The International Journal of Targeted Therapies in Cancer April 2013

Journal North American Edition | V.2 | N.2 | 4.13

The International

Journal of Targeted Therapies in Cancer

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Clinical Articles

From the Editor

Thyroid Cancer

Alex A. Adjei, MD, PhD

Targeted Treatment Update® Selumetinib Is Active, Well-Tolerated in Low-Grade Serous Disease Adoptive T-Cell Therapy and Dendritic Cell Vaccine in Advanced Ovarian Cancer AKT Inhibitor AZD5363 Well Tolerated, Demonstrates a Response in Advanced Solid Tumors Data Needed on Combinations and Sequences of Novel Therapies Bone-Targeted Therapies Evolve in Prostate Cancer Trastuzumab Increases Risk of First Metastases in CNS in HER2+ Disease

Cabozantinib in Medullary Thyroid Cancer Daniel W. Bowles, MD, and Antonio Jimeno, MD, PhD Breast Cancer

PI3K Inhibitors in Breast Cancer Treatment Jose M. Pacheco, MD, and Cynthia X. Ma, MD, PhD N o n - Sma l l C e l l L u n g C a n c e r

Turning Concept Into Reality: Modulating the Immune System to Treat Non-Small Cell Lung Cancer Patrick M. Forde, MD, and Julie R. Brahmer, MD, MSc

Evidence for Combining Anti-HER2 Therapies Putting New Therapeutic Options into Practice

Feature Article

Preliminary Positive Results Observed for TVEC

The Challenges of Clinical Trial Participation in the Age of Targeted Therapy

Ibrutinib Receives Additional Breakthrough Designation for Chronic Lymphocytic Leukemia

Clinical Trial Profile BELLE-2 and 3: BKM120 With Fulvestrant in Postmenopausal Patients With Hormone Receptor-Positive, HER2-Negative Locally Advanced or Metastatic Breast Cancer

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North American Edition www.TargetedHC.com

e d i t o r i a l & p r o d uct i o n Editor Devera Pine dpine@onclive.com Vice President, Oncology and Managed Markets Lyn Beamesderfer lbeamesderfer@onclive.com Senior Editors Anita T. Shaffer Jason M. Broderick Beth Fand Incollingo

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Feature Article

Clinical Articles

18 The Challenges of Clinical Trial Participation in the Age of Targeted Therapy

P e e r R e v i e w e d

Clinical Trial Profile 22 BELLE-2 and -3:

BKM120 With Fulvestrant in Postmenopausal Patients With Hormone Receptor-Positive, HER2-Negative Locally Advanced or Metastatic Breast Cancer

Departments 2 4

ISSN 2168-2119 (print) ISSN 2168-2127 (online) BPA Membership Application Filed April 2013.

The content contained in this publication is for general information purposes only. The reader is encouraged to confirm the information presented with other sources.

The International Journal of Targeted Therapies in Cancer makes no representations or warranties of any kind about the completeness, accuracy, timeliness, reliability, or suitability of any of the information, including content or advertisements, contained in this publication and expressly disclaims liability for any errors and omissions that may be presented in this publication. The International Journal of Targeted Therapies in Cancer reserves the right to alter or correct any error or omission in the information it provides in this publication, without any obligations. The International Journal of Targeted Therapies in Cancer further disclaims any and all liability for any direct, indirect, consequential, special, exemplary, or other damages arising from the use or misuse of any material or information presented in this publication.

The views expressed in this publication are those of the authors and do not necessarily reflect the opinion or policy of The International Journal of Targeted Therapies in Cancer.

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Cabozantinib in Medullary Thyroid Cancer Daniel W. Bowles, MD, and Antonio Jimeno, MD, PhD Cabozantinib is a novel, small-molecule, multitargeted receptor tyrosine kinase inhibitor with particular activity against MET, VEGFR-2, and RET. This review evaluates cabozantinib’s preclinical pharmacology, pharmacokinetics, and clinical activity in medullary thyroid cancer (MTC) in phase I and phase III studies.

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B r e a s t c a n c e r

From the Editor

PI3K Inhibitors in Breast Cancer Treatment

Targeted Treatment Update®

Jose M. Pacheco, MD, and Cynthia X. Ma, MD, PhD Aberrant activation of the PI3K pathway occurs frequently in breast cancer and contributes to treatment resistance to standard therapy.

Although PI3K-specific inhibitors are in the early stages of clinical development, promising antitumor activity has been observed in phase I studies. However, combination therapies are likely required for the most effective use of these agents. In addition, the development of predictors of response remains a challenge.

Alex A. Adjei, MD, PhD

Selumetinib Is Active, Well-Tolerated in Low-Grade Serous Disease Adoptive T-Cell Therapy and Dendritic Cell Vaccine in Advanced Ovarian Cancer AKT Inhibitor AZD5363 Well Tolerated, Demonstrates a Response in Advanced Solid Tumors Data Needed on Combinations and Sequences of Novel Therapies Bone-Targeted Therapies Evolve in Prostate Cancer

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Thyroid Cancer

Trastuzumab Increases Risk of First Metastases in CNS in HER2+ Disease Evidence for Combining Anti-HER2 Therapies Putting New Therapeutic Options Into Practice Preliminary Positive Results Observed for TVEC Ibrutinib Receives Additional Breakthrough Designation for Chronic Lymphocytic Leukemia

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Turning Concept Into Reality: Modulating the Immune System to Treat Non-Small Cell Lung Cancer Patrick M. Forde, MD, and Julie R. Brahmer, MD, MSc For many years, non-small cell lung cancer (NSCLC) was thought to be a nonimmunogenic tumor unlikely to benefit from therapies aimed at augmenting endogenous antitumor immunity. Recent early-phase trial data with several agents that target immune checkpoint molecules responsible for suppression of T-cell–mediated immunity have challenged this perception. In this article, we summarize early-phase trial results in NSCLC with immune checkpoint inhibitors and vaccines, and look forward to future developments in this rapidly expanding field.

Interested in contributing?

If you’d like to submit an article outline or abstract for consideration in an upcoming issue, please e-mail Devera Pine at dpine@onclive.com.

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From the Editor Alex A. Adjei, MD, PhD e d i t o r i a l b o a r d ph y s i c i a n e d i t o r - i n - ch i e f Alex A. Adjei, MD, PhD Professor and Chair, Department of Medicine Katherine Anne Gioia Chair in Cancer Medicine Senior Vice President, Clinical Research Roswell Park Cancer Institute Buffalo, NY

Colleagues,

a s s o c i at e e d i to r s

Welcome to the second bimonthly issue of The International Journal of Targeted Therapies in Cancer for 2013.

There are many exciting new findings and clinical trial results with a variety of targeted agents. In addition, several important pivotal trials are ongoing. Consistent with our mission of providing up-to-date information for the practicing oncologist, this issue of the journal has a particular focus on targeted therapy updates that provide information on recent results of important clinical trials, and highlights important ongoing targeted therapy trials. Of interest are the BELLE-2 and -3 studies of the PI3 kinase inhibitor BKM120 in advanced or metastatic breast cancer.

One of the most challenging issues in oncology care in the United States is the low accrual rate for clinical trials (less than 5% of our patients) as compared with European countries, where participation is consistently greater than 10% of the cancer population.

It is well accepted that progress in oncology is not possible without well-designed clinical trials. Any study that does not meet accrual goals or drags on so long that, in effect, the results are irrelevant, is a failed study. A feature article in this issue explores this important topic and sheds light on some of the causes of low clinical trial participation, along with providing some ideas regarding potential solutions.

This issue also provides reviews on PI3 kinase inhibitor therapy in breast cancer, cabozantinib in medullary thyroid cancer, and modulating the immune system to treat non-small cell lung cancer.

And finally, in our news section, we present highlights of the major scientific breakthroughs reported at this month’s American Association for Cancer Research (AACR) meeting.

Please write to us with your suggestions and comments, and enjoy this issue of The International Journal of Targeted Therapies in Cancer.

Roger B. Cohen, MD Professor of Medicine Associate Director of Clinical Research Abramson Cancer Center University of Pennsylvania Philadelphia, PA Grace Dy, MD Assistant Professor Department of Medicine Roswell Park Cancer Institute Buffalo, NY

Edward Chu, MD Chief, Division of Hematology-Oncology University of Pittsburgh School of Medicine Deputy Director, University of Pittsburgh Cancer Institute Pittsburgh, PA Robert L. Coleman, MD, FACOG, FACS Professor of Gynecologic Oncology Vice Chair, Clinical Research, Department of Gynecologic Oncology The University of Texas MD Anderson Cancer Center Houston, TX Jorge Eduardo Cortes, MD Chair, CML Section, Department of Leukemia Division of Cancer Medicine The University of Texas MD Anderson Cancer Center Houston, TX Ramaswamy Govindan, MD Professor Department of Medicine Oncology Division Washington University School of Medicine St. Louis, MO Axel Grothey, MD Professor of Oncology Consultant, Medical Oncology Mayo Clinic Rochester, MN Francisco J. Hernandez-Ilizaliturri, MD Associate Professor of Medicine Department of Medical Oncology Assistant Professor of Immunology Department of Immunology Roswell Park Cancer Institute Buffalo, NY

— Alex A. Adjei, MD, PhD ph y s i c i a n E d i t o r - i n - C h i e f

Jonathan L. Kaufman, MD Assistant Professor Associate Director, Fellowship Program Department of Hematology and Medical Oncology Winship Cancer Institute Emory University Atlanta, GA

Wen Wee Ma, MBBS Assistant Professor Phase I and GI Oncology Department of Medicine Roswell Park Cancer Institute Buffalo, NY Igor Puzanov, MD, MSCI, FACP Associate Professor of Medicine Associate Director of Phase I Drug Development Clinical Director, Renal Cancer Melanoma/ Renal Cancer Program Division of Hematology-Oncology Vanderbilt University Medical Center Nashville, TN

Sagar Lonial, MD Professor, Emory School of Medicine Vice Chair of Clinical Affairs, Department of Hematology and Medical Oncology Director, Translational Research, B-cell Malignancy Program Emory University School of Medicine Atlanta, GA Joyce A. O’Shaughnessy, MD Co-Director, Breast Cancer Research Baylor Charles A. Sammons Cancer Center/Texas Oncology US Oncology Dallas, TX Roberto Pili, MD Professor of Oncology Chief, Genitourinary Section Leader, Genitourinary Program, Department of Medicine Roswell Park Cancer Institute Buffalo, NY Antoni Ribas, MD, PhD Associate Professor, HematologyOncology and Surgical Oncology Assistant Director for Clinical Programs, UCLA Human Gene Medicine Program Director, JCCC Cell and Gene Therapy Core Facility David Geffen School of Medicine University of California, Los Angeles Los Angeles, CA Hope Rugo, MD Clinical Professor, Department of Medicine (Hematology/Oncology) Director, Breast Oncology Clinical Trials Program University of California, San Francisco San Francisco, CA Oliver Sartor, MD Piltz Professor of Cancer Research Departments of Medicine and Urology Tulane University School of Medicine New Orleans, LA

To reach Dr. Adjei and/or the journal’s editorial staff, please e-mail: dpine@onclive.com.

