revealed adverse effects on the epiphyseal growth plate (thickening and osteochondropathy) at all doses tested (5-50 mg/kg). Ramucirumab exposure at the lowest weekly dose tested in the cynomolgus monkey was 0.2 times the exposure in humans at the recommended dose of ramucirumab as a single agent. Geriatric Use Of the 563 CYRAMZA-treated patients in two randomized gastric cancer clinical studies, 36% were 65 and over, while 7% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. Of the 1253 patients in Study 3, 455 (36%) were 65 and over and 84 (7%) were 75 and over. Of the 627 patients who received CYRAMZA plus docetaxel in Study 3, 237 (38%) were 65 and over, while 45 (7%) were 75 and over. In an exploratory subgroup analysis of Study 3, the hazard ratio for overall survival in patients less than 65 years old was 0.74 (95% CI: 0.62, 0.87) and in patients 65 years or older was 1.10 (95% CI: 0.89, 1.36). Renal Impairment No dose adjustment is recommended for patients with renal impairment based on population pharmacokinetic analysis. Hepatic Impairment No dose adjustment is recommended for patients with mild (total bilirubin within upper limit of normal [ULN] and aspartate aminotransferase [AST] >ULN, or total bilirubin >1.0-1.5 times ULN and any AST) or moderate (total bilirubin >1.5-3.0 times ULN and any AST) hepatic impairment based on population pharmacokinetic analysis. Clinical deterioration was reported in patients with Child-Pugh B or C cirrhosis who received single-agent CYRAMZA. DOSAGE AND ADMINISTRATION Do not administer CYRAMZA as an intravenous push or bolus. Recommended Dose and Schedule The recommended dose of CYRAMZA is 10 mg/kg administered by intravenous infusion over 60 minutes on day 1 of a 21-day cycle prior to docetaxel infusion. Continue CYRAMZA until disease progression or unacceptable toxicity. Premedication Prior to each CYRAMZA infusion, premedicate all patients with an intravenous histamine H1 antagonist (e.g., diphenhydramine hydrochloride). For patients who have experienced a Grade 1 or 2 infusion reaction, also premedicate with dexamethasone (or equivalent) and acetaminophen prior to each CYRAMZA infusion. Dose Modifications Infusion-Related Reactions (IRR) • Reduce the infusion rate of CYRAMZA by 50% for Grade 1 or 2 IRRs. • Permanently discontinue CYRAMZA for Grade 3 or 4 IRRs. Hypertension • Interrupt CYRAMZA for severe hypertension until controlled with medical management. • Permanently discontinue CYRAMZA for severe hypertension that cannot be controlled with antihypertensive therapy. Proteinuria • Interrupt CYRAMZA for urine protein levels ≥2 g/24 hours. Reinitiate treatment at a reduced dose of 8 mg/kg every 3 weeks once the urine protein level returns to <2 g/24 hours. If the protein level ≥2 g/24 hours reoccurs, interrupt CYRAMZA and reduce the dose to 6 mg/kg every 3 weeks once the urine protein level returns to <2 g/24 hours. • Permanently discontinue CYRAMZA for urine protein level >3 g/24 hours or in the setting of nephrotic syndrome. Wound Healing Complications • Interrupt CYRAMZA prior to scheduled surgery until the wound is fully healed. Arterial Thromboembolic Events, Gastrointestinal Perforation, or Grade 3 or 4 Bleeding • Permanently discontinue CYRAMZA. For toxicities related to docetaxel, refer to the current respective prescribing information. PATIENT COUNSELING INFORMATION • Hemorrhage: Advise patients that CYRAMZA can cause severe bleeding. Advise patients to contact their health care provider for bleeding or symptoms of bleeding including lightheadedness. • Arterial thromboembolic events: Advise patients of an increased risk of an arterial thromboembolic event. • Hypertension: Advise patients to undergo routine blood pressure monitoring and to contact their health care provider if blood pressure is elevated or if symptoms from hypertension occur including severe headache, lightheadedness, or neurologic symptoms. • Gastrointestinal perforations: Advise patients to notify their health care provider for severe diarrhea, vomiting, or severe abdominal pain. • Impaired wound healing: Advise patients that CYRAMZA has the potential to impair wound healing. Instruct patients not to undergo surgery without first discussing this potential risk with their health care provider. • Pregnancy and fetal harm: Advise females of reproductive potential of the potential risk for maintaining pregnancy, risk to the fetus, and risk to postnatal newborn and infant development and to use effective contraception during CYRAMZA therapy and for at least 3 months following the last dose of CYRAMZA. • Lactation: Advise patients not to breastfeed during CYRAMZA treatment. • Infertility: Advise females of reproductive potential regarding potential infertility effects of CYRAMZA.

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FDA Update

Inotuzumab Ozogamicin Receives FDA Breakthrough Therapy Designation for Acute Lymphoblastic Leukemia

fizer recently announced that the U.S. Food and Drug Administration (FDA) has granted Breakthrough Therapy designation to the company’s investigational antibody-drug conjugate inotuzumab ozogamicin for acute lymphoblastic leukemia (ALL). The FDA’s decision was based on the results of the phase III INO-VATE ALL trial, which enrolled 326 adult patients with

relapsed or refractory CD22-positive ALL and compared inotuzumab ozogamicin to standard-of-care chemotherapy. Efficacy and safety results from the trial were announced in April 2015 and presented at the 20th Congress of the European Hematology Association in Vienna.1 Inotuzumab ozogamicin is an investigational antibody-drug conjugate comprised of a monoclonal antibody

targeting CD22, a cell-surface antigen expressed on approximately 90% of Bcell malignancies, linked to a cytotoxic agent. When inotuzumab ozogamicin binds to the CD22 antigen on malignant B cells, it is internalized into the cell, where the cytotoxin calicheamicin is released to destroy the cell. Mace Rothenberg, MD, Senior Vice President of Clinical Development and Medical Affairs and Chief Medical Officer for Pfizer Oncology, said in a press release “Breakthrough therapy designation will allow us to work more closely with the FDA to bring this important therapy to patients as rapidly as possible.” n Reference 1. DeAngelo DJ, Stelljes M, Martinelli G, et al: Efficacy and safety of inotuzumab ozogamicin vs standard of care in salvage 1 or 2 patients with acute lymphoblastic leukemia: An ongoing global phase 3 study. 2015 Congress of the European Hematology Association. Abstract LB2073. Presented June 14, 2015.

Moments in History

Additional information can be found at www.CYRAMZAhcp.com.

RB-L HCP BS 04MAY2015

History of Medicine Division, new reading room, date: ca 1963: The gleaming new reading room of the History of Medicine Division, NIH, Bethesda campus beckons from the entrance near the service desk. Division Chief John B. Blake leans over the desk and speaks with a librarian. Source: National Library of Medicine.

The ASCO Post | NOVEMBER 10, 2015

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Physiatry in Oncology Breast Cancer

Management of Aromatase Inhibitor–Induced Musculoskeletal Symptoms: A Physiatric Approach By Eric Wisotzky, MD

romatase inhibitors have demonstrated efficacy in reducing the risk of breast cancer recurrence in hormone receptor–positive patients, but medication compliance can be limited by uncomfortable side effects, including musculoskeletal pain and dysfunction. Musculoskeletal symptoms have been reported in 5% to 61% of patients on aromatase inhibitors,1 with one study demonstrating that 20% of patients may discontinue the drug due to these side effects.2

may hypersensitize patients to pain. Patients with preexisting musculoskeletal disorders may be more prone to these side effects, and a pretreatment evaluation can be helpful. Some studies have demonstrated that these symptoms have resulted in an “unmasking” of previously undiagnosed rheumatologic disorders,6 potentially necessitating that a preexisting rheumatologic disorder is ruled out prior to treatment initiation. Diagnostic criteria for aromatase inhibitor–induced musculoskeletal

Role of the Physiatrist in Cancer Care ■■ Aromatase inhibitor–induced musculoskeletal symptoms are common side effects of aromatase inhibitors, and exact etiologies for the symptoms require further study. ■■ While there are many potential treatment options, more research is needed to give a strong evidence basis for therapeutic interventions. ■■ A physiatric approach to aromatase inhibitor–induced musculoskeletal symptoms is beneficial because the physiatrist takes a holistic approach and formulates a patient-centered care plan to maximize the function and quality of life.

These symptoms can present as multijoint arthralgias but may also focally affect specific joints, including the small joints of the hands and feet, hips, shoulders, and low back. In addition, patients may develop focal inflammation with edema, causing symptoms such as trigger finger, carpal tunnel syndrome, and De Quervain’s tenosynovitis of the wrist.

symptoms have been published but not validated. One suggested criterion is that the patient must have musculoskeletal symptoms that start while on the medication, improve within 2 weeks of stopping the medication, and restart when the aromatase inhibitor is resumed again.7 However, further research is needed to identify and validate appropriate criteria for diagnosis.

Pathophysiology and Diagnosis

Treatment and Its Side Effects

The etiology of these symptoms is not completely clear, but there are several theories. One is that estrogen deprivation leads to degradation of joint cartilage and joint inflammation,3 and radiographic studies have demonstrated an increase in joint and tenosynovial fluid in patients on these drugs.4 Another theory is that estrogen may have antinociceptive effects5 and that estrogen deprivation brought on by an aromatase inhibitor Dr. Wisotzky is the Director of Cancer Rehabilitation at MedStar National Rehabilitation Hospital and Assistant Professor of Rehabilitation Medicine at Georgetown University School of Medicine in Washington, DC.

To date, there is a dearth of highquality research into therapeutic interventions for these symptoms. A physiatric approach will take into account all of the patient’s physical symptoms and how they impact his or her function, using a biopsychosocial model. In addition, it may be helpful to talk to patients about their attitude toward the aromatase inhibitor, as some patients strongly consider discontinuing the medication due to its side effects. Other patients may report that they would never consider discontinuation, regardless of side effects. A sensible approach to the management of musculoskeletal side effects is to provide a global approach that will improve symptoms in multiple body regions as well as a focused approach

on particularly symptomatic areas. As a more global approach, exercise has been studied to improve musculoskeletal symptoms, with a recent study looking at 150 minutes per week of moderate-intensity cardiovascular exercise and 2 days a week of resistance training, showing a statistically significant improvement in pain scores in patients on aromatase inhibitors.8 Medications could also be considered for these symptoms, although, again, research is lacking on what is appropriate. Common pain medications such as acetaminophen, topical or oral nonsteroidal anti-inflammatory drugs, tramadol, or opioids, should be considered although there is little available evidence-based literature on these treatments. A single-arm trial of duloxetine—up to 120 mg/d— showed clinically significant improvement in pain scores in patients on aromatase inhibitors.9 Glucosamine (1,500 mg/d) and chondroitin sulfate (1,200 mg/d) showed moderate improvement in musculoskeletal symptoms after 24 weeks of treatment.10 Vitamin D levels may or may not be significant contributors to aromatase inhibitor–induced musculoskeletal symptoms, as studies have been conflicting.11,12 Acupuncture has also been studied with mixed results.13,14

GUEST EDITOR

Sean Smith, MD

hysiatry in Oncology explores the benefits of cancer rehabilitation in oncology clinical practice to screen survivors for physical and cognitive impairments along the care continuum to minimize survivors’ disability and maximize their quality of life. The column is guest edited and occasionally written by Sean Smith, MD, Director of the Cancer Rehabilitation Program at the University of Michigan Department of Physical Medicine and Rehabilitation in Ann Arbor. been a very helpful adjunct to other treatments for moderate to severe pain. Given how common wrist and hand pain is in patients on aromatase inhibitors, correct diagnosis of the etiology of

Patients often feel encouraged when coming to see a physiatrist and learning that there are solutions to help relieve their symptoms. As a result, they may be more willing to ‘ride out’ their treatment side effects. —Eric Wisotzky, MD

For focal symptoms, different approaches can be considered. If there is a particularly symptomatic joint or region, physical or occupational therapy can be considered for pain reduction, range of motion, and joint protection. Physiatric management is helpful, as other interventions such as bracing of the joint or therapeutic injections with corticosteroid or hyaluronic acid (for the knee) can be utilized. In my clinical practice, periodic joint injections for the most symptomatic region(s) have

this pain is essential. Physiatric workup and management of wrist pain (including carpal tunnel syndrome, De Quervain’s tenosynovitis, and carpometacarpal osteoarthritis) and trigger finger can optimize patient care. Examples of musculoskeletal disorders attributable to aromatase inhibitors and their respective physiatric interventions are listed in Table 1. As a last resort, a permanent or temporary holiday from the aromatase inhibitor could be considered. Alterna-

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Physiatry in Oncology Table 1: Musculoskeletal Disorders Associated With Aromatase Inhibitors and Corresponding Physiatric Interventions Diagnosis

Management

De Quervain’s tenosynovitis

Splinting, injection, topical and oral analgesics, progressive range of motion

Trigger finger

Injections (sometimes a series), topical and oral medication, splinting, hand therapy

Carpal tunnel syndrome

Electromyographic diagnosis, splinting, injections, medications, neural gliding exercises, surgical referral if refractory

Generalized arthralgias

Medications, patient education, exercise, investigation of focal and evolving symptoms

tively, switching to a different aromatase inhibitor, or even tamoxifen, may be beneficial. Consideration of this option should involve a discussion between the patient and her oncologist about the risks and benefits of such a decision.

Providing Patient Encouragement Finally, patient encouragement can be helpful. It helps when a patient’s symptoms are validated. Patients may feel frustrated if their physicians minimize the side effects of hormone therapy. Likewise, they may feel relieved to know that this is a potentially normal experience while on these drugs and that symptoms should subside after the course of hormone therapy is completed (depending on the necessary duration of treatment). In addition, some data suggest that aromatase inhibitor–induced musculoskeletal symptoms may be associated with a survival benefit,15 which obviously could be heartening to the patient. Patients often feel encouraged when coming to see a physiatrist and learning that there are solutions to help relieve their symptoms. As a result, they may be more willing to “ride out” their treatment side effects. n Disclosure: Dr. Wisotzky reported no potential conflicts of interest

References 1. Gaillard S, Stearns V: Aromatase inhibitor-associated bone and musculo-

skeletal effects: New evidence defining etiology and strategies for management. Breast Cancer Res 13:205, 2011. 2. Presant CA, Bosserman L, Young T, et al: Aromatase inhibitor-associated arthralgia and/or bone pain: Frequency and characterization in non-clinical trial patients. Clin Breast Cancer 7:775-778, 2007. 3. Tsai CL, Liu TK, Chen TJ: Estrogen and osteoarthritis: A study of synovial estradiol and estradiol receptor binding in human osteoarthritic knees. Biochem Biophys Res Commun 183:1287-1291, 1992. 4. Lintermans A, Laenen A, Van Calster B, et al: Prospective study to assess fluid accumulation and tenosynovial changes in the aromatase inhibitor-induced musculoskeletal syndrome: 2-year follow-up data. Ann Oncol 24:350-355, 2013. 5. Felson DT, Cummings SR: Aromatase inhibitors and the syndrome of arthralgias with estrogen deprivation. Arthritis Rheum 52:2595-2598, 2005. 6. Shanmugam VK, McCloskey J, Elston B, et al: The CIRAS study: A case control study to define the clinical, immunologic, and radiographic features of aromatase inhibitor-induce musculoskeletal symptoms. Breast Cancer Res Treat 131:699-708, 2012. 7. Nivavath P: Aromatase inhibitorinduced arthralgia: A review. Ann Oncol 24:1443-1449, 2013. 8. Irwin ML, Cartmel B, Gross C, et al: Randomized exercise trial of aromatase inhibitor-induced arthralgia in breast

cancer survivors. J Clin Oncol 33:11041111, 2015. 9. Henry NL, Banerjee M, Wicha M, et al: Pilot study of duloxetine for treatment of aromatase inhibitor-associated musculoskeletal symptoms. Cancer 117:54695475, 2011. 10. Greenlee H, Crew KD, Shao T, et al: Phase II study of glucosamine with chondroitin on aromatase inhibitorassociated joint symptoms in women with breast cancer. Support Care Cancer 21:1077-1087, 2013. 11. Khan QJ, Reddy PS, Kimler BF, et al: Effect of vitamin D supplementation on serum 25-hydroxy vitamin D levels, joint

pain, and fatigue in women starting adjuvant letrozole treatment for breast cancer. Breast Cancer Res Treat 119:111-118, 2010. 12. Singh S, Cuzick J, Mesher D, et al: Effect of baseline serum vitamin D levels on aromatase inhibitors induced musculoskeletal symptoms: Results from the IBIS-II, chemoprevention study using anastrozole. Breast Cancer Res Treat 132:625-629, 2012. 13. Crew KD, Capodice JL, Greenlee H, et al: Randomized, blinded, shamcontrolled trial of acupuncture for the management of aromatase inhibitor-associated joint symptoms in women. J Clin Oncol 28:1154-1160, 2010. 14. Bao T, Cai L, Giles JT, et al: A dual-center randomized controlled double blind trial assessing the effect of acupucture in reducing musculoskeletal symptoms in breast cancer patients taking aromatase inhibitors. Breast Cancer Res Treat 138:167-174, 2013. 15. Fontein DB, Seynaeve C, Hadji P, et al: Specific adverse events predict survival benefit in patients treated with tamoxifen or aromatase inhibitors: An international tamoxifen exemestane adjuvant multinational trial analysis. J Clin Oncol 31:2257-2264, 2013.

San Antonio Breast Cancer Symposium

Watch future issues of The ASCO Post for coverage of the 2015 San Antonio Breast Cancer Symposium, taking place December 8–12, 2015, at the Henry B. Gonzalez Convention Center in San Antonio. Photo by © AHA/Scott Morgan 2014.

Visit The ASCO Post website at ASCOPost.com

In patients 18 years and older...

DIFICID: Proven efficacy for treatment of Clostridium difficile–associated diarrhea (CDAD) Bactericidal therapy that targets C difficile Primarily active against species of clostridia, including C difficile, in vitro. The clinical significance of in vitro data is unknown.

DIFICID: Comparable initial clinical response rate vs vancomycin at end of 10-day treatment Clinical response rate

Hypothetical patient.

Patients (%)

Trial 1 (95% CI)a: 2.6% (-2.9%, 8.0%)

88%

86%

60 40 20

100 80 Patients (%)

100

Trial 2 (95% CI)a: 1.0% (-4.8%, 6.8%)

88%

87%

60 40 20 0

DIFICID 200 mg BID (n=289)

Vancomycin 125 mg QID (n=307)

DIFICID 200 mg BID (n=253)

Vancomycin 125 mg QID (n=256)

CI was derived using the Wilson score method.

Study description: Two Phase 3, randomized, double-blind, noninferiority studies (N=1,105) comparing the efficacy and safety of oral DIFICID 200 mg BID vs oral vancomycin 125 mg QID for 10 days for the treatment of adults (aged ≥18 years) with CDAD (defined by >3 unformed bowel movements or >200 mL of unformed stool for subjects having rectal collection devices in the 24 hours before randomization and presence of either C difficile toxin A or B in the stool within 48 hours of randomization). An additional efficacy end point was a sustained response 25 days after the end of treatment. Sustained response was evaluated only for patients who were clinical successes at the end of treatment. Sustained response was defined as clinical response at the end of treatment and survival without proven or suspected CDAD recurrence through 25 days beyond the end of treatment.

Indication and Usage DIFICID is a macrolide antibacterial drug indicated in adults (≥18 years of age) for treatment of Clostridium difficile-associated diarrhea (CDAD). To reduce the development of drug-resistant bacteria and maintain the effectiveness of DIFICID and other antibacterial drugs, DIFICID should be used only to treat infections that are proven or strongly suspected to be caused by C difficile.

Important Safety Information DIFICID is contraindicated in patients with hypersensitivity to fidaxomicin. DIFICID should not be used for systemic infections. Acute hypersensitivity reactions, including dyspnea, rash pruritus, and angioedema of the mouth, throat, and face have been reported with fidaxomicin. If a severe hypersensitivity reaction occurs, DIFICID should be discontinued and appropriate therapy should be instituted. Only use DIFICID for infection proven or strongly suspected to be caused by C difficile. Prescribing DIFICID in the absence of a proven or strongly suspected C difficile infection is unlikely to provide benefit to the patient and increases the risk of development of drugresistant bacteria. The most common adverse reactions reported in clinical trials are nausea (11%), vomiting (7%), abdominal pain (6%), gastrointestinal hemorrhage (4%), anemia (2%), and neutropenia (2%).

In the same studiesâ&#x20AC;Ś

Superior sustained response rate vs vancomycin through 25 days after end of treatment Sustained response rate Trial 1 (95% CI)b: 12.7% (4.4%, 20.9%)

100

70%

60 40

57%

Patients (%)

80 Patients (%)

Trial 2 (95% CI)b: 14.6% (5.8.%, 23.3%)

100

72%

60 40

57%

DIFICID 200 mg BID (n=289)

Vancomycin 125 mg QID

DIFICID 200 mg BID

Vancomycin 125 mg QID

(n=307)

(n=253)

(n=256)

CI was derived using the Wilson score method. Approximately 5% to 9% of the data in each trial and treatment arm were missing sustained response information and were imputed using the multiple imputation method.

Since clinical success at the end of treatment and mortality rates were similar across treatment arms (approximately 6% in each group), differences in sustained response were due to lower rates of proven or suspected CDAD during the follow-up period in DIFICID patients. In patients infected with a BI isolate, similar rates of clinical response at the end of treatment and during the follow-up period were seen in fidaxomicin-treated and vancomycin-treated patients. However, DIFICID did not demonstrate superiority in sustained response when compared with vancomycin in these patients. Initial C difficile group BI isolates

Trial 1

Non-BI isolates BI isolates

Trial 2

Non-BI isolates

DIFICID n/N (%)

Vancomycin n/N (%)

Difference (95% CI)c

44/76 (58%)

52/82 (63%)

-5.5% (-20.3%, 9.5%)

105/126 (83%)

87/131 (66%)

16.9% (6.3%, 27.0%)

42/65 (65%)

31/60 (52%)

12.9% (-4.2%, 29.2%)

109/131 (83%)

77/121 (64%)

19.6% (8.7%, 30.0%)

CI was derived using the Wilson score method. Interaction test between the effect on sustained response rate and BI vs non-BI isolates using logistic regression (P values: trial 1: 0.009; trial 2: 0.29). Approximately 25% of the mITT population were missing data for the REA group.

Important Safety Information (continued) Among patients receiving DIFICID, 33 (5.9%) withdrew from trials as a result of adverse reactions. Vomiting was the primary adverse reaction leading to discontinuation of dosing (incidence of 0.5% for both DIFICID and vancomycin patients). The safety and effectiveness of DIFICID in patients <18 years of age have not been established.

Please see the Brief Summary of Prescribing Information on adjacent page. BID=twice a day; mITT=modified intent to treat; QID=4 times a day; REA=restriction endonuclease analysis.

Product support and access for patients A program that provides patients with product support and access related to researching insurance benefits, information on co-pay assistance for eligible privately insured patients, product distribution questions, and alternate independent sources of funding.

For insurance coverage and reimbursement information, please visit www.accessdificid.com or call 1-844-282-4782 (M-F, 8 AM-8 PM; Sat, 9 AM-1 PM, ET). Eligibility restrictions apply for the Co-pay Assistance Program and the Patient Assistance Program. Please see Terms and Conditions for the Co-pay Assistance Program, available on the Enrollment Form.

BRIEF SUMMARY OF PRESCRIBING INFORMATION DIFICID (fidaxomicin) tablets, for oral use INDICATIONS AND USAGE To reduce the development of drug-resistant bacteria and maintain the effectiveness of DIFICID® and other antibacterial drugs, DIFICID should be used only to treat infections that are proven or strongly suspected to be caused by Clostridium difficile. Clostridium difficile-Associated Diarrhea DIFICID is a macrolide antibacterial drug indicated in adults (≥18 years of age) for treatment of Clostridium difficile-associated diarrhea (CDAD). CONTRAINDICATIONS Hypersensitivity to fidaxomicin. WARNINGS AND PRECAUTIONS Not for Systemic Infections Since there is minimal systemic absorption of fidaxomicin, DIFICID is not effective for treatment of systemic infections. Hypersensitivity Reactions Acute hypersensitivity reactions, including dyspnea, rash pruritus, and angioedema of the mouth, throat, and face have been reported with fidaxomicin. If a severe hypersensitivity reaction occurs, DIFICID should be discontinued and appropriate therapy should be instituted. Some patients with hypersensitivity reactions also reported a history of allergy to other macrolides. Physicians prescribing DIFICID to patients with a known macrolide allergy should be aware of the possibility of hypersensitivity reactions. Development of Drug-Resistant Bacteria Prescribing DIFICID in the absence of a proven or strongly suspected C. difficile infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria. ADVERSE REACTIONS Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse event rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of any other drug and may not reflect the rates observed in practice. The safety of DIFICID 200 mg tablets taken twice a day for 10 days was evaluated in 564 patients with CDAD in two active-comparator controlled trials with 86.7% of patients receiving a full course of treatment. Thirty-three patients receiving DIFICID (5.9%) withdrew from trials as a result of adverse reactions (AR). The types of AR resulting in withdrawal from the study varied considerably. Vomiting was the primary adverse reaction leading to discontinuation of dosing; this occurred at an incidence of 0.5% in both the fidaxomicin and vancomycin patients in Phase 3 studies. Table 1. Selected Adverse Reactions with an Incidence of ≥2% Reported in DIFICID Patients in Controlled Trials DIFICID (N=564) n (%) Blood and Lymphatic System Disorders Anemia 14 (2%) Neutropenia 14 (2%) Gastrointestinal Disorders Nausea 62 (11%) Vomiting 41 (7%) Abdominal Pain 33 (6%) Gastrointestinal Hemorrhage 20 (4%) System Organ Class Preferred Term

Vancomycin (N=583) n (%) 12 (2%) 6 (1%) 66 (11%) 37 (6%) 23 (4%) 12 (2%)

The following adverse reactions were reported in <2% of patients taking DIFICID tablets in controlled trials: Gastrointestinal Disorders: abdominal distension, abdominal tenderness, dyspepsia, dysphagia, flatulence, intestinal obstruction, megacolon Investigations: increased blood alkaline phosphatase, decreased blood bicarbonate, increased hepatic enzymes, decreased platelet count Metabolism and Nutrition Disorders: hyperglycemia, metabolic acidosis Skin and Subcutaneous Tissue Disorders: drug eruption, pruritus, rash Post Marketing Experience Adverse reactions reported in the post marketing setting arise from a population of unknown size and are voluntary in nature. As such, reliability in estimating their frequency or in establishing a causal relationship to drug exposure is not always possible. Hypersensitivity reactions (dyspnea, angioedema, rash, and pruritus) have been reported. DRUG INTERACTIONS Fidaxomicin and its main metabolite, OP-1118, are substrates of the efflux transporter, P-glycoprotein (P-gp), which is expressed in the gastrointestinal tract. Cyclosporine Cyclosporine is an inhibitor of multiple transporters, including P-gp. When cyclosporine was co-administered with DIFICID, plasma concentrations of fidaxomicin and OP-1118 were significantly increased but remained in the ng/mL range. Concentrations of fidaxomicin and OP-1118 may also be decreased at the site of action (i.e., gastrointestinal tract) via P-gp inhibition; however, concomitant P-gp inhibitor use had no attributable effect on safety or treatment outcome of fidaxomicin-treated patients in controlled clinical trials. Based on these results, fidaxomicin may be co-administered with P-gp inhibitors and no dose adjustment is recommended. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category B. Reproduction studies have been performed in rats and rabbits by the intravenous route at doses up to 12.6 and 7 mg/kg, respectively. The plasma exposures (AUC0-t) at these doses were approximately 200- and 66-fold that in humans, respectively, and have revealed no evidence of harm to the fetus due to fidaxomicin. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Nursing Mothers It is not known whether fidaxomicin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when DIFICID is administered to a nursing woman. Pediatric Use The safety and effectiveness of DIFICID in patients <18 years of age have not been established. Geriatric Use Of the total number of patients in controlled trials of DIFICID, 50% were 65 years of age and over, while 31% were 75 and over. No overall differences in safety or effectiveness of fidaxomicin compared to vancomycin were observed between these subjects and younger subjects. In controlled trials, elderly patients (≥65 years of age) had higher plasma concentrations of fidaxomicin and its main metabolite, OP-1118, versus non-elderly patients (<65 years of age). However, greater exposures in elderly patients were not considered to be clinically significant. No dose adjustment is recommended for elderly patients.

Before prescribing DIFICID, please read the full Prescribing Information, available at dificid.com. 0500004-00 Revised: 04/2014 Copyright © 2015 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. All rights reserved. AINF-1158143-0000 08/15

ASCOPost.com | NOVEMBER 10, 2015

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In the Clinic Thoracic Oncology

Nivolumab in Metastatic NSCLC After Platinum Therapy 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 October 9, 2015, the anti–programmed cell death protein 1 (PD-1) monoclonal antibody nivolumab (Opdivo) was approved for treatment of patients with metastatic non–small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy.1,2 The approval expands the indication for nivolumab in metastatic NSCLC to include nonsquamous NSCLC; approval for treatment of squamous metastatic NSCLC in patients with progression on or after platinum treatment was granted in March 2015. Patients with EGFR or ALK alterations should have disease progression on the U.S. Food and Drug Administration–approved therapy for these aberrations prior to receiving nivolumab.