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The International Journal of Targeted Therapies in Cancer

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August 16-17, 2013

Renaissance Washington, DC Downtown Hotel Washington, DC The 11th International Congress on Targeted Therapies in Cancer® will provide participants with cutting-edge information on novel targeted anticancer therapies now in development, including the most current clinical data on those agents and information on their mechanisms of action. The Congress will provide a unique opportunity for medical oncologists, translational researchers, and those engaged in drug development to learn from and interact with international leaders in novel therapeutic and drug discovery platforms.

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CHAIRS Alex. J Adjei, MD, PhD Professor and Chair Department of Medicine Katherine Anne Gioia Chair Roswell Park Cancer Institute Buffalo, NY

John Wright, MD, PhD Associate Branch Chief Investigational Drug Branch National Cancer Institute Bethesda, MD

Join us as we: • Assess the clinical data and treatment guidelines concerning the use of existing targeted agents for the treatment of cancer • Evaluate emerging clinical data regarding novel and existing targeted agents for the treatment of cancer • Identify appropriate clinical trials examining novel targeted agents that are designed to benefit patients with cancer

For more information and registration for this and all our live CME events, visit us today. online at

Physicians’ Education Resource is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

Physicians’ Education Resource designates this live activity for a maximum of 13.25 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Section contributors: Anna Azvolinsky, PhD, Beth Fand Incollingo, Ben Leach, and Devera Pine.

O v arian cancer

Selumetinib Is Active, Well Tolerated in Low-Grade Serous Disease The novel small-molecule inhibitor selumetinib was well tolerated and achieved an objective response in a phase II study in patients with low-grade serous carcinoma of the ovary or peritoneum. The study was published in The Lancet Oncology.1 Although women diagnosed with low-grade serous ovarian cancer tend to live longer than women with the high-grade version of the disease, their disease also tends to be chemo-resistant to first-line therapies, as well as to therapies for recurrent disease. Because of this, researchers have been exploring ways to utilize targeted therapies to treat the disease.

“After surgery, with or without pre-surgical chemotherapy, when low-grade serous ovarian cancer persists or returns, chemotherapy and hormonal therapy are relatively ineffective,” said David Gershenson, MD, professor in the Department of Gynecologic Oncology and Reproductive Medicine at The University of Texas MD Anderson Cancer Center in Houston and senior author of the study, in a statement.

Selumetinib is a selective inhibitor David Gershenson, MD of the MEK1 and MEK2 kinases found as part of the MAPK pathway. Alterations of this pathway are frequently associated with low-grade serous ovarian cancers.

In this open-label, single-arm study, 52 patients with recurrent low-grade serous ovarian or peritoneal carcinoma received oral selumetinib 50 mg twice daily until their disease progressed.

The primary endpoint was the proportion of patients who had an objective tumor response according to RECIST. Additionally, the researchers looked at whether there was any correlation between BRAF or KRAS mutational status and response to selumetinib.

O v arian C ancer

Adoptive T-Cell Therapy and Dendritic Cell Vaccine in Advanced Ovarian Cancer A two-step immunotherapy approach consisting of adoptive T-cell therapy and a dendritic cell vaccine has shown activity in a phase I advanced ovarian cancer clinical trial. The results were presented at the 2013 American Association for Cancer Research (AACR) Annual Meeting held in Washington, DC, by Lana Kandalaft, PharmD, PhD, assistant professor and director of Clinical Development and Operations at the Ovarian Cancer Research Center at the Perel4

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Eight patients (15%) had an objective response to treatment, with one patient achieving a complete response and seven patients achieving partial responses. A total of 34 patients (65%) had stable disease. No treatment-related deaths were observed.

“These are remarkably encouraging results for what can ultimately be a devastating disease,” Gershenson said.

Grade 4 toxicities observed in the study included one cardiac event, one pain event, and one pulmonary event. Grade 3 toxicities that occurred in more than one patient included gastrointestinal, dermatologic, metabolic, fatigue, anemia, pain, constitutional, and cardiac events. In this study population, 42% of patients had dose reductions and 25% of patients discontinued selumetinib due to toxicity.

The mutational status analysis found that some patients had mutations of KRAS and BRAF, but the authors noted that the differences in the percentage of patients with an objective response for any mutation were not significant.

In an accompanying editorial, Sven Mahner and Jacobus Pfisterer, of the Department of Gynecology and Gynecologic Oncology at the University Medical Center Hamburg-Eppendorf in Germany, wrote that sufficient paraffin-embedded tissue needed to analyze the biological markers associated with these tumors was only available for 65% of the patients in the study, which may have contributed to a lack of correlation between mutation status and response and outcome. However, they also wrote that the encouraging results of this trial warrant further investigation, including the investigation of the optimum dosage of the drug so as to avoid dose reductions and drug-related toxicities.2

REFERENCES 1. Farley J, Brady WE, Vathipadiekal V, et al. Selumetinib in women with recurrent low-grade serous carcinoma of the ovary or peritoneum: an open-label, singlearm, phase 2 study. Lancet Oncol. 2013;14(2):134-140.

2. Mahner S, Pfisterer J. Towards individualised treatment in ovarian cancer. Lancet Oncol. 2013;14(2):101-102.

man School of Medicine, University of Pennsylvania, Philadelphia.

All patients had recurrent, progressive, stage 3 and 4 ovarian cancer. Out of 31 patients treated with the vaccine, 19 (61%) showed a clinical benefit from the combination immunotherapy.

Eight of the 19 patients had no measurable disease at the end of the trial but remained on maintenance vaccine therapy. One patient remains disease-free after 42 months in complete remission.

Ovarian cancer is the fifth leading cause of death from cancer among women. It remains difficult to treat partly because it is typically diagnosed at an advanced stage, and there is a high unmet need for better, more durable treatment of advanced ovarian cancer. The 5-year survival rate for stage 4 invasive epithelial ovarian cancer is approximately 18%.

The new immunotherapy requires a sample of the patient’s The International Journal of Targeted Therapies in Cancer

“We are planning to take the dendritic vaccine into the primary setting with a clinical trial for patients who are in remission.”

– L ana K andalaft , P h arm D , P h D

tumor taken at the time of surgery in order to create a personalized vaccine. Researchers isolate dendritic cells (immune cells) from the tumor sample. Six of the patients in the trial received an initial version of the vaccine, and the subsequent 25 received an optimized version developed at the Penn Ovarian Cancer Research Center. According to Kandalaft, the team is continuing to work to improve the vaccine. As long as the tumor tissue from the patient is resected at the time of surgery in a sterile manner and preserved while the tissue is still alive using cryogenics, the vaccine can be created, according to Kandalaft.

Eleven patients in total were treated with the combination of dendritic cell vaccine and adoptive T-cell therapy. All of these patients initially received the vaccine but still had residual disease and went on to receive adoptive T-cell therapy. The patients’ T-cells were removed from peripheral blood samples, expanded in the laboratory, and then re-injected into patients. Seven of the 11 patients had stable disease and one had a complete response.

Analyses showed that because the patients’ immune systems were already primed by the dendritic cell vaccine to attach tumor cells, the subsequent adoptive T-cell transfer magnified the immune response further.

One of the current goals of the research team is to identify what was unique about the patient who achieved complete remission. “The patient had tumor infiltrating lymphocytes in her

o v arian cancer

AKT Inhibitor AZD5363 Well Tolerated, Demonstrates a Response in Advanced Solid Tumors The novel oral AKT inhibitor AZD5363 was well tolerated in cancer patients and resulted in two partial responses, one in a patient with ovarian cancer and one in a patient with cervical cancer. Both patients had advanced disease, had been treated previously and progressed, and had a mutation in either the AKT1 or PIK3CA gene. A third patient with ovarian cancer had prolonged stable disease as a result of treatment.

TargetedHC.com

tumor tissue at time of surgery,” said Kandalaft. Not all patients have evidence of such a spontaneous immune response in the form of immune cells that are able to infiltrate into the tumor.

Other patients in the trial who had a clinical benefit also had such a spontaneous immune response.

Both the vaccine and combination immunotherapy treatments were combined with bevacizumab, a monoclonal antibody against vascular endothelial growth factor A (VEGF-A), which blocks blood vessel formation and growth.

Patients tolerated the vaccination regimen well, according to researchers. These results suggest that further development of the two-step immunotherapy regimen is promising for treatment of ovarian cancer.

“We are planning to take the dendritic vaccine into the primary setting with a clinical trial for patients who are in remission,” said Kandalaft. Treating this population of patients who are likely to have a healthier immune system compared to patients with more advanced cancer could help prevent recurrence and may provide more benefit in this setting compared to patients with advanced cancer who have already been exposed to multiple therapies.

The study was funded by the National Institutes of Health, the Ovarian Cancer Immunotherapy Initiative, and a National Cancer Institute Ovarian Specialized Program of Research Excellence grant.

REFERENCE Kandalaft LE, Tanyi J, Chiang C, Powell D, Coukos G. Autologous whole-tumor antigen vaccination in combination with adoptive T cell therapy for patients with recurrent ovarian cancer. Presented at: AACR Annual Meeting 2013; April 6-10, 2013; Washington, DC. Abstract LB-335.

The results, from two advanced phase I trials, were presented at the American Association for Cancer Research (AACR) Annual Meeting 2013 by Udai Banerji, MD, PhD, clinical senior lecturer at the Institute of Cancer Research and The Royal Marsden NHS Foundation Trust in London, United Kingdom.

Both trials tested the safety and efficacy of AZD5363 for advanced cancer patients with solid tumors who had run out of treatment options. A Western study enrolled patients in the United Kingdom and the Netherlands. The second trial tested the oral AKT inhibitor for Japanese patients with advanced solid tumors. Two drug-dosing schedules—continuous twice daily for 7 days and intermittent twice daily for 4 days followed by 3 days of no drug—were tested.

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“The half-life of AZD5363 is shorter, which leads to twice a day dosing, and this allows considerable flexibility of dosing schedules to avoid toxicity.”

– U dai B anerji , M D , P h D

According to Banerji, previous clinical trials with other agents targeting AKT tested continuous drug doses that resulted in serious toxicities that patients could not tolerate. Testing an intermittent dose may offer more tolerable toxicities that could result in patients being able to stay on treatment and achieve a clinical response.