Supporting Efficacy Data Approval was based on the finding of improved overall survival with nivolumab in a phase III trial in 582 patients with nonsquamous disease comparing nivolumab at 3 mg/kg every 2 weeks (n = 292) vs docetaxel at 75 mg/m2 every 3 weeks (n = 290).2,3 The trial excluded patients with autoimmune disease, medical conditions requiring systemic immunosuppression, symptomatic interstitial lung disease, or untreated brain metastasis. Overall, patients had a median age of 62 years (37% of nivolumab group and 47% of docetaxel group ≥ 65 years), 55% were male, 92% were white, 12% had previously treated brain metastases, ECOG performance status was 0 in 31% and 1 in 69%, 3.6% had ALK rearrangement, and 14% had EGFR mutation. Median overall survival was 12.2 months in the nivolumab group vs 9.4

months in the docetaxel group (hazard ratio [HR] = 0.73, P = .0015). The objective response rate was 19% vs 12% (P = .02), and median duration of response was 17 vs 6 months. There was no significant difference between groups in progression-free survival (median, 2.3 vs 4.2 months, HR = 0.92, P = .39). Evaluation for tumor PD-1 ligand (PD-L1) expression in archived specimens in 78% of patients after study completion showed that 46% were PDL1–negative (< 1% of cells expressing PD-L1) and 54% of patients were PDL1–positive (≥ 1% expression). Prespecified subgroup analysis suggested that patients with PD-L1–positive NSCLC had a larger survival treatment effect.

How It Works Nivolumab is a human immunoglobulin G4 (IgG4) monoclonal antibody that binds the PD-1 receptor on T cells and prevents its interaction with the ligands PD-L1 and PD-L2, thereby blocking PD-1 pathway–mediated inhibition of immune response, including antitumor immune response. Binding of PD-L1 and PD-L2 to the PD-1 receptor inhibits T-cell proliferation and cytokine production. Upregulation of PD-1 ligands occurs in some tumors, and signaling through this pathway can contribute to inhibition of active T-cell tumor immune surveillance. In syngeneic mouse tumor models, blocking PD-1 activity resulted in decreased tumor growth.

How It Is Used The recommended dose of nivolumab in metastatic NSCLC is 3 mg/kg administered as an intravenous infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity. Infusion should be interrupted or slowed in patients with mild or moderate infusion reactions. Nivolumab should be discontinued for severe or life-threatening infusion reactions. In patients with metastatic NSCLC,

Expanded Indication for Nivolumab ■■ Nivolumab (Opdivo) has been approved for treatment of patients with metastatic non–small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy. The approval expands the drug’s indication in metastatic NSCLC to include nonsquamous NSCLC; earlier approval was for treatment of squamous metastatic NSCLC. ■■ The recommended dose of nivolumab in metastatic NSCLC is 3 mg/kg administered as an intravenous infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity.

nivolumab treatment should be withheld for grade 2 pneumonitis, grade 2 or 3 diarrhea or colitis, alanine transanimase (ALT) or aspartate transanimase (AST) > 3 to 5 times the upper limit of normal or total bilirubin > 1.5 to 3 times the upper limit of normal, serum creatinine > 1.5 to 6 times the upper limit of normal or > 1.5 times baseline level, grade 2 or 3 hypophysitis, grade 2 adrenal insufficiency, grade 3 rash, encephalitis (new onset moderate or severe neurologic signs or symptoms), and first occurrence of other grade 3 adverse reactions.

OF NOTE Nivolumab carries warnings/precautions for immune-mediated adverse reactions and embryofetal toxicity.

There are no recommended dose modifications for hypothyroidism or hyperthyroidism. No dose adjustment is required in patients with renal impairment or mild hepatic impairment; the drug has not been studied in patients with moderate or severe hepatic impairment. Nivolumab should be discontinued for grade 4 hypophysitis, grade 3 or 4 adrenal insufficiency, grade 4 rash, immune-mediated encephalitis, any life-threatening or grade 4 adverse reaction, grade 3 or 4 pneumonitis, grade 4 diarrhea or colitis, AST or ALT > 5 times the upper limit of normal or total bilirubin > 3 times the upper limit of normal, serum creatinine > 6 times the upper limit of normal, any recurring severe or grade 3 treatment-related adverse reaction, inability to reduce corticosteroid dose to ≤ 10 mg/d of prednisone or equivalent within 12 weeks, and persistent grade 2 or 3 treatment-related adverse reactions that do not recover to grade 0 or 1 within 12 weeks after the last dose.

Safety Profile In the phase III trial in nonsquamous metastatic NSCLC, the most common adverse events of any grade in the nivolumab group included fatigue/asthenia (49%, grade 3 or 4 in 6%), musculoskeletal pain (36%), cough (30% vs 25% in docetaxel group), decreased appetite (29% vs 22%), and constipation (23% vs 17%); pruritus was more common with nivolumab (11% vs 2%). Pleural effusion was observed in 5.6% and pulmonary embolism in 4.2% of nivolumab patients.

The most common grade 3 or 4 adverse events in the nivolumab group (≥ 2% of patients) were dyspnea, fatigue, pneumonia, pulmonary embolism, pleural effusion, hyperglycemia, respiratory failure, and pain. The most common grade 3 or 4 laboratory abnormalities (≥ 2% of patients) included lymphopenia, hyponatremia (6% vs 2.7%), anemia, increased AST (2.8% vs 0.4%), and increased ALT (2.4% vs 0.4%). Immune-mediated adverse events occurring in patients receiving nivolumab included hypothyroidism/thyroiditis, rash, pneumonitis, diarrhea/colitis, hyperthyroidism, hepatitis, nephritis, limbic encephalitis, and polymyalgia rheumatica. Serious adverse events occurred in 47% of nivolumab patients, with the most common (≥ 2% of patients) being pneumonia, pulmonary embolism, dyspnea, pleural effusion, and respiratory failure. Adverse events led to nivolumab delay in 29% of patients and discontinuation in 13%. Among nivolumab patients, there were seven deaths due to infection (including one case of Pneumocystis jirovecii pneumonia), four due to pulmonary embolism, and one due to limbic encephalitis. Nivolumab carries warnings/precautions for immune-mediated adverse reactions, including immune-mediated pneumonitis, colitis, hepatitis, endocrinopathies (including hypophysitis, adrenal insufficiency, hypothyroidism, and hyperthyroidism), nephritis, renal dysfunction, rash, and encephalitis. It also carries warnings/ precautions for embryofetal toxicity. Patients should be monitored for liver, kidney, thyroid, and neurologic function. Breastfeeding women should discontinue breastfeeding while receiving nivolumab. n References 1. U.S. Food and Drug Administration: Nivolumab injection. Available at www. fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm466576.htm. Accessed October 15, 2015. 2. Opdivo (nivolumab) injection for intravenous use prescribing information, Bristol-Myers Squibb Company, October 2015. Available at www.accessdata.fda.gov/drugsatfda_docs/label/2015/125554s005lbl. pdf. Accessed October 15, 2015. 3. Borghaei H, Paz-Ares L, Horn L, et al: Nivolumab versus docetaxel in advanced nonsquamous non–small-cell lung cancer. N Engl J Med. September 27, 2015 (early release online).

The ASCO Post | NOVEMBER 10, 2015

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Direct From ASCO

Spotlight on ASCO’s 2016 Presidential Election

The Future of ASCO: President-Elect Candidates Share Their Vision ASCO has announced the candidates for its 2016 Election, including three candidates for the office of President-Elect.

S. Gail Eckhardt, MD, FASCO

. Gail Eckhardt, MD, FASCO, is a tenured Professor at the University of Colorado School of Medicine, where she also holds the Stapp Harlow Chair in Cancer Research. She has been a faculty member at the institution since 1999 and was Division Head of Medical Oncology from 2006–2014. Currently, she serves as the Associate Director for Translational Research at the University of Colorado Comprehensive Cancer Center and Director of the Phase I Program and Fellowship. An ASCO member since 1994, Dr. Eckhardt has served most recently on the New Drugs in Oncology Seminar Planning Committee (2013–2014), the ASCO Connection Editorial Board (2008–2013), and the ASCO-American Association for Cancer Research (AACR) Methods in Clinical Cancer Research Workshop Program Com-

hy do you want to serve as ASCO President?

Dr. Eckhardt: I served on the ASCO Board of Directors from 2004–2007 and, like many Board members, was struck by the breadth and depth of ASCO’s involvement, engagement, and leadership in the global oncology community. When I rotated off the Board of Directors, I was nominated for ASCO President, but my sons were still at home and I was very committed to maximizing the time I had left with them. Interestingly, I think that ASCO has grown and matured during the past 8 years into a distinctly different, more interventional organization, which really appeals to me. For example,

Bruce E. Johnson, MD, FASCO

mittee (2005–2012). She has served on the ASCO Board of Directors, was Co-Chair of the Molecular Oncology Task Force, and Chair of the Gastrointestinal Cancers Symposium Steering Committee, among other positions. She served as Course Director for the ASCO-AACR Methods in Clinical Cancer Research Workshop for 4 years, and in 2014 and 2015 she was awarded the Merrill J. Egorin Outstanding Mentor of the Year Award. Bruce E. Johnson, MD, FASCO, is Chief Clinical Research Officer and Institute Physician at the Dana-Farber Cancer Institute and Professor of Medicine at Harvard Medical School. He is Director of the Dana-Farber/Harvard Cancer Center (DF/HCC) Lung Cancer Program, and Principal Investigator of the DF/HCC Lung Cancer Specialized Program of Research Excellence (SPORE). He recently stepped down the Quality Oncology Practice Initiative (QOPI®), Targeted Agent and Profiling Utilization Registry (TAPUR), and CancerLinQTM represent just a small subset of initiatives that ASCO is leading that represent tangible, interventional advances that will have real impact on physicians and patients. Thus, becoming ASCO President provides an unparalleled opportunity to be part of a collaborative effort to shape global cancer research and care and greatly impact patients. Dr. Johnson: I consider service as a prospective ASCO President a fulfillment of my most significant professional and academic career goal. ASCO is the leading organization of oncology professionals

Robin T. Zon, MD, FACP, FASCO

as the Director of the Lowe Center for Thoracic Oncology, a position he held beginning in 1998. An ASCO member since 1985, Dr. Johnson is currently a member of the Bylaws Committee. He has served in numerous volunteer and leadership roles, including the Board of Directors (2008–2011); Chair of the Audit, Cancer Education, and Cancer Communications Committees; and on the Journal of Clinical Oncology Editorial Board, among other positions. In 2008, he was awarded the Translational Research Professorship from the Conquer Cancer Foundation of ASCO. Robin T. Zon, MD, FACP, ASCO, is Vice President/Partner, F Medical Oncology, at Michiana Hematology-Oncology, PC, as well as Quality Care Assurance/Compliance Liaison Officer and Chair of the practice’s Quality and Finance Commitin the world, and I would be honored and proud to serve as its volunteer leader. Previous presidents have set high marks guiding our association, and it would be a privilege to join their ranks as a leader of our Society. I believe that my established experience in translational research can help make an impact for our members, our Society, and our patients. In addition, the extraordinary volunteers, management, and professional staff of ASCO make guiding the organization particularly appealing. My goals as a potential ASCO President include playing a part in formulating the strategic directions of our professional society; anticipating and responding to evolving heath-care policies; using big data to guide treatment of our patients;

tees. She has been at Michiana Hematology-Oncology, PC since 1998. Since joining ASCO in 1997, Dr. Zon has held numerous leadership and volunteer positions within the Society. She has served on the Board of Directors (2010–2013), and is currently Immediate Past Chair of the Clinical Practice Committee (Chair, 2014–2015). She is a current member of the CEO Search Advisory Committee; CancerLinQTM Data Governance Oversight Committee; Chair of the Pathways Task Force; and recently completed her terms with thePractice Guidelines Implementation Network, Breast Cancer Consensus Panel, and International Clinical Trial Workshop Committee. Her practice has received ASCO’s Clinical Trials Participation Award twice, in 2008 and 2014, and was Quality Oncology Practice Initiative (QOPI®) certified in 2010 and recertified in 2013. and helping provide the necessary tools for our members to adapt to the professional and financial aspects of oncology practice. My service on ASCO committees and the Board of Directors has prompted me to seek the position of ASCO President and continue to have an impact on the future direction of clinical oncology professionals and our patients. Dr. Zon: These are the most challenging times that oncology providers, and ASCO as the leading professional oncology society, have ever encountered. The face of oncology care is constantly changing due to scientific and technologic advances and practice environment requirecontinued on page 77

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ments. In a number of cases these changes have threatened the viability of the cancer care delivery model. During this time of volatility, our members need the continued attention of ASCO leadership and services to support our ability to deliver high-quality, high-value, and evidencebased care for patients worldwide. I would be honored to serve as your President during these transformative times, capitalizing on my background as a community oncologist, clinical investigator, and business owner. I would work to empower our members by closely collaborating with the Board of Directors, organizational leaders, volunteers, staff, patient advocates, and government agencies. I believe we must change together with a tour de force. Our success will rely on integrating our Society’s diverse strengths, sharing successful strategies, and developing practical resources and solutions. As President, I would pledge to dedicate myself to the mission of ASCO, address the needs of our membership and patients, and value our diversity as our strength. What do you see as the future of ASCO and the field of cancer research and care in

Tell Your Patients About ASCO’S Award-Winning Cancer.Net Mobile App

ancer.Net Mobile app offers your patients and their caregivers trusted, oncologist-approved cancer information and the tools and resources they need to help plan and manage cancer care. The newest version of Cancer.Net Mobile is optimized for the latest iOS versions, and offers an all-new visual design, with real-time updates from the Cancer.Net website on information about treating cancer, managing side effects, coping, and more. Users whose primary device language is set to Spanish will now be able to use all of the features of the app in that language. The app is available for download in Google Play for Android or iTunes for iOS/Apple. n

the next 5 and 10 years? What is the most important role for the Society in shaping the global oncology community within the next 10 years? Dr. Eckhardt: I think that over the next 5 to 10 years, there will be an expansion of personalized and genomically driven therapy, immune-based approach-

es to treatment, and prevention and early detection, all within the context of increasing demand for oncologic services at all levels. ASCO will need to stay at the cutting edge of research and technology and provide the interconnectivity among all constituents, and, in my opinion, continue to maintain a more interventional role as it has in recent years.

I think that ASCO will need, at times, to lead by example, and CancerLinQ, TAPUR, and QOPI represent that ethos. This is important because of the diverse membership that ASCO represents, which is truly global, so that important initiatives transcend regional barriers. In terms of public cancer health policy, continued on page 78

NOW ENROLLING Rociletinib Expanded Access Program For patients with previously treated EGFR mutation– positive NSCLC and the T790M resistance mutation Access for eligible patients in the US who have no other available rociletinib clinical trial options Key inclusion criteria • Documented evidence of a tumor with the T790M mutation • Prior treatment with an approved or experimental EGFR-directed therapy • Central nervous system metastases, other than leptomeningeal disease, are permitted if asymptomatic and stable • Prior chemotherapy is permitted if the last treatment occurred >14 days prior to the ﬁrst dose of rociletinib

Key exclusion criteria • EGFR exon 20 insertion activating mutation • Prior participation in a rociletinib clinical trial or eligibility for a current rociletinib clinical trial Upon FDA approval of rociletinib, patients will be transitioned to the commercially available drug. Visit TIGERtrials.com to learn more

The ASCO Post | NOVEMBER 10, 2015

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Direct From ASCO President-Elect Candidates continued from page 77

ASCO will remain at the forefront, and I foresee substantial need in the areas of drug costs and supply; patient access to quality care; promotion of healthy cancer prevention and survivorship practices; sharing of outcomes and research data; and promoting workforce expansion and diversity. These are just a few examples, but knowing that we cannot predict the research breakthroughs of the future, more than anything ASCO needs to remain agile, responsive, and relevant to the changing nature of cancer prevention, treatment, research, and delivery. Dr. Johnson: I am proud to have served on the Board of Directors when we generated the document “Shaping the Future of Oncology: Envisioning Cancer Care in 2030,” which addressed the longterm future of oncology. I participate in many of these initiatives at my own institutions. The first is the ongoing studies of the complex networks of molecular pathways and the tumor microenvironments that drive the cancers. Multiple activated pathways within each cancer will need to be effectively targeted, and the approach has the potential to be curative in some of our patients and, ultimately, lead to successful preventive strategies. The second is the enormous amount of health information that can be shared by our oncology community and enable our members to collect, analyze, and learn from the patients’ characteristics, their tumors, and the outcomes following their pathway-directed treatments based on the patients. The last issue that will need to be addressed is assuring that the patients’ evaluation and treatments can be carried out in a manner that is sensitive to both the patients’ and society’s costs. ASCO and its members will need to be aware of the financial burden that can be generated by our evaluation procedures and the latest treatments, highlighted by costs of the recent approval of the checkpoint inhibitors. ASCO and its members will need to rationally assess the value of our innovative cancer care in terms of the ability of our payers and government to provide the needed support. Dr. Zon: I see a very encouraging and hopeful future for ASCO, cancer research, and oncology care. We are now witnessing the advances in science and technology, changing the lives of our patients in ways we had only imagined in the past. I truly believe these experiences will be amplified in the next 5 to 10 years.

Cancer research is changing. I believe the path for discovery will always include basic, translational, and clinical application research. However, I envision a more scientifically precise and efficient system in the future. In addition, I anticipate the research system will be informed by real-world experiences from rapid learning systems such as CancerLinQ. Moreover, the increased demand for service, by virtue of an increased number of individuals at risk for cancer accompanied by an increase in survivors, will affect the cancer care delivery model in the next 5 to 10 years. I can easily imagine a team-based model led by a physician,

utilizing physician extenders and other paraprofessionals.… I could also envision harnessing information technology to educate, aid, and enhance the patient experience in a different, not yet fully realized manner. Since cancer research and the delivery of care are at the core of ASCO’s mission, ASCO must be willing to evolve, be nimble, and seek nonphysician professionals to help members prepare for the future. The most important role our Society can play in increasing globalization of oncology is to encourage unification of worldwide efforts to raise the bar of patient care regardless of geography— improving quality performance and

enabling learning intelligence should be extended to all countries in this coming decade. I believe harnessing worldwide patient experiences will assist scientists in answering the many questions regarding ethnic and genetic variation in cancer outcomes. More detailed biographical information and extended interviews are available at ASCO.org/election. Voting for the ASCO Election ends December 3, and results will be announced in midDecember. n Originally printed in ASCO Connection. © American Society of Clinical Oncology. connection.asco.org. All rights reserved.

Dear Friends: This is the time of year when I often receive cards from patients celebrating their holiday season. Most cards include photos of my patients on vacation or alongside their growing families, conquering cancer in the simplest and most perfect way—with happiness and hope. I am grateful to know the stories of these cancer survivors, and I proudly hang their cards in my office for visitors to see. The Conquer Cancer Foundation of ASCO (CCF) also receives cards and messages all year long. Doctors, researchers, and patient advocates share with us how your generous gifts are helping conquer cancer in the most purposeful and powerful ways—through research and education. I am lucky to chair the Board of Directors for CCF, and it is my honor, as Thanksgiving nears, to pass along the gratitude our colleagues and patients around the world feel toward CCF donors. One letter of appreciation the Foundation received this year is especially inspiring because it is a message of thanks turned to giving. The Foundation awarded 20 International Development and Education Award (IDEA) scholarships in 2015, which allowed physicians in developing countries to attend ASCO’s Annual Meeting. One physician awarded a scholarship this year, Khaoula Mazouzi, MD, a medical oncology resident from Algeria, wrote to us after the Meeting. “Being at the ASCO Annual Meeting as an IDEA recipient is an old dream that came true,” Dr. Mazouzi said. “My IDEA experience was more than perfect, and I never imagined that it would be as enriching for me as it was.” Dr. Mazouzi took the groundbreaking research shared in Chicago back home to Algeria, where she still maintains the relationships she made with global leaders in oncology. Your contribution to CCF not only made Dr. Mazouzi a better doctor, but it also inspired her to become a CCF donor. This year, Dr. Mazouzi began donating 20% of her salary to the Conquer Cancer Foundation. “For me, a donation is like a chain that would be never broken. Yesterday someone helped you; today is your turn to help others,” Dr. Mazouzi said. As the momentum continues with The Campaign to Conquer Cancer–CCF’s effort to raise $150 million to fund breakthrough cancer research, educate patients and caregivers, and boost the careers of young physicians and scientists, there will be more stories like Dr. Mazouzi’s. I can only hope that means there are more holiday cards hanging in all of our offices in the future. As we enter a season of gratitude, I am so pleased we are working together to take down cancer. Your kindness has led to the best resources for doctors and patient advocates, placing the future of cancer research in the hands of brilliant young investigators. We thank you—and the next generation of patients with cancer will thank you—for supporting the Conquer Cancer Foundation. Wishing you and yours a happy holiday season. Sincerely,

W. Charles Penley, MD, FASCO Chair of the Conquer Cancer Foundation Board of Director

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Direct From ASCO

New Study Indicates Key Differences Between Trial Enrollees and Patients Receiving Treatments

Congress Passes Continuing Resolution, Research Funding Dips Slightly

new article published in the Journal of Oncology Practice evaluates differences between the treatment of patients with metastatic renal cell cancer who participated in clinical trials vs those who received the same therapy in routine clinical practice. Nearly 40% of patients in the realworld registry would not have qualified for the clinical trials testing the therapies they ultimately received. The characteristics of the real-world patients with cancer are often not well represented in clinical trials as a result of specific eligibility criteria. Clinical research with more inclusive eligibility criteria during phase III testing and/or postmarketing studies may improve the generalizability of research find-

ings to the broader patient population. As rapid changes to the practice of oncology continue, it is vital to monitor and respond to practice patterns and outcomes, so oncologists can best understand treatment choices and generate clinically relevant research. In addition to higher participation, the authors note that rapid-learning health systems may additionally offer oncologists a way to readily access all available data. To read the article, go to: http://www. asco.org/advocacy/new-study-indicateskey-differences-between-trial-enrolleesand-patients-receiving. n © 2015. American Society of Clinical Oncology. All rights reserved.

n September 30, Congress passed a Continuing Resolution that will fund the government at current levels through December 11. Funding for both the National Institutes of Health (NIH) and the National Cancer Institute (NCI) dipped slightly as part of a 0.21% cut to all nondefense discretionary agencies. “We have made tremendous progress in our understanding and treatment of cancer over the last four decades, progress that will result in the number of people living with cancer expected to increase from 1.66 million to 2.14 million over the next 15 years. But our nation’s investment in cancer research has remained stagnant since

2003, not even keeping pace with biomedical inflation. We cannot afford to continue on this path, as it will surely result in missed or delayed opportunities to continue to accelerate progress against cancer,” said ASCO Chief Medical Officer Richard L. Schilsky, MD, FASCO. ASCO is monitoring this situation closely and will continue to urge lawmakers to increase research funding through NIH and NCI. Please continue to visit ASCO in Action at www.asco.org/advocacy for the latest information. n © 2015. American Society of Clinical Oncology. All rights reserved.

ASCO Announces Candidates for 2016 Election

eventeen distinguished ASCO members have been selected by the ASCO Nominating Committee as candidates for open leadership positions within the Society. They include the office of President-Elect, four seats on the Society’s Board of Directors, and three seats on the ASCO Nominating Committee.

President-Elect Candidates (One Seat)

• S. Gail Eckhardt, MD, FASCO University of Colorado School of Medicine • Bruce E. Johnson, MD, FASCO Dana-Farber Cancer Institute • Robin T. Zon, MD, FACP, FASCO Michiana Hematology-Oncology, PC Board of Directors—International Oncologist Candidates (One Seat)

• Nagi S. El Saghir, MD, FACP American University of Beirut Medical Center • Jaap Verweij, MD, PhD Erasmus University Medical Center Board of Directors—Pediatric Oncologist Candidates (One Seat)

• Peter C. Adamson, MD The Children’s Hospital of Philadelphia, University of Pennsylvania School of Medicine • Brenda J. Weigel, MD, MSc Masonic Children’s Hospital, University of Minnesota Medical Center

Board of Directors—Undesignated Specialty Candidates (Two Seats)

• Arti Hurria, MD City of Hope • Maha H. A. Hussain, MD, FACP, FASCO University of Michigan Comprehensive Cancer Center • Michael P. Kosty, MD, FACP, FASCO Scripps Green Cancer Center • Blase N. Polite, MD, MPP University of Chicago, Section of Hematology/Oncology Nominating Committee— Designated Community Oncologist Candidates (One Seat)

• James N. Frame, MD, FACP Charleston Area Medical Center • Ray D. Page, DO, PhD, FACOI The Center for Cancer and Blood Disorders

Nominating Committee— Undesignated Specialty Candidates (Two Seats)

• Michael B. Atkins, MD Georgetown-Lombardi Comprehensive Cancer Center • Carolyn D. Runowicz, MD, FASCO Herbert Wertheim College of Medicine, Florida International University • Joseph A. Sparano, MD, FACP Montefiore-Einstein Center for Cancer Care • Antoinette R. Tan, MD, MHSc, FACP Levine Cancer Institute, Carolinas HealthCare System

the proposed amendment, as well as biographical information on each candidate, including video interviews with the President-Elect candidates, is available at ASCO.org/election. Eligible ASCO members can vote for their chosen leaders and on the proposed Bylaws amendment until December 3, 2015 at ASCO.org/election. Election results will be announced mid-December, and the newly elected President-Elect, Directors, and Nominating Committee members will begin their terms of service at the conclusion of the 2016 ASCO Annual Meeting in Chicago. n

This year, the election ballot will also include a proposed amendment to the ASCO Bylaws to change the qualifying age for Emeritus membership in the Society. Detailed information on

Be a Voice in The Campaign to Conquer Cancer

e’ll provide the resources. You provide the voice. The Campaign to Conquer Cancer is raising $150 million to support a world free from the fear of cancer. Our potential to raise money increases with every new person who learns about our work. We need the most trusted leaders in the oncology community to share the message about our criti-

cal movement—that’s you. Most people outside the oncology community are unaware that in just 15 years, the Conquer Cancer Foundation (CCF) has granted more than $150 million to fund patient and caregiver education, boost the careers of young oncologists, and support clinical research around the world. Let the people who turn to you for advice on

medicine and health know CCF resources are at the core of cancer treatment and discoveries. To learn more, sign up at conquer.org/asco, and we’ll share some ways you can help us connect others to The Campaign to Conquer Cancer. n © 2015. American Society of Clinical Oncology. All rights reserved.

In metastatic breast cancer patients whose disease is resistant to an anthracycline, a taxane, and capecitabine

Consider

IXEMPRA® (ixabepilone) monotherapy1

Indication ◗ IXEMPRA® (ixabepilone) is indicated as monotherapy for the treatment of metastatic or locally advanced breast cancer in patients whose tumors are resistant or refractory to anthracyclines, taxanes, and capecitabine

◗ Caution should be used when using IXEMPRA as monotherapy in patients with AST or ALT >5 x ULN. Use of IXEMPRA in patients with AST or ALT >10 x ULN or bilirubin >3 x ULN is not recommended

Warning: Toxicity in hepatic impairment1

◗ With monotherapy, grade 4 neutropenia, febrile neutropenia, and serious adverse reactions were more frequent in patients with hepatic impairment

◗ IXEMPRA in combination with capecitabine is contraindicated in patients with AST or ALT >2.5 x ULN or bilirubin >1 x ULN due to increased risk of toxicity and neutropenia-related death ◗ In combination with capecitabine, the overall frequency of grade 3/4 adverse reactions, febrile neutropenia, serious adverse reactions, and toxicity-related deaths was greater in patients with hepatic impairment

Please see Important Safety Information, including boxed WARNING regarding hepatic impairment, on next page.

Important Safety Information Warning: Toxicity in hepatic impairment Hypersensitivity reaction ® ◗ Premedicate with an H1 and an H2 antagonist approximately ◗ IXEMPRA (ixabepilone) in combination with 1 hour before IXEMPRA (ixabepilone) infusion and observe for capecitabine is contraindicated in patients with hypersensitivity reactions (eg, flushing, rash, dyspnea, AST or ALT >2.5 x ULN or bilirubin >1 x ULN due and bronchospasm) to increased risk of toxicity and neutropenia◗ In case of severe hypersensitivity reactions, infusion of related death IXEMPRA should be stopped and aggressive supportive ◗ In combination with capecitabine, the overall frequency of treatment (eg, epinephrine, corticosteroids) started grade 3/4 adverse reactions, febrile neutropenia, serious ◗ Patients who experience a hypersensitivity reaction in one cycle adverse reactions, and toxicity-related deaths was greater in of IXEMPRA must be premedicated in subsequent cycles with patients with hepatic impairment a corticosteroid in addition to the H1 and H2 antagonists, and ◗ Caution should be used when using IXEMPRA as extension of the infusion time should be considered monotherapy in patients with AST or ALT >5 x ULN. Use of IXEMPRA in patients with AST or ALT >10 x ULN or bilirubin Pregnancy >3 x ULN is not recommended ◗ Women should be advised not to become pregnant when ◗ With monotherapy, grade 4 neutropenia, febrile neutropenia, taking IXEMPRA. If this drug is used during pregnancy and serious adverse reactions were more frequent in patients or the patient becomes pregnant, the patient should be with hepatic impairment apprised of the potential hazard to the fetus Contraindications Cardiac adverse reactions ◗ IXEMPRA is contraindicated in patients: ◗ Caution should be exercised in patients with a history of • with a known history of a severe (CTC grade 3/4) cardiac disease. Discontinuation of IXEMPRA should be hypersensitivity reaction to agents containing considered in patients who develop cardiac ischemia or Cremophor® EL or its derivatives such as impaired cardiac function due to reports of cardiovascular polyoxyethylated castor oil adverse reactions (eg, myocardial ischemia, supraventricular • who have a baseline neutrophil count <1500 cells/mm3 arrhythmia, and ventricular dysfunction). The frequency or a platelet count <100,000 cells/mm3 of cardiac adverse reactions (myocardial ischemia and Peripheral neuropathy ventricular dysfunction) was higher in the IXEMPRA in combination with capecitabine (1.9%) than in the capecitabine ◗ Peripheral neuropathy was common. Patients treated with alone (0.3%) treatment group IXEMPRA should be monitored for symptoms of neuropathy, such as burning sensation, hyperesthesia, hypoesthesia, Potential for cognitive impairment from excipients paresthesia, discomfort, or neuropathic pain ◗ IXEMPRA contains dehydrated alcohol USP. Consideration ◗ Neuropathy occurred early during treatment; ~75% of should be given to the possibility of central nervous system new onset or worsening neuropathy occurred during the and other effects of alcohol first 3 cycles. Patients experiencing new or worsening Adverse reactions peripheral neuropathy may require changes in the dose or ◗ The most common adverse reactions (≥20%) reported discontinuation of IXEMPRA by patients receiving IXEMPRA were peripheral sensory ◗ Neuropathy was the most frequent cause of treatment neuropathy, fatigue/asthenia, myalgia/arthralgia, alopecia, discontinuation due to drug toxicity. Caution should be used nausea, vomiting, stomatitis/mucositis, diarrhea, and when treating patients with diabetes mellitus or preexisting musculoskeletal pain. The following additional events peripheral neuropathy occurred in ≥20% in combination treatment: palmar-plantar Myelosuppression erythrodysesthesia (hand-foot) syndrome, anorexia, abdominal ◗ Myelosuppression is dose-dependent and primarily pain, nail disorder, and constipation. Drug-associated manifested as neutropenia. hematologic abnormalities (>40%) include neutropenia, ◗ Patients should be monitored for myelosuppression; frequent leukopenia, anemia, and thrombocytopenia peripheral blood cell counts are recommended for all patients receiving IXEMPRA Cremophor is a registered trademark of BASF AG. ◗ Patients who experience severe neutropenia or AST = aspartate aminotransferase thrombocytopenia should have their dose reduced. NeutropeniaALT = alanine aminotransferase related deaths occurred in 1.9% of 414 patients with normal ULN = upper limit of normal hepatic function or mild hepatic impairment treated with CTC = common terminology criteria IXEMPRA in combination with capecitabine. Neutropeniarelated death occurred in 0.4% of 240 patients with IXEMPRA as monotherapy Please see brief summary of Full Prescribing Information on adjacent pages. Reference: 1. IXEMPRA (ixabepilone) Prescribing Information; 2011. For additional information, visit www.IXEMPRA.com. Ixempra® is a registered trademark of R-Pharm US Operating LLC, a wholly owned subsidiary of R-Pharm US LLC. © 2015, R-PHARM US. All rights reserved. IXE-00009 9/15

IXEMPRA® Kit (ixabepilone) for Injection, for intravenous infusion only Brief Summary of Prescribing Information. For complete prescribing information consult official package insert. WARNING: TOXICITY IN HEPATIC IMPAIRMENT IXEMPRA in combination with capecitabine is contraindicated in patients with AST or ALT >2.5 x ULN or bilirubin >1 x ULN due to increased risk of toxicity and neutropenia-related death [see Contraindications and Warnings and Precautions]. INDICATIONS AND USAGE IXEMPRA (ixabepilone) is indicated in combination with capecitabine for the treatment of patients with metastatic or locally advanced breast cancer resistant to treatment with an anthracycline and a taxane, or whose cancer is taxane resistant and for whom further anthracycline therapy is contraindicated. Anthracycline resistance is defined as progression while on therapy or within 6 months in the adjuvant setting or 3 months in the metastatic setting. Taxane resistance is defined as progression while on therapy or within 12 months in the adjuvant setting or 4 months in the metastatic setting. IXEMPRA is indicated as monotherapy for the treatment of metastatic or locally advanced breast cancer in patients whose tumors are resistant or refractory to anthracyclines, taxanes, and capecitabine. CONTRAINDICATIONS IXEMPRA is contraindicated in patients with a history of a severe (CTC grade 3/4) hypersensitivity reaction to agents containing Cremophor® EL or its derivatives (eg, polyoxyethylated castor oil) [see Warnings and Precautions]. IXEMPRA is contraindicated in patients who have a neutrophil count <1500 cells/mm3 or a platelet count <100,000 cells/mm3 [see Warnings and Precautions]. IXEMPRA in combination with capecitabine is contraindicated in patients with AST or ALT >2.5 x ULN or bilirubin >1 x ULN [see Boxed Warning and Warnings and Precautions]. WARNINGS AND PRECAUTIONS Peripheral Neuropathy Peripheral neuropathy was common (see Table 1). Patients treated with IXEMPRA should be monitored for symptoms of neuropathy, such as burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, or neuropathic pain. Neuropathy occurred early during treatment; ~75% of new onset or worsening neuropathy occurred during the first 3 cycles. Patients experiencing new or worsening symptoms may require a reduction or delay in the dose of IXEMPRA [see Dosage and Administration (2.2) in Full Prescribing Information]. In clinical studies, peripheral neuropathy was managed through dose reductions, dose delays, and treatment discontinuation. Neuropathy was the most frequent cause of treatment discontinuation due to drug toxicity. In Studies 046 and 081, 80% and 87%, respectively, of patients with peripheral neuropathy who received IXEMPRA had improvement or no worsening of their neuropathy following dose reduction. For patients with grade 3/4 neuropathy in Studies 046 and 081, 76% and 79%, respectively, had documented improvement to baseline or grade 1, twelve weeks after onset. Table 1: Treatment-related Peripheral Neuropathy

Peripheral neuropathy (all grades)a,b Peripheral neuropathy (grades 3/4)a,b Discontinuation due to neuropathy Median number of cycles to onset of grade 3/4 neuropathy Median time to improvement of grade 3/4 neuropathy to baseline or to grade 1 a b

IXEMPRA with capecitabine Study 046

IXEMPRA as monotherapy Study 081

67% 23% 21% 4

63% 14% 6% 4

6.0 weeks

4.6 weeks

Sensory and motor neuropathy combined. 24% and 27% of patients in 046 and 081, respectively, had preexisting neuropathy (grade 1).

A pooled analysis of 1540 cancer patients treated with IXEMPRA indicated that patients with diabetes mellitus or preexisting peripheral neuropathy may be at increased risk of severe neuropathy. Prior therapy with neurotoxic chemotherapy agents did not predict the development of neuropathy. Patients with moderate to severe neuropathy (grade 2 or greater) were excluded from studies with IXEMPRA. Caution should be used when treating patients with diabetes mellitus or preexisting peripheral neuropathy. Myelosuppression Myelosuppression is dose-dependent and primarily manifested as neutropenia. In clinical studies, grade 4 neutropenia (<500 cells/mm3) occurred in 36% of patients treated with IXEMPRA in combination with capecitabine and 23% of patients treated with IXEMPRA monotherapy. Febrile neutropenia and infection with neutropenia were reported in 5% and 6% of patients treated with IXEMPRA in combination with capecitabine, respectively, and 3% and 5% of patients treated with IXEMPRA as monotherapy, respectively. Neutropenia-related death occurred in 1.9% of 414 patients with normal hepatic function or mild hepatic impairment treated with IXEMPRA in combination with capecitabine. The rate of neutropenia-related deaths was higher (29%, 5 out of 17) in patients with AST or ALT >2.5 x ULN or bilirubin >1.5 x ULN [see Boxed Warning, Contraindications, and Warnings and Precautions]. Neutropenia-related death occurred in 0.4% of 240 patients treated with IXEMPRA as monotherapy. No neutropenia-related deaths were reported in 24 patients with AST or ALT >2.5 x ULN or bilirubin >1.5 x ULN treated with IXEMPRA monotherapy. IXEMPRA must not be administered to patients with a neutrophil count <1500 cells/mm3. To monitor for myelosuppression, frequent peripheral blood cell counts are recommended for all patients receiving IXEMPRA. Patients who experience severe neutropenia or thrombocytopenia should have their dose reduced [see Dosage and Administration (2.2) in Full Prescribing Information]. Hepatic Impairment Patients with baseline AST or ALT >2.5 x ULN or bilirubin >1.5 x ULN experienced greater toxicity than patients with baseline AST or ALT ≤2.5 x ULN or bilirubin ≤1.5 x ULN when treated with IXEMPRA at 40 mg/m2 in combination with capecitabine or as monotherapy in breast cancer studies. In combination with capecitabine, the overall frequency of grade 3/4 adverse reactions, febrile neutropenia, serious adverse reactions, and toxicity-related deaths was greater [see Warnings and Precautions]. With monotherapy, grade 4 neutropenia, febrile neutropenia, and serious adverse reactions were more frequent. The safety and pharmacokinetics of IXEMPRA as monotherapy were evaluated in a dose escalation study in 56 patients with varying degrees of hepatic impairment. Exposure was increased in patients with elevated AST or bilirubin [see Use in Specific Populations]. IXEMPRA in combination with capecitabine is contraindicated in patients with AST or ALT >2.5 x ULN or bilirubin >1 x ULN due to increased risk of toxicity- and neutropenia-related death [see Boxed Warning, Contraindications, and Warnings and Precautions]. Patients who are treated with IXEMPRA as monotherapy should receive a reduced dose depending on the degree of hepatic impairment [see Dosage and Administration (2.2) in Full Prescribing Information]. Use in patients with AST or ALT >10 x ULN or bilirubin >3 x ULN is not recommended. Limited data are available for patients with AST or ALT >5 x ULN. Caution should be used when treating these patients [see Dosage and Administration (2.2) in Full Prescribing Information]. Hypersensitivity Reactions Patients with a history of a severe hypersensitivity reaction to agents containing Cremophor® EL or its derivatives (eg, polyoxyethylated castor oil) should not be treated with IXEMPRA. All patients should be premedicated with an H1 and an H2 antagonist approximately 1 hour before IXEMPRA infusion and be observed for hypersensitivity reactions (eg, flushing, rash, dyspnea, and bronchospasm). In case of severe hypersensitivity reactions, infusion of IXEMPRA should be stopped and aggressive supportive treatment (eg, epinephrine, corticosteroids) started. Of the 1323 patients treated with IXEMPRA in clinical studies, 9 patients (1%) had experienced severe hypersensitivity reactions (including anaphylaxis). Three of the 9 patients were able to be retreated. Patients who experience a hypersensitivity reaction in one cycle of IXEMPRA must be premedicated in subsequent cycles with a corticosteroid in addition to the H1 and H2 antagonists, and extension of the infusion time should be considered [see Dosage and Administration (2.3) in Full Prescribing Information and Contraindications]. Pregnancy Pregnancy Category D. IXEMPRA may cause fetal harm when administered to pregnant women. There are no adequate and well-controlled studies with IXEMPRA in pregnant women. Women should be advised not to become pregnant when taking IXEMPRA. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Ixabepilone was studied for effects on embryo-fetal development in pregnant rats and rabbits given IV doses of 0.02, 0.08, and 0.3 mg/kg/day and 0.01, 0.03, 0.11, and 0.3 mg/kg/day, respectively. There were no teratogenic effects. In rats, an increase in resorptions and post-implantation loss and a decrease in the number of live fetuses and fetal weight was observed at the maternally

toxic dose of 0.3 mg/kg/day (approximately one-tenth the human clinical exposure based on AUC). Abnormalities included a reduced ossification of caudal vertebrae, sternebrae, and metacarpals. In rabbits, ixabepilone caused maternal toxicity (death) and embryo-fetal toxicity (resorptions) at 0.3 mg/kg/day (approximately one-tenth the human clinical dose based on body surface area). No fetuses were available at this dose for evaluation. Cardiac Adverse Reactions The frequency of cardiac adverse reactions (myocardial ischemia and ventricular dysfunction) was higher in the IXEMPRA (ixabepilone) in combination with capecitabine (1.9%) than in the capecitabine alone (0.3%) treatment group. Supraventricular arrhythmias were observed in the combination arm (0.5%) and not in the capecitabine alone arm. Caution should be exercised in patients with a history of cardiac disease. Discontinuation of IXEMPRA should be considered in patients who develop cardiac ischemia or impaired cardiac function. Potential for Cognitive Impairment from Excipients Since IXEMPRA contains dehydrated alcohol USP, consideration should be given to the possibility of central nervous system and other effects of alcohol [see Description (11) in Full Prescribing Information]. ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections. • Peripheral neuropathy [see Warnings and Precautions] • Myelosuppression [see Warnings and Precautions] • Hypersensitivity reactions [see Warnings and Precautions] Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in clinical practice. Unless otherwise specified, assessment of adverse reactions is based on one randomized study (Study 046) and one single-arm study (Study 081). In Study 046, 369 patients with metastatic breast cancer were treated with IXEMPRA 40 mg/m2 administered intravenously over 3 hours every 21 days, combined with capecitabine 1000 mg/m2 twice daily for 2 weeks followed by a 1-week rest period. Patients treated with capecitabine as monotherapy (n=368) in this study received 1250 mg/m2 twice daily for 2 weeks every 21 days. In Study 081, 126 patients with metastatic or locally advanced breast cancer were treated with IXEMPRA 40 mg/m2 administered intravenously over 3 hours every 3 weeks. The most common adverse reactions (≥20%) reported by patients receiving IXEMPRA were peripheral sensory neuropathy, fatigue/asthenia, myalgia/arthralgia, alopecia, nausea, vomiting, stomatitis/mucositis, diarrhea, and musculoskeletal pain. The following additional reactions occurred in ≥20% in combination treatment: palmar-plantar erythrodysesthesia (hand-foot) syndrome, anorexia, abdominal pain, nail disorder, and constipation. The most common hematologic abnormalities (>40%) include neutropenia, leukopenia, anemia, and thrombocytopenia. Table 2 presents nonhematologic adverse reactions reported in 5% or more of patients. Hematologic abnormalities are presented separately in Table 3. Table 2:

Nonhematologic Drug-related Adverse Reactions Occurring in at Least 5% of Patients with Metastatic or Locally Advanced Breast Cancer Treated with IXEMPRA

System Organ Classa/ Preferred Term Infections and Infestations Upper respiratory tract infectionb Blood and Lymphatic System Disorders Febrile neutropenia Immune System Disorders Hypersensitivityb Metabolism and Nutrition Disorders Anorexiab Dehydrationb Psychiatric Disorders Insomniab Nervous System Disorders Peripheral neuropathy Sensory neuropathy b,e Motor neuropathyb Headache Taste disorderb Dizziness Eye Disorders Lacrimation increased Vascular Disorders Hot flushb Respiratory, Thoracic, and Mediastinal Disorders Dyspneab Coughb Gastrointestinal Disorders Nausea Vomitingb Stomatitis/mucositisb Diarrheab Constipation Abdominal painb Gastroesophageal reflux diseaseb Skin and Subcutaneous Tissue Disorders Alopeciab Skin rashb Nail disorderb Palmar-plantar erythrodysesthesia syndromeb,f Pruritus Skin exfoliationb Skin hyperpigmentationb Musculoskeletal, Connective Tissue, and Bone Disorders Myalgia/arthralgiab Musculoskeletal painb General Disorders and Administration Site Conditions Fatigue/astheniab Edemab Pyrexia Painb Chest painb

Study 046 IXEMPRA with Capecitabine capecitabine n=369 n=368 Total Grade 3/4 Total Grade 3/4 (%) (%) (%) (%)

Study 081 IXEMPRA monotherapy n=126 Total Grade 3/4 (%) (%)

34 5

3d 2

15 2

1d <1d

19 2

2d 1d

<1d

65 16 8 12 8

21 5d <1d 0 1d

16 <1 3 4 5

0 0 0 0 1d

62 10 11 6 7

14 1d 0 0 0

<1d

7 6

1 0

4 2

1 0

9 2

1d 0

53 39 31 44 22 24 7

3d 4d 4 6d 0 2d 1d

40 24 20 39 6 14 8

2d 2 3d 9 <1d 1d 0

42 29 29 22 16 13 6

2d 1d 6 1d 2d 2d 0

31 17 24 64

0 1d 2d 18d

3 7 10 63

0 0 <1d 17d

48 9 9 8

0 2d 0 2d

5 5 11

0 <1d 0

2 3 14

0 0 0

6 2 2

1d 0 0

39 23

8d 2d

5 5

<1d 0

49 20

8d 3d

60 8 10 9 4

16 0 1d 1d 1d

29 5 4 2 <1

4 <1d 0 0 0

56 9 8 8 5

13 1d 1d 3d 1d (Continued)

Table 2: (Continued)

Nonhematologic Drug-related Adverse Reactions Occurring in at Least 5% of Patients with Metastatic or Locally Advanced Breast Cancer Treated with IXEMPRA

System Organ Classa/ Preferred Term

Study 046 IXEMPRA with Capecitabine capecitabine n=369 n=368 Total Grade 3/4 Total Grade 3/4 (%) (%) (%) (%)

Study 081 IXEMPRA monotherapy n=126 Total Grade 3/4 (%) (%)

System organ class presented as outlined in Guidelines for Preparing Core Clinical Safety Information on Drugs by the Council for International Organizations of Medical Sciences (CIOMS). b A composite of multiple MedDRA Preferred Terms. c NCI CTC grading for febrile neutropenia ranges from Grade 3 to 5. Three patients (1%) experienced Grade 5 (fatal) febrile neutropenia. Other neutropenia-related deaths (9) occurred in the absence of reported febrile neutropenia [see Warnings and Precautions]. d No grade 4 reports. e Peripheral sensory neuropathy (graded with the NCI CTC scale) was defined as the occurrence of any of the following: areflexia, burning sensation, dysesthesia, hyperesthesia, hypoesthesia, hyporeflexia, neuralgia, neuritis, neuropathy, neuropathy peripheral, neurotoxicity, painful response to normal stimuli, paresthesia, pallanesthesia, peripheral sensory neuropathy, polyneuropathy, polyneuropathy toxic and sensorimotor disorder. Peripheral motor neuropathy was defined as the occurrence of any of the following: multifocal motor neuropathy, neuromuscular toxicity, peripheral motor neuropathy, and peripheral sensorimotor neuropathy. f Palmar-plantar erythrodysesthesia (hand-foot syndrome) was graded on a 1-3 severity scale in Study 046. Table 3:

Hematologic Abnormalities in Patients with Metastatic or Locally Advanced Breast Cancer Treated with IXEMPRA

Hematology Parameter Neutropeniaa Leukopenia (WBC) Anemia (Hgb) Thrombocytopenia

Study 046 IXEMPRA with Capecitabine capecitabine n=369 n=368 Grade 3 Grade 4 Grade 3 Grade 4 (%) (%) (%) (%) 32 41 8 5

36 16 2 3

9 5 4 2

2 1 1 2

Study 081 IXEMPRA monotherapy n=126 Grade 3 Grade 4 (%) (%) 31 36 6 5

23 13 2 2

G-CSF (granulocyte colony stimulating factor) or GM-CSF (granulocyte macrophage colony stimulating factor) was used in 20% and 17% of patients who received IXEMPRA in Study 046 and Study 081, respectively.

The following serious adverse reactions were also reported in 1323 patients treated with IXEMPRA as monotherapy or in combination with other therapies in Phase 2 and 3 studies. Infections and Infestations: sepsis, pneumonia, infection, neutropenic infection, urinary tract infection, bacterial infection, enterocolitis, laryngitis, lower respiratory tract infection Blood and Lymphatic System Disorders: coagulopathy, lymphopenia Metabolism and Nutrition Disorders: hyponatremia, metabolic acidosis, hypokalemia, hypovolemia Nervous System Disorders: cognitive disorder, syncope, cerebral hemorrhage, abnormal coordination, lethargy Cardiac Disorders: myocardial infarction, supraventricular arrhythmia, left ventricular dysfunction, angina pectoris, atrial flutter, cardiomyopathy, myocardial ischemia Vascular Disorders: hypotension, thrombosis, embolism, hemorrhage, hypovolemic shock, vasculitis Respiratory, Thoracic, and Mediastinal Disorders: pneumonitis, hypoxia, respiratory failure, acute pulmonary edema, dysphonia, pharyngolaryngeal pain Gastrointestinal Disorders: ileus, colitis, impaired gastric emptying, esophagitis, dysphagia, gastritis, gastrointestinal hemorrhage Hepatobiliary Disorders: acute hepatic failure, jaundice Skin and Subcutaneous Tissue Disorders: erythema multiforme Musculoskeletal, Connective Tissue, and Bone Disorders: muscular weakness, muscle spasms, trismus Renal and Urinary Disorders: nephrolithiasis, renal failure General Disorders and Administration Site Conditions: chills Investigations: increased transaminases, increased blood alkaline phosphatase, increased gamma-glutamyltransferase Postmarketing Experience Radiation recall has been reported during postmarketing use of IXEMPRA. Because this reaction was reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure. DRUG INTERACTIONS Effect of Other Drugs on Ixabepilone Drugs That May Increase Ixabepilone Plasma Concentrations CYP3A4 Inhibitors: Coadministration of ixabepilone with ketoconazole, a potent CYP3A4 inhibitor, increased ixabepilone AUC by 79% compared to ixabepilone treatment alone. If alternative treatment cannot be administered, a dose adjustment should be considered. The effect of mild or moderate inhibitors (eg, erythromycin, fluconazole, or verapamil) on exposure to ixabepilone has not been studied. Therefore, caution should be used when administering mild or moderate CYP3A4 inhibitors during treatment with IXEMPRA, and alternative therapeutic agents that do not inhibit CYP3A4 should be considered. Patients receiving CYP3A4 inhibitors during treatment with IXEMPRA should be monitored closely for acute toxicities (eg, frequent monitoring of peripheral blood counts between cycles of IXEMPRA) [see Dosage and Administration (2.2) in Full Prescribing Information]. Drugs That May Decrease Ixabepilone Plasma Concentrations CYP3A4 Inducers: IXEMPRA is a CYP3A4 substrate. Coadministration of IXEMPRA with rifampin, a potent CYP3A4 inducer, decreased ixabepilone AUC by 43% compared to IXEMPRA treatment alone. Other strong CYP3A4 inducers (eg, dexamethasone, phenytoin, carbamazepine, rifabutin, and phenobarbital) may also decrease ixabepilone concentrations leading to subtherapeutic levels. Therefore, therapeutic agents with low enzyme induction potential should be considered for coadministration with IXEMPRA. St. John’s Wort may decrease ixabepilone plasma concentrations unpredictably and should be avoided. If patients must be coadministrated a strong CYP3A4 inducer, a gradual dose adjustment may be considered [see Dosage and Administration (2.2) in Full Prescribing Information]. Effect of Ixabepilone on Other Drugs Ixabepilone does not inhibit CYP enzymes at relevant clinical concentrations and is not expected to alter the plasma concentrations of other drugs [see Clinical Pharmacology (12.3) in Full Prescribing Information]. Capecitabine In patients with cancer who received ixabepilone (40 mg/m2) in combination with capecitabine (1000 mg/m2), ixabepilone Cmax decreased by 19%, capecitabine Cmax decreased by 27%, and 5-fluorouracil AUC increased by 14%, as compared to ixabepilone or capecitabine administered separately. The interaction is not clinically significant given that the combination treatment is supported by efficacy data. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category D [see Warnings and Precautions]. Nursing Mothers It is not known whether ixabepilone is excreted into human milk. Following intravenous administration of radiolabeled ixabepilone to rats on days 7 to 9 postpartum, concentrations of radioactivity in milk were comparable with those in plasma and declined in parallel with the plasma concentrations. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from ixabepilone, a decision must be made whether to discontinue nursing or to discontinue IXEMPRA taking into account the importance of the drug to the mother.

Pediatric Use The effectiveness of IXEMPRA (ixabepilone) in pediatric patients has not been established. IXEMPRA was evaluated in one Phase 1 and one Phase 2 trial. The pediatric patients had a safety profile consistent with that seen in adults, and no new safety signals were identified. In the Phase 1 open-label, dose-finding trial, the safety of IXEMPRA was evaluated in 19 pediatric patients with advanced or refractory solid tumors and 2 with acute leukemias. IXEMPRA was administered as a one-hour IV infusion daily for the first five days of a 21-day cycle at one of 5 dose levels, ranging from 3 to 10 mg/m2. Among the 21 patients, 12 ranged in age from 2 to 12 years and 9 ranged from 13 to 18 years. The maximum tolerated dose was 8 mg/m2 IV daily for 5 days every 21 days. No significant activity was observed. The pharmacokinetics of ixabepilone were characterized by population pharmacokinetic analysis of data for 16 patients from this trial, who were aged 2 to 18 years (median 12 years). The pharmacokinetic parameters of ixabepilone in these pediatric patients were compared to the corresponding parameters of 130 adult patients enrolled in clinical trials using the same dosing schedule. The median BSA normalized clearance of ixabepilone in pediatric patients (17 L/h/m2) was similar to that in adult patients (20 L/h/m2). In the Phase 2 trial of 59 patients with advanced or refractory solid tumors, 28 ranged in age from 3 to 12 years and 19 ranged in age from 13 to 18 years. Twelve additional patients over the age of 18 were treated in this trial. IXEMPRA was administered at a dose of 8 mg/m2 IV daily for 5 days every 21 days. This trial was terminated early due to lack of efficacy. Geriatric Use Clinical studies of IXEMPRA did not include sufficient numbers of subjects aged sixty-five and over to determine whether they respond differently from younger subjects. Forty-five of 431 patients treated with IXEMPRA in combination with capecitabine were ≥65 years of age and 3 patients were ≥75. Overall, the incidence of grade 3/4 adverse reactions was higher in patients ≥65 years of age versus those <65 years of age (82% versus 68%) including grade 3/4 stomatitis (9% versus 1%), diarrhea (9% versus 6%), palmar-plantar erythrodysesthesia syndrome (27% versus 20%), peripheral neuropathy (24% versus 22%), febrile neutropenia (9% versus 3%), fatigue (16% versus 12%), and asthenia (11% versus 6%). Toxicity-related deaths occurred in 2 (4.7%) of 43 patients ≥65 years with normal baseline hepatic function or mild impairment. Thirty-two of 240 breast cancer patients treated with IXEMPRA as monotherapy were ≥65 years of age and 6 patients were ≥75. No overall differences in safety were observed in these patients compared to those <65 years of age. Hepatic Impairment IXEMPRA was evaluated in 56 patients with mild to severe hepatic impairment defined by bilirubin levels and AST levels. Compared to patients with normal hepatic function (n=17), the area under the curve (AUC0-infinity) of ixabepilone increased by: • 22% in patients with a) bilirubin >1 – 1.5 x ULN or b) AST >ULN but bilirubin <1.5 x ULN; • 30% in patients with bilirubin >1.5 – 3 x ULN and any AST level; and • 81% in patients with bilirubin >3 x ULN and any AST level. Doses of 10 and 20 mg/m2 as monotherapy were tolerated in 17 patients with severe hepatic impairment (bilirubin >3 x ULN). IXEMPRA in combination with capecitabine must not be given to patients with AST or ALT >2.5 x ULN or bilirubin >1 x ULN [see Boxed Warning, Contraindications, and Warnings and Precautions]. Dose reduction is recommended when administering IXEMPRA as monotherapy to patients with hepatic impairment [see Dosage and Administration (2.3) in Full Prescribing Information]. Because there is a need for dosage adjustment based upon hepatic function, assessment of hepatic function is recommended before initiation of IXEMPRA and periodically thereafter. Renal Impairment Ixabepilone is minimally excreted via the kidney. No controlled pharmacokinetic studies were conducted with IXEMPRA in patients with renal impairment. IXEMPRA in combination with capecitabine has not been evaluated in patients with calculated creatinine clearance of <50 mL/min. IXEMPRA as monotherapy has not been evaluated in patients with creatinine >1.5 times ULN. In a population pharmacokinetic analysis of IXEMPRA as monotherapy, there was no meaningful effect of mild and moderate renal insufficiency (CrCL >30 mL/min) on the pharmacokinetics of ixabepilone. OVERDOSAGE Experience with overdose of IXEMPRA is limited to isolated cases. The adverse reactions reported in these cases included peripheral neuropathy, fatigue, musculoskeletal pain/myalgia, and gastrointestinal symptoms (nausea, anorexia, diarrhea, abdominal pain, stomatitis). The highest dose mistakenly received was 100 mg/m2 (total dose 185 mg). There is no known antidote for overdosage of IXEMPRA. In case of overdosage, the patient should be closely monitored and supportive treatment should be administered. Management of overdose should include supportive medical interventions to treat the presenting clinical manifestations. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies with ixabepilone have not been conducted. Ixabepilone did not induce mutations in the microbial mutagenesis (Ames) assay and was not clastogenic in an in vitro cytogenetic assay using primary human lymphocytes. Ixabepilone was clastogenic (induction of micronuclei) in the in vivo rat micronucleus assay at doses ≥0.625 mg/kg/day. There were no effects on male or female rat mating or fertility at doses up to 0.2 mg/kg/day in both males and females (approximately one-fifteenth the expected human clinical exposure based on AUC). The effect of ixabepilone on human fertility is unknown. However, when rats were given an IV infusion of ixabepilone during breeding and through the first 7 days of gestation, a significant increase in resorptions and pre- and post-implantation loss and a decrease in the number of corpora lutea was observed at 0.2 mg/kg/day. Testicular atrophy or degeneration was observed in 6-month rat and 9-month dog studies when ixabepilone was given every 21 days at intravenous doses of 6.7 mg/kg (40 mg/m2) in rats (approximately 2.1 times the expected clinical exposure based on AUC) and 0.5 and 0.75 mg/kg (10 and 15 mg/m2) in dogs (approximately 0.2 and 0.4 times the expected clinical exposure based on AUC). Animal Toxicology Overdose In rats, single intravenous doses of ixabepilone from 60 to 180 mg/m2 (mean AUC values ≥8156 ng•h/mL) were associated with mortality occurring between 5 and 14 days after dosing, and toxicity was principally manifested in the gastrointestinal, hematopoietic (bone-marrow), lymphatic, peripheral-nervous, and male-reproductive systems. In dogs, a single intravenous dose of 100 mg/m2 (mean AUC value of 6925 ng•h/mL) was markedly toxic, inducing severe gastrointestinal toxicity and death 3 days after dosing. PATIENT COUNSELING INFORMATION [see FDA-Approved Patient Labeling in Full Prescribing Information] Peripheral Neuropathy Patients should be advised to report to their physician any numbness and tingling of the hands or feet [see Warnings and Precautions]. Fever/Neutropenia Patients should be instructed to call their physician if a fever of 100.5° F or greater or other evidence of potential infection such as chills, cough, or burning or pain on urination develops [see Warnings and Precautions]. Hypersensitivity Reactions Patients should be advised to call their physician if they experience urticaria, pruritus, rash, flushing, swelling, dyspnea, chest tightness or other hypersensitivity-related symptoms following an infusion of IXEMPRA [see Warnings and Precautions]. Pregnancy Patients should be advised to use effective contraceptive measures to prevent pregnancy and to avoid nursing during treatment with IXEMPRA [see Warnings and Precautions and Use in Specific Populations]. Cardiac Adverse Reactions Patients should be advised to report to their physician chest pain, difficulty breathing, palpitations or unusual weight gain [see Warnings and Precautions]. IXEMPRA® (ixabepilone) for injection Manufactured by: Baxter Oncology GmbH, 33790 Halle/Westfalen, Germany DILUENT for IXEMPRA Manufactured by: Baxter Oncology GmbH, 33790 Halle/Westfalen, Germany Distributed by Bristol-Myers Squibb Company, Princeton, NJ 08543 USA