Thus far, a total of 92 patients have been treated in the doseescalation studies. The 480-mg twice-daily intermittent dose was generally well tolerated in both the Western and Japanese studies. Common adverse events included hyperglycemia, rash, and diarrhea. Banerji noted that a rise in blood sugar is a consequence of targeting the AKT pathway and provides proof that the drug is working. The two patients who responded to the treatment did not have a toxicity profile that was different from other patients in the trial.

“Surprisingly, the hyperglycemia or high blood sugar for short periods of time while the patients are on an intermittent schedule is very well tolerated by patients, and the blood sugar stabilizes back to normal on the days the patient is off treatment,” said Banerji. “Rash and diarrhea are minimal and very well controlled in the intermittent schedules.”

“The half-life of AZD5363 is shorter, which leads to twice a day dosing, and this allows considerable flexibility of dosing schedules to avoid toxicity,” said Banerji.

Treatment with AZD5363 led to a more than 30% reduction in the levels of two proteins, pPRAS40 and pGSK3 beta, in both hair and blood samples from patients, suggesting that the oral therapy was inhibiting AKT. Both proteins are targets of the AKT protein kinase.

AZD5363 is being developed by UK-based AstraZeneca. The drug targets all three forms of AKT—AKT1, AKT2, and AKT3. The drug prevents phosphorylation of AKT substrates, as well as inhibits proteins downstream of AKT in the signaling cascade.

Preclinical testing showed antitumor activity, with the highest level of sensitivity exhibited by breast cancer cell lines. The presence of a PIK3CA or PTEN mutation, both of which are part of the PI3K-AKT cell-signaling pathway, correlated with a response in preclinical tumor models. The PI3K-AKT pathway is generally important in cancer, with many tumors having mutations in this signaling network.

While the presence of a mutation in the PI3K-AKT pathway was not a prerequisite for enrollment in the trial thus far, Banerji noted that an expansion of the phase I trial for patients harboring a mutation in the pathway is being considered.

AZD5363 is also being tested in two other phase I trials that are currently ongoing. One trial is testing the treatment for advanced breast cancer in combination with the chemotherapy paclitaxel. A second trial is ongoing to test the oral AKT inhibitor as a monotherapy for treatment of metastatic castration-resistant prostate cancer.

REFERENCE Banerji U, Ranson M, Schellens JHM, et al. Results of two phase I multicenter trials of AZD5363, an inhibitor of AKT1, 2 and 3: biomarker and early clinical evaluation in Western and Japanese patients with advanced solid tumors. Presented at: AACR Annual Meeting 2013; April 6-10, 2013; Washington, DC. Abstract LB-66.

P rostate C ancer

Data Needed on Combinations and Sequences of Novel Therapies Following recent FDA approvals of several new therapies for prostate cancer, oncologists are grappling with questions about which combinations or sequences of therapies will improve outcomes.

Clinical trials are needed to resolve that uncertainty, according to Robert Dreicer MD, MS, who spoke at the 6th Annual Interdisciplinary Prostate Cancer Congress held on March 16 in New York City.

Dreicer, chairman of the Department of Solid Tumor Oncology at the Taussig Cancer Institute and professor of Medicine 6

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“If a patient takes abiraterone and then enzalutamide, does he benefit by adding denosumab or zoledronic acid, or are those drugs not needed because there are such effective therapies now?”

– R obert D reicer M D , M S

The International Journal of Targeted Therapies in Cancer

at the Cleveland Clinic in Ohio, said that trials will be crucial in determining which drugs are synergistic and which are toxic in combination—as was the case with sunitinib and bevacizumab in the treatment of renal cell carcinoma.

Potential Combinations A recently published case report may provide the basis for exploring the combination of sipuleucel-T and enzalutamide.1 The case report describes a patient with metastatic castration-resistant prostate cancer (mCRPC) who responded well to enzalutamide as part of a phase I study. When the patient’s prostate-specific antigen (PSA) level rose after 14 months, sipuleucel-T was added to the treatment regimen. Six months later, the patient had an undetectable PSA level and went on to maintain his disease status for a year without radiographic change. The authors noted that sipuleucel-T generally does not produce significant PSA reductions, and that there has been only one previously published report of a durable complete PSA response in a patient with metastatic disease.

Emerging data also suggest a benefit from the combination of next-generation androgen receptor (AR) antagonists, such as enzalutamide, and testosterone-suppressing lyase inhibitors, such as abiraterone. In a study presented at the 2011 American Society of Clinical Oncology Annual Meeting, 47 patients with progressive mCPRC were treated with enzalutamide and underwent serial bone marrow biopsies.2 Based on increases in mean plasma testosterone and decreases in PSA, investigators concluded that the efficacy of enzalutamide in CRPC can be attributed to potent inhibition of AR signaling. Enzalutamide increases bone marrow testosterone and decreases nuclear AR, the authors wrote, whereas previous research had shown that abiraterone decreased testosterone and increased AR copy number.3 These results suggest evaluation of the two androgen signaling inhibitors in combination.

A phase II safety and tolerability trial of the two drugs in combination in patients with mCRPC is being conducted at The University of Texas MD Anderson Cancer Center, with results expected in the fall or winter (ClinicalTrials.gov Identifier: NCT01650194).

In the phase III AFFIRM4 and COU-AA-3015 studies, respectively, enzalutamide and abiraterone delayed time to first skeletal-related event (SRE) in patients with mCRPC. That raises questions, Dreicer said, about whether such patients also need osteoclast inhibitors. “If a patient takes abiraterone and then enzalutamide, does he benefit by adding denosumab or zoledronic acid, or are those drugs not needed because there are such effective therapies now?”

Because radium-223 also demonstrated a delay in time to first SRE in the ALSYMPCA trial,6 and because its nonhematologic toxicity profile is very low, trials of radium-223 in combination with AR-targeted agents may provide important information.

Clinical Trial Endpoints and Reimbursement Concerns To support the process of testing potential drug combinations for the treatment of prostate cancer, the FDA should change its stance on what constitutes a valid endpoint in clinical trials, Dreicer said. “Can you continue to anticipate, in an era where multiple trials are going to be done with multiple overlapping mechanisms, that we can still use overall survival as an endpoint? The likelihood, as we begin to start thinking about these new combinations, is that it’s not going to be acceptable.”

Furthermore, the stage of disease for which agents are currently approved does not necessarily represent the most rational way to use them. “These are drugs with unique mechanisms that most likely will work through the spectrum of disease,” Dreicer said of treatments including enzalutamide and radium-223.

A further complication on the horizon is a change in the reimbursement paradigm to favor value-based care. “Payers will say, ‘Do what you think is best for the patient. Here’s the amount of money you have to do it,’” he said. “Whether a treatment that makes scientific sense will be the most cost-effective way to take care of patients—we will have to think differently about trial design. It’s not just, ‘Can we think about adding three drugs together because we can put three drugs together,’ but whether the mechanism and outcome will drive what we want—improved patient outcome.”

Sequencing New Therapies

REFERENCES

Another aim of clinical trials should be to determine the order in which therapies should be given, both as a cost-effectiveness measure and in order to avoid toxicities, Dreicer said. One area where that information will be important is in patients with mCRPC who are asymptomatic. Treatment choices may soon include either abiraterone or enzalutamide, but there is no information yet on how to sequence the two drugs for maximum effectiveness.

“We have sipuleucel-T as an approved agent in this clinical space,” Dreicer said, “but is there a rationale to give it with enzalutamide or abiraterone? Does sequence matter, and does it impact the immune response? We don’t know.” It will also be worthwhile to study whether, when using new therapies, oncologists will be able to drop older medications out of combination regimens or sequences for patients with mCRPC, he said.

1. Graff JN, Drake CG, Beer TM. Complete biochemical (prostate-specific antigen) response to sipuleucel-T with enzalutamide in castration-resistant prostate cancer: a case report with implications for future research. Urology. 2013;81(2):381-383.

2. Efstathiou E, Titus MA, Tsavachidou D, et al. MDV3100 effects on androgen receptor (AR) signaling and bone marrow testosterone concentration modulation: a preliminary report. J Clin Oncol. 2011;29(15 suppl; abstr 4501).

3. Efstathiou E, Titus M, Tsavachidou D, et al. Effects of abiraterone acetate on androgen signaling in castrate-resistant prostate cancer in bone. J Clin Oncol. 2012;30(6):637-643.

4. Scher HI, Fizazi K, Saad F, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med. 2012;367:1187-1197.

5. Logothetis CJ, Basch E, Molina A, et al. Effect of abiraterone acetate and prednisone compared with placebo and prednisone on pain control and skeletal-related events in patients with metastatic castration-resistant prostate cancer: exploratory analysis of data from the COU-AA-301 randomised trial. Lancet Oncol. 2013;13(12):1210-1217.

6. Parker C, Nilsson S, Heinrich D. Updated analysis of the phase III, double-blind, randomized, multinational study of radium-223 chloride in castration-resistant prostate cancer (CRPC) patients with bone metastases (ALSYMPCA). J Clin Oncol.

2012;30(suppl; abstr LBA4512).

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Jakafi® (JAK-ah-fye)—First and Only FDA-Approved Agent for MYELOFIBROSIS (MF)*

REGULATE REDUCE JAK signaling

splenomegaly and symptoms of MF

JAK2

JAK1

Jakafi

*Intermediate or high-risk MF.

Indications and Usage Jakafi is indicated for treatment of patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, post–polycythemia vera myelofibrosis and post–essential thrombocythemia myelofibrosis.

Important Safety Information • Treatment with Jakafi can cause hematologic adverse reactions, including thrombocytopenia, anemia and neutropenia, which are each dose-related effects, with the most frequent being thrombocytopenia and anemia. A complete blood count must be performed before initiating therapy with Jakafi. Complete blood counts should be monitored as clinically indicated and dosing adjusted as required

Jakafi is a registered trademark of Incyte Corporation. © 2012, Incyte Corporation. All rights reserved. RUX-1160B 07/12

• The three most frequent non-hematologic adverse reactions were bruising, dizziness and headache • Patients with platelet counts <200 × 109/L at the start of therapy are more likely to develop thrombocytopenia during treatment.

Thrombocytopenia was generally reversible and was usually managed by reducing the dose or temporarily withholding Jakafi.

If clinically indicated, platelet transfusions may be administered • Patients developing anemia may require blood transfusions.

Dose modifications of Jakafi for patients developing anemia may also be considered • Neutropenia (ANC <0.5 × 109/L) was generally reversible and was managed by temporarily withholding Jakafi • Patients should be assessed for the risk of developing serious bacterial, mycobacterial, fungal and viral infections. Active serious infections should have resolved before starting Jakafi.