1236925A7

5645-0006

Rev October 2011 RPH-00001

The ASCO Post | NOVEMBER 10, 2015

PAGE 84

Book Review

A Pandemic’s Story of Tragedy and Success By Ronald Piana

IDS is a global phenomenon that recognizes neither national boundaries nor social strata. The AIDS pandemic was one of the disruptive events that marked the turn of the 21st century. Who could have predicted the worst pandemic in modern history since the Spanish influenza, when in June 1980, a syndrome of unknown origin was described in just a few lines about five homosexual white men in the United States? And, despite major advances in prevention and treatment, HIV/AIDS is expected to kill about 1.5 million people worldwide this year. Not only does AIDS still pose a

fan of the genre after several chapters. Professor Piot does not make that mistake. AIDS Between Science and Politics is a compact work, broken into short chapters and then into subheads. It is presented in a linear style, with a bit of history first and then a terrific explanation on the epidemiology of HIV/AIDS, which oncologists fond of statistics will find interesting. In simple language, the author describes how HIV numbers are estimated in a heterogeneous and still-evolving population. He also breaks down the infection rates into treatment strategies, again offering good content for the oncology

Beyond the absolute number and distribution in given regions over time, national AIDS programs seek to understand which groups are affected by recent infection, as this is where the efforts for HIV prevention should be focused. —Peter Piot

major public health crisis, it remains a pointed issue in socioeconomics and politics, all of which are covered in great detail in a book by Peter Piot, aptly titled AIDS Between Science and Politics. The author, Professor Piot, has a formidable pedigree. He is Director of the London School of Hygiene and Tropical Medicine, former Under Secretary General of the United Nations, founding Executive Director of the Joint United Nations Programme on HIV/AIDS (UNAIDS), co-discoverer of the Ebola virus, and former President of the International AIDS Society. Although the book is a bit arid, it is chock-full of valuable information and deep introspection about global health policy, making it a good choice for those readers of The ASCO Post interested in international health issues. Transmitted largely by sex and intravenous drug usage, AIDS is a disease that still battles with stigmatization. As Professor Piot writes, “Early AIDS research was stifled because of a deep prejudice and stigmatization of those living with the virus: homosexual men, illicit drug users, people with hemophilia, as well as Haitians and Africans. That era is not over: Although now subtler, discrimination and stigmatization explain at least what is possible and the continuing global epidemic.”

A Closer Look at Epidemiology Public health policy books generally are telephone book–thick tomes that lose through boredom all but the most ardent

community, in that it’s akin to organizing a tumor registry in a developing country. The approach is similar to the work well-known oncologists such as Larry Schulman, MD, and Bruce Chabner, MD, have done in sub-Saharan Africa. Professor Piot explains, “Beyond the absolute number and distribution in given regions over time, national AIDS programs seek to understand which groups are affected by recent infection, as this is where the efforts for HIV prevention should be focused.” Although the advent of multidrug cocktails such as highly active antiretroviral therapy has made HIV/AIDS a manageable disease, it is expensive and must be taken every day for life. In this section about epidemiology, the author ends with this sobering line: “The future of the HIV epidemic depends on numerous unknowns, and no model can fully determine the extent of long-term changes, either in prevention or treatment.”

Still a Hyperepidemic for Some In the United States, we had an AIDS crisis that erupted into a sociopolitical movement, championed by movie stars and politicians. It was a convulsive national process that took time and understanding, but eventually prevention strategies were implemented and efficacious drugs developed. The author reminds us that AIDS is still a hyperepidemic in parts of the world, such as Southern Africa, which is experiencing an exceptionally severe AIDS epidemic,

with adult HIV prevalence rates up to 24.7% in Swaziland. It’s sobering to read that the Southern African region accounts for more than one-third of all people living with HIV in the world. More sobering is that AIDS, unlike breast or prostate cancer, is largely preventable. Like lung cancer, which is largely caused by smoking, AIDS has a main driver of incidence: sex. The author points out (rightly so) that lung cancer has been stigmatized as a “preventable” disease, putting blame on smokers who develop the disease. Given that HIV is mainly transmitted sexually, Professor Piot wades into the thorny area of searching for a clue to the massive AIDS burden in Southern Africa, and it proves to be one of the most interesting sections of the book. When he looks at each parameter of sexual behavior separately, such as the number of partners, frequency of commercial sex, and age at first sexual intercourse, studies have shown little difference with other regions of the world. After looking at various sociomathematic models, he states what seems obvious: “A reduction of concurrent sexual partners and the total number of sex partners (which is extraordinarily high in Southern Africa) should be part of any HIV prevention program.” This is important epidemiologic research, which is generalizable over many preventable disease states. In the United States, we’ve seen the results in behavior modification in smoking-related lung cancer; because of science-driven public policy, smoking dropped from 60% of the population down to 18%. The United States has also seen a huge drop in the incidence of AIDS, due largely to public health information stating the simple message: Do not have unprotected sex and engage in intravenous drug use. Unfortunately, the author softens his thesis about irresponsible sex driving the AIDS epidemic in Southern Africa, concluding that it is unlikely there is a single cause for hyperendemic HIV infection in Southern Africa. He adds, “Apartheid in South Africa, and its ramifications in neighboring states, has played a determining role in the current sexual behavior, hence the spread of HIV.”

Social Justice and Moral Imperatives After fully examining the historical and sociopolitical context of the AIDS pandemic, Professor Piot does a fine

Bookmark Title: AIDS Between Science and Politics Author: Peter Piot Publisher: Columbia University Press Publication date: May 2015 Price: $29.95; hardcover, 216 pages

job of breaking down the enormous financial burden this disease places on developing countries, calling for AIDS treatment to be classified by the World Health Organization as a basic human right. He makes a compelling argument. However, toward the end of this book, the author’s bent on social justice and moral imperatives lead him into areas that are ripe for criticism. “Often HIV is a motive for preexisting discrimination. Thus foreigners or immigrants are suspected of having introduced the virus and contaminated the healthy population. Prostitutes are stigmatized as a vector of infection…homophobia is one of the most common forms of structured discrimination.” He concludes with a short chapter on how to prevent discrimination, which many readers may find preachy and ineffective. No doubt his heart is in the right place, but these final messages, not backed by data, stray from his solid scholarship and dilute the power of this otherwise well-researched and worthwhile book. n

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The ASCO Post | NOVEMBER 10, 2015

PAGE 86

Book Review

A Chemist Exposes Dangerous Chemicals By Ronald Piana

onona Rossol is a chemist and “industrial hygienist” who is a frequent contributor to various media outlets in the New York area. Loosely defined, an industrial hygienist is a scientist dedicated to protecting and enhancing the health and safety of people at work and in their communities. Health and safety hazards cover a wide range of chemical, physical, biological, and ergonomic stressors. Ms. Rossol describes herself in the preface of her book Pick Your Poison: How Our Mad Dash to Chemical Utopia Is Making Lab Rats of Us All: “I’m a chemist, but I don’t make my living mixing chemicals for a multinational company. Most of my colleagues in lab coats don’t think much about the effects that their products have on the rest of the world. Very few end up devoting their lives to education and prevention as I have.” Weighing in at a slender 210 pages, Pick Your Poison is well written and chock-full of information, which is dispensed in an enjoyable format of 13 reader-friendly chapters. And although Ms. Rossol’s tone is wry and entertaining, her fact-filled treatise exposes the truth, among other things, about government labeling and product testing, including why terms such as “nontoxic,” “hypoallergenic,” and “U.S. Food and Drug Administration–approved” can be misleading. However, Ms. Rossol’s book will also provoke challenges from the chemical industry and other concerned parties, when she starts linking purported increased rates of cancer, autism, obesity, and asthma to chemical exposures.

Tales of Chemical Mishaps and Exploitation The trial-and-error history of product development has had many unfortunate episodes, during which unwitting workers and consumers have been victimized by ignorance and sometime pure avarice. The history of chemical mishaps is interesting and sets the stage for Ms. Rossol’s examination of the current state of how “our mad dash to chemical utopia is making lab rats of us all.” For example, the author focuses on the entrepreneurial use of the discovery of radium to show how “companies can profit by harming both consumers and their workers.” She falls back to 1917 and the U.S. Radium Corporation’s attempt at creating a novel prod-

uct by mixing radium with a little glue to make a paint that glowed in the dark. The company dubbed it “Undark” and decided to use the radium mixture to make watch and instrument dials that glowed in the dark. Big contracts with the military followed, and then ordinary citizens began clamoring for a wide array of glow-in-the-dark products. However, after 3 years of huge profits at U.S. Radium, it became clear that something was clearly wrong with the dial painters, who were mostly women. “The women were suffering from anemia, bone fractures, and necrosis of the jaw, a condition now known as ‘radium jaw.’ However, workers were told that the paints were nontoxic, and they believed their superiors…. U.S. Radium and other watch-dial companies began a campaign of disinformation and bogus tests,” writes Ms. Rossol. Readers are aware of worker-consumer exploitation tales; the big one of course is the asbestos-related illnesses such as mesothelioma. And while revisiting previous chemical-related in-

Bookmark Title: Pick Your Poison: How Our Mad Dash to Chemical Utopia Is Making Lab Rats of Us All Author: Monona Rossol Publisher: John Wiley & Sons Publication date: October 2015 Price: E-book, 210 pages

it made sense, and the public wanted these brave people compensated. However, it is impossible to draw a corollary between this type of toxic exposure and pancreatic or colon cancer. The sad reality is that the oncogenic process had most likely begun in the people who were eventually diagnosed with can-

Most of my colleagues in lab coats don’t think much about the effects that their products have on the rest of the world. Very few end up devoting their lives to education and prevention as I have. —Monona Rossol

might be related. Consider the American Cancer Society estimates that in the United States, 40.84% of us will develop cancer in our lifetime. That’s roughly two in every five.” Besides the muddy logic, she should remember that cancer is largely an age-related disease. The cancer incidence in Somalia may not be alarming, because the life expectancy is about 45 years. Ms. Rossol makes two more stabs at linking toxic exposure to cancer, with similar clumsy results. However, once she puts cancer aside, she picks up steam, and the book regains its footing.

Author at Her Best justices makes for compelling humaninterest stories, Ms. Rossol spends a tad too much time in the past, using phrases such as “What followed was the same sickening scenario that repeatedly plays out in almost every health workers dispute,” which gives her serious book an unnecessarily histrionic tone.

Chemical Exposure and Cancer Naturally, readers of The ASCO Post will be on the lookout for the inevitable link between chemical exposure and cancer. This is very difficult territory, because emotions often trump science, no more so than when the World Trade Centers were destroyed on 9/11. First responders and those working on the subsequent cleanup were exposed to thousands of tons of toxic debris, which consisted of more than 2,500 contaminants, many of which were known carcinogens. In 2006, several mainstream news publications began connecting the dots between first responders and cancer incidence. In the lay public’s mind,

cer. As Donald Berry, MD, the noted statistician from MD Anderson Cancer Center, put it in an article in The ASCO Post: “A person watching the cleanup on TV in Houston is about as likely to develop cancer as someone working at Ground Zero.” When Ms. Rossol ventures into this thorny territory, she drops the ball, and her discussions on cancer prove the weakest part of her otherwise solid book. For instance, she cited a study from the Centers for Disease Control and Prevention that monitored 212 chemicals appearing in the blood and serum of 2,500 human subjects. However, she never gives the results of the study. Instead she writes: “The data do not mean that these chemicals cause disease, only that people are carrying low levels of theses chemicals in their bodies.” In a leap of faith, she segues into a bankrupt line of reasoning. “Yet we humans are perhaps showing the effects without really understanding the cause…. The high rates of cancer just

The author is at her best when exploring the real dangers of common household chemicals and appliances, such as air filters. In this chapter, she runs down the list of air filters and exposes the bogus promises made about their health benefits. She also gives a good explanation about how the Obama administration has tried to balance public safety with corporate sovereignty. Namely, she turns to the Toxic Substances Act, which was essentially designed to protect corporate trade secrets. To his credit, President Obama has reformed the Act, making it more transparent and safer for the American public. Ms. Rossol does a good job elucidating complex policy issues and epidemiology, not an easy task. Besides a few missteps, Pick Your Poison is a sturdy, informative read. We live in a world filled with chemicals; it’s good to know what they do. This book is recommended for readers of The ASCO Post who read the small print on labels before buying and using a product. n

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Announcements

NCI Division of Cancer Control and Population Sciences Names Kathy J. Helzlsouer, MD, MHS, Associate Director

athy J. Helzlsouer, MD, MHS, has been named Associate Director and Chief Medical Officer in NCI’s Division of Cancer Control and Population Sciences. She will direct the Epidemiology and Genomics Research Program,

tional research. Dr. Helzlsouer is a recipient of the Martin D. Abeloff Award for Excellence in Public Health and Cancer Control for her service on the Maryland State Council on Cancer Control.

Dr. Helzlsouer completed her medical degree at the University of Pittsburgh School of Medicine, her internal medicine residency at the University of Virginia, and her medical oncology

fellowship at Johns Hopkins University. She also earned a Master of Health Science at Johns Hopkins University. Dr. Helzlsouer is board certified in medical oncology. n

Kathy J. Helzlsouer, MD, MHS

which includes the Office of the Associate Director, Clinical and Translational Epidemiology Branch, Environmental Epidemiology Branch, Genomic Epidemiology Branch, Methods and Technologies Branch, and Risk Factor Assessment Branch.

Valuable Blend of Skills Robert Croyle, PhD, Director of the Division, said, “Dr. Helzlsouer is a highly accomplished epidemiologist and clinician with a broad vision of cancer epidemiology, prevention, and control. She brings a valuable blend of medical, scientific, and leadership skills, which will be a strong asset for NCI and the Division of Cancer Control and Population Sciences.” Prior to joining NCI, she was a Professor in the Department of Epidemiology at the Johns Hopkins Bloomberg School of Public Health and, since 2004, she directed The Prevention & Research Center, which she established at Mercy Medical Center in Baltimore. Dr. Helzlsouer led a team of health-care specialists in cancer risk assessments, clinical research, and support programs for cancer patients and their families. Dr. Helzlsouer also is an associate editor of the Journal of the National Cancer Institute and a member of NCI’s PDQ® Screening and Prevention Editorial Board. Her research interests are focused in cancer etiology and prevention, cancer survivorship, and clinical and transla-

Send Us Your NEWS Write to editor@ASCOPost.com. All submissions will be considered for publication

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2015-2016 Oncology Meetings November Best of ASTRO November 13-14 • San Diego, CA For more information: www.astro.org/ Meetings-and-Events/2015-Best-ofASTRO/Index.aspx 2015 Oncologic Emergency Medicine Conference November 13-14 • Houston, Texas For more information: http:// www.mdanderson.org/educationand-research/education-andtraining/schools-and-programs/ cme-conference-management/ conferences/d114243-2015-oncologicemergency-medicine-conference.html 8th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved November 13-16 • Atlanta, Georgia For more information: http:// www.aacr.org/Meetings/Pages/ MeetingDetail.aspx?EventItemID=68#. Vba1EqTbJjq

11th Annual Personalized Medicine Conference November 18-19 • Boston, Massachusetts For more information: http://personalizedmedicine. partners.org/Education/PersonalizedMedicine-Conference/Program.aspx 12th International Congress of the Society for Melanoma Research November 18-21 • San Francisco, California For more information: www.melanomacongress.com/ 20th Annual Scientific Meeting of the Society for Neuro-Oncology November 19-22 • San Antonio, Texas For more information: www.soc-neuro-onc.org ESMO Symposium on Immuno-Oncology November 20-21 • Lausanne, Switzerland For more information: www.esmo.org

December

Joint Conference: Acupuncture, Oncology, and Fascia November 14 • Boston, Massachusetts For more information: http:// oshercenter.org/joint-conferenceacupuncture-oncology-fascia/ Society for Integrative Oncology 12th International Conference November 14-16 • Boston, Massachusetts For more information: http://www. integrativeonc.org/conference

9th European Colorectal Congress (ECC) December 1-4 • St. Gallen, Switzerland For more information: www.colorectalsurgery.eu

4th Cancer Epigenetics Conference November 16-17 • San Francisco, California For more information: www.gtcbio.com/conferences

Advances in Cancer ImmunotherapyTM December 4 • New Orleans, Louisiana For more information: www.sitcancer.org/sitc-meetings/ aci2015/la

Advances in Cancer ImmunotherapyTM November 18 • San Francisco, California For more information: www.sitcancer.org/sitc-meetings/ aci2015/casf

10th Annual Practical Course in Dermoscopy & Update on Malignant Melanoma 2015 December 4-6 • Scottsdale, Arizona For more information: https://ce.mayo.edu/dermatology/ node/2463

2015-2016

57th Annual ASH Meeting & Exposition December 5-8 • Orlando, Florida For more information: www.hematology.org/ San Antonio Breast Cancer Symposium December 8-12 • San Antonio, Texas For more information: www.sabcs.org American Society for Cell Biology Annual Meeting December 12-16 • San Diego, Callifornia For more information: http://ascb.org/2015meeting/

European Society for Medical Oncology Asia 2015 Congress December 18-21 • Singapore For more information: www.esmo.org/Conferences/ESMOAsia-2015-Congress

January 2016 4th AACR-IASLC International Joint Conference: Lung Cancer Translational Science January 4-7 • San Diego, California For more information: http://www.aacr. org/Meetings/Pages/MeetingDetail. aspx?EventItemID=74#.VbbijqTbJjo Genitourinary Cancers Symposium January 7-9 • San Francisco, CA For more information: http://gucasym.org Cancer Survivorship Symposium: Primary Care and Oncology Collaboration January 15-16 • San Francisco, California For more information: www.survivorsym.org/ Gastrointestinal Cancers Symposium January 21-23 • San Francisco, California For more information: http://gicasym.org

Personalized World Medicine Conference January 24-27 • Mountain View, California For more information: http://2016sv. pmwcintl.com/index.php 8th Immunotherapeutics & Immunomonitoring Conference January 25-26 • San Diego, California For more information: https:// www.gtcbio.com/conferences/ immunotherapeuticsimmunomonitoring-overview 3rd Annual University of Southern California Multidisciplinary Breast Cancer Symposium January 30 • Los Angeles, California For more information: http://keck. usc.edu/About/Administrative_ Offices/Office_of_Continuing_ Education/Courses/~/media/ Office%20of%20CME/FINAL_ brochure_2016%20breast%20 cancer.pdf

February 4th State of the Science Cancer Survivorship Research Symposium February 4 • Houston, Texas For more information: www.mdanderson.org/educationand-research/education-andtraining/schools-and-programs/ cme-conference-management/ conferences/cme/conferencemanagement-fourth-state-ofthe-science-cancer-survivorshipresearch-symposium.html 18th Annual Symposium on Anti-Angiogenesis and Immune Therapies for Cancer: Recent Advances and Future Directions in Basic and Clinical Cancer Research February 4-6 • San Diego, California For more information: www.imedex.com/antiangiogenesis-and-immunetherapies/ 10th AACR-JCA Joint Conference on Breakthroughs in Cancer Research: From Biology to Therapeutics February 16-20 • Maui, Hawaii For more information: www.aacr.org

continued on page 90

-ADVERTORIAL-

Innovation in squamous non-small cell lung cancer therapy There is an urgent need for effective treatment options to improve outcomes for patients with squamous non-small cell lung cancer (NSCLC). The importance of incremental improvements in squamous carcinoma therapies should not be underestimated. Despite the wealth of medical knowledge afforded by years of scientific research, lung cancer continues to have one of the highest incidence rates and the highest mortality rate of any cancer.1 In 2012, lung cancer was responsible for 1.825 million new cases and 1.59 million deaths worldwide.1 Despite changes in patient behaviors, such as reduced tobacco smoking, the number of people dying from this disease is expected to increase to 2.95 million over the next 20 years.1 Squamous NSCLC is an aggressive form of lung cancer that is hard to treat. NSCLC accounts for 85% to 90% of all lung cancers and comprises several subtypes.2 These subtypes include nonsquamous and squamous, which represent two-thirds and one-third of all NSCLC cases, respectively.2 Nonsquamous NSCLC can be further divided into different subtypes, including adenocarcinoma (approximately 40% of all NSCLC cases), large cell carcinoma (approximately 10% to 15% of all NSCLC cases), and other less common subtypes.2 Tumors in squamous NSCLC are often centrally located, making them more likely to invade larger blood vessels and bronchi, leading to potentially fatal complications.3,4 Squamous NSCLC tumors also grow quickly5,6 and commonly metastasize to other parts of the body.7 Furthermore, patients with squamous NSCLC are more likely to have a history of smoking and serious comorbidities, factors that make the disease more challenging to treat.8 In the 1st-line treatment of this disease, overall survival (OS) is approximately 8 to 10 months.9,10 There is, therefore, an urgent need for effective therapies that will

improve outcomes for patients with squamous NSCLC. In the 1st-line setting, progress in squamous NSCLC is lagging behind progress in nonsquamous NSCLC. For the majority of patients with advanced squamous NSCLC, platinum-based doublet chemotherapy remains the standard of care in 1st line,11,12 with an OS of approximately 8 to 10 months.9,10 This is in contrast to the progress made in nonsquamous NSCLC, where treatment advances—including therapies targeting oncogenic drivers—have extended survival.10,13,14 These oncogenic drivers— mutations in the epidermal growth factor receptor kinase and fusions involving anaplastic lymphoma kinase—rarely occur in squamous NSCLC, and as a result, few patients with squamous NSCLC can benefit from these treatments.15,16 Improved outcomes for patients with squamous NSCLC are needed. While chemotherapy produces a moderate survival improvement in patients with advanced squamous NSCLC, no regimen is associated with a clear survival benefit in this group of patients.9 It is likely that improved outcomes will continue to occur in modest, stepwise increments in unselected squamous NSCLC patients,13,14,17,18 although efforts to identify clinical or molecular signatures with potential predictive value for currently available treatments are continuing.19,20 Ongoing genomic studies may identify novel therapeutic targets.21 Current clinical trials testing immune checkpoint inhibitors and agents to improve supportive care20 may also provide new, individual therapeutic strategies that have the potential to enhance the effectiveness of currently available treatments. More treatment options are needed for patients with squamous NSCLC.

Visit SQUAMOUSNSCLC.COM to learn more. CONTRIBUTING AUTHORS: David R. Spigel, MD SCRI (Sarah Cannon Research Institute) Nashville, TN Philip Bonomi, MD Rush University Medical Center Chicago, IL Edward Kim, MD Levine Cancer Institute Carolinas HealthCare System Charlotte, NC

References 1. From Ferlay J., Soerjomataram I., Ervik M., Dikshit R., Eser S., Mathers C., Rebelo M., Parkin D.M., Forman D., Bray, F. GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer; 2013. Available from: http://globocan.iarc.fr, accessed on 23/02/2015. 2. American Cancer Society. What is non-small cell lung cancer? http://www.cancer.org/cancer/lungcancer-non-smallcell/detailedguide/non-small-cell-lung-cancer-whatis-non-small-cell-lung-cancer. Accessed December 4, 2014. 3. Rosado-de-Christenson ML, Templeton PA, Moran CA. Bronchogenic carcinoma: radiologic-pathologic correlation. Radiographics. 1994;14(2):429-446. 4. Nichols L, Saunders R, Knollmann FD. Causes of death of patients with lung cancer. Arch Pathol Lab Med. 2012;136(12):1552-1557. 5. Wilson DO, Ryan A, Fuhrman C, et al. Doubling times and CT screen-detected lung cancers in the Pittsburgh lung screening study. Am J Respir Crit Care Med. 2012;185(1):85-89. 6. Veronesi G, Maisonneuve P, Bellomi M, et al. Estimating overdiagnosis in low-dose computed tomography screening for lung cancer: a cohort study. Ann Intern Med. 2012;157(11):776-784. 7. Rubin E, Reisner HM, eds. Essentials of Rubin’s Pathology. 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2009:268-270. 8. Asmis TR, Ding K, Seymour L, et al. Age and comorbidity as independent prognostic factors in the treatment of non small-cell lung cancer: a review of National Cancer Institute of Canada Clinical Trials Group trials. J Clin Oncol. 2008;26(1):54-59. 9. Hoang T, Dahlberg SE, Schiller JH, Johnson DH. Does histology predict survival of advanced non-small cell lung cancer patients treated with platin-based chemotherapy? An analysis of the Eastern Cooperative Oncology Group Study E1594. Lung Cancer. 2013;81(1):47-52. 10. Ellis LM, Bernstein DS, Voest EE, et al. American Society of Clinical Oncology perspective: raising the bar for clinical trials by defining clinically meaningful outcomes. J Clin Oncol. 2014;32(12):12771280. 11. Referenced with permission from The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Small Cell Lung Cancer V.5.2015. © National Comprehensive Cancer Network, Inc 2015. All rights reserved. Accessed December 4, 2014. To view the most recent and complete version of the guidelines, go online to http://nccn.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN content are trademarks owned by the National Comprehensive Cancer Network, Inc. 12. Reck M, Popat S, Reinmuth N, et al. Metastatic non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2014;25(suppl 3):iii27-iii39. 13. Scagliotti GV, Parikh P, von Pawel J, et al. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol. 2008;26:3543-3551. 14. Morgensztern D, Waqar S, Subramanian J, Gao F, Govindan R. Improving survival for stage IV non-small cell lung cancer: a surveillance, epidemiology, and end results survey from 1990 to 2005. J Thorac Oncol. 2009;4:1524-1529. 15. Pao W, Girard N. New driver mutations in non-small-cell lung cancer. Lancet Oncol. 2011;12(2):175-180. 16. Perez-Moreno P, Brambilla E, Thomas R, Soria JC. Squamous cell carcinoma of the lung: molecular subtypes and therapeutic opportunities. Clin Cancer Res. 2012;18(9):2443-2451 17. Schiller JH, Harrington D, Belani CP, et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med. 2002;346:92-98. 18. Socinski MA, Bondarenko I, Karaseva NA, et al. Weekly nab-paclitaxel in combination with carboplatin versus solvent-based paclitaxel plus carboplatin as first-line therapy in patients with advanced non-small-cell lung cancer: final results of a phase III trial. J Clin Oncol. 2012;30:2055-2062. 19. Aydiner A, Yildiz I, Seyidova A. Clinical outcomes and prognostic factors associated with the response to erlotinib in non-small-cell lung cancer patients with unknown EGFR mutational status. Asian Pac J Cancer Prev. 2013;14:3255-3261. 20. Creelan BC. Update on immune checkpoint inhibitors in lung cancer. Cancer Control. 2014;21:80-89. 21. Cancer Genome Atlas Research Network. Comprehensive genomic characterization of squamous cell lung cancers. Nature. 2012;489:519-525.