Physicians should carefully observe patients receiving Jakafi for signs and symptoms of infection (including herpes zoster)

Jakafi demonstrated superior reductions in spleen volume and improvements in symptom scores at Week 241,2,a,b Percent Change in Total Symptom Score (TSS) in Individual Patients From Baseline to Week 24 or Last Observation1,a,b

Percent Change in Spleen Volume in Individual Patients From Baseline to Week 24 or Last Observation1,a

150

20 0 -20 -40

35% Reduction

-60 -80

Upper 50th Percentile

Jakafi (n = 155)

Upper 50th Percentile

100 50 0 -50

-100

IMPROVEMENT WORSENING

40

Change From Baseline (%)

60 IMPROVEMENT WORSENING

Change From Baseline (%)

80

50% Improvement Upper 50th Percentile

Placebo (n = 153)

In these charts, each bar represents an individual patient’s response.

Upper 50th Percentile

Jakafi (n = 145)

Placebo (n = 145)

Worsening of TSS is truncated at 150%.

At Week 24, significantly more patients receiving Jakafi vs placebo had — A ≥35% reduction in spleen volume (41.9% vs 0.7%, respectively; P < 0.0001)1,2,a — A ≥50% improvement in TSS (45.9% vs 5.3%, respectively; P < 0.0001)1,2,a,b Reductions in spleen volume and improvements in TSS were seen with Jakafi in both JAK2 V617F-positive patients and JAK2 V617F-negative patients, relative to placebo2

Visit www.jakafi.com/explore for more information on Jakafi and MF, plus valuable educational resources.

and initiate appropriate treatment promptly • A dose modification is recommended when administering Jakafi with strong CYP3A4 inhibitors or in patients with renal or hepatic impairment [see Dosage and Administration]. Patients should be closely monitored and the dose titrated based on safety and efficacy • There are no adequate and well-controlled studies of Jakafi in pregnant women. Use of Jakafi during pregnancy is not recommended and should only be used if the potential benefit justifies the potential risk to the fetus • Women taking Jakafi should not breast-feed. Discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother

a As studied in COMFORT-I, a randomized, double-blind, placebo-controlled phase III study

with 309 total patients (United States, Canada, Australia). The primary endpoint was the proportion of subjects achieving a ≥35% reduction in spleen volume from baseline to Week 24 as measured by magnetic resonance imaging (MRI) or computed tomography (CT) .

A secondary endpoint was the proportion of subjects with a ≥50% reduction in TSS from baseline to Week 24 as measured by the daily patient diary, the modified Myelofibrosis Symptom Assessment Form (MFSAF v2.0).1,2

b Symptom scores were captured by a daily patient diary recorded for 25 weeks.

TSS encompasses debilitating symptoms of MF, including abdominal discomfort, early satiety, pain under left ribs, pruritus, night sweats and bone/muscle pain.

Symptom scores ranged from 0 to 10 with 0 representing symptoms “absent” and 10 representing “worst imaginable” symptoms. These scores were added to create the daily total score, which has a maximum of 60. At baseline, mean TSS was 18.0 in the Jakafi group and 16.5 in the placebo group.1,2

References: 1. Jakafi Prescribing Information. Incyte Corporation. June 2012. 2. Verstovsek S, Mesa RA, Gotlib J, et al. N Engl J Med. 2012;366:799-807.

Please see Brief Summary of Full Prescribing Information on the following page.

JAK targeted to make a difference

Table 2: Worst Hematology Laboratory Abnormalities in the Placebo-controlled Studya Jakafi Placebo (N=155) (N=151) Laboratory All All Grade 4 Grades Grade 3 Grade 4 Parameter Gradesb Grade 3 BRIEF SUMMARY: For Full Prescribing Information, see package insert. (%) (%) (%) (%) (%) (%) INDICATIONS AND USAGE Jakafi is indicated for treatment of patients with intermediate or high-risk Thrombocytopenia 69.7 9.0 3.9 30.5 1.3 0 myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essential Anemia 96.1 34.2 11.0 86.8 15.9 3.3 thrombocythemia myelofibrosis.

Neutropenia 18.7 5.2 1.9 4.0 0.7 1.3 CONTRAINDICATIONS None.

WARNINGS AND PRECAUTIONS Thrombocytopenia, Anemia and Neutropenia Treatment a Presented values are worst Grade values regardless of baseline b National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0 with Jakafi can cause hematologic adverse reactions, including thrombocytopenia, anemia and neutropenia.

A complete blood count must be performed before initiating therapy with Jakafi [see Dosage and Additional Data from the Placebo-controlled Study 25.2% of patients treated with Jakafi and 7.3% of Administration (2.1) in Full Prescribing Information]. Patients with platelet counts of less than 200 X 109/L patients treated with placebo developed newly occurring or worsening Grade 1 abnormalities in alanine transat the start of therapy are more likely to develop thrombocytopenia during treatment. Thrombocytopenia was aminase (ALT). The incidence of greater than or equal to Grade 2 elevations was 1.9% for Jakafi with 1.3% Grade 3 and no Grade 4 ALT elevations. 17.4% of patients treated with Jakafi and 6.0% of patients treated generally reversible and was usually managed by reducing the dose or temporarily withholding Jakafi. If with placebo developed newly occurring or worsening Grade 1 abnormalities in aspartate transaminase clinically indicated, platelet transfusions may be administered [see Dosage and Administration (2.2) in Full (AST). The incidence of Grade 2 AST elevations was 0.6% for Jakafi with no Grade 3 or 4 AST elevations.

Prescribing Information, and Adverse Reactions]. Patients developing anemia may require blood trans16.8% of patients treated with Jakafi and 0.7% of patients treated with placebo developed newly occurring or fusions. Dose modifications of Jakafi for patients developing anemia may also be considered. Neutropenia worsening Grade 1 elevations in cholesterol. The incidence of Grade 2 cholesterol elevations was 0.6% for (ANC less than 0.5 X 109/L) was generally reversible and was managed by temporarily withholding Jakafi Jakafi with no Grade 3 or 4 cholesterol elevations. [see Adverse Reactions]. Complete blood counts should be monitored as clinically indicated and dosing DRUG INTERACTIONS Drugs That Inhibit or Induce Cytochrome P450 Enzymes Ruxolitinib adjusted as required [see Dosage and Administration (2.2) in Full Prescribing Information, and Adverse is predominantly metabolized by CYP3A4. Strong CYP3A4 inhibitors: The C max and AUC of ruxolitinib Reactions]. Infections Patients should be assessed for the risk of developing serious bacterial, mycobac- increased 33% and 91%, respectively, with Jakafi administration (10 mg single dose) following ketoconazole terial, fungal and viral infections. Active serious infections should have resolved before starting therapy with 200 mg twice daily for four days, compared to receiving Jakafi alone in healthy subjects. The half-life was also Jakafi. Physicians should carefully observe patients receiving Jakafi for signs and symptoms of infection and prolonged from 3.7 to 6.0 hours with concurrent use of ketoconazole. The change in the pharmacodynamic initiate appropriate treatment promptly. Herpes Zoster Physicians should inform patients about early signs marker, pSTAT3 inhibition, was consistent with the corresponding ruxolitinib AUC following concurrent adminand symptoms of herpes zoster and advise patients to seek treatment as early as possible [see Adverse istration with ketoconazole. When administering Jakafi with strong CYP3A4 inhibitors a dose reduction is Reactions]. recommended [see Dosage and Administration (2.4) in Full Prescribing Information]. Patients should be ADVERSE REACTIONS Clinical Trials Experience Because clinical trials are conducted under closely monitored and the dose titrated based on safety and efficacy. Mild or moderate CYP3A4 inhibitors: widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly There was an 8% and 27% increase in the Cmax and AUC of ruxolitinib, respectively, with Jakafi administration compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The (10 mg single dose) following erythromycin, a moderate CYP3A4 inhibitor, at 500 mg twice daily for 4 days, safety of Jakafi was assessed in 617 patients in six clinical studies with a median duration of follow-up of 10.9 compared to receiving Jakafi alone in healthy subjects. The change in the pharmacodynamic marker, pSTAT3 months, including 301 patients with myelofibrosis in two Phase 3 studies. In these two Phase 3 studies, inhibition was consistent with the corresponding exposure information. No dose adjustment is recommended patients had a median duration of exposure to Jakafi of 9.5 months (range 0.5 to 17 months), with 88.7% of when Jakafi is coadministered with mild or moderate CYP3A4 inhibitors (eg, erythromycin). CYP3A4 patients treated for more than 6 months and 24.6% treated for more than 12 months. One hundred and inducers: The Cmax and AUC of ruxolitinib decreased 32% and 61%, respectively, with Jakafi administration eleven (111) patients started treatment at 15 mg twice daily and 190 patients started at 20 mg twice daily. In (50 mg single dose) following rifampin 600 mg once daily for 10 days, compared to receiving Jakafi alone in a double-blind, randomized, placebo-controlled study of Jakafi, 155 patients were treated with Jakafi. The healthy subjects. In addition, the relative exposure to ruxolitinib’s active metabolites increased approximately most frequent adverse drug reactions were thrombocytopenia and anemia [see Table 2]. Thrombocytopenia, 100%. This increase may partially explain the reported disproportionate 10% reduction in the pharmacoanemia and neutropenia are dose related effects. The three most frequent non-hematologic adverse reactions dynamic marker pSTAT3 inhibition. No dose adjustment is recommended when Jakafi is coadministered with were bruising, dizziness and headache [see Table 1]. Discontinuation for adverse events, regardless of a CYP3A4 inducer. Patients should be closely monitored and the dose titrated based on safety and efficacy. causality, was observed in 11.0% of patients treated with Jakafi and 10.6% of patients treated with placebo. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C: There are no adequate Following interruption or discontinuation of Jakafi, symptoms of myelofibrosis generally return to and well-controlled studies of Jakafi in pregnant women. In embryofetal toxicity studies, treatment with pretreatment levels over a period of approximately 1 week. There have been isolated cases of patients discon- ruxolitinib resulted in an increase in late resorptions and reduced fetal weights at maternally toxic doses. tinuing Jakafi during acute intercurrent illnesses after which the patient’s clinical course continued to worsen; Jakafi should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. however, it has not been established whether discontinuation of therapy contributed to the clinical course in Ruxolitinib was administered orally to pregnant rats or rabbits during the period of organogenesis, at doses these patients. When discontinuing therapy for reasons other than thrombocytopenia, gradual tapering of the of 15, 30 or 60 mg/kg/day in rats and 10, 30 or 60 mg/kg/day in rabbits. There was no evidence of teratodose of Jakafi may be considered [see Dosage and Administration (2.6) in Full Prescribing Information]. genicity. However, decreases of approximately 9% in fetal weights were noted in rats at the highest and maternally toxic dose of 60 mg/kg/day. This dose results in an exposure (AUC) that is approximately 2 times Table 1 presents the most common adverse reactions occurring in patients who received Jakafi in the doublethe clinical exposure at the maximum recommended dose of 25 mg twice daily. In rabbits, lower fetal weights blind, placebo-controlled study during randomized treatment. of approximately 8% and increased late resorptions were noted at the highest and maternally toxic dose of Table 1: Adverse Reactions Occurring in Patients on Jakafi in the Double-blind, Placebo-controlled 60 mg/kg/day. This dose is approximately 7% the clinical exposure at the maximum recommended dose. In Study During Randomized Treatment a pre- and post-natal development study in rats, pregnant animals were dosed with ruxolitinib from implanJakafi Placebo tation through lactation at doses up to 30 mg/kg/day. There were no drug-related adverse findings in pups for (N=155) (N=151) fertility indices or for maternal or embryofetal survival, growth and development parameters at the highest Adverse All All dose evaluated (34% the clinical exposure at the maximum recommended dose of 25 mg twice daily).