GLOONC00049a APRIL 2015

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2015-2016 Oncology Meetings Meetings Calendar continued from page 88

The Biomarker Conference February 18-20 • San Diego, California For more information: www.mnmconferences.com/thebiomarker-conference-florida.html Multidisciplinary Head and Neck Cancer Symposium February 18-20 • Scottsdale, Arizona For more information: www.headandnecksymposium.org 25th Conference of the Asian Pacific Association for the Study of the Liver February 20-24 • Tokyo, Japan For more information: http://www.apasl2016.org 3rd Annual International Conference on Advances in Cancer Medical Research (ACMR 2016) February 22-23 • Singapore For more information: http://cancerresearch-conf.org/ Cancer Center Business Summit February 24-25 • Phoenix, Arizona For more information: http://cancerbusinesssummit.com

ASCO Quality Care Symposium February 26-27 • Phoenix, Arizona For more information: http://quality.asco.org Winship Cancer Institute 2016 Melanoma Conference February 27 • Atlanta, Georgia For more information: www.winshipmelanomaconference .com

2015-2016

March

Clinical Immunology Society Annual Meeting April 14-17 • Boston, Massachusetts For more information: www.clinimmsoc.org/education/ meetings/2016-annual-meeting

Society of Surgical Oncology Annual Cancer Symposia March 2-5 • Boston, Massachusetts For more information: www.surgonc.org 22nd Annual Blood-Brain Barrier and Neuro-oncology Meeting March 3-5 • Stevenson, Washington For more information: www.ohsu.edu/bbb 4th Annual UC San Diego Essentials and Advances in Apheresis Therapies March 3-5 • San Diego, California For more information: https://cme.ucsd.edu/apheresis/ 8th Annual Asian Oncology Summit March 3-6 • Kyoto, Japan For more information: www.asianoncologysummit.com Second Annual New Treatments in Oncology March 5-6 • Scottsdale, Arizona For more information: www.cvent.com/events/annualnew-treatments-in-oncologyconference-presented-by-cancertreatment-centers-of-america-/ event-summary-2fb116562f6447cca49 2c89064760b02.aspx ILCA School of Liver Cancer 2016 March 7-8 • Barcelona, Spain For more information: www.ilca-online.org/sitecore/ content/be-bruga/ilca-online/ School%20of%20Liver%20 Cancer/2016.aspx 3rd St. Gallen International Gastrointestinal Cancer Conference March 10-12 • St. Gallen, Switzerland For more information: www.oncoconferences.ch/dynasite .cfm?dsmid=500294

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 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 European Lung Cancer Conference April 13-16 • Geneva, Switzerland For more information: www.esmo.org/Conferences/ ELCC-2016-Lung-Cancer American Society for Colposcopy and Cervical Pathology (ASCCP) Annual Meeting April 13-16 • New Orleans, Louisiana For more information: www.asccp.org/2016annualmeeting

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 19th SIS World Congress on Breast Healthcare May 5-8 • Warsaw, Poland For more information: www.siscongress.org IMPAKT 2016 Breast Cancer Conference May 12-14 • Brussels, Belgium For more information: www.esmo.org/Conferences/IMPAKT2016-Breast-Cancer Lymphoma: State-of-the-Art in Biology Therapy, and Patient Care May 13-14 • New York, New York For more information: www.mskcc.org/event/lymphomastate-art-biology-therapy-andpatient-care

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Hematology Expert Review

Primary Diffuse Large B-Cell Lymphoma of the Central Nervous System Part 2: Assessment of Disease Burden and Prognosis in the Immunocompetent Host By Syed A. Abutalib, MD, and Rimas V. Lukas, MD

he ASCO Post is pleased to present Hematology Expert Review, an occasional feature that includes a case report detailing a particular hematologic condition followed by questions. Answers to each question appear on page 92 with expert commentary. In the October 25 issue of The ASCO Post, part 1 of a case report was published and focused on the approach to diagnosis of diffuse large Bcell lymphoma of the central nervous system in the immunocompetent host. Here, in part 2, the disease burden for this patient is assessed and the prognosis discussed. Part 3 of this case study, which will focus on therapeutic considerations and response assessment, will appear in an upcoming issue of The ASCO Post. Summary of Case Study: A 70-year-old man presented with complaints of newly developed neurologic symptoms and atypical behaviors over the course of 2 weeks. He reported no headaches or visual symptoms and is otherwise healthy, with no medical or surgical history. The neurologic exam was normal. The complete blood cell count and complete metabolic profile were also normal. The hepatitis panel and human immunodeficiency virus (HIV) test were negative.

These constellations of new symptoms led to brain imaging. Magnetic resonance imaging (MRI) with contrast demonstrated a homogeneously enhancing lesion in the left frontal lobe. A similar, smaller, noncontiguous lesion was also noted in the right frontal lobe (Fig. 1). A diagnosis of primary central nervous system (CNS) lymphoma was made and confirmed by immediate stereotactic biopsy. Following successful biopsy and staging, steroids were started to ameliorate the current symptomatology.

Question 1 What is next best step in the management of this patient? A. Testicular ultrasound B. Lumbar puncture C. Ophthalmoscopy/slit lamp examination

Question 2 Which statement is true about the ocular manifestation of primary CNS lymphoma? A. Vitrectomy specimens are highly sensitive for diagnosis. B. Ocular lymphoma can appear as widening of the optic nerve. C. Visual symptoms are always present in patients with ocular involvement.

GUEST EDITORS

Syed A. Abutalib, MD

Syed A. Abutalib, MD, Assistant Director, Hematology & Bone Marrow Transplantation Service, Cancer Treatment Centers of America, Zion, Illinois Continued Case Study: The patient underwent staging with an ophthalmologic slit lamp examination, PET-CT scan of the body, and cerebrospinal fluid studies. All of these tests were unremarkable. Serum LDH was elevated at 340 U/L (normal range, 116–245 U/L). Following stereotactic brain biopsy and staging, the patient was started on steroids. He quickly returned to his premorbid baseline, with a Karnofsky performance status of 100%.

Rimas V. Lukas, MD

Rimas V. Lukas, MD, Director of Medical Neuro-Oncology, Associate Professor, Department of Neurology, University of Chicago

Question 3 Which prognostic variables are common to both the International Extranodal Lymphoma Study Group and Memorial Sloan-Kettering Cancer Center prognostic models? A. Age and involvement of deep brain structures B. Age and performance status C. Serum LDH and cerebrospinal fluid protein levels See page 92 for answers.

Fig. 1: (A) This axial T1-weighted postcontrast brain MRI image shows a homogeneously enhancing lesion in the left frontal lobe. A smaller similar appearing lesion (not shown) was also present in the right frontal lobe of the brain. (B) Axial diffusion-weighted imaging sequence demonstrates restricted diffusion throughout the area of the enhancing lesion, which was confirmed on the apparent diffusion coefficient sequence (not shown).

The ASCO Post | NOVEMBER 10, 2015

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Hematology Expert Review

Primary Diffuse Large B-Cell Lymphoma of the Central Nervous System Part 2: Assessment of Disease Burden and Prognosis in the Immunocompetent Host Question 1: What is next best step in the management of this patient? Correct Answer: C. Ophthalmoscopy/slit lamp examination.

Expert Perspective Ophthalmic involvement should be sought by noninvasive procedures such as slit lamp examination and ophthal-

moscopy and abnormal findings must be confirmed by invasive procedures, including vitreous biopsy, subretinal aspiration, and/or chorioretinal biopsy.1 Patients treated with steroids prior to staging can have false-negative vitrectomy results. In patients with HIV/AIDS, other important infectious causes for intraocular lesions must also

Table 1: Baseline Evaluation in the Immunocompetent Host With Primary CNS Lymphoma* Testing

Comments

Pathology

• Report by histopathologist with expertise in neuropathology, ocular pathology, and/or hematopathology and access to specialist in neuropathology, ocular pathology, and/or hematopathology • Immunophenotyping and where appropriate molecular testing

Clinical

• Complete medical and neurologic examination • Dilated eye examination, including slit lamp examination and fundoscopy • Fluorescein angiography may be helpful to confirm lymphomatous involvement of the retina • Color photography of the posterior pole of the eye should be obtained in those patients with ocular involvement to follow and document response to therapy • Record prognostic factors • Serial evaluation of cognitive function • It is important to record corticosteroid dosing at baseline and at each evaluation

Laboratory

Imaging

• HIV serology • Complete blood cell count, complete metabolic profile, and serum LDH • Coagulation profile prior to biopsy • If ocular involvement is suspected, vitreous biopsy ± chorioretinal biopsy, immunohistochemistry, IgH-PCR • Cerebrospinal fluid cytology, flow cytometry, IgH-PCR (authors’ practice to perform lumbar puncture in non-HIV patients with primary CNS lymphoma is individualized) a) Flow cytometry is more sensitive than routine cytology to assay for occult leptomeningeal lymphoma b) Cerebrospinal fluid cytology (if done) should be sampled before or 1 week after stereotactic biopsy to avoid falsepositive results c) Minimum of 3 mL and ideally 10 mL should be sent for cytologic evaluation • Contrast-enhanced cranial MRI scan (CT scan if MRI contraindicated) • CT of chest, abdomen and pelvis can be replaced by PET‑CT scan¶ • Bone marrow aspirate and trephine biopsy • Testicular ultrasound may be considered in older men to exclude an occult testicular lymphoma metastatic to the brain. In cases with a normal exam and a negative PET-CT scan, its utility is minimal. • Involvement of the spinal cord parenchyma is sufficiently rare in that gadolinium-enhanced MRI of the total spine is warranted only in patients with spinal symptoms.

* IgH-PCR = polymerase chain reaction for detection of immunoglobulin heavy chain rearrangements. ¶ = PET-CT is preferred for staging of FDG-avid lymphomas over CT scans (The Lugano Classification). Adapted from the International Primary CNS Lymphoma Collaborative Group (Abrey LE, et al: J Clin Oncol 23:5034-5043, 2005).

be considered. Our patient tested negative for HIV infection, so any type of intraocular lesions should be followed by a confirmatory biopsy. At this time, management of patients with primary CNS lymphoma with or without ocular involvement is similar. However, for patients with ocular involvement, ocular restaging has substantial importance. Testicular ultrasound can also be considered in male patients, as the testes represent a relatively immunoprivileged site where lymphoma may be detected.2 However, data regarding the utility of testicular ultrasound in patients with a negative PET-CT scan are limited. A large, single-institution case series did not note any additional diagnoses of extra-CNS involvement in male patients undergoing testicular ultrasound in the setting of a negative PET-CT scan3 (Table 1). Given the tendency of CNS diffuse large B-cell lymphoma to involve the leptomeninges, a lumbar puncture should be considered, especially in patients with a history of extracranial diffuse large B-cell lymphoma. The utility of cerebrospinal fluid analyses for staging in patients with histologically

diagnosed primary CNS lymphoma is not well defined (Table 1). Results of cerebrospinal fluid protein levels influence one of the two prognostic models (discussed later), but they do not alter the therapeutics for primary CNS lymphoma.4 It is important to note that cerebrospinal fluid findings largely underestimate the rate of leptomeningeal seeding in primary CNS lymphoma.5-8 Obstructive hydrocephalus, large posterior fossa lesions, or substantial mass effects from tumor are contraindications for lumbar puncture. Question 2: Which statement is true about the ocular manifestation of primary central nervous system lymphoma? Correct Answer: B. Ocular lymphoma can appear as widening of the optic nerve.

Expert Perspective Ocular primary CNS lymphoma may occur prior to detection of cerebral involvement. Of patients with isolated ocular lymphoma, 50% to 80% eventually develop cerebral lymphoma, at a mean of approximately 23 months continued on page 98

Table 2: Pros and Cons of Prognostic Models for Patients With Primary Central Nervous System Lymphoma IELSG model13 Analysis period: 1980–1999 (N = 105)

IELSG model13 Analysis period: 1980–1999 (N = 105)

Pros • Multicenter (23 centers) study • Only immunocompetent patients

• Model validated using data collected from two to three prospective Radiation Therapy Oncology Group primary CNS lymphoma trials • Simple and widespread applicability • Failure to confirm any variable other than age and Karnofsky performance status on multivariate testing • Only immunocompetent patients

Cons • Median follow-up of patients was only 2 years, and no patient had follow-up beyond 3 years • Variables are not uniformly obtained or reported • Retrospective study • Use of cerebrospinal fluid variables could introduce a bias, because they can be assessed in only a selected and, possibly, favorable subgroup of patients

• Large, single-institution series • Retrospective study • Inherent selection bias resulting in better-than-usual outcomes

IELSG = International Extranodal Lymphoma Study Group; MSKCC = Memorial Sloan-Kettering Cancer Center.

If she has ovarian cancer

TEST FOR BRCA

If indicated* TREAT WITH LYNPARZA

Help her continue the ﬁght with the ﬁrst approved PARP inhibitor1

* INDICATION LYNPARZA is indicated as monotherapy in patients with deleterious or suspected deleterious germline BRCA mutated (as detected by an FDA-approved test) advanced ovarian cancer who have been treated with three or more prior lines of chemotherapy. The indication is approved under accelerated approval based on objective response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

SELECT SAFETY INFORMATION Myelodysplastic syndrome/Acute Myeloid Leukemia (MDS/AML) have been conﬁrmed in 2% of patients enrolled in both a single arm monotherapy trial (6 out of 298) and a randomized placebo controlled trial (3 out of 136). Overall, MDS/AML were reported in <1% of patients (22 out of 2,618) treated with LYNPARZA. The majority of MDS/AML cases were fatal (17 out of 22) and the duration of therapy in patients who developed secondary MDS/AML varied from <6 months to >2 years. Monitor complete blood count testing at baseline and monthly thereafter. Do not start LYNPARZA until patients have recovered from hematological toxicity caused by previous chemotherapy (≤CTCAE Grade 1). For prolonged hematological toxicities, interrupt LYNPARZA and monitor blood counts weekly until recovery. If the levels have not recovered to CTCAE Grade 1 or less after 4 weeks, refer the patient to a hematologist for further investigations, including bone marrow analysis and blood sample for cytogenetics. If MDS/AML is conﬁrmed, discontinue LYNPARZA.

Please see the following pages for additional Safety Information and Brief Summary of the full Prescribing Information.

LYNPARZA demonstrated an objective response rate of 34% in patients with BRCA-mutated advanced ovarian cancer who had been treated with 3 or more lines of chemotherapy1 The efficacy of LYNPARZA was investigated in a single-arm study of patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm) advanced cancer. A total of 137 patients with measurable gBRCAm-associated ovarian cancer treated with three or more prior lines of chemotherapy were enrolled. Efficacy was based on objective response rate and duration of response.1 Objective response rate was defined as a ≥30% reduction in target lesion size, according to RECIST criteria, as measured by CT or MRI and confirmed at least 4 weeks later.2

OBJECTIVE RESPONSE RATE (95% CI: 26, 42)

PERCENTAGE OF PATIENTS WHO RESPONDED TO THERAPY

• The rate of partial response was 32% and the rate of complete response was 2%1

7.9

MEDIAN DURATION OF RESPONSE

MONTHS (95% CI: 5.6, 9.6)

Please see the following pages for additional Safety Information and Brief Summary of the full Prescribing Information.

Warnings and Precautions Myelodysplastic syndrome/Acute Myeloid Leukemia Myelodysplastic syndrome/Acute Myeloid Leukemia (MDS/AML) have been confirmed in 6 out of 298 (2%) patients enrolled in a single arm trial of LYNPARZA monotherapy, in patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm) advanced cancers. In a randomized placebo controlled trial, MDS/AML occurred in 3 out of 136 (2%) patients with advanced ovarian cancer treated with LYNPARZA. Overall, MDS/AML were reported in 22 of 2,618 (<1%) patients treated with LYNPARZA. The majority of MDS/AML cases (17 of 22 cases) were fatal, and the duration of therapy with LYNPARZA in patients who developed secondary MDS/cancer-therapy related AML varied from <6 months to >2 years. All patients had previous chemotherapy with platinum agents and/or other DNA damaging agents. Monitor complete blood count testing at baseline and monthly thereafter. Do not start LYNPARZA until patients have recovered from hematological toxicity caused by previous chemotherapy (≤CTCAE Grade 1). For prolonged hematological toxicities, interrupt LYNPARZA and monitor blood counts weekly until recovery. If the levels have not recovered to CTCAE Grade 1 or less after 4 weeks, refer the patient to a hematologist for further investigations, including bone marrow analysis and blood sample for cytogenetics. If MDS/AML is confirmed, discontinue LYNPARZA. Pneumonitis Pneumonitis, including fatal cases, occurred in <1% of patients treated with LYNPARZA. If patients present with new or worsening respiratory symptoms such as dyspnea, fever, cough, wheezing, or a radiological abnormality occurs, interrupt treatment with LYNPARZA and initiate prompt investigation. If pneumonitis is confirmed, discontinue LYNPARZA. Embryo-Fetal Toxicity LYNPARZA can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. Olaparib was teratogenic and caused embryo-fetal toxicity in rats at exposures below those in patients receiving the recommended human dose of 400 mg twice daily. If the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus. Advise females of reproductive potential to avoid becoming pregnant while taking LYNPARZA. If contraceptive methods are being considered, use effective contraception during treatment and for at least one month after receiving the last dose of LYNPARZA.

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

Safety and tolerability of LYNPARZA • LYNPARZA 400 mg twice daily was evaluated as monotherapy in 223 patients with BRCA-mutated advanced ovarian cancer who had 3 or more prior lines of chemotherapy in 6 clinical trials1

Adverse Reactions Reported in ≥20% of Patients1

LYNPARZA 400 MG TWICE DAILY n=223 CTCAE GRADES 1-4 (%)

CTCAE GRADES 3-4 (%)

Abdominal pain/discomfort

Decreased appetite

Nausea

Vomiting

Diarrhea

Dyspepsia

Arthralgia/musculoskeletal pain

Myalgia

BLOOD AND LYMPHATIC DISORDERS

Anemia GASTROINTESTINAL DISORDERS

GENERAL DISORDERS

Fatigue/asthenia INFECTIONS AND INFESTATIONS

Nasopharyngitis/URI MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS

Please see accompanying Brief Summary of Full Prescribing Information. References: 1. LYNPARZA [package insert]. Wilmington, DE: AstraZeneca; 2014. 2. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228-247.

Laboratory Abnormalities

LYNPARZA 400 MG TWICE DAILY n=223 CTCAE GRADES 1-4 (%)

CTCAE GRADES 3-4 (%)

Decrease in hemoglobin (anemia)

Decrease in absolute neutrophil count (neutropenia)

Decrease in platelets (thrombocytopenia)

Decrease in lymphocytes (lymphopenia)

Mean corpuscular volume elevation

Increase in creatininea

Patients were allowed to enter clinical studies with laboratory values of CTCAE Grade 1.

The safety and tolerability of LYNPARZA were also evaluated in a randomized, placebo-controlled study1 â&#x20AC;˘ LYNPARZA 400 mg twice daily was evaluated as maintenance monotherapy in a randomized, placebo-controlled clinical trial of 96 patients with germline BRCA-mutated platinum-sensitive ovarian cancer who had received 2 or more lines of platinum-containing chemotherapy 1 â&#x20AC;˘ Frequently occurring adverse reactions and lab abnormalities were consistent with those seen in the 6 clinical trials, with the addition of back pain, headache, cough, rash, and dysgeusia 1

To learn more, including how to order LYNPARZA, please visit www.lynparza.com

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Hematology Expert Review DLBCL of the CNS continued from page 92

after ocular diagnosis, making isolated primary intraocular lymphoma an extremely rare entity.1,9 Concurrent ocular lymphoma with primary CNS lymphoma may present in 30% of the patients.10 Visual symptomatology may often be vague and can include floaters, visual

blurring, or segmental visual loss due to retinal detachment from subretinal lymphoma deposits. Additionally, a subset of patients (≤ 8%) without visual symptomatology and primary CNS lymphoma may have occult ocular involvement.10,11 On examination, ocular lymphoma can appear as widening of the optic nerve, presence of vitreous

debris, or choroidal sclera thickening. Diagnosis is achieved by performing vitreous biopsy, preferably combined with a subretinal aspirate or chorioretinal biopsy. The vitrectomy specimens are notoriously paucicellular and difficult to interpret, so diagnostic failure rates up to 30% have been reported.1,9 These specimens, which should be sent

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LYNPARZA™ (olaparib) capsules, for oral use Brief Summary of Prescribing Information. For complete prescribing information consult official package insert. INDICATIONS AND USAGE Treatment of gBRCA-mutated advanced ovarian cancer Lynparza is indicated as monotherapy in patients with deleterious or suspected deleterious germline BRCA mutated (as detected by an FDA-approved test) advanced ovarian cancer who have been treated with three or more prior lines of chemotherapy. The indication is approved under accelerated approval based on objective response rate and duration of response [see Clinical Studies (14) in the full Prescribing Information]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. DOSAGE AND ADMINISTRATION Patient Selection Select patients for the treatment of advanced ovarian cancer with Lynparza based on the presence of deleterious or suspected deleterious germline BRCA-mutations [see Indications and Usage (1) and Clinical Studies (14) in the full Prescribing Information]. Information on FDA-approved test for the detection of BRCA-mutations is available at http://www.fda.gov/companiondiagnostics. Recommended Dosing The recommended dose of Lynparza is 400 mg (eight 50 mg capsules) taken twice daily, for a total daily dose of 800 mg. Continue treatment until disease progression or unacceptable toxicity. If a patient misses a dose of Lynparza, instruct patients to take their next dose at its scheduled time. Swallow capsule whole. Do not chew, dissolve, or open capsule. Do not take capsules which appear deformed or show evidence of leakage [see How Supplied/Storage and Handling (16.2) in the full Prescribing Information]. Dose Adjustments for Adverse Reactions To manage adverse reactions, consider dose interruption of treatment or dose reduction. The recommended dose reduction is to 200 mg (four 50 mg capsules) taken twice daily, for a total daily dose of 400 mg. If a further final dose reduction is required, then reduce to 100 mg (two 50 mg capsules) taken twice daily, for a total daily dose of 200 mg. Dose Modifications for Use with CYP3A Inhibitors Avoid concomitant use of strong and moderate CYP3A inhibitors and consider alternative agents with less CYP3A inhibition. If the inhibitor cannot be avoided, reduce the Lynparza dose to 150 mg (three 50 mg capsules) taken twice daily for a strong CYP3A inhibitor or 200 mg (four 50 mg capsules) taken twice daily for a moderate CYP3A inhibitor [see Drug Interactions (7.2) in the full Prescribing Information]. CONTRAINDICATIONS None WARNINGS AND PRECAUTIONS Myelodysplastic syndrome/Acute Myeloid Leukemia Myelodysplastic syndrome/Acute Myeloid Leukemia (MDS/AML) have been confirmed in 6 out of 298 (2%) patients enrolled in a single arm trial of Lynparza monotherapy, in patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm) advanced cancers. In a randomized placebo controlled trial, MDS/AML occurred in 3 out of 136 (2%) patients with advanced ovarian cancer treated with Lynparza. Overall, MDS/AML were reported in 22 of 2,618 (<1%) patients treated with Lynparza. The majority of MDS/AML cases (17 of 22 cases) were fatal, and the duration of therapy with Lynparza in patients who developed secondary MDS/cancer-therapy related AML varied from <6 months to >2 years. All patients had previous chemotherapy with platinum agents and/or other DNA damaging agents. Monitor complete blood count testing at baseline and monthly thereafter. Do not start Lynparza until patients have recovered from hematological toxicity caused by previous chemotherapy ( CTCAE Grade 1). For prolonged hematological toxicities, interrupt Lynparza and monitor blood counts weekly until recovery. If the levels have not recovered to CTCAE Grade 1 or less after 4 weeks, refer the patient to a hematologist for further investigations, including bone marrow analysis and blood sample for cytogenetics. If MDS/AML is confirmed, discontinue Lynparza. Pneumonitis Pneumonitis, including fatal cases, occurred in <1% of patients treated with Lynparza. If patients present with new or worsening respiratory symptoms such as dyspnea, fever, cough, wheezing, or a radiological abnormality occurs, interrupt treatment with Lynparza and initiate prompt investigation. If pneumonitis is confirmed, discontinue Lynparza. Embryo-Fetal Toxicity Lynparza can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. Olaparib was teratogenic and caused embryo-fetal toxicity in rats at exposures below those in patients receiving the recommended human dose of 400 mg twice daily. If the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus [see Use in Specific Populations (8.1) in the full Prescribing Information]. Advise females of reproductive potential to avoid becoming pregnant while taking Lynparza. If contraceptive methods are being considered, use effective contraception during treatment and for at least one month after receiving the last dose of Lynparza [see Use in Specific Populations (8.6) in the full Prescribing Information]. ADVERSE REACTIONS The following adverse reactions are discussed elsewhere in the labeling: • Myelodysplastic syndrome/Acute Myeloid Leukemia [see Warnings and Precautions (5.1) in the full Prescribing Information] • Pneumonitis [see Warnings and Precautions (5.2) in the full Prescribing Information]

rapidly in cytofixatives, are examined for morphology, immunophenotype and rearrangements of the immunoglobulin, and/or TCR gene using polymerase chain reaction (IgH and/or TCR-PCR, respectively12), depending on the amount of material available for examination. In patients with visible subretinal deposits, additional chorio-

Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reﬂect the rates observed in practice. Lynparza 400 mg twice daily as monotherapy, has been studied in 300 patients with gBRCA-mutated advanced ovarian cancer, and 223 of these patients had received 3 or more prior lines of chemotherapy. In the 223 patients with gBRCA-mutated ovarian cancer who received 3 or more prior lines of chemotherapy (including 137 patients in Study 1 with measureable disease) [see Clinical Studies (14) in the full Prescribing Information] adverse reactions led to dose interruption in 40% of patients, dose reduction in 4%, and discontinuation in 7%. There were 8 (4%) patients with adverse reactions leading to death, two were attributed to acute leukemia, and one each was attributed to COPD, cerebrovascular accident, intestinal perforation, pulmonary embolism, sepsis, and suture rupture. Table 1 presents the frequency of adverse reactions reported in 20% of 223 patients (in 6 studies) with gBRCA-mutated advanced ovarian cancer who had received 3 or more prior lines of chemotherapy who were treated with Lynparza 400 mg twice daily. The median exposure to Lynparza in these patients was 158 days. Table 1 Adverse Reactions Reported in 20% of Patients with gBRCA-Mutated Advanced Ovarian Cancer Receiving Lynparza Adverse Reaction Blood and Lymphatic disorders Anemia Gastrointestinal disorders Abdominal pain/discomfort Decreased appetite Nausea Vomiting Diarrhea Dyspepsia General disorders Fatigue/asthenia Infections and infestations Nasopharyngitis/URI Musculoskeletal and Connective Tissue disorders Arthralgia/musculoskeletal pain Myalgia

3 or more lines of prior chemotherapy Grades 1-4 Grades 3-4 N=223 N=223 % % 34

43 22 64 43 31 25

8 1 3 4 1 0

21 22

0 0

Table 2 presents the frequency of abnormal laboratory ﬁndings in the 223 patients with gBRCA-mutated advanced ovarian cancer who had received three or more prior lines of chemotherapy receiving Lynparza 400 mg twice daily. Table 2 Laboratory Abnormalities Reported in Patients with gBRCA-Mutated Advanced Ovarian Cancer Receiving Lynparza Laboratory Parameter* 3 or more lines of prior chemotherapy Grades 1-4 Grades 3-4 N=223 N=223 % % Decrease in hemoglobin (anemia) 90 15 Decrease in absolute neutrophil count 25 7 (neutropenia) Decrease in platelets (thrombocytopenia) 30 3 Decrease in lymphocytes (lymphopenia) 56 17 Mean corpuscular volume elevation 57 Increase in creatinine* 30 2 * Patients were allowed to enter clinical studies with laboratory values of CTCAE Grade 1.

The following adverse reactions and laboratory abnormalities have been identified in 10 to <20% of the 223 patients receiving Lynparza and not included in the table: cough, constipation, dysgeusia, peripheral edema, back pain, dizziness, headache, urinary tract infection, dyspnea, and rash. The following adverse reactions and laboratory abnormalities have been identified in 1 to <10% of the 223 patients receiving Lynparza and not included in the table: leukopenia, stomatitis, peripheral neuropathy, pyrexia, hypomagnesemia, hyperglycemia, anxiety, depression, insomnia, dysuria, urinary incontinence, vulvovaginal disorder, dry skin/ eczema, pruritis, hypertension, venous thrombosis (including pulmonary embolism), and hot flush. Table 3 presents adverse reactions reported in 20% of patients from a randomized trial of Lynparza 400 mg twice daily as maintenance monotherapy compared to placebo in patients with platinum sensitive, relapsed, high-grade serous ovarian cancer following treatment with 2 or more platinum-containing regimens. Table 4 presents the laboratory abnormalities in patients from this randomized trial. Of the 96 patients with gBRCAmutation, 53 received Lynparza, and 43 received placebo. The median duration on treatment with Lynparza was 11.1 months for patients with a gBRCA mutation compared to 4.4 months for patients with gBRCA mutation on placebo. Adverse reactions led to dose interruptions in 26% of those receiving Lynparza and 7% of those receiving placebo; dose reductions in 15% of Lynparza and 5% of placebo patients; and discontinuation in 9% of Lynparza and 0% in placebo patients. One (2%) patient on Lynparza died as a result of an adverse reaction.