Reactions Gradesa Grade 3 Grade 4 Grades Grade 3 Grade 4 Nursing Mothers It is not known whether ruxolitinib is excreted in human milk. Ruxolitinib and/or its metabolites were excreted in the milk of lactating rats with a concentration that was 13-fold the maternal (%) (%) (%) (%) (%) (%) plasma. Because many drugs are excreted in human milk and because of the potential for serious adverse Bruisingb 23.2 0.6 0 14.6 0 0 reactions in nursing infants from Jakafi, a decision should be made to discontinue nursing or to discontinue Dizzinessc 18.1 0.6 0 7.3 0 0 the drug, taking into account the importance of the drug to the mother. Pediatric Use The safety and effecHeadache 14.8 0 0 5.3 0 0 tiveness of Jakafi in pediatric patients have not been established. Geriatric Use Of the total number of Urinary Tract Infectionsd 9.0 0 0 5.3 0.7 0.7 myelofibrosis patients in clinical studies with Jakafi, 51.9% were 65 years of age and older. No overall differWeight Gaine 7.1 0.6 0 1.3 0.7 0 ences in safety or effectiveness of Jakafi were observed between these patients and younger patients. Renal Impairment The safety and pharmacokinetics of single dose Jakafi (25 mg) were evaluated in a study in Flatulence 5.2 0 0 0.7 0 0 healthy subjects [CrCl 72-164 mL/min (N=8)] and in subjects with mild [CrCl 53-83 mL/min (N=8)], Herpes Zosterf 1.9 0 0 0.7 0 0 moderate [CrCl 38-57 mL/min (N=8)], or severe renal impairment [CrCl 15-51 mL/min (N=8)]. Eight (8) a National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0 b includes contusion, ecchymosis, hematoma, injection site hematoma, periorbital hematoma, vessel puncture site additional subjects with end stage renal disease requiring hemodialysis were also enrolled. The pharmacokinetics of ruxolitinib was similar in subjects with various degrees of renal impairment and in those with hematoma, increased tendency to bruise, petechiae, purpura c includes dizziness, postural dizziness, vertigo, balance disorder, Meniere’s Disease, labyrinthitis normal renal function. However, plasma AUC values of ruxolitinib metabolites increased with increasing d includes urinary tract infection, cystitis, urosepsis, urinary tract infection bacterial, kidney infection, pyuria, bacteria severity of renal impairment. This was most marked in the subjects with end stage renal disease requiring urine, bacteria urine identified, nitrite urine present hemodialysis. The change in the pharmacodynamic marker, pSTAT3 inhibition, was consistent with the e includes weight increased, abnormal weight gain corresponding increase in metabolite exposure. Ruxolitinib is not removed by dialysis; however, the removal f includes herpes zoster and post-herpetic neuralgia of some active metabolites by dialysis cannot be ruled out. When administering Jakafi to patients with Description of Selected Adverse Drug Reactions Anemia In the two Phase 3 clinical studies, median moderate (CrCl 30-59 mL/min) or severe renal impairment (CrCl 15-29 mL/min) with a platelet count time to onset of first CTCAE Grade 2 or higher anemia was approximately 6 weeks. One patient (0.3%) between 100 X 109/L and 150 X 109/L and patients with end stage renal disease on dialysis a dose reduction discontinued treatment because of anemia. In patients receiving Jakafi, mean decreases in hemoglobin is recommended [see Dosage and Administration (2.5) in Full Prescribing Information]. Hepatic reached a nadir of approximately 1.5 to 2.0 g/dL below baseline after 8 to 12 weeks of therapy and then Impairment The safety and pharmacokinetics of single dose Jakafi (25 mg) were evaluated in a study in gradually recovered to reach a new steady state that was approximately 1.0 g/dL below baseline. This pattern healthy subjects (N=8) and in subjects with mild [Child-Pugh A (N=8)], moderate [Child-Pugh B (N=8)], or was observed in patients regardless of whether they had received transfusions during therapy. In the severe hepatic impairment [Child-Pugh C (N=8)]. The mean AUC for ruxolitinib was increased by 87%, 28% randomized, placebo-controlled study, 60% of patients treated with Jakafi and 38% of patients receiving and 65%, respectively, in patients with mild, moderate and severe hepatic impairment compared to patients placebo received red blood cell transfusions during randomized treatment. Among transfused patients, the with normal hepatic function. The terminal elimination half-life was prolonged in patients with hepatic median number of units transfused per month was 1.2 in patients treated with Jakafi and 1.7 in placebo impairment compared to healthy controls (4.1-5.0 hours versus 2.8 hours). The change in the pharmacotreated patients. Thrombocytopenia In the two Phase 3 clinical studies, in patients who developed Grade 3 dynamic marker, pSTAT3 inhibition, was consistent with the corresponding increase in ruxolitinib exposure or 4 thrombocytopenia, the median time to onset was approximately 8 weeks. Thrombocytopenia was except in the severe (Child-Pugh C) hepatic impairment cohort where the pharmacodynamic activity was generally reversible with dose reduction or dose interruption. The median time to recovery of platelet counts more prolonged in some subjects than expected based on plasma concentrations of ruxolitinib. When above 50 X 109/L was 14 days. Platelet transfusions were administered to 4.7% of patients receiving Jakafi administering Jakafi to patients with any degree of hepatic impairment and with a platelet count between and to 4.0% of patients receiving control regimens. Discontinuation of treatment because of thrombo- 100 X 109/L and 150 X 109/L, a dose reduction is recommended [see Dosage and Administration (2.5) in cytopenia occurred in 0.7% of patients receiving Jakafi and 0.9% of patients receiving control regimens. Full Prescribing Information].

Patients with a platelet count of 100 X 109/L to 200 X 109/L before starting Jakafi had a higher frequency of Grade 3 or 4 thrombocytopenia compared to patients with a platelet count greater than 200 X 109/L (16.5% Jakafi is a registered trademark of Incyte Corporation. All rights reserved. versus 7.2%). Neutropenia In the two Phase 3 clinical studies, 1.0% of patients reduced or stopped Jakafi U.S. Patent No. 7,598,257 because of neutropenia. Table 2 provides the frequency and severity of clinical hematology abnormalities © 2011-2012 Incyte Corporation. All rights reserved. reported for patients receiving treatment with Jakafi or placebo in the placebo-controlled study.

Issued: June 2012 RUX-1040a

prostate cancer

“Bisphosphonates used to be the only option, but treatment has evolved over the years.”

Bone-Targeted Therapies Evolve in Prostate Cancer The treatment of bone metastases in prostate cancer has changed over the years, and several options are now either available or under development. Daniel P. Petrylak, MD, director of the Genitourinary Oncology Program at Yale Cancer Center in New Haven, Connecticut, spoke about advances in bone-targeted therapy at the 6th Annual Interdisciplinary Prostate Cancer Congress, which was held in New York City on March 16. “Bisphosphonates used to be the only option,” he said, “but treatment has evolved over the years.”

Bone resorption and bone formation are dysregulated in prostate cancer, and clinical evidence indicates that both processes contribute to bone metastases. The mechanisms for bone metastases are complex, and include tumor stimulation of osteoclasts and osteoblasts, and the response of the bone microenvironment. In addition, factors independent of the tumor may contribute to bone resorption.1 The bisphosphonate zoledronic acid is approved for the treatment of bone metastases in hormone-refractory prostate cancer and has been shown to reduce time to first skeletal-related event (SRE),2 and denosumab, a RANKL inhibitor, has been shown to prevent osteoclast-mediated bone resorption.3 In randomized trials, the incidence of osteonecrosis of the jaw (ONJ) and renal toxicity were about the same for denosumab and bisphosphonates, Petrylak said. “ONJ needs to be monitored for in all bone-targeted therapy.”

Two radionuclides—samarium 153 lexidronam and strontium 89—are FDA-approved for treatment of bone metastases. Clinicians are sometimes reluctant to use these agents in combination with chemotherapy, and as a result, Petrylak said, “we tend to use these too late.” But clinical trials have demonstrated that both agents can be successfully combined with chemotherapy, he said.

The phase III ALSYMPCA) trial analyzed the use of radium-223 chloride in patients with castration-resistant prostate cancer with bone metastases.4 Radium-223 is an alpha-emitter that targets bone metastases with high-energy alpha-particles of short range.

The study randomized 921 patients to radium-223 plus best standard of care or placebo plus best standard of care. Radium-223 significantly improved overall survival (OS), the primary endpoint, with patients in the experimental arm achieving a median OS of 14.9 months versus 11.3 months for the placebo arm (hazard ratio [HR] = .695; 95% CI, 0.581-0.832; P = .00007).These results represent a 30.5% reduction in the risk of death. The survival benefit was preserved both with and without current use of bisphosphonates and with and without prior use of docetaxel.

TargetedHC.com

– D aniel P. P etr y lak , M D

Radium-223 significantly prolonged time to first SRE (median, 15.6 months in the treatment arm vs 9.8 months for placebo; HR = 0.658; 95% CI, 0.522-0.830; P = .00037).

The safety and tolerability of radium-223 were favorable, with low myelosuppression. “The safety profile was basically the same as the placebo arm,” Petrylak said. Combination studies with hormonal and chemotherapeutic agents are now under way.

REFERENCES 1. Guise TA, Mohammad KS, Clines G, et al. Basic mechanisms responsible for osteolytic and osteoblastic bone metastases. Clin Cancer Res. 2006;12:6213s-6216s.

2. Saad F, Gleason DM, Murray R, et al. A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma.

J Natl Cancer Inst. 2002;94(19):1458-1468.