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Hematology Expert Review

retinal biopsies and aspirates may improve diagnostic accuracy.

Correct Answer: B. Age and performance status.

Question 3: Which prognostic variables are common to both the International Extranodal Lymphoma Study Group (IELSG) and Memorial SloanKettering Cancer Center (MSKCC) prognostic models?

Expert Perspective Currently, two different prognostic systems are employed in patients with newly diagnosed primary CNS lymphoma: the IELSG and the MSKCC models.13,14 The IELSG prognostication

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LYNPARZATM (olaparib) capsules Table 3 Adverse Reactions Reported in 20% of Patients with gBRCA-Mutated Ovarian Cancer in the Randomized Trial Adverse Reactions Lynparza Placebo N=53 N=43 Grades 1-4 Grades 3-4 Grades 1-4 Grades 3-4 % % % % Blood and Lymphatic disorders Anemia 25 4 7 2 Gastrointestinal disorders Abdominal pain/discomfort 47 0 58 2 Decreased appetite 25 0 14 0 Nausea 75 2 37 0 Vomiting 32 4 9 0 Diarrhea 28 4 21 2 Dyspepsia 25 0 14 0 Dysgeusia 21 0 9 0 General disorders Fatigue (including asthenia, lethargy) 68 6 53 2 Infections and infestations Nasopharyngitis/Pharyngitis/URI 43 0 16 0 Musculoskeletal and Connective tissue disorders Arthralgia/Musculoskeletal pain 32 4 21 0 Myalgia 25 2 12 0 Back pain 25 6 21 0 Nervous system disorder Headache 25 0 19 2 Respiratory, Thoracic, Mediastinal disorders Cough 21 0 14 0 Skin and Subcutaneous Tissue Dermatitis/Rash 25 0 14 0 Table 4 Laboratory Abnormalities in Patients with gBRCA-Mutated Ovarian Cancer in the Randomized Trial Laboratory parameter* Lynparza Placebo N=53 N=43 Grades 1-4 Grades 3-4 Grades 1-4 Grades 3-4 % % % % Decrease in hemoglobin 85 8 58 2 Decrease in absolute neutrophil count 32 8 23 0 Decrease in platelets 26 6 19 0 Mean corpuscular volume elevation 85 44 Increase in creatinine* 26 0 5 0 * Patients were allowed to enter clinical studies with laboratory values of CTCAE Grade 1.

DRUG INTERACTIONS Olaparib is primarily metabolized by CYP3A. Anticancer Agents Clinical studies of Lynparza in combination with other myelosuppressive anticancer agents, including DNA damaging agents, indicate a potentiation and prolongation of myelosuppressive toxicity. Drugs that may Increase Olaparib Plasma Concentrations In patients (N=57), co-administration of itraconazole, a strong CYP3A inhibitor, increased AUC of olaparib by 2.7-fold. A moderate CYP3A inhibitor, fluconazole, is predicted to increase the AUC of olaparib by 2-fold. Avoid concomitant use of strong CYP3A inhibitors (e.g., itraconazole, telithromycin, clarithromycin, ketoconazole, voriconazole, nefazodone, posaconazole, ritinovir, lopinavir/ ritinovir, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) and moderate CYP3A inhibitors (e.g., amprenavir, aprepitant, atazanavir, ciprofloxacin, crizotinib, darunavir/ ritonavir, diltiazem, erythromycin, fluconazole, fosamprenavir, imatinib, verapamil). If the strong or moderate CYP3A inhibitors must be co-administered, reduce the dose of Lynparza [see Dosage and Administration (2.4) in the full Prescribing Information]. Avoid grapefruit and Seville oranges during Lynparza treatment [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3) in the full Prescribing Information]. Drugs that may Decrease Olaparib Plasma Concentrations In patients (N=22), co-administration of rifampicin, a strong CYP3A inducer, decreased AUC of olaparib by 87%. A moderate CYP3A inducer, efavirenz, is predicted to decrease the AUC of olaparib by 50-60%. Avoid concomitant use of strong CYP3A inducers (e.g., phenytoin, rifampicin, carbamazepine, St. John’s Wort) and moderate CYP3A4 inducers (e.g., bosentan, efavirenz, etravirine, modafinil, nafcillin). If a moderate CYP3A inducer cannot be avoided, be aware of a potential for decreased efficacy of Lynparza [see Clinical Pharmacology (12.3) in the full Prescribing Information]. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category D [see Warnings and Precautions (5.3) in the full Prescribing Information] Risk summary Lynparza can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. Olaparib was teratogenic and caused embryo-fetal toxicity in rats at exposures below those in patients receiving the recommended human dose of 400 mg twice daily. If this drug is used during pregnancy, or if a patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for loss of the pregnancy. Animal Data In a fertility and early embryonic development study in female rats, olaparib was administered orally for 14 days before mating through to day 6 of pregnancy, which

system has five prognostic variables: age > 60, Eastern Cooperative Oncology Group (ECOG) performance status of between 2 and 4, elevated serum LDH, elevated cerebrospinal fluid total protein concentration (cutoff for normal cerebrospinal fluid protein concentration is 45 mg/dL in patients ≤ 60 years old and 60 mg/dL in patients more

2 resulted in increased post-implantation loss at a dose level of 15 mg/kg/day (with maternal systemic exposures approximately 11% of the human exposure (AUC0-24h) at the recommended dose). In an embryo-fetal development study, pregnant rats received oral doses of 0.05 and 0.5 mg/kg/day olaparib during the period of organogenesis. A dose of 0.5 mg/kg/day (with maternal systemic exposures approximately 0.3% of human exposure (AUC0-24h) at the recommended dose) caused embryo-fetal toxicities including increased post-implantation loss and major malformations of the eyes (anophthalmia, microphthalmia), vertebrae/ribs (extra rib or ossification center; fused or absent neural arches, ribs, and sternebrae), skull (fused exoccipital) and diaphragm (hernia). Additional abnormalities or variants included incomplete or absent ossification (vertebrae/sternebrae, ribs, limbs) and other findings in the vertebrae/sternebrae, pelvic girdle, lung, thymus, liver, ureter and umbilical artery. Some findings noted above in the eyes, ribs and ureter were observed at a dose of 0.05 mg/kg/day olaparib at lower incidence. Nursing Mothers It is not known whether olaparib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from olaparib, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use The safety and efficacy of Lynparza has not been established in pediatric patients. Geriatric Use In clinical studies of Lynparza enrolling 735 patients with advanced solid tumors [the majority (69%) of whom had ovarian cancer] who received Lynparza 400 mg twice daily as monotherapy, 148 (20%) of patients were aged 65 years. The safety profile was similar irrespective of age with the exception of AEs of CTCAE 3 which were reported more frequently in patients aged 65 years (53.4%) than those <65 years (43.4%). No individual adverse event or System Organ Class accounted for this observed difference. Females of Reproductive Potential Lynparza can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1) in the full Prescribing Information]. Advise female patients of reproductive potential to avoid pregnancy while taking Lynparza. If contraceptive methods are being considered, use highly effective contraception during treatment with Lynparza and for at least one month following the last dose of Lynparza. Instruct patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking Lynparza. Hepatic Impairment The effect of hepatic impairment on exposure to Lynparza has not been studied. Patients with bilirubin >1.5 X ULN and AST/ALT 2.5 X ULN ( 5 X ULN in the presence of liver metastases) were excluded from Lynparza clinical trials. There are no data in patients with baseline hepatic impairment (serum bilirubin >1.5 X ULN) [see Clinical Pharmacology (12.3) in the full Prescribing Information]. Renal Impairment Based on preliminary data, a 1.5 fold increase in mean exposure (AUC) was observed in patients with mild renal impairment (CLcr = 50-80 mL/min) compared to patients with normal renal function (CLcr >80 mL/min). No dose adjustment to the starting dose is required in patients with CLcr of 50 to 80 mL/min, but patients should be monitored closely for toxicity. There are no data in patients with moderate or severe renal impairment (CLcr <50 mL/min) or patients on dialysis [see Clinical Pharmacology (12.3) in the full Prescribing Information]. OVERDOSAGE There is no specific treatment in the event of Lynparza overdose, and symptoms of overdose are not established. In the event of an overdose, physicians should follow general supportive measures and should treat symptomatically. 17 PATIENT COUNSELING INFORMATION SEE FDA-APPROVED PATIENT LABELING (MEDICATION GUIDE) • Dosing Instructions: Inform patients on how to take Lynparza [see Dosage and Administration (2.1) in the full Prescribing Information]. Lynparza should be taken twice daily. Instruct patients that if they miss a dose of Lynparza, not to take an extra dose to make up for the one that they missed. They should take their next normal dose at the usual time. Each capsule should be swallowed whole. Do not chew, dissolve, or open the capsule. Patient should not take Lynparza with grapefruit or Seville oranges. • MDS/AML: Advise patients to contact their healthcare provider if they experience weakness, feeling tired, fever, weight loss, frequent infections, bruising, bleeding easily, breathlessness, blood in urine or stool, and/or laboratory findings of low blood cell counts, or a need for blood transfusions. This may be a sign of hematological toxicity or a more serious uncommon bone marrow problem called ‘myelodysplastic syndrome’ (MDS) or ‘acute myeloid leukemia’ (AML) which have been reported in patients treated with Lynparza [see Warnings and Precautions (5.1) in the full Prescribing Information]. • Pneumonitis: Advise patients to contact their healthcare provider if they experience any new or worsening respiratory symptoms including shortness of breath, fever, cough, or wheezing [see Warnings and Precautions (5.2) in the full Prescribing Information]. • Pregnancy and Females of Reproductive Potential: Advise females to inform their healthcare provider if they are pregnant or become pregnant. Inform female patients of the risk to a fetus and potential loss of the pregnancy [see Use in Specific Populations (8.1) in the full Prescribing Information]. Advise females of reproductive potential to use effective contraception during treatment with Lynparza and for at least one month after receiving the last dose of Lynparza [see Warnings and Precautions (5.3) and Use in Specific Populations (8.1, 8.6) in the full Prescribing Information]. • Nursing Mothers: Advise patients not to breastfeed while taking Lynparza [see Use in Special Populations (8.3) in the full Prescribing Information]. • Nausea/vomiting: Advise patients that mild or moderate nausea and/or vomiting is very common in patients receiving Lynparza and that they should contact their healthcare provider who will advise on available antiemetic treatment options. Distributed by: AstraZeneca Pharmaceuticals LP, Wilmington, DE 19850 3079901 12/14 Issued: 12/2014

than 60 years old), and involvement of deep brain structures (periventricular regions, basal ganglia, corpus collosum, brainstem, and/or cerebellum).13 In 105 assessable patients for which complete data of all five variables were available, the 2-year overall survival ± standard deviation was 80% ± 8%, 48% ± 7%, and 15% ± 7% (P = .00001) for patients with zero to one, two to three, and four to five unfavorable features, respectively. Our patient has three unfavorable factors (age > 60, elevated serum LDH, and involvement of deep brain structures). Unfortunately, the IELSG score has prognostic variables that are not uniformly obtained or reported. As a result, many patients with primary CNS lymphoma cannot be categorized according to this model (Table 2). The MSKCC prognostication system has the advantage of simplicity and widespread applicability, relying only on age and Karnofsky performance status. It divides an otherwise heterogeneous population into three clear prognostic groups, which predict failurefree and overall survival regardless of treatment.14 The most favorable outcomes were seen in patients younger than age 50, regardless of performance status, who had a median survival of 8.5 years (95% confidence interval [CI], 4.7–16.8); these patients were defined as class 1 in terms of prognosis. In patients older than age 50, the most significant variable that affected survival was a Karnofsky performance status ≥ 70. Older patients with a Karnofsky performance status ≥ 70 had a median survival of 3.2 years (95% CI, 2.6–4.3), and these patients became class 2 in terms of prognosis. Our patient would belong to the class 2 prognostic group. Survival of patients in the class 2 prognostic group was significantly different from those in the class 1 prognostic group (P < .001) and those who were older than age 50 and had a Karnofsky performance status < 70 (P < .001). Older patients with a Karnofsky performance status < 70 had the worst prognosis, with a median survival of only 1.1 years (95% CI, 0.7–1.6), and these patients became class 3 in terms of prognosis. n

Disclosure: Drs. Abutalib and Lukas reported no potential conflicts of interest.

References 1. Coupland SE, Heimann H, Bechrakis NE: Primary intraocular lymphoma: A review of the clinical, histopathological and continued on page 100

The ASCO Post | NOVEMBER 10, 2015

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Journal Spotlight

A Cancer Diagnosis Can Lead to Significant Loss of Working Hours, Income

new analysis indicates that when American adults are diagnosed with cancer, they experience significant decreases in the probability of working, in the number of hours they work, and correspondingly, in their incomes. Such negative impacts of a cancer diagnosis

Anna Zajacova, PhD

are particularly pronounced among working-age men. Published by Zajacova et al, the study illustrates some of the financial challenges that accompany a cancer diagnosis and highlights the need for efforts to mitigate the economic hardships associated with cancer.1 While studies have analyzed what happens economically to adults who are diagnosed with cancer, they have

DLBCL of the CNS continued from page 99

molecular biological features. Graefes Arch Clin Exp Ophthalmol 242:901-913, 2004. 2. Abrey LE, Batchelor TT, Ferreri AJ, et al: Report of an international workshop to standardize baseline evaluation and response criteria for primary CNS lymphoma. J Clin Oncol 23:5034-5043, 2005. 3. O’Neill BP, Dinapoli RP, Kurtin PJ, Habermann TM: Occult systemic nonHodgkin’s lymphoma in patients initially diagnosed as primary central nervous system lymphoma: How much staging is enough? J Neurooncol 25:67-71, 1995. 4. Fine HA, Mayer RJ: Primary central nervous system lymphoma. Ann Intern Med 119:1093-1104, 1993. 5. Ferreri AJ, Reni M, Villa E: Primary central nervous system lymphoma in immunocompetent patients. Cancer Treat Rev 21:415-446, 1995. 6. Hochberg FH, Miller DC: Primary central nervous system lymphoma. J Neurosurg 68:835-853, 1988. 7. DeAngelis LM, Yahalom J, Heinemann MH, et al: Primary CNS lymphoma: Combined treatment with chemotherapy and radiotherapy. Neurology 40:80-86, 1990. 8. Loeffler JS, Ervin TJ, Mauch P, et al: Primary lymphomas of the central nervous

tended to be small, retrospective, subjective, and not representative of large populations. To address these shortcomings, Anna Zajacova, PhD, of the University of Wyoming in Laramie, and her colleagues analyzed data from 1999 to 2009 from the Panel Study of Income Dynamics, a nationally representative, prospective population-based observational study with individual and family level economic information. The researchers used models to estimate the impact of cancer on employment, hours worked, individual income, and total family income.

Study Findings After a cancer diagnosis, the probability of a patient being employed dropped by almost 10%, and hours worked declined by up to 200 hours (or about 5 weeks of full-time work) in the first year. Annual labor market earnings dropped almost 40% within 2 years after a diagnosis, and they remained lower than before the diagnosis. Total family income declined by 20%, although it recovered within 4 years after the system: Patterns of failure and factors that influence survival. J Clin Oncol 3:490-494, 1985. 9. Coupland SE, Damato B: Understanding intraocular lymphomas. Clin Exp Ophthalmol 36:564-578, 2008. 10. Blondin NA, Baehring JM, Hochberg FH: Primary CNS lymphoma, in Abutalib SA, Markman M (eds): Cancer Consult: Expertise for Clinical Practice, ch 48, pp 308-315. New York, NY, WileyBlackwell, 2014. 11. Ferreri AJ, Reni M, Pasini F, et al: A multicenter study of treatment of primary CNS lymphoma. Neurology 58:15131520, 2002. 12. Coupland, SE, Loddenkemper C, Smith JR, et al: Expression of immunoglobulin transcription factors in primary intraocular lymphoma and primary central nervous system lymphoma. Invest Ophthalmol Vis Sci 46:3957-3964, 2005. 13. Ferreri AJ, Blay JY, Reni M, et al: Prognostic scoring system for primary CNS lymphomas: The International Extranodal Lymphoma Study Group experience. J Clin Oncol 21:266-272, 2003. 14. Abrey LE, Ben-Porat L, Panageas KS, et al: Primary central nervous system lymphoma: The Memorial Sloan-Kettering Cancer Center prognostic model. J Clin Oncol 24:5711-5715, 2006.

Impact of Cancer Diagnosis on Work, Income ■■ After a cancer diagnosis, the probability of a patient being employed dropped by almost 10%, and hours worked declined by up to 200 hours (or about 5 weeks of full-time work) in the first year. ■■ Annual labor market earnings dropped almost 40% within 2 years after a diagnosis, and they remained lower than before the diagnosis. Total family income declined by 20%, although it recovered within 4 years after the diagnosis. ■■ These effects were primarily driven by losses among male survivors; for women who were diagnosed with cancer, the losses were largely not statistically significant.

diagnosis. These effects were primarily driven by losses among male survivors; for women who were diagnosed with cancer, the losses were largely not statistically significant. “Fifteen million American adults are cancer survivors, and American families need economic support while they are dealing with the rigors of cancer treatment,” said Dr. Zajacova. “Our paper suggests that families where an adult— especially a working-age male—is diagnosed with cancer suffer short-term and

long-term declines in their economic well-being. We need to improve workplace and insurance safety nets so families can focus on dealing with the cancer treatment, rather than deal with the financial and employment fallout.” n Reference 1. Zajacova A, Dowd JB, Schoeni RF, et al: Employment and income losses among cancer survivors: Estimates from a national longitudinal survey of American families. Cancer. October 26, 2015 (early release online).

Osteosarcoma Cell

This image shows an osteosarcoma cell with DNA in blue, mitochondria in yellow, and actin filaments, part of the cellular skeleton, in purple. One of the few cancers that originate in the bones, osteosarcoma is extremely rare, with less than 1,000 new cases diagnosed each year in the United States. Credit: Dylan Burnette and Jennifer Lippincott-Schwartz, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health. Life Magnified:https://www.nigms.nih.gov/education/life-magnified/Pages/11B_actin_mitochondria.aspx

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Announcements

NCI Names Thomas Kensler, PhD, Outstanding Investigator

homas Kensler, PhD, Professor of Pharmacology and Chemical Biology and Co-Leader for the Cancer Epidemiology and Prevention Program at the University of Pittsburgh Cancer Institute (UPCI), was awarded a $6.3 million Outstanding Investigator Award from the National Cancer Institute (NCI). This new award acknowledges experienced researchers and provides them with long-term support for their exceptional work.

ing cancer; however, environmental toxins such as fossil fuel combustion products are more difficult to mitigate. Past studies by Dr. Kensler’s team in China, where environmental controls are less rigorous, have examined the bioactive molecules in broccoli and how they may help

people there detoxify air pollutants. “Pollution is a global problem, and its effects are seen most often among the elderly, disabled, children, and minorities. We need effective and affordable interventions, and using foodbased strategies could be the ideal way

to address this,” Dr. Kensler said. He and his team will focus on a biologic pathway known to play a role in detoxification, identify and validate biomarkers of its activity, and examine the molecular consequences of its chronic activation. n

Thomas Kensler, PhD

Dr. Kensler’s research focuses on chemoprevention, or how food can be used to lower the risk of developing cancer caused by unavoidable environmental toxins. “The NCI Outstanding Investigator Award addresses a problem that many cancer researchers experience: finding a balance between focusing on their science, while ensuring that they will have funds to continue their research in the future,” said Dinah Singer, PhD, Director of NCI’s Division of Cancer Biology. “With 7 years of uninterrupted funding, NCI is providing investigators the opportunity to fully develop exceptional and ambitious cancer research programs.” The 7-year grant is 1 of just 60 awarded in its inaugural year. Research has shown that controlling diet, increasing exercise, and quitting smoking can decrease the risk of develop-

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Reflections

Equanimity By S. Vincent Rajkumar, MD

The following essay by S. Vincent Rajkumar, MD, is adapted from The Big Casino: America’s Best Cancer Doctors Share Their Most Powerful Stories, which was coedited by Stan Winokur, MD, and Vincent Coppola and published in May 2014. The book is available on Amazon.com and thebigcasino.org.

an enthusiastic handshake that practically broke my hand. He was bright, cheerful, and full of hope. I started to wonder whether he knew what the diagnosis was. However, within the next hour I realized that Charlie was well aware of what he had. He knew that myeloma was a devastating, incurable malignancy. He also knew that treatment options were limited and that we had very few drugs that really worked.

The Resilience of Patients

t was August 1999, and I was barely 2 months out of my fellowship training. One of my first patients was Charlie, a 58-year-old man with newly diagnosed multiple myeloma. Accompanied by his wife and two adult children, Charlie had traveled hundreds of miles to be seen at the Mayo Clinic. His was not a straightforward diagnosis, since there were several atypical clinical features. One of the advantages of working at the Mayo Clinic is that it gives you instant credibility. Even though I was literally just starting my career, I was seeing patients from far and wide, most seeking a second or third opinion—perhaps a more optimistic one than they had been given at home. But this was a burden as well. Patients had great expectations, and seeing a newbie oncologist for an incurable cancer is not why people fly across the country. Further, I usually had very little to offer. Multiple myeloma was a disease for which we’d had no new drugs for nearly 4 decades. I hesitantly introduced myself to the crowd of hopeful eyes and held out my hand to the patient. Charlie gave me

Dr. Rajkumar is Professor of Medicine and Chair of the Myeloma, Amyloidosis, Dysproteinemia Group at Mayo Clinic in Rochester, Minnesota.

Over the next 2 days, I confirmed the diagnosis and explained the various treatments available. I told him that since he was relatively young, stem cell transplantation was an option. I also told him that we were starting clinical trials with thalidomide (Thalomid), a notorious teratogen. In the 1950s, thalidomide, prescribed as an anti–morning sickness treatment for pregnant women, caused thousands of birth defects, the most prominent one being malformed limbs. It was now being tested as a possible new treatment for multiple myeloma. I was hoping that I’d lay out some options and he’d pick one. Instead, Charlie said he trusted me completely and was going to do whatever I recommended. I hurriedly excused myself and went out to discuss the situation with my senior colleagues who specialized in myeloma. I returned, a bit more confident, and after a lot of discussion, enrolled Charlie in the thalidomide clinical trial. We talked about my 1-year-old son, whose picture he saw on my desk. What I mostly remember is that we had a lot of laughs and warmth. As Charlie and his family departed for home to initiate therapy on this promising trial, I actually felt more confident in my step that day. A little over a month had passed when I received the call. Charlie’s myeloma had progressed on the thalidomide therapy, and he now had a spinal plasmacytoma with impending spinal cord compression. He was being rushed into radiation therapy. I was sick to my stomach. This was not supposed to happen! He was supposed to return to see me with a great response to treatment. The next month, after completing emergency radiation therapy, Charlie came back to see me and I was greeted by the same hopeful eyes: Charlie’s, his

wife’s, and their children’s. I held out my hand; his handshake was as firm as the first time. He seemed to relish the fact that he was able to literally crush my hand. “So, what’s next?” he asked. I was amazed that this person still had any kind of trust in me. Did he not realize that the treatment I prescribed a couple of months ago had completely failed to work for him? Did he realize he’d almost been paralyzed due to disease progression? It’s true that there is no guarantee that any given medicine will work for myeloma, but still…. We talked options again. I told him that we should try more standard che-

There was one faint ray of hope. We were just opening a trial of PS-341, a new drug that had shown promise in two patients with myeloma. It was from a new drug class, one that had not been tested in humans before, called proteasome inhibitors. In simple terms, it wrecks the garbage disposal system of the cell, leading to accumulation of unwanted proteins and eventually tumor cell death. I hesitantly brought this option forward to Charlie. I was nervous, considering what had happened in the thalidomide trial. By now, I should have known not to worry. Charlie was thrilled with the idea.

Failing to get into medical school is a setback; failing to respond to myeloma is not the type of failure I could have possibly rebounded from. And here was Charlie, happy and peaceful amidst the worst possible situation. —S. Vincent Rajkumar, MD

motherapy regimens and then a stem cell transplant. He listened carefully, and nodded in agreement. We talked about my son again, and then he left to start treatment at home. Charlie’s next year was not pleasant. Two different types of chemotherapy regimens failed to work. His bone marrow was packed with myeloma, and a heroic attempt to harvest his stem cells failed. This was November 2001, and all we had after 2 years was myeloma refractory to everything we tried and no real options on the table. Each time they returned, I was constantly jolted by the love and affection of this family. As always, Charlie was full of hope and joy. He was imperturbable.

Rebounding From Failure I am no stranger to failure. I’d desperately wanted to be a doctor, but for 2 years every medical school in India that I applied to had turned me down. I finally got accepted into medical school after 3 years. Failing to get into medical school is a setback; failing to respond to myeloma is not the type of failure I could have possibly rebounded from. And here was Charlie, happy and peaceful amidst the worst possible situation.

“Let’s do it,” he said,, and crushed my hand one more time. What followed was nothing short of a miracle. He responded dramatically to the new drug. Although the median duration of response in this trial and many others subsequently was only a few months, Charlie had a sustained response as long as he stayed on the therapy. Months passed, years passed, and he continued to respond. PS-341 was the blockbuster drug for myeloma that was eventually named bortezomib (Velcade). The trial was over, but Charlie’s response was not. We were able to switch him to a commercial drug. Over the next 10 years, I saw Charlie and his family many times. He always chuckled with every firm handshake. He never met my kids in person, but he watched them grow by looking at pictures on my computer and then on my phone. He never met my wife, but he always asked about her. By 2012, however, we slowly started to lose the battle. In the last year of his life, I watched Charlie slowly lose weight and lose color but never hope. A month before he died, he stopped by to thank me and asked his son to take a continued on page 103

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Announcements

Frances Giles, MB, MD, FRCPI, FRCPath, Appointed Chief of Hematology/Oncology at Northwestern

rancis Giles, MB, MD, FRCPI, FRCPath, has been appointed Chief of the Division of Hematology/ Oncology in the Department of Medicine at Northwestern. In his new role, he

will continue to advance the division’s clinical, research, and academic pursuits. Dr. Giles joined the faculty of the Division of Hematology/Oncology in 2013. Since then, he has led the launch and

growth of the Northwestern Medicine Developmental Therapeutics Institute (NMDTI). He also started the NMDTI Developmental Therapeutics Fellowship, which offers a mentorship environment

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Francis Giles, MB, MD, FRCPI, FRCPath

for clinical investigators. In 2014, he was appointed Deputy Director of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University. Dr. Giles has focused his clinical and research efforts on providing therapy for patients suffering from treatmentresistant or refractory cancer. He has pioneered the use of many agents that are now in regular use as targeted therapies for patients with cancer. Dr. Giles is a fellow of the European Academy of Cancer Sciences, the Royal College of Physicians of Ireland, and the Royal College of Pathologists. Before joining Feinberg, Dr. Giles served as Director the Institute for Drug Development and Deputy Director of the Cancer Therapy and Research Center at the University of Texas Health Science Center in San Antonio. n

Reflections continued from page 102

picture of the two of us, which I cherish. His death saddened me, but it gave me an opportunity to reflect on the things I learned from him.

The Lesson of True Imperturbability Charlie taught me a lot about hope, trust, and determination. But most importantly, he taught me aequanimitas—true imperturbability, not just an external show of calm, but calmness and peace of mind internally. I’d read William Osler’s essay “Aequanimitas” as a medical student. Dr. Osler wanted physicians not only to appear to be imperturbable, but also to be truly in that frame of mind internally, without sacrificing empathy. This was a difficult concept to put into practice. As much as I was reminded of it, I always found myself being exactly the opposite. Now, Charlie—and many other patients like him, despite all the challenges and realities of cancer—had showed me the path to equanimity. n

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Patient’s Corner

Shadowed by Cancer

After losing my father, aunt, husband, and sister to cancer and overcoming my own bout with breast cancer, I’m convinced that being proactive in my care saved my life. By Linette Atwood, as told to Jo Cavallo

lthough genetic testing has not turned up any inherited mutations that might explain the number of cancers that have plagued my immediate family, over the past 15 years, I have lost my father, aunt, and sister to the disease. In 2001, my husband, Wayne, died of acute promyelocytic leukemia, and the following year, I was diagnosed with breast cancer. Determined not to make my young daughter an orphan, I decided to take aggressive steps to save my life. When my sister was diagnosed with breast cancer in 2000 (she died in 2002), I enrolled in a breast cancer prevention program at a breast center near my home. The program required that I have a fine-needle biopsy every 6 months to check for any changes in my breast cells. My first biopsy showed epithelial hyperplasia cells in my left breast, and atypical hyperplasia cells were found in that breast at the next biopsy. Worried that these cells would soon turn into cancer, I made the decision to have a contralateral prophylactic mastectomy after consulting with my sister’s oncologist. I know that my actions seem drastic, but 10 days after the surgery, the pathology report from the breast tissue showed that I already had cancer. Actually, I had two types of breast cancer in my left breast: ductal carcinoma in situ and stage I invasive ductal carcinoma. Although biopsies of 17 lymph nodes removed from my under my left arm did not find any spread of cancer, I soon made another controversial choice. Because my aunt had died of ovarian cancer, my oncologist recommended that I have a prophylactic oo-

phorectomy and hysterectomy. Anxious to be as proactive as I could to prevent any additional cancer and to be around to raise my daughter, I agreed. I’ve never regretted those decisions, and today I remain cancer-free. Thankfully, my daughter, who is now 25 and enrolled in the same breast cancer prevention program, is healthy. Recently, she and I had genetic sequencing on 28 genes associated with hereditary cancer, and we do not have any mutations, so I’m hopeful that cancer ends with me.

Dedicated to Patient Advocacy Having had cancer and losing so many loved ones to the disease led me to dedicate my life to patient advocacy and education, so that other cancer survivors can have the most accurate information they need to make the best informed decisions about their health care. It is my conviction that informed and educated patients will find a way to get better care than patients who are not proactive in their medical decisions, and they will live longer. I saw how effective being proactive was in my own medical care, and I witnessed its impact on my husband’s care as well. When Wayne was diagnosed in 1994 with acute promyelocytic leukemia, his chance of surviving more than 3 years was about 20%. Multiple rounds of grueling chemotherapy and a bone marrow transplant had only limited effect on his cancer, sending him in and out of nine remissions. In 1996, we read about an experimental therapy called arsenic trioxide being tested in Shanghai, China, in the treatment of acute promyelocytic leu-

It is my conviction that informed and educated patients will find a way to get better care than patients who are not proactive in their medical decisions, and they will live longer. —Linette Atwood

kemia. After getting permission from the U.S. Food and Drug Administration (FDA) to bring arsenic trioxide into this country for compassionate use, we flew to China to obtain the drug. Wayne’s oncologist then obtained approval from his center’s Institutional Review Board to administer the therapy. The drug enabled Wayne to live 7 years—4 years beyond his prognosis— long enough to give our young daughter a lasting memory of her father. (Arsenic trioxide [Trisenox] is now approved by the FDA in the treatment of relapsed/refractory acute promyelocytic leukemia.)

Knowledge Really Is Power I know treating cancer has never been more complex and oncologists have limited time, but one of the most important components of good medical care is providing patients with the tools they need to make educated decisions about their care. I know it sounds cliché, but knowledge really is power. Cancer has taught me the importance of being your own best advocate in your health-care decisions. Neither

Patient Guides Available Through ASCO University Bookstore • ASCO Answers: Managing the Cost of Cancer Care explains the various costs associated with cancer treatment, including health-care coverage through the Affordable Care Act. It also provides a list of financial resources available to help offset expenses related to care and tips for organizing financial paperwork. Learn more at www.cancer.net/managingcostofcare. • ASCO Answers: Survivorship helps patients transition into life after active treatment has finished. In addition to information on the challenges survivors may face and the importance of follow-up care, it includes a blank treatment summary and survivorship care form that patients can fill out with the help of their health-care team. Learn more at www.cancer.net/survivorship. Copies of these booklets can be purchased through the ASCO University Bookstore at www.cancer.net/estore. All booklets ship for free, and ASCO members receive a 20% discount. n

Wayne nor I was going to stop asking questions and pursuing information about our cancers until we got what we needed to be informed partners with our oncologists in deciding the appropriate course of treatment for our diseases, and it is what I encourage other patients and survivors to do as well. Being a well-informed patient allowed my husband Wayne to have many productive years after his diagnosis and give his family the gift of a lasting legacy of his accomplishments. It also allowed me to be cured of cancer, to remarry, to see our daughter grow into a wonderful adult, and to make it my mission to ensure that every patient with cancer gets the same chance at a longer life. n Ms. Atwood lives in Lake Quivira, Kansas, and is the Founder and Publisher of Patient Resource, an educational publishing company for people with cancer. In 2012, Ms. Atwood was recognized for her patient advocacy efforts with the Bloch Cancer Survivorship Award, which honors cancer survivors who have made a difference in patients’ lives.

The ASCO Post Wants to Hear From You

We encourage readers to share their opinions and thoughts on issues of interest to the oncology community. Write to The ASCO Post at editor@ASCOPost.com

ASCOPost.com | NOVEMBER 10, 2015

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JCO Spotlight Guidelines

ASCO Endorses ASTRO Guideline on Postoperative Radiation Therapy for Endometrial Cancer By Matthew Stenger

s reported in the Journal of Clinical Oncology by Larissa A. Meyer, MD, MPH, and colleagues, ASCO has endorsed the recently published American Society for Radiation Oncology (ASTRO) guideline on postoperative radiation therapy for endometrial cancer.1 The ASCO clinical practice guideline endorsement panel was co-chaired by Dr. Meyer, of The University of Texas MD Anderson Cancer Center, and Alexi Wright, MD, MPH, of Dana-Farber Cancer Institute. The ASTRO guideline was reported by Klopp et al in Practical Radiation Oncology in 2014.2

Alexi Wright, MD, MPH

“The endorsement represents common ground as we work collaboratively with our radiation oncology colleagues to care for women with endometrial cancer,” Dr. Meyer told The ASCO Post. “It highlights areas of mutual agreement as well as areas where further research needs to be done to optimize evidencebased medical care.” Key recommendations of the A STRO guideline with qualifying statements by the ASCO endorsement panel, in italics, are reproduced below.

No Additional Therapy Which patients with endometrioid endometrial cancer require no additional therapy after hysterectomy? Following total abdominal hysterectomy with or without node dissection, no radiation therapy is a reasonable option for patients with cancer of any grade without residual disease in the hysterectomy specimen, despite positive biopsy (despite a positive prehysterectomy biopsy of any grade). Following total abdominal hysterectomy with or without node dissection, no radiation therapy is a reasonable option for patients with grade 1 or 2 cancers with either no invasion or

< 50% myometrial invasion. Vaginal cuff brachytherapy may be considered in patients with negative node dissection with grade 3 tumor without myometrial invasion. Vaginal cuff brachytherapy may be considered in patients with negative node dissection with grade 1 or 2 tumors with < 50% myometrial invasion and higher-risk features, such as age > 60 years or lymphovascular space invasion.

tion therapy is reasonable. Chemotherapy without externalbeam radiation may be considered for some patients with positive nodes or involved uterine serosa, ovaries/fallopian tubes, vagina, bladder, or rectum

The endorsement represents common ground as we work collaboratively with our radiation oncology colleagues to care for women with endometrial cancer. It highlights areas of mutual agreement as well as areas where further research needs to be done to optimize evidence-based medical care.

Vaginal Cuff Irradiation Which patients with endometrioid endometrial cancer should receive vaginal cuff irradiation? Vaginal cuff brachytherapy is as effective as pelvic radiation at preventing vaginal recurrence for patients with grade 1 or 2 tumors with ≥ 50% myometrial invasion or grade 3 tumors with < 50% myometrial invasion. Vaginal cuff brachytherapy is preferred to pelvic radiation in patients with the above risk factors, particularly in patients who have had comprehensive nodal assessment.

External-Beam Radiation Which patients should receive postoperative external-beam radiation? Patients with grade 3 cancer with ≥ 50% myometrial invasion or cervical stroma invasion of any grade may benefit from pelvic radiation to reduce the risk of pelvic recurrence. Patients with grade 1 or 2 tumors with ≥ 50% myometrial invasion may also benefit from pelvic radiation to reduce pelvic recurrence if other risk factors are present, such as age > 60 years or lymphovascular space invasion. Vaginal brachytherapy may be a better option for patients with these features, especially if surgical staging was adequate and nodes were negative. The best available evidence at this time suggests that reasonable options for adjuvant treatment of patients with positive nodes or involved uterine serosa, ovaries/fallopian tubes, vagina, bladder, or rectum include external-beam radiation therapy, as well as adjuvant chemotherapy. The best evidence for this population supports the use of chemotherapy, but consideration of external-beam radia-

followed by adjuvant chemotherapy is indicated for patients with positive nodes or involved uterine serosa, ovaries/fallopian tubes, vagina, bladder, or rectum. Evidence regarding concurrent chemoradiation is limited at

—Larissa A. Meyer, MD, MPH

based on pathologic risk factors for pelvic recurrence. Radiation therapy without chemotherapy may be considered for some patients with positive nodes or involved uterine serosa, ovaries/fallopian tubes, vagina, bladder, or rectum based on pathologic risk factors for pelvic recurrence. Patients receiving chemotherapy seem to have improved survival compared with radiation therapy alone.

Brachytherapy Plus External-Beam Radiotherapy When should brachytherapy be used in addition to external-beam radiation? Prospective data are lacking to validate the use of vaginal brachytherapy after pelvic radiation, and most retrospective studies show no evidence of benefit, albeit with small patient numbers. Use of vaginal brachytherapy in patients also undergoing pelvic external-beam radiation is not generally warranted, unless risk factors for vaginal recurrence are present.

Radiotherapy Plus Chemotherapy How should radiation therapy and chemotherapy be integrated in the management of stage I to III endometrioid endometrial cancer? The best available evidence suggests that concurrent chemoradiation

this time, and this recommendation is based on expert opinion; we anticipate level 1 evidence from upcoming prospective randomized clinical trials (GOG 0258 and PORTEC-3). Chemotherapy may also be considered in certain patients with high-risk earlystage endometrial cancer, and clinical trials addressing this question are underway. Alternative sequencing strategies with external-beam radiation and chemotherapy are also acceptable. Prospective trials have examined sequential radiation therapy and chemotherapy. Evidence supporting sandwich-type therapy is currently limited. n

Disclosure: Dr. Meyer has received travel and accommodation support from AstraZeneca. Dr. Wright reported no potential conflicts of interest. For full disclosures of the other authors, visit jco.ascopubs.org.

References 1. Meyer LA, Bohlke K, Powell MA, et al: Postoperative radiation therapy for endometrial cancer: American Society of Clinical Oncology clinical practice guideline endorsement of the American Society for Radiation Oncology evidence-based guideline. J Clin Oncol 33:2908-2913, 2015. 2. Klopp A, Smith BD, Alektiar K, et al: The role of postoperative radiation therapy for endometrial cancer: Executive summary of an American Society for Radiation Oncology evidence-based guideline. Pract Radiat Oncol 4:137-144, 2014.

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Perspective

ASCO-Endorsed ASTRO Guidelines: Searching for Consensus on Radiotherapy for Endometrial Cancer By Ann H. Klopp, MD, PhD, Patricia J. Eifel, MD, and Akila Viswanathan, MD, MPH

ndometrial cancer is the most common gynecologic cancer, but there has been little consensus about the appropriate indications for adjuvant therapy. One reason for the lack of consensus is the absence of randomized studies in endometrial cancer that report an overall survival benefit. This may be attributed to the frequency of comorbidities in women with endometrial cancer, which increases the risk of death from causes other than cancer. Furthermore, many trials have “lumped” patients with diverse risk factors, raising questions about the applicability of study findings to subsets of patients meeting the eligibility criteria. Despite these limitations, there have been many large studies conducted in endometrial cancer that provide insights into the best treatment recommendations to improve disease-free survival and quality of life. ASTRO developed evidencebased guidelines on the role of postoperative adjuvant therapy in endometrial cancer as a resource for the oncology community.1 In July 2015, these guidelines were endorsed by ASCO, which determined that the recommendations from the ASTRO guideline were clear, thorough, and based on the most relevant scientific evidence.2 The ASCO-endorsed guidelines are summarized in this issue of The ASCO Post.

Key Points The ASTRO guidelines were developed through a systematic multistep process that included: (1) identifying five key questions to be addressed; (2) convening a panel of multidisciplinary experts, including radiation oncologists, gynecology oncologists, and medical oncologists; (3) performing a comprehensive litDr. Klopp is Associate Professor and Dr. Eifel is Professor, Department of Radiation Oncology, Division of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston. Dr. Viswanathan is Associate Professor, Radiation Oncology, Harvard Medical School, and Attending Physician, Radiation Oncology, DanaFarber Cancer Institute, Boston.

erature review; (4) organizing a series of conference calls to discuss each key question; (5) formulating a literature discussion and summary recommendations for each of the key questions; (6) revising recommendations based on feedback from the panel, three independent expert reviewers, and the public; (7) assessing the level of consensus among the panelists using a modified Delphi approach; and (8) scoring the quality of the evidence using the American College of Physicians’ strength-of-evidence rating. The first key question in the ASTRO guidelines addressed which patients do not require radiation therapy. The panel recommended observation for patients with minimally invasive grade 1 to 2 endometrioid en-

therapy and chemotherapy. Concurrent chemoradiotherapy followed by adjuvant chemotherapy for patients with locally advanced disease was recommended, although it was acknowledged that evidence in support of a particular sequencing strategy was limited. The panel also noted that pathologic risk factors for local or distant recurrence might identify patients for whom chemotherapy or radiotherapy alone could be considered.

ASCO Endorsement and Noted Discrepancies The ASCO endorsement panel favorably reviewed the methodology of the ASTRO guideline and performed an updated literature review, which did not reveal any new evidence war-

The ASCO-endorsed ASTRO guidelines will hopefully improve the consistency of treatment recommendations for women with endometrial cancer across the United States. —(Left to right) Ann H. Klopp, MD, PhD, Patricia J. Eifel, MD, and Akila Viswanathan, MD, MPH

dometrial cancers without other risk factors following hysterectomy. Best available evidence supported the use of vaginal cuff brachytherapy for patients with grade 1 or 2 cancer and > 50% myometrium invasion or grade 3 cancer and < 50% myometrium invasion. Pelvic radiation is recommended for patients with deeply invasive highgrade disease, cervix invasion, or local extension into adjacent tissues, including the nodes. The guidelines panel thought that there was limited evidence for the use of brachytherapy after pelvic radiation. Finally, the guidelines addressed the optimal integration of radiation

ranting modification of the guidelines. The ASCO endorsement reprinted the ASTRO guidelines statements, with the addition of supplementary qualifying statements. With regard to the recommendation for combined-modality treatment in locally advanced disease, the ASCO endorsement added the note that “the best evidence for this population supports the use of chemotherapy, but consideration of external-beam radiation is reasonable.” However, the available data comparing radiation with chemotherapy include three randomized trials: Maggi et al,3 Susumu et al,4 and Randall et al,5 the first two

of which reported no significant difference in outcome. The third study, GOG 122, would have also reported similar rates of survival in both arms, apart from the process of stage adjustment that was performed in the analysis to rebalance the number of stage IV patients in the two arms. Selective adjustment of risk factors in the arms of a trial negates the purpose of a randomized trial, which is designed to avoid selection bias, and limits the value of this study in measuring the impact of chemotherapy. In fact, the only randomized trial in endometrial cancer that reported an improvement in progression-free survival with chemotherapy delivered chemotherapy in combination with external-beam radiation.6 This finding suggests that perhaps chemotherapy is particularly effective when delivered in combination with pelvic radiation. Additionally, the ASCO panel added the following supplementary qualifying statement: “Chemotherapy may be considered in certain patients with high-risk early-stage endometrial cancer.” Although retrospective studies suggest that patients with serous cancer may benefit from chemotherapy, there are no randomized trials demonstrating that chemotherapy improves outcome in early-stage endometrial cancer. In fact, the GOG 249 study, which has been reported only in abstract form, compared pelvic radiation with vaginal cuff brachytherapy and chemotherapy; the investigators found no difference in progression-free survival but higher rates of acute toxicity in patients treated with chemotherapy.

Future Outlook The ASCO-endorsed ASTRO guidelines will hopefully improve the consistency of treatment recommendations for women with endometrial cancer across the United States. The areas of debate regarding the role of chemotherapy in early and advanced endometrial cancer may find more clarity with the publication of critical trials, including PORTEC-3, GOG 249, and GOG 258. n Disclosure: Drs. Klopp, Eifel, and Visvanathan reported no potential conflicts of interest.

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Perspective

References 1. Klopp A, Smith BD, Alektiar K, et al: The role of postoperative radiation therapy for endometrial cancer: Executive summary of an American Society for Radiation Oncology evidence-based guideline. Pract Radiat Oncol 4:137-144, 2014. 2. Meyer LA, Bohlke K, Powell MA, et al: Postoperative radiation therapy for endometrial cancer: American Society of Clinical Oncology clinical practice guideline endorsement of the American Society for Radiation Oncology evidence-based guideline. J Clin Oncol 33:2908-2913, 2015. 3. Maggi R, Lissoni A, Spina F, et al: Adjuvant chemotherapy vs radiotherapy in high-risk endometrial carcinoma: Results of a randomised trial. Br J Can-

cer 95:266-271, 2006. 4. Susumu N, Sagae S, Udagawa Y, et al: Randomized phase III trial of pelvic radiotherapy versus cisplatin-based combined chemotherapy in patients with intermediate- and high-risk endometrial cancer: A Japanese Gynecologic Oncolo-

gy Group study. Gynecol Oncol 108:226233, 2008. 5. Randall ME, Filiaci VL, Muss H, et al: Randomized phase III trial of wholeabdominal irradiation versus doxorubicin and cisplatin chemotherapy in advanced endometrial carcinoma: A Gynecologic

Oncology Group Study. J Clin Oncol 24:36-44, 2006. 6. Hogberg T, Signorelli M, de Oliveira CF, et al: Sequential adjuvant chemotherapy and radiotherapy in endometrial cancer—Results from two randomised studies. Eur J Cancer 46:2422-2431, 2010.

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T790M is an acquired mutation and has been identified as the most common mechanism of acquired resistance in nearly 2 out of 3 patients with advanced NSCLC.1,2 When patients with EGFRm+ status progress, prior to changing therapy, a biopsy is reasonable to identify mechanisms of acquired resistance, as stated in NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®).3 Find out how the T790M mutation could affect the future of NSCLC at: EGFRevolution.com.

AstraZeneca is conducting ongoing research to understand the science of the T790M mutation

as a driver of resistance. References: 1. Yu HA, et al. Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers. Clin Cancer Res. 2013;19: 2240-2247. 2. Arcila ME, et al. Rebiopsy of lung cancer patients with acquired resistance to EGFR inhibitors and enhanced detection of the T790M mutation using a locked nucleic acid-based assay. Clin Cancer Res. 2011;17:1169-1180. 3. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Small Cell Lung Cancer V.7.2015. ©National Comprehensive Cancer Network, Inc. 2015. All rights reserved. Accessed June 12, 2015. To view the most recent and complete version of the guideline, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc. ©2015 AstraZeneca. All rights reserved. 3140405 6/15

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In the Literature

Emerging Clinical Data on Cancer Management BREAST CANCER Tamoxifen Use and Access to Fertility-Preservation Options Among Premenopausal Women With Breast Cancer A multivariable analysis of clinical factors associated with tamoxifen use among premenopausal women with hormone receptor–positive breast cancer showed that fertility preservation was a significant factor and “the only predictor of both noninitiation and early cessation” of tamoxifen. “Among patients who delayed or declined initiation, 34% cited pursuit of fertility as the reason for noninitiation. Furthermore, 25% of patients who discontinued stated they prioritized fertility,” Natalia C. Llarena of Northwestern University Feinberg School of Medicine, Chicago, and colleagues reported in the Journal of the National Cancer Institute. The researchers identified 515 premenopausal patients younger than 45 years of age with stage 0 to III hormone receptor–positive breast cancer treated at Northwestern Memorial Hospital’s Lynn Sage Comprehensive Breast Center from 2007 to 2012. “The study was restricted to premenopausal patients for whom adjuvant tamoxifen was recommended,” the authors noted. A total of 366 women (71.1%) were using tamoxifen. Those who did not start or discontinued use of tamoxifen were contacted by telephone “for a semistructured interview to further evaluate

reasons for tamoxifen noninitiation and nonpersistence,” the authors explained. Among the 69 patients (13.4%) who delayed or did not start tamoxifen, 39 patients (56%) agreed to participate; among the 80 patients (15.5%) who discontinued tamoxifen before 5 years, 49 (61%) agreed to participate. Fourteen factors were considered in univariate analyses for potential association with not starting or discontinuing use of tamoxifen: age at diagnosis, race/ ethnicity, marital status, smoking status, alcohol use, parity, insurance status, fertility concerns, anxiety/depression, obesity, surgery (mastectomy or lumpectomy), chemotherapy for stage I to III disease, radiation therapy, and stage of disease. “Based on multivariable analysis, fertility concerns were statistically associated with both noninitiation (odds ratio = 5.04, 95% confidence interval (CI) = 2.29–11.07) and early discontinuation of tamoxifen (hazard ratio = 1.78, 95% CI = 1.09–3.38),” the researchers reported. Other independent predictors of noninitiation included a diagnosis of ductal carcinoma in situ, declining radiation, and not receiving chemotherapy (stage I-III). Additionally, smoking and not receiving radiation therapy were statistically significant predictors of early withdrawal from therapy.”

Patient Counseling Patients who are likely not to initiate tamoxifen, including those with

early-stage disease and who decline other adjuvant treatments, “may benefit from education about personal recurrence risk and benefits of tamoxifen,” the authors wrote. “Young patients who decline to initiate should also receive focused counseling about side effects. Importantly, 24% of patients cited concerns about tamoxifen and risk of endometrial cancer as a reason for noninitiation.” As the authors noted, however, “premenopausal women treated with tamoxifen have not been found to be at increased risk for endometrial cancer.” The investigators listed several available options that can be discussed with young patients concerned about preserving their reproductive potential. “Embryo cryopreservation is the most established method, and oocyte cryopreservation is also a viable option. Ovarian tissue cryopreservation remains an experimental procedure, and technologies to expand this technique are evolving,” the researchers wrote. “Gonadotropin-releasing hormone analogs are also being investigated to help preserve ovarian function during exposure to chemotherapy,” the authors added. Although recent results “were encouraging,” the authors noted that prior studies with gonadotropin-releasing hormone analogs “failed to show benefit,” and both ASCO and National Comprehensive Cancer Network (NCCN) guidelines currently consider this treatment to be “‘unproven or inconclusive’ until additional data are obtained.” Despite the availability of fertility options and the importance of fertility to young patients, “fertility preservation is often underutilized and underdiscussed in clinical settings,” the authors concluded. Llarena NC, et al: J Natl Cancer Inst. August 25, 2015 (early release online).

MECHANISMS OF RESISTANCE Multiple Copies of TP53 Tumor-Suppressor Gene Potentially Related to Lower-Than-Expected Cancer Rate in Elephants

A lower-than-expected rate of cancer among elephants could be potentially related to multiple copies of TP53, “a crucial tumor suppressor gene mutated in the majority of human cancers,” according to a study published online by The Journal of the American Medical As-

sociation. “Compared with human cells, elephant cells demonstrated increased apoptotic response following DNA damage. These findings, if replicated, could represent an evolutionary-based approach for understanding mechanisms related to cancer suppression,” the investigators concluded. Joshua D. Schiffman, MD, of the University of Utah School of Medicine, Salt Lake City, and colleagues investigated the cancer rate in different mammals, including 644 elephants, identified potential molecular mechanisms of cancer resistance, and compared response to DNA damage in elephants with that in healthy human controls and patients with Li-Fraumeni syndrome (a genetic syndrome with a high lifetime risk of cancer). Information on disease and cause of death was obtained for 36 mammalian species, from the striped grass mouse (weight, 51 g, with a maximum lifespan of 4.5 years) to the elephant (weight, 4,800 kg, with a maximum lifespan of 65 years). Cancer risk did not increase with body size and maximum lifespan among the 36 species analyzed. “No significant relationship was found with any combinations of mass, lifespan, and basal metabolic rate and cancer incidence,” the authors reported.

Shedding Light on Cancer Resistance “Despite their large body size and long lifespan, elephants remain cancer resistant, with an estimated cancer mortality of 4.81% (95% confidence interval [CI], 3.14%–6.49%), compared with humans, who have 11% to 25% cancer mortality,” the investigators stated. The African and Asian elephant genomes were analyzed for potential mechanisms of cancer resistance. Peripheral blood lymphocytes from elephants, healthy human controls, and patients with Li-Fraumeni syndrome were tested in vitro in the laboratory for DNA-damage response. The study included African and Asian elephants (n = 8), patients with Li-Fraumeni syndrome (n = 10), and age-matched human controls (n = 11). “While humans have 1 copy (2 alleles) of TP53, African elephants have at least 20 copies (40 alleles), including 19 retrogenes (38 alleles) with evidence of transcriptional activity measured by reverse transcription polymerase chain reaction,” the researchers reported. “In response to DNA damage, elephant lymphocytes

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In the Literature

underwent p53-mediated apoptosis at higher rates than human lymphocytes proportional to TP53 status.” After exposure to 2 Gy of ionizing radiation, the rates of apoptosis were 2.71% (95% CI, 1.93%–3.48%) for patients with Li-Fraumeni syndrome, vs 7.17% (95% CI, 5.91%–8.44%) for human controls and 14.64% (95% CI, 10.91%–18.37%) for elephants (P < .001). After doxorubicin exposure, the rates of apoptosis were 8.10% (95% CI, 6.55%–9.66%) for human controls vs 24.77% (95% CI, 23.0%–26.53%) for elephants (P < .001).

Mel Greaves, PhD, and Luca Ermini, PhD, of the Institute of Cancer Research in London, wrote in an accompanying editorial. “The human genome is replete with footprints of positive selection in the not too distant historical past,” the editorialists noted. In other respects, however, “modern humans appear to be exceptionally vulnerable to cancer, espe-

cially in more developed societies.” The risks of lifestyle behaviors, such as smoking and sun-soaking, “far exceed prior and otherwise effective cancer suppressor mechanisms that were inherited from primate ancestors. Contrariwise, humans have inadvertently become maladapted via mismatches between current lifestyles and inherent

genetics that was adaptively forged in a very different ancestral environment.” n Abegglen LM, et al: JAMA. Oct 8:111, 2015. Greaves M, Ermini L: JAMA. Oct 8:13, 2015. In the Literature is compiled and written for The ASCO Post by Charlotte Bath.

Further Commentary “Perhaps the main message from this innovative investigation is to bring into focus the question of why humans appear to be so ill-adapted to cancer, given the average size and lifespan,”

Don’t Miss These Important Reports in This Issue of The ASCO Post

Early bird registration expires Wednesday, February 17, 2016 Agenda Topics*: • B-cell Lymphomas: Optimizing Treatment with Small Molecule Inhibitors

• Multigene Testing in Prostate Cancer Risk Stratification

• Cancer Pain Management: Strategies for Safe and Effective Opioid Prescribing

• NCCN Guidelines Updates: Breast Cancer

• CNS: Notable Developments in the Management of Primary and Recurrent Gliomas

• Role of Biosimilars

• Controversies in Breast Cancer Screening Strategies Diana J. Mason, RN, PhD, FAAN, on End-of-Life Clinical Decisions and Improving Care see page 33

Thomas J. Smith, MD, FACP, FASCO and James O. Armitage, MD, FASCO, on ASCO’s Clinical Practice Guideline Update on White Blood Cell Growth Factors see page 38

• Diagnosis and Staging of Pancreatic Cancer: The Role of Imaging • Emerging Paradigms in the Treatment of Localized Rectal Cancer

• Selection of Optimal Treatment Strategies in Metastatic Colorectal Cancer • Sexual Function in Cancer Survivors: Updates to the NCCN Guidelines for Survivorship • Strategies for Management of Early Stage Breast Cancer in Older Women

• Evolving Treatment Strategies for Cervical Cancer

• The NCCN Value Initiative: Using NCCN Evidence Blocks™ in Clinical Decisions

• Evolving Uses of Androgen Deprivation Therapy (ADT) in Prostate Cancer Management

• Understanding and Utilizing Patient Preferences in Cancer Treatment Decisions

• Guideline Update: Locoregional Treatment Approaches for Hepatocellular Carcinoma

• Updates on Diagnostic Criteria and Management of Multiple Myeloma

• Hereditary Breast and Ovarian Cancers: Risk Management Recommendations

• Venous Thromboembolism in Patients with Cancer: Assessment of Risk and Safe Prophylaxis

• Major Changes in Systemic Therapy for Advanced Melanoma • Management of Advanced Phase CML • Management of EGFR-Mutation Positive Metastatic NSCLC • Metastatic Gastroesophageal Cancers: Current and Emerging Treatment Options

Visit The ASCO Post online at ASCOPost.com

• New NCCN Guidelines for Vulvar Cancer

*Agenda Topics are subject to change This conference is approved for AMA PRA Category 1 Credit™ for physicians and is also certified for nurses, pharmacists, and other oncology professionals. NCCN will also seek approval for case manager and tumor registrar clock hours.