3. Fizazi K, Carducci M, Smith M, et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet. 2011;377(9768):813-822.

4. Parker C, Nilsson S, Heinrich, D. Updated analysis of the phase III, double-blind, randomized, multinational study of radium-223 chloride in castration-resistant prostate cancer (CRPC) patients with bone metastases (ALSYMPCA). J Clin Oncol.

2012;30(suppl; abstr LBA4512).

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B reast C ancer

Trastuzumab Increases Risk of First Metastases in CNS in HER2+ Disease Patients with human epidermal growth factor receptor 2 (HER2)positive breast cancer who receive adjuvant treatment with trastuzumab are at an increased risk of developing central nervous system (CNS) metastases as the site of first recurrence, according to the results of a retrospective review of studies involving the targeted agent. The results were published in the journal Annals of Oncology.

Trastuzumab is a monoclonal antibody that binds to HER2 on the tumor cell surface, where it is then able to induce an antibody-dependent cell-mediated cytotoxicity against those cells.

Previous studies have sporadically reported that CNS mestatases are the first site of recurrence in patients who receive adjuvant trastuzumab. Prior to the use of trastuzumab, the incidence of CNS disease as the first site of recurrence was relatively uncommon.

The meta-analysis included 9020 patients across four randomized trials in which adjuvant trastuzumab was administered for 1 year to patients with HER2-positive breast cancer who reported CNS metastases as the first site of disease recurrence. The authors analyzed the incidence and relative risk (RR) of these metastases.

A total of 2.56% of HER2-positive patients who received adjuvant trastuzumab experienced CNS metastases as the first site of disease recurrence (95% CI, 2.07%-3.01%) compared with 1.94% of

breast cancer

Evidence for Combining Anti-HER2 Therapies Approximately 20% of human breast cancers are characterized by overexpression of the HER2 receptor tyrosine kinase molecule. Multiple antibodies have been designed to specifically target HER2, and each one is able to target the molecule at a different epitope, or a specific site on the molecule.

Using this knowledge, researchers have looked at ways of combining multiple antibodies that bind at different HER2 sites to maximize the effect of both therapies, and several novel combinations are being researched for future use in HER2-positive breast cancer. Mark Pegram, MD, director of the Breast Cancer Program at the Stanford Women’s Cancer Center in California, discussed this research in a presentation at the 30th Annual Miami Breast Cancer Conference, held March 7-10, 2013.

Trastuzumab was one of the first monoclonal antibodies designed to target HER2. Once trastuzumab binds to HER2 on the tumor cell surface, the drug induces an antibody-dependent cellmediated cytotoxicity against the tumor cell.

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HER2-positive patients who did not receive adjuvant trastuzumab (95% CI, 1.54%-2.38%). The RR of the CNS as the first site of relapse in the patients treated with trastuzumab was 1.35 (95% CI, 1.02-1.78; P = .038) compared with the control arms of patients who did not receive trastuzumab.

The ratio of CNS metastases to the total number of recurrence events was 16.94% in the trastuzumab-treated patients (95% CI, 10.85%-24.07%) compared with 8.33% in the control group (95% CI, 6.49%-10.86%).

The authors reported a number of limitations of the study, including a lack of available patient data, no knowledge of the timing and subsequent outcomes of these metastases, and an inability to determine whether the prognosis or clinical course of these patients differs from patients who only develop an extracranial relapse after adjuvant trastuzumab.

However, because the proportion of patients with CNS metastases as the first site of recurrence nearly doubled in HER2-positive breast cancer patients who received adjuvant trastuzumab, the authors stated that clinicians should be aware of this increased incidence and monitor patients closely after treatment.

REFERENCE Olson EM, Abdel-Rasoul M, Maly J, et al. Incidence and risk of central nervous system metastases as site of first recurrence in patients with HER2-positive breast cancer treated with adjuvant trastuzumab [published online ahead of print March 4, 2013]. Ann Oncol.

2013. doi:10.1093/annonc/mdt036.

Pertuzumab is a second-generation humanized monoclonal antibody that has the same amino acid sequence as trastuzumab. However, it binds at a different epitope than trastuzumab: the dimerization interface of the HER2 molecule.

Dimerization is a critical part of how tumor cells are able to proliferate since it allows members of the HER family to pair up, which then allows for the activation of downstream signaling.

Increased dimerization is associated with HER2 overexpression.

“This research suggests that there might be an opportunity for yet another axis to perturb HER family signaling, including HER2, if you could disrupt not only heterodimers but also heterotetramers.”

– M ark P egram , M D

The International Journal of Targeted Therapies in Cancer

Pertuzumab blocks dimerization between HER2 and the three other members of the HER family.. “[Pertuzumab] has a unique mechanism of action,” Pegram said. “Since it binds to a different part of the HER2 receptor, you can actually give both trastuzumab and pertuzumab, and they can both bind at the same time, and that pairing results in even more potent inhibition and perturbation of HER2 signaling than does either antibody alone.”

The phase III CLEOPATRA trial, which resulted in the approval of pertuzumab when given with trastuzumab and docetaxel, explored this combination. In that trial, 808 patients with HER2positive metastatic breast cancer were randomized to receive either pertuzumab and trastuzumab plus docetaxel or trastuzumab plus docetaxel and a placebo as first-line treatment. The results, published in The New England Journal of Medicine, demonstrated a median progression-free survival (PFS) in the pertuzumab group of 18.5 months compared with 12.4 months in the control group (hazard ratio [HR] = 0.62; 95% CI, 0.51-0.75; P < .001).1 At the 2012 San Antonio Breast Cancer Symposium, an interim analysis of overall survival (OS) results from the CLEOPATRA trial was presented. A 34% reduction in mortality was observed in patients who received pertuzumab plus trastuzumab and docetaxel compared with those who received trastuzumab and docetaxel plus a placebo (HR = 0.66; 95% CI, 0.52-0.84; P = .0008). The median OS of patients in the placebo arm was 37.6 months, but it had not yet been reached in the pertuzumab arm.2 Numerous other trials are under way to test combination therapy in HER2 breast cancer. The phase III APHINITY trial is investigating the efficacy of of pertuzumab plus trastuzumab as adjuvant therapy in patients with operable HER2-positive primary breast cancer.

“The adjuvant data are still probably a couple of years away, but the study accrued very well, and we’ll test that hypothesis

M ultiple M y eloma

Putting New Therapeutic Options Into Practice With the approval of carfilzomib in July 2012 and pomalidomide in February 2013, new therapeutic options are available for the treatment of multiple myeloma (MM). At the International Congress on Hematologic Malignancies, held in New York City in February, Sundar Jagannath, MD, professor of Medicine and Director, Multiple Myeloma Program, The Tisch Cancer Institute at Mount Sinai Medical Center, New York City, spoke about evidence for use of these treatment options in clinical practice.

Thalidomide, lenalidomide, and pomalidomide are structurally similar, but functionally they are different, both qualitatively and quantitatively, Jagannath said. “That’s very important when we talk about that we have a new drug for the treatment of relapsed TargetedHC.com

that two antibodies are better than one,” Pegram said.

In another study, the phase II VELVET trial, patients with metastatic or locally advanced HER2-positive breast cancer will receive a combination of pertuzumab, trastuzumab, and vinorelbine in either sequential administration or single infusion.

“Hopefully that will show similar results with agents other than taxanes,” Pegram said.

The next HER2-targeted antibodies could come about as a result of research into RNA aptamers, which are ribonucleotide sequences that operate in a complementary manner with epitopes and inhibit tumor growth, Pegram said. RNA aptamers may have potential as therapy to target complexes of HER family members that are more involved than dimers. Such complexes may instead involve the combination of two heterodimers that form a heterotetramer. Aptamers have been shown to disrupt the binding of the heterodimers and their ability to form a heterotetramer.

“This research suggests that there might be an opportunity for yet another axis to perturb HER family signaling, including HER2, if you could disrupt not only heterodimers but also heterotetramers,” Pegram said. “The aptamer is already very well characterized, but now that suggests that it might be possible to make antibody reagents that could do the same thing.”

REFERENCES 1. Baselga J, Cortés J, Kim SB, et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012;366(2):109-119.

2. Swaim SM, Kim S-B, Cortes J, et al. Confirmatory overall survival (OS) analysis of CLEOPATRA: a randomized, double-blind, placebo-controlled phase III study with pertuzumab (P), trastuzumab (T), and docetaxel (D) in patients (pts) with HER2positive first-line (1L) metastatic breast cancer (MBC). Cancer Res. 2012;72(24; suppl 3). Abstract P5-18-26.

and refractory multiple myeloma.” Mechanisms that lead to resistance with lenalidomide and thalidomide do not necessarily impact the use of pomalidomide, he said.

MM-002 was the pivotal trial that led to the approval of pomalidomide.1 The study examined the use of pomalidomide in combination with low-dose dexamethasone in patients with relapsed and refractory MM who had received two or more prior therapies, including lenalidomide and bortezomib. At the 2012 American Society of Hematology (ASH) meeting in December, Jagannath presented updated results of the phase II study, including an age subgroup analysis.

A total of 221 patients were randomized 1:1 to receive either pomalidomide (4 mg/day for days 1 to 21 in a 28-day cycle) plus low-dose dexamethasone (40 mg/week; n = 113) or pomalidomide alone (n = 108). Patients randomized to the pomalidomidealone group were allowed to add low-dose dexamethasone upon disease progression; approximately 60% of patients in that arm eventually took dexamethasone.

The overall response rate (ORR) was 34% in the combination V.2

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“So, clearly, these two drugs [pomalidomide and carfilzomib] are going to improve the survival of myeloma patients under your care.”

– S undar J agannat h , M D

therapy group versus 15% in the pomalidomide-alone group. The median progression-free survival (PFS) in the pomalidomide/ dexamethasone group was 4.6 months versus 2.6 months for the pomalidomide-alone group (hazard ratio [HR] = 0.67; P = .002).

However, the median duration of response was the same in both groups: 8.3 months for pomalidomide plus dexamethasone versus 8.8 months for pomalidomide alone (HR = 0.89; P = .734). “At this stage [of the disease], it’s not that dexamethasone is the key. It does synergize, but pomalidomide is the key, and there is a durability of the response if [patients] do respond,” Jagannath said.

Overall survival (OS) was the same in the two treatment arms (16.5 months for pomalidomide/dexamethasone vs 13.6 months for pomalidomide alone; HR = 0.92; P = .609).