NCCN.org/AC2016 Sponsorship and exhibit opportunities are available! Sponsorship and exhibit opportunities available! For more information, e-mail exhibits@nccn.org. For more information, e-mail exhibits@nccn.org JNCCN-N-0213-1115

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Announcements

National Academy of Medicine Elects New Members

he National Academy of Medicine (NAM), formerly the Institute of Medicine, announced the election of 70 regular members and 10 international members during its Annual Meeting October 19. Election to the Academy is considered one of the highest honors in the fields of health and medicine and recognizes individuals who have demonstrated outstanding professional achievement and commitment to service. This is the inaugural Annual Meeting as the National Academy of Medicine and the 45th year since the establishment of the Institute of Medicine. New members are elected by current active members through a selective process that recognizes individuals who have made major contributions to the advancement of the medical sciences, health care, and public health. A diversity of talent among NAM’s membership is assured by its Articles of Organization, which stipulate that at least one-quarter of the membership is selected from fields outside the health professions—for example, from such fields as law, engineering, social sciences, and the humanities. The newly elected members raise NAM’s total active membership to 1,826, and the number of international members to 137. Ten of the newly inducted members are specialists in the field of oncology: • Otis Webb Brawley, MD, MACP, FASCO, FACE, Professor of Hematology, Medical Oncology, Medicine, and Epidemiology, Emory University; and Chief Medical Officer, Ameri-

Otis Webb Brawley, MD, MACP, FASCO, FACE

Napoleone Ferrara, MD

Amato J. Giaccia, PhD

Gary Gilliland, MD, PhD

Michael R. Green, MD, PhD

Beth Y. Karlan, MD

Kenneth W. Kinzler, PhD

Nikola P. Pavletich, PhD

Alexander Rudensky, PhD

Nahum Sonenberg, PhD

can Cancer Society, Atlanta • Napoleone Ferrara, MD, Distinguished Professor of Pathology and Ophthalmology, University of California, San Diego • Amato J. Giaccia, PhD, Jack, Lulu, and Sam Willson Professor of Cancer Biology, Department of Radiation Oncology, Stanford University School of Medicine • Gary Gilliland, MD, PhD, President and Director, Fred Hutchinson Cancer Research Center • Michael R. Green, MD, PhD, Investigator, Howard Hughes Medical Institute; and Director, Cancer Center, and Professor and Chair, Department of Molecular, Cell, and Cancer

Biology, University of Massachusetts Medical School • Beth Y. Karlan, MD, Professor, Obstetrics and Gynecology; Director, Women’s Cancer Program, Samuel Oschin Comprehensive Cancer Institute; and Director, Division of Gynecologic Oncology, Cedars-Sinai Medical Center • Kenneth W. Kinzler, PhD, Professor of Oncology; Director, Ludwig Center; and Associate Director of Basic Research, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University • Nikola P. Pavletich, PhD, Investigator, Howard Hughes Medical Institute; and Stephen and Barbara

Friedman Chair, Structural Biology Program, Memorial Sloan Kettering Cancer Center • Alexander Rudensky, PhD, Investigator, Howard Hughes Medical Institute; and Chairman, Immunology Program, and Director, Ludwig Center for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center • Nahum Sonenberg, PhD, James McGill Professor, Department of Biochemistry and Rosalind and Morris Goodman Cancer Research Centre, McGill University For a full list of newly elected members, visit http://nam.edu/nam-elects80-new-members. n

ASH Honors Aaron J. Marcus, MD, Posthumously With Award for Lifetime Achievement in Hematology

he American Society of Hematology (ASH) will recognize the late Aaron J. Marcus, MD, of Weill Cornell Medical College and the Veterans Affairs New York Harbor Healthcare System with the 2015 Wallace H. Coulter Award for Lifetime Achievement in Hematology. Dr. Marcus, who passed away in May 2015, will be honored for his groundbreaking research in hemostasis and thrombosis and his unwavering dedication to the field throughout his nearly 60-year career. The Wallace H. Coulter Award for Lifetime Achievement in Hematology is named for the late Wallace Henry Coulter, a prolific inventor who made important contributions to hematology and to ASH. The award commemorates

ing the 57th ASH Annual Meeting and Exposition in Orlando, Florida.

5-Decade Career

Aaron J. Marcus, MD

Mr. Coulter’s innovative spirit, visionary leadership, and entrepreneurship and is bestowed on an individual who has demonstrated lifetime achievement and leadership in education, research, mentoring, and practice. ASH President David A. W illiams, MD, will present the award to Dr. Marcus’ children on Sunday, December 6, dur-

Dr. Marcus began his medical career in 1953 after earning his medical degree from New York Medical College. Following medical school, he completed an internship at the Jewish Hospital of Brooklyn and served as a resident and fellow at Montefiore Hospital in New York. From 1958 until his death, Dr. Marcus served as Chief of Hematology-Oncology at the Veterans Affairs New York Harbor Healthcare System and as Attending Physician at New York-Presbyterian Hospital. In 1973, Dr. Marcus began work at Weill Cornell Medical College, first serving as Professor of Medicine, then as Professor

of Medicine in Pathology and Professor of Pathology and Laboratory Medicine. Over the course of his long career, Dr. Marcus made many contributions to hematology, specifically in the area of hemostasis and thrombosis. His pioneering study of platelets laid the foundation for modern antithrombotic therapy for heart attack and stroke. His research on cell-cell interactions led to the concept of transcellular metabolism and the discovery of “thromboresistance,” a term he coined to describe how platelets are incapable of being activated by known platelet agonists. Dr. Marcus’ recent research focused on a new compound, CD39, that he hoped would one day become a novel, effective, and safe therapy for arterial diseases. n

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Perspective Gregory H. Jones, BS Hagop Kantarjian, MD continued from page 1

spouse in dying when cancer recurs. Its double meaning is the demise of mercy in the era of modern health care. Profit, the killer of mercy in the for-profit health-care industry, aims to maximize profits, even when this harms patients. Because of the terrible consequences of the lack of health care for millions of Americans, an important question is whether health care in the United States should be considered a basic human right, or is it only a privilege or an entitlement?

the fittest” or “not-liberty, equality, and survival of the un-fittest. The former would carry society forward and favor its best members. The latter would carry society downwards and favor the worst members.” Mr. Sumner theorized that the pressure of a competitive system would strengthen a society over generations. An inference of this theory is that govern-

mental intervention would interfere with natural selection and weaken societies. Societal Darwinism may have cast its long shadow over health care in the United States in the form of medical Darwinism (survival of the fittest), hence the acceptance of unequal health care or health care as an entitlement rather than a human right. The 20th

century nurtured the idea of fairness in reaching the American Dream, and the need for equal opportunities and social safety nets that protect Americans at times of vulnerability. This shift in attitude has varied with the ideologies of governments in power. A Texas legislator asked in 2003: continued on page 112

Health Care in Europe vs United States Most European nations have had some form of national insurance for more than a century. The primary reasons for these insurance programs were not payment of medical expenses, but income stabilization and protection of wage loss when sick.2 In some ways, this is analogous to the American Social Security program. European social insurance programs have evolved over time into vibrant universal health-care systems. Both the European Union and the United Nations recognize health care as a basic human right; 38% of the constitutions of the members of the United Nations guarantee medical care.3 The United States is a rare nation in the Organization for Economic Cooperation and Development (OECD): It does not recognize universal health care as a human right. South Africa established universal health care in 1996, 2 years after ending apartheid. In contrast, it took the United States 50 years after the Civil Rights Act of 1964 before it enacted the Patient Protection and Affordable Care Act (ACA)—our first attempt to establish universal health care in more than 200 years.4

Diverse Ideologies The reluctance of America to embrace universal health care may have been influenced by earlier ideologic movements in the 19th century. William Graham Sumner brought Darwinian evolution and Malthusian economic theory into the American sociopolitical arena.5 His ideology, aligned with capitalism in many aspects, was readily accepted then by most Americans. Mr. Sumner’s view is that the world population was increasing geometrically and resources increasing arithmetically. Therefore, “civilization has a simple choice”: “liberty, inequality, survival of

Advancing Cancer Care and Research ASCO’s interactive website chronicles advances in cancer treatment, detection, and prevention. This unique website is the only comprehensive online resource that documents the tremendous advances that have occurred in the fight against cancer. Explore the following features: Progress timeline of milestones for 17 cancers and all types of patient care Stories of cancer survivors and leading cancer researchers Data visualizer tools to explore cancer statistics Top 5 Oncology Advances During Past 50 Years The Cancer Progress Timeline was developed and curated under the guidance of an editorial board of more than 20 of the nation’s leading oncologists.

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Perspective Gregory H. Jones, BS Hagop Kantarjian, MD continued from page 111

“Where did this idea come from that everybody deserves free education? Free medical care? Free whatever? It comes from Moscow. From Russia. It comes straight out of the pit of hell.”6 Today, politicians avoid making such public statements because most Americans believe health care should be guaranteed—83% believe health insurance is absolutely essential or very important, and 70% believe the United States should have universal health care (similar to Medicare for Americans 65 years or older).7 Americans believe in reward for hard work but also in equal opportunity, hence fair access to health care and education. Children with poor health care or poor education are doomed to failure in adulthood. Health-care inequality leads inevitably to poverty and to compromises on ethical principles to access basic necessities.

protection of patients from harm and injustice. Lack of needed health care is both harmful and unjust.9 Physicians should advocate for universal health care as a human right. America is aberrant among advanced nations in not guaranteeing basic health care. Our country promulgates fairness,

Freedom should not translate into denial of other human rights, including affordable health care to all. The American Dream implies fairness for equal opportunity. Medical Darwinism is not consistent with fairness in a country that spends so much on health care but fails to distribute it effectively.

America is among the richest nations in the world and spends more on health care than any other country. Yet we rank poorly in objective measures of health-care outcomes. —Gregory H. Jones, BS, and Hagop Kantarjian, MD

Excessive Resources Yet Suboptimal Outcomes America is among the richest nations in the world and spends more on health care than any other country (18% of our gross domestic product—two to three times more than other advanced nations). Yet we rank poorly in objective measures of health-care outcomes.8 Why is there this dichotomy between excessive resources and suboptimal outcomes? In the European healthcare systems, most financial resources are directed toward patient care. However, the for-profit nature of the healthcare system in the United States results in less than one-third of the dollars being directed to patient care. The rest is diverted as profits for the health-care industry. Also, large sums of money are spent by insurance companies to deny (rather than provide) health care (“denial management”). Thus, universal health care (opposed by some for being prohibitively expensive) can in the long run become more efficient and more affordable if implemented properly.

Equal Access to Health Care Physicians abide by two universal principles of the Hippocratic Oath:

equal opportunity, and the potential to achieve the American Dream. However, American exceptionalism, the for-profit health-care industry, and physician concerns over income may be the triad that hindered progress toward universal health care.10 The reasons, stated and implied over time, have varied: opposition to “socialized medicine,” anticommunism, fears of hospital desegregation, antiwelfare sentiment, and more recently the unaffordable costs of universal health care. Signed into law by President Johnson in 1965, Medicare and Medicaid were the first steps toward universal health care. Fifty years later, the ACA was the first endeavor to provide better and more expanded health care at affordable costs.11 One year into the implementation of the ACA, the rate of uninsured Americans fell from 18% to 10%, even lower in states that accepted the ACA Medicaid expansion (7% vs 14%).12 More people approve of the ACA, and 81% of people enrolled in ACA plans are satisfied.13 Most important, it is saving lives.14,15

To live up to the ideals of America, equal access to health care is critical, and health care should be a basic human right. n Note: An expanded version of this editorial was published in the October 2015 issue of Annals of Oncology (26:2193-2195, 2015). Disclosure: Mr. Jones and Dr. Kantarjian reported no potential conflicts of interest.

References 1. Mercy Killers, The One-Man Show. Performed by Michael Milligan Available at http://mercykillerstheplay.com/. Accessed October 20, 2015. 2. Palmer K: A brief history: Universal health care efforts in the US: Physicians for a national health program. 1999. Available at http://www.pnhp.org/facts/a-brief-history-universal-health-care-efforts-in-theus. Accessed October 20, 2015. 3. Heymann J, Cassola A, Raub A, Mishra L: Constitutional rights to health, public health and medical care: The status of health protections in 191 countries. Global Public Health 8:639653, 2013.

4. Price CC, Eibner C: For states that opt out of Medicaid expansion: 3.6 Million fewer insured and $8.4 billion less in federal payments. Health Aff (Millwood) 32:10301036, 2013. 5. Wikipedia. William Graham Sumner. Available at http://en.wikipedia.org/wiki/ William_Graham_Sumner. Accessed October 20, 2015. 6. Ivins M: Bucking the Texas lockstep. The Washington Post. May 15, 2003. 7. Deam J: Health care survey yields surprises for the medical community. Houston Chronicle. Available at http://www. houstonchronicle.com/business/medical/ article/Health-care-survey-yields-surprises-for-the-6227381.php. Accessed October 20, 2015. 8. Kantarjian H: Does the United States have the best health-care system in the world? The ASCO Post 5(Aug):172-174, 2014. 9. Kantarjian H, Steensma DP: Relevance of the Hippocratic Oath in the 21st century. The ASCO Post 5(Oct):1, 101, 104, 2014. 10. Krugman P: The politics of the welfare state, in The Conscience of a Liberal, pp 57-78. New York, W.W. Norton & Company, 2007. 11. Zwelling L, Kantarjian HM: Obamacare: Why should we care? J Oncol Pract 10:12-14, 2014. 12. Ho V, Marks E: Health Reform Monitoring Survey—Texas. Episcopal Health Foundation, Rice University’s Baker Institute, 2015. Available at http://www.episcopalhealth.org/files/7814/3040/3719/ Issue_Brief_11_FINAL.pdf. Accessed October 20, 2015. 13. Collins SR, Rasmussen PW, Doty MM, Beutel S: Americans’ experiences with marketplace and Medicaid coverage. Findings from the Commonwealth Fund Affordable Care Act Tracking Survey, March–May 2015. June 2015. Available at http://www. commonwealthfund.org/publications/ issue-briefs/2015/jun/experiences-marketplace-and-medicaid. Accessed October 20, 2015. 14. Polite BN, Griggs JJ, Moy B, et al: American Society of Clinical Oncology policy statement on Medicaid reform. J Clin Oncol 32:4162-4166, 2014. 15. Sommers BD, Baicker K, Epstein AM: Mortality and access to care among adults after state Medicaid expansions. N Engl J Med 367:1025-1034, 2012.

What's On Your Mind? The ASCO Post invites readers to submit an op-ed discussing an issue of interest to the oncology community. This can be in regard to a clinical, policy, or personal issue you wish to share. Length should be approximately 750 to 800 words. For more information, contact editor@ASCOPost.com.

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Issues in Oncology Legislation

Physician-Assisted Suicide continued from page 1

been legal in Oregon for nearly 2 decades, but has largely remained under the nation’s public radar. Then, in 2014, came the highly publicized case of Brittany Maynard, a young woman diagnosed with aggressive glioblastoma. Following two resections, her oncologist told her that she would likely die of the tumor within 6 months. Ms. Maynard’s quality of life was rapidly deteriorating, but instead of receiving palliative radiation, the 29-year-old opted to relocate to Oregon and enter the legal process of having a physician prescribe life-ending drugs. As she was going through the strict legal process associated with Oregon’s physician-assisted suicide law, Ms. Maynard became a prominent advocate for the Compassion and Choices campaign that works to legalize Death With Dignity in all states. According to her family, Ms. Maynard died peacefully on November 1, 2014, in the company of her loved ones after taking the prescribed lethal dose of medication.

A Battle of Ethics During the contentious run-up to the passage of Oregon’s Death With Dignity Act, the medical establishment was divided by the ethical conflict posed by physician participation in patient suicide. The American Medical Association (AMA) adopted a policy opposing doctor-aided death in 1993 and has since reaffirmed that position numerous times. In a press release, an AMA spokesperson commented, “Physician-assisted suicide is fundamentally incompatible with the physician’s role as healer, would be difficult or impossible to control, and would pose serious societal risks.”

Kathleen M. Foley, MD

In a spirited public debate in 1997, internationally recognized pain and palliative care expert Kathleen M. Foley, MD, of Memorial Sloan Kettering Cancer Center, argued against legalizing physician-assisted suicide with then Editor-in-Chief of The New England Journal of Medicine, Marcia Angell, MD, who—under certain clinical circumstances—supported the use of physician-assisted suicide.

Marcia Angell, MD

At the time, Dr. Foley’s major argument against physician-assisted suicide concerned the reasons patients give for seeking it. According to Dr. Foley, most patients who request physician-assisted suicide do so because of profound existential issues, not issues of pain. Existential distress includes patients’ fears of being a burden, of being dependent on others, and of suffering a loss of dignity—clinical challenges that physicians are not trained to address. On the other hand, Dr. Angell’s support of physician-assisted suicide was strengthened by the death of her father, who committed suicide while suffering terribly during the late stages of prostate cancer. “Long before my father’s death, I believed that physician-assisted suicide ought to be permissible under some circumstances, but his death strengthened my conviction that it is simply a part of good medical care—something to be done reluctantly and sadly, as a last resort, but done nonetheless,” said Dr. Angell in a public statement. In a 2012 article in The New York Review of Books,1 Dr. Angell reaffirmed her belief in physician-assisted suicide under limited circumstances. She deftly connected the historical dots that have led us to this ongoing debate over physician-assisted suicide, beginning with the case of Karen Ann Quinlan. In 1976, Ms. Quinlan, a young woman whose brain was irreversibly damaged by an alcohol-and-diazepam overdose, was kept alive in a vegetative state for months. Her family decided to disconnect the ventilator, resulting in a strident court battle, culminating in a landmark decision that allowed the family to stop life-sustaining treatments. In effect, the court allowed intervention to end life in a hopeless medical case. Dr. Angell argued that, similar to disconnecting a ventilator, proper and compassionate use of physician-assisted suicide is a medical intervention to end suffering in the imminently dying, which should be allowed by law.

‘Slippery Slope’ Argument Opponents of physician-assisted suicide use the “slippery slope” theory, in which a first step leads to a chain of related

steps culminating in a significant and unwanted effect. The Netherlands and Belgium are often cited in the slippery slope argument. Physician-assisted suicide and euthanasia (ie, active physician participation) was legalized in both the Netherlands and Belgium in 2002. Although quite different from the United States in terms of demographics and sociopolitical structure, the data from these two nations are important in the overall discussion of physician-assisted suicide. In 2012, 3% of total yearly deaths in the Netherlands were the result of physician-assisted suicide or euthanasia; 7% of those patients were euthanized without their explicit consent. Moreover, since 2006, the number of euthanasia procedures has increased each successive year by about 15%. Data from Belgium are even more disconcerting. According to a study published this year in The New England Journal of Medicine,2 Belgian doctors deliberately “hasten the death” of patients “without an explicit request” at a rate constituting 1.7% of all deaths in the country. There were 61,621 deaths in Belgium during 2013 for which there

The American palliative care community contends that when highquality palliative care is implemented, suicidal ideation becomes far less frequent. Asked about his thoughts on that, Dr. Lerner replied, “Yes, there are exciting emerging data suggesting that high-quality palliative care can help to relieve both physical and emotional suffering of patients with cancer and other diseases.” He added, “It is a challenge to get physicians to use these services and to get them paid for, but these goals should be a huge priority. The aim should be the alleviation of suffering, not the administration of medications that provide a ‘quick fix’ to complicated medical and social situations.”

The Oregon Experience According to a report from the Oregon Public Health Division,3 from 1998 through 2014, a total of 1,327 people have had lethal prescriptions written and 859 patients have died from ingesting medications prescribed under the Death With Dignity Act. Since the legalization of physician-assisted suicide in Oregon, there has

Good palliative care and hospice services do limit the expansion of physician-assisted suicide. —Linda Ganzini, MD, MPH

are comprehensive data, which means, according to the study authors, that doctors are now euthanizing more than 1,000 patients a year without their having requested it. In an interview with The ASCO Post, Baron Lerner, MD, PhD, Professor of Medicine at New York University Langone Medical Center, addressed the Belgium experience: The trend seems to be due to the related ideas of patients’ rights and a ‘humanistic’ (as opposed to a religious) approach to death and dying. The earlier doctor-driven emphasis on prolonging life at all costs and relieving suffering is being replaced, in some circles, by the acceptance of the patient’s ability to determine when they have lived long enough. To some degree, these are radical concepts, even in the case of patients with terminal cancer. To apply them to people with psychological suffering is a huge—and worrisome— leap from what most of us were taught in medical school.

been a slow, incremental increase in its use. According to a survey of Oregon hospice nurses,4 the most important reasons for requesting assistance with suicide among patients who received prescriptions for lethal medications were a desire to control the circumstances of death, a desire to die at home, the belief that continuing to live was pointless, and being ready to die. The ASCO Post asked one of the authors of the survey, Linda Ganzini, MD, MPH, Professor of Psychiatry and Medicine Senior Scholar at Oregon Health & Science University, whether the gradually increased use of physician-assisted suicide in Oregon is a worrisome trend. She said: First off, we have very accessible and comprehensive palliative care services in Oregon, which tends to divert the requests for physician-assisted suicide. Moreover, Oregon has very strict control over the process that limits the excontinued on page 114

The ASCO Post | NOVEMBER 10, 2015

PAGE 114

FDA Update

FDA Approves First Oncolytic Viral Therapy in the United States

he U.S. Food and Drug Administration (FDA) has approved the biologics license application for talimogene laherparepvec (Imlygic), a genetically modified oncolytic viral therapy indicated for the local treatment of unresectable cutaneous, subcutaneous, and nodal lesions in patients with melanoma recurrent after initial surgery.

leasing tumor-derived antigens, which along with GM-CSF, may promote an antitumor immune response. However, the exact mechanism of action is unknown.

Pivotal Phase III Trial

Talimogene laherparepvec has not been shown to improve overall survival or have an effect on visceral metastases. The agent is the first oncolytic viral therapy approved by the FDA based on therapeutic benefit demonstrated in a pivotal study.1-3 Talimogene laherparepvec is a genetically modified herpes simplex virus type 1 designed to replicate within tumors and produce granulocyte-macrophage colony-stimulating factor (GM-CSF). It is injected directly into melanoma lesions. The agent causes cell lysis, which ruptures tumors, re-

The approval of talimogene laherparepvec is based on data from a phase III, multicenter, open-label, randomized clinical trial (OPTiM) comparing talimogene laherparepvec to GM-CSF in patients with advanced melanoma (stage IIIB, IIIC, or IV) that was not surgically resectable.2 The primary endpoint of the study was durable response rate, defined as the percent of patients with complete response or partial response maintained continuously for a minimum of 6 months. OPTiM enrolled 436 patients. In the study, 16.3% of patients treated with talimogene laherparepvec achieved a durable response compared to 2.1% of patients treated with GM-CSF (P < .0001). Of the patients who experienced a durable response, 29.1% had a durable complete response and 70.8% had a durable partial response. In the study, the median time to response was

Physician-Assisted Suicide

Conclusions

continued from page 113

The European data out of Belgium and the Netherlands are relevant, to a degree, in the important debate over physician-assisted suicide in the United States. If anything, the data appear to bolster the slippery slope argument. Along with the five U.S. states that have legalized physician-assisted suicide, 25 state legislatures and the District of Columbia have considered legislation related to physicianassisted dying during 2015. And a 2014 Gallup poll found that 7 of 10 Americans believe physicians should be allowed to “legally end a patient’s life by some painless means.”5 Physicians will continue to disagree about the wisdom of prescribing lethal doses of medication to ter-

pansion of its use. Also, our studies show that many people who initially express the desire for physician-assisted suicide, once they enter hospice, ultimately change their minds. So good palliative care and hospice services do limit the expansion of physician-assisted suicide.

In Oregon, there are no data validating a concern among some experts that physician-assisted suicide will somehow inordinately affect poor and underserved populations. Indeed, more than 97% of the patients who died from ingesting a lethal dose of medication were white. More than 98% had health insurance; 90% were enrolled in hospice, and more than 72% had college degrees.

Howard L. Kaufman, MD

4.1 months (range, 1.2–16.7 months) in the talimogene laherparepvec arm. The most common adverse drug reactions in talimogene laherparepvec– treated patients were fatigue, chills, pyrexia, nausea, influenza-like illness, and injection-site pain. Most adverse reactions reported were mild or moderate in severity and generally resolved within 72 hours. The most common grade 3 or higher adverse reaction was cellulitis.2 “Advanced melanoma remains a complex disease to treat, requiring the use of several modalities over the course of a patient’s therapeutic journey,” said Howard L. Kaufman, MD, the principal investigator for the pivotal trial, who is also the Associate Director for Clinical Science at the Rutgers minally ill people who want to hasten their own deaths. Nonetheless, the states that currently have legal physician-assisted suicide and the potential for similar legal changes in other states provide the medical profession with an opportunity to evaluate what more can be done to continue to improve care at the end of life—including the use of physician-assisted suicide. n

Disclosure: Drs. Lerner and Ganzini reported no potential conflicts of interest.

References 1. Angell M: May doctors help you to die? New York Rev Books, October 11, 2012. 2. Chambaere K1, Vander Stichele R, Mortier F, et al: Recent trends in eutha-

Cancer Institute of New Jersey, and President of the Society for Immunotherapy of Cancer. “As an oncolytic viral therapy, [talimogene laherparepvec] has a unique approach and provides another option for treating eligible patients with unresectable disease that has recurred after initial surgery.” Amgen, the manufacturer of talimogene laherparepvec, intends to make the drug available imminently to patients with stage III melanoma in the United States. Amgen anticipates the average cost of therapy to be approximately $65,000. n References 1. Review of FDA hematology/oncology approvals from March 2013 to September 13, 2015 via http://www.fda.gov/ Drugs/InformationOnDrugs/ApprovedDrugs/ucm279174.htm. Accessed September 14, 2015. 2. Andtbacka H, Kaufman HL, Collichio F, et al: J Clin Oncol 33(25):28122814, 2015. 3. Lawler SE, Chiocca EA: Oncolytic virus-mediated immunotherapy: A combinatorial approach for cancer treatment. J Clin Oncol 33:2812-2814, 2015

nasia and other end-of-life practices in Belgium. N Engl J Med 372:1179-1181, 2015. 3. Oregon Public Health Division: Oregon’s Death With Dignity Act—2014. Available at https://public.health.oregon. gov/ProviderPartnerResources/EvaluationResearch/DeathwithDignityAct/ Documents/year17.pdf. Accessed October 20, 2015. 4. Ganzini L, Harvath TA, Jackson A, et al: Experiences of Oregon nurses and social workers with hospice patients who requested assistance with suicide. N Engl J Med 347:582-588, 2002. 5. McCarthy J: Seven in 10 Americans back euthanasia. Available at http://www. gallup.com/poll/171704/seven-americans-back-euthanasia.aspx. Accessed October 20, 2015.

Coming Soon in The ASCO Post Watch future issues of The ASCO Post for coverage of data presented at upcoming oncology meetings, including the Lynn Sage Breast Cancer Conference, ASH Annual Meeting, and San Antonio Breast Cancer Symposium. Visit ASCOPost.com for more information.

Quality Cancer Care: Recognizing Excellence

The QOPI® Certification Program (QCP™) congratulates the over 250 practices who have received QOPI® Certification! The QOPI® Certification Program recognizes medical oncology and hematology/oncology practices that are committed to delivering the highest quality of cancer care. QCP™ evaluates an individual practice’s performance in areas that affect patient care and safety. QCP™ recognizes the following practices who have received QOPI Certification and distinguished their practice:

ARIZONA Arizona Oncology Associates, PC Saguaro Cancer Center CALIFORNIA Moores UCSD Cancer Center FLORIDA Advanced Medical Specialtiese Holy Cross Hospital, Michael and Dianne Bienes Comprehensive Cancer Center GEORGIA Longstreet Cancer Center HAWAII OnCare Hawaii, Inc. ILLINOIS Northwestern Medical Group Oncology

MISSOURI SSM Cancer Care Truman Medical Center NEBRASKA St. Francis Cancer Treatment Center NEW MEXICO Hematology Oncology Associates, P.C. NEW YORK Roswell Park Cancer Institute Wilmot Cancer Institute OHIO Taussig Cancer Center at Cleveland Clinic – Mansfield Genesis Hematology and Cancer Care Center

The Cancer Center at Springfield Center for Cancer Care at OSF Saint Anthony Medical Center Oncology Specialists, S.C. Joliet Oncology-Hematology Associates, Ltd. Affiliated Oncologists, LLC MASSACHUSETTS Beth Israel Deaconess Medical Center Cancer Center MICHIGAN UP Health System: Marquette Hematology Oncology, ID 1920 MINNESOTA HCMC Comprehensive Cancer Center

OREGON Providence Cancer Center RHODE ISLAND Rhode Island Hospital, The Comprehensive Cancer Center SOUTH CAROLINA Coastal Cancer Center Palmetto Hematology Oncology SOUTH DAKOTA Sanford Cancer Center Hematology & Oncology TEXAS Oncology Consultants VIRGINIA Virginia Cancer Institute

5 7 1

32 6

1-2

4 5

3-4 5-6

7-8

3 1

267 QOPI Certified Practices September 2015

4 10

Hawaii

Puerto Rico Washington, DC

*Certified Practice List as of 9/28/2015. Only practices that have given permission are listed.

IS LONG-TERM TREATMENT A KEY TO SUSTAINING DEEP RESPONSES IN MYELOMA? Hear from myeloma experts and explore critical debates in multiple myeloma today. GAIN NEW DEPTHS OF UNDERSTANDING AT DEBATINGMYELOMA.COM

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