Pomalidomide was generally well tolerated and did not cause as significant neutropenia as generally occurs with lenalidomide, or as significant neuropathy as occurs with thalidomide, Jagannath said. The most common grade 3 or 4 adverse events (AEs) occurring in more than 5% of study participants were neutropenia (41%), anemia (22%), pneumonia (22%), thrombocytopenia (19%), fatigue (14%), dyspnea (13%), leukopenia (10%), back pain (10%), and urinary tract infection (9%).1 Neutropenia occurred in nearly 60% of patients older than 65 years in the pomalidomide-only group, Jagannath said, “so there are significant adverse events in these patients.” Furthermore, he said, “when you combine [pomalidomide] with dexamethasone, especially in the elderly patient, you have to be careful… because the incidence of pneumonia is a little higher.” Jagannath also noted that rates of deep vein thrombosis were very low (2%, all grades) because patients received anticoagulation.

Dose reductions occurred in approximately 30% of patients, but 90% of patients maintained dose intensity. “So this was really well tolerated even in the very advanced patient,” Jagannath said. “Why? Because the study did allow liberal use of Neupogen [filgrastim; granulocyte colony-stimulating factor].”

Pomalidomide can be combined with bortezomib, Jagannath said, as demonstrated by study results presented at the 2012 American Society of Hematology meeting, which found favorable efficacy and tolerability for the combination of pomalidomide, bortezomib, and dexamethasone in relapsed/refractory disease.2 The study is ongoing.

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In July 2012, carfilzomib, a next-generation proteasome inhibitor, was approved for treatment of patients with MM who have received at least two prior therapies, including bortezomib and an immunomodulatory agent, and have demonstrated disease progression or are within 60 days of completion of their last therapy.

Other next-generation proteasome inhibitors are in development, and include ixazomib (MLN9708) and oprozomib (ONX 0912).

The phase II PX-171-003-A1 study of carfilzomib enrolled patients with relapsed or refractory MM who had received at least two prior lines of therapy; participants had a median of five prior lines of therapy.3 Patients received single-agent carfilzomib 20 mg/m2 intravenously twice weekly for 3 of 4 weeks in cycle 1, then 27 mg/m2 for up to 12 cycles. A total of 266 patients were evaluable for safety and 257 for efficacy.

In this heavily pretreated population, the ORR was 24%, and the mediation duration of response was 8.3 months (95% CI, 6.59.7). Median PFS was 3.7 months (95% CI, 2.8-4.6) and median OS was 15.6 months (95% CI, 13.0-19.2).

“So, clearly, these two drugs [pomalidomide and carfilzomib] are going to improve the survival of myeloma patients under your care,” Jagannath said.

Common AEs in the trial were fatigue (49%), anemia (46%), nausea (45%), and thrombocytopenia (39%). Peripheral neuropathy, primarily grades 1 or 2, occurred in 33 patients (12.4%).

One-third of patients in the trial developed dyspnea, 17% of which was due to carfilzomib. Rates of grade 3-4 dyspnea were low, however, and occurred in only 3.4% of patients. Congestive heart failure occurred in 3.8% of patients in the trial, and myocardial infarction or cardiac arrest occurred in 2.3%. Jagannath noted that physicians should be aware of and monitor for cardiac safety in patients.

Carfilzomib can be readily combined with other agents for the treatment of MM, including pomalidomide and low-dose dexamethasone, Jagannath said.4 Clinical trials are currently exploring various combination therapies, as well as different dosages of carfilzomib.

REFERENCES 1. Jagannath S, Hofmeister CC, Siegel DS, et al. Pomalidomide (POM) with low-dose dexamethasone (LoDex) in patients (Pts) with relapsed and refractory multiple myeloma who have received prior therapy with lenalidomide (LEN) and bortezomib (BORT): updated phase 2 results and age subgroup analysis. Presented at: 54th ASH Annual Meeting; December 8-11, 2012; Atlanta, GA. Abstract 450.

2. Richardson PG, Hofmeister CC, Siegel D, et al. MM-005: a phase 1, multicenter, open-label, dose-escalation study to determine the maximum tolerated dose for the combination of pomalidomide, bortezomib, and low-dose dexamethasone in subjects with relapsed or refractory multiple myeloma. Presented at: 54th ASH Annual Meeting; December 8-11, 2012; Atlanta, GA. Abstract 727.

3. Siegel DS, Martin T, Wang M, et al. A phase 2 study of single-agent carfilzomib (PX-171-003-A1) in patients with relapsed and refractory multiple myeloma. Blood.

2012;120(14):2817-2825.

4. Shah JJ, Stadtmauer EA, Abonour R, et al. A multi-center phase I/II trial of carfilzomib and pomalidomide with dexamethasone (Car-Pom-d) in patients with relapsed/ refractory multiple myeloma. Presented at: 54th ASH Annual Meeting; December 8-11, 2012; Atlanta, GA. Abstract 74.

The International Journal of Targeted Therapies in Cancer

Enrolling in

Investigating dacomitinib, an irreversible pan-HER inhibitor, versus erlotinib in secondor third-line therapy for advanced NSCLC1 Phase 3, randomized, double blind, multinational, multicenter study in NSCLC patients after at least one prior course of chemotherapy

Patients with locally advanced or metastatic NSCLC following progression after, or intolerance to, at least one prior course of chemotherapy N = 800

R A N D O M I Z A T I O N*

Dacomitinib 45 mg orally once daily 1:1 Erlotinib 150 mg orally once daily

Coprimary populations: all enrolled NSCLC patients and NSCLC patients confirmed for KRAS wild type

End Points Primary: Progression-free survival Secondary: Overall survival, objective response rate, duration of response, safety and tolerability, and patient-reported outcomes

For more information, please contact the Pfizer Oncology Clinical Trial Information Service at: 1-877-369-9753 in the United States and Canada (toll-free) +1-646-277-4066 outside the United States For more information, please visit www.pfizercancertrials.com or www.clinicaltrials.gov (NCT01360554) * Stratified by histology (adenocarcinoma vs non-adenocarcinoma), race (Asian vs non-Asian and Indian subcontinent), ECOG performance status score (0-to-1 vs 2), smoking status (never-smoker vs ever smoker).

NSCLC = non-small cell lung cancer; ECOG = Eastern Cooperative Oncology Group.

Reference: 1. Data on file. Pfizer Inc, New York, NY. This information is current as of October 2011.

Dacomitinib (PF-00299804) is an investigational compound

PFW 00029-B

Š 2012 Pfizer Inc.

All rights reserved.

Advanced NSCLC

M elanoma

Preliminary Positive Results Observed for TVEC In top-line results from a phase III trial comparing talimogene laherparepvec (TVEC) with granulocyte-macrophage colonystimulating factor (GM-CSF) in melanoma, TVEC met its primary endpoint of a durable response rate (DRR), according to a state-

“These are the first phase III results of this novel approach to cancer therapy. A high unmet need exists in melanoma, and we believe the innovative mechanism of action of talimogene laherparepvec may offer a promising approach for these patients.”

– S ean E . Harper , M D

C h ronic L y mp h oc y tic L eukemia

Ibrutinib Receives Additional Breakthrough Designation for Chronic Lymphocytic Leukemia After receiving breakthrough therapy designation from the FDA for the treatment of two B-cell malignancies earlier this year, ibrutinib has received an additional breakthrough designation for the treatment of chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) with deletion of the short arm of chromosome 17.

Ibrutinib is a selective tyrosine kinase inhibitor of the Bruton’s tyrosine kinase enzyme, which is associated with apoptosis, cell adhesion, cell migration, and other cellular processes that can help a tumor survive. In addition to CLL/SLL, ibrutinib is being investigated in multiple myeloma, follicular lymphoma, and diffuse large B-cell lymphoma. In February, ibrutinib received breakthrough designation for Waldenström’s macroglobulinemia and mantle cell lymphoma.

Patients with CLL with this chromosome 17 deletion (del 17p) often have poor outcomes if they receive treatment with chemotherapy.

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ment from Amgen, which is developing the immunotherapy. The preliminary results also demonstrated a trend in overall survival (OS) favoring the new treatment.

TVEC is a modified herpes simplex virus engineered to express GM-CSF, a white blood cell growth factor. When injected into the tumor tissue, TVEC is able to replicate until it causes tumor cell lysis. Upon lysis, the engineered virus expresses GMCSF in the tumor tissue, with the goal of stimulating a systemic immune response and killing tumor cells throughout the body.

In the phase III trial, researchers assessed the efficacy and safety of TVEC in unresected stage IIIB, IIIC, or IV melanoma compared with treatment with subcutaneous GM-CSF alone. A total of 439 patients were randomized in a 2:1 ratio to receive either TVEC (up to 4 mL of 10^8 pfu/mL/per injection) or GMCSF (125 µg/m2 daily subcutaneously for 14 consecutive days followed by 14 days of rest). The study met its primary endpoint of DRR, or the rate of complete or partial response that lasted for at least 6 months. The DRR rate in the TVEC arm was 16% compared with 2% in the GM-CSF arm. Though the OS data are not yet mature, a pre-planned interim analysis showed a trend favoring TVEC compared with GM-CSF. “These are the first phase III results of this novel approach to cancer therapy,” said Sean E. Harper, MD, executive vice president of Research and Development at Amgen, in a statement. “A high unmet need exists in melanoma, and we believe the innovative mechanism of action of talimogene laherparepvec may offer a promising approach for these patients.”

According to the 2012 FDA Safety and Innovation Act (FDASIA), breakthrough therapy designation is assigned to drugs designed to treat a life-threatening condition when “preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development.” The purpose of the breakthrough designation is to expedite the review process for ibrutinib for CLL/SLL. Ibrutinib is being co-developed and co-commercialized through a collaborative agreement between Janssen Biotech, Inc, part of the Janssen Pharmaceutical Companies of Johnson & Johnson, and Pharmacyclics. The manufacturers are still allowed to seek fast-track designation, accelerated approval, and priority review for ibrutinib for this indication during the review process.

“Ibrutinib continues to demonstrate promise for patients living with B-cell malignancies, and we are pleased that the FDA has recognized its potential for people living with CLL and the del17p mutation,” said Peter F. Lebowitz, MD, PhD, head of Peter F. Lebowitz, MD, PhD Global Oncology Therapeutic Area at JansThe International Journal of Targeted Therapies in Cancer

“Ibrutinib was highly efficacious as a single agent in patients with untreated, relapsed and unresponsive CLL, irrespective of their del 17p status.”

– A drian W iestner , M D , P h D

sen, in a statement. “This third breakthrough therapy designation reflects the potential importance of ibrutinib for patients diagnosed with a 17p deletion chromosomal abnormality in CLL/SLL, and we are committed to working with Pharmacyclics and the FDA to expedite development and review of ibrutinib as quickly as possible.”

The news of the additional breakthrough designation came on the same day that new data on ibrutinib’s effectiveness for the treatment of CLL were presented at the 2013 American Association for Cancer Research (AACR) Annual Meeting held in April in Washington, DC. In the ongoing phase II study, 53 patients with CLL were divided into two cohorts, with 29 patients with del 17p and 24 patients without del 17p who were at least 65 years old. Patients received 420 mg of ibrutinib daily, and their responses were evaluated at 6 months and every 6 months thereafter until disease progression.

TargetedHC.com

At 12 months, the estimated event-free survival rate was 94%.

After 6 months, at least a 50% reduction in lymph node disease was observed in 95% of patients, with a median reduction in lymph node size of 73%. A median decrease of 82% in tumor infiltration in bone marrow was observed in patients who received a bone marrow biopsy. All patients showed a reduction in spleen enlargement, with a median reduction of 55%.

The drug was also well tolerated, with most adverse events reported as mild, with nonhematologic toxicities of grade 3 or higher occurring in less than 13% of patients. Two patients on the study died, but their deaths were not related to the treatment.

“Ibrutinib was highly efficacious as a single agent in patients with untreated, relapsed and unresponsive CLL, irrespective of their del 17p status,” said Adrian Wiestner, MD, PhD, investigator and head of the Lymphoid Malignancies Section in the Hematology Branch at the National Heart, Lung, and Blood Institute at the National Institutes of Health (NIH) in Bethesda, Maryland, in a statement. “Responses appear to be durable, and the drug is effective against the disease in lymph nodes, spleen, and bone marrow. This is important because existing therapies often fail to effectively eliminate cancer cells in these tissue sites. Targeted therapy for CLL is becoming a reality, and this new approach will greatly improve the lives of patients with this disease.”

REFERENCE Wiestner A, Herman S, Mustafa R, et al. Potent single agent activity of Ibrutinib (PCI32765) in patients with chronic lymphocytic leukemia (CLL): clinical and translational results from an ongoing phase II study. Presented at: AACR Annual Meeting 2013; April 6-10, 2013; Washington, DC. Abstract LB-141.

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The Challenges of Clinical Trial Participation in the Age of Targeted Therapy

By Cheryl Zigrand

With an estimated 12.7 million cases of cancer around the world in 2008 and 7.6 million deaths in the same year, with projections to increase to 13.1 million deaths a year by 2030, cancer is a major burden shared by the entire world population.1,2 Scientific advances in oncology depend on well-designed clinical trials with sufficient enrollment numbers. Unfortunately, clinical trial participation has traditionally been low, and now that cancers are being broken down not just by tumor site but also by specific molecular pathways, finding enough patients to participate in these new targeted therapy trials has become even more difficult.

General Barriers to Accrual in Clinical Trials Only approximately 3% of adult cancer patients in the United States participate in clinical trials, and 40% of trials fail to achieve their predetermined minimum patient enrollment.3 A systematic review of oncology studies found that common barriers to participation cited by patients included the inconvenience of participation, concern about receiving a placebo, potential side effects, and concern that the investigational agent might not be the best option.3,4

“I have a protocol that, even though it is a phase I study and we’ll probably enroll only 40 or 60 patients, will require 10 sites in order to identify those patients because of how rare the mutation being studied is.”

– Dav i d H o n g , M D

David Hong, MD, associate professor, Department of Investigational Cancer Therapeutics and clinical medical director of the Clinical Center for Targeted Therapy at MD Anderson Cancer Center in Houston, Texas, agrees with 18

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patients about the role of inconvenience in preventing participation in trials. “A lot of our patients fly in from other parts of the country, or even other parts of the world, which can be very inconvenient if you are in a clinical trial,” he said. For protocols requiring frequent study visits, it is easy to see how this kind of travel schedule would be prohibitive. While this experience may be limited to patients who seek treatment at the larger cancer centers, even patients treated in community oncology practices may encounter frequent visits and procedures if they consent to participate in a clinical trial, which can lead to an overall perception of inconvenience that can be detrimental to participation.

Some of the concerns of patients, and possibly even of physicians, regarding clinical trials may point to differences in cultural perception. According to Gail Roboz, MD, associate professor of Medicine and director of the Leukemia Program Gail Roboz, MD at Weill Medical College of Cornell University in New York City, “the culture in the United States has not been promoting of clinical trial participation in general.” In contrast, she notes that “in Europe, patients get worried when their institution doesn’t offer clinical trials.”

Lack of encouragement or even active discouragement by treating physicians was also cited as a barrier to clinical trial participation, according to a US-based survey of an online community of women with metastatic breast cancer. Many of the survey participants also viewed clinical trials as a last-ditch effort.3 Thus, at least in the United States, the perceptions of both patients and physicians can have a negative effect on clinical trial enrollment. In Roboz’s opinion, “I think that, with the correct education and outreach, we may be able to overcome the public’s hesitation to participate in trials.”

In addition to issues of perception, socioeconomic considerations may act as barriers to trial participation.

According to a survey of 5499 patients in which the overall clinical trial participation rate was 9%, income The International Journal of Targeted Therapies in Cancer

Photo by © ASCO/Scott Morgan 2012

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was a statistically significant predictor of cancer clinical trial participation (P =.001).5 Income remained a predictor of participation in a multivariable model (odds ratio, 0.73; 95% CI, 0.57 to 0.94; P =.01).

In addition, cost concerns were much more evident in the patients with lower income (P <.001). The lead author of this study, Joseph Unger, MS, PhC, biostatistician and health services researcher with the SWOG Statistical Center of the Fred Joseph Unger, MS, PhC Hutchinson Cancer Research Center in Seattle, Washington, observed that, “Patients with lower income tend to have underlying anxiety about how to pay for clinical trials.” Out-of-pocket costs to the patient can include logistical costs such as parking fees, tolls, fuel, or even transportation costs such as bus, train, or airline tickets and hotel bills if the clinical trial is far away from the patient’s home. Any of these considerations could deter patients from participating, particularly for patients with lower income levels. Other socioeconomic factors that were also found by Unger’s study to be associated with low rates of clinical trial participation were advanced age (P =.002) and lower levels of education (P =.02), raising issues of how well clinical trial results can be generalized across the entire oncology population.5 According to the US Census Bureau, lower-income patients are more likely to be uninsured, which may also present difficulties or concerns regarding clinical trial participation.6 However, even with health insurance, it can be difficult for patients to participate in trials, as Hong observed that, “About 30% of our patients were denied [participation] because their insurance denied them getting onto a phase I clinical trial.” Beginning in 2014, under the Patient Protection and Affordable Care Act, plans cannot deny coverage for related services for qualified individuals enrolled in approved clinical trials.

Targeted Therapy–Specific Barriers to Accrual in Clinical Trials The advent of targeted therapies, while bringing important advances in treatment, carries its own challenges to clinical trial participation. Clinical trials of standard therapies can often include broad populations of patients with cancers of like locations (eg, lung cancer, breast cancer).

Now, because targeted therapies home in on specific pathways, study populations are limited to subsets of patients with activations of certain molecular pathways or with one particular mutation. This greatly reduces the eligible enrollment pool, which in turn reduces the number of patients who will actually participate.

Furthermore, clinical trials may now have to include TargetedHC.com

“If we’re studying only patients with abnormalities that we think will be targeted by the drug, then we miss an opportunity to see if there are unexpected effects of that drug that might not act through its proposed target, but might benefit patients without that specific target.”

– J o h n G e r e c i ta n o , M D , P h D

more investigational sites in order to find enough patients with the required mutations or pathway activations. “I have a protocol that, even though it is a phase I study and we’ll probably enroll only 40 or 60 patients, will require 10 sites in order to identify those patients because of how rare the mutation being studied is,” Hong said.

The process of determining whether a patient might be eligible for a targeted therapy trial can also create challenges. Many of these clinical trials require detailed information about a tumor’s biology via a biopsy that takes a good deal of time to acquire and analyze. “It causes us to lose some patients to other non-trial therapies or just lose the patient altogether, unfortunately, before we’re able to give them a drug that might benefit them,” said John Gerecitano, MD, PhD, assistant attending physician on the Lymphoma Service at Memorial Sloan-Kettering Cancer Center and assistant professor of Medicine at Weill Cornell Medical College in New York City. Gerecitano is principal investigator on several phase I and phase II clinical trials. Requiring such detailed information upfront for a clinical trial is a relatively recent phenomenon and a potential road block on the path to participation.

There are also tradeoffs to selecting patients for trials based on tumor markers. “If we’re studying only patients with abnormalities that we think will be targeted by the drug, then we miss an opportunity to see if there are unexpected effects of that drug that might not act through its proposed target, but might benefit patients without that specific target,” Gerecitano said.

“Personalized medicine should not become anecdotal medicine,” Roboz said. She explained that news of a novel drug that works wonders would not be very relevant to patients with cancer in general if the drug’s data applied only to one or two patients in the world.

Overcoming Barriers to Accrual in the Future One of the ways to overcome the hurdles to trial participation posed by the specificity of targeted therapies may be V.2

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to make molecular testing more widespread and to remove the cost burden to patients of performing this testing. “Certain cancer centers are starting to roll out programs for patients to get prescreened not at [the patients’] expense for many of these potential actionable tumor targets/driver gene mutations,” Gerecitano said. This trend bodes well for patients, who will need this information as quickly as possible to determine their trial eligibility, and who may not be able to afford the cost of the tests required.

A cultural shift in the medical community that trickles down to patients could also go a long way to overcoming the negative associations that the public has toward clinical trial participation. “Broad participation in a publicly sponsored clinical trials system by investigators, community physicians, cancer centers, and patients will enhance the system’s impact by efficiently providing practicechanging evidence,” wrote the authors of A National Cancer Clinical Trials System for the 21st Century.7 This conclusion points to the most powerful tool available for overcoming the various barriers, which is positive data.

As Hong noted, “Information spreads fast, and if patients start to recognize that something works, you’ll get patients knocking on your door to enroll in a clinical trial.”

As indicated by Roboz’s insights, many of the changes that are needed must start with opening the mind to a new way of thinking. Roboz believes that both patients and their physicians must be more open to participation in clinical trials. “Doctors must recognize that if they want to be able to use less-toxic and more targeted approaches, which will ultimately be of more benefit and better tolerated by their patients, they’re going to need to be willing to refer patients for clinical trial participation, especially those with rare diagnoses,” Roboz said. She added that

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doctors and patients should not assume that trials will be successfully completed without their participation.

Now that targeted therapies are firmly part of both the treatment of oncology and a major subject of oncology research, it is imperative to understand all of the barriers to clinical trial participation, and it is even more pressing to take steps to eliminate as many of the old concerns and new challenges as possible. Every new opportunity that becomes available to patients today owes itself to the clinical trials that healthcare practitioners and patients participated in yesterday.

R E F E R EN C E S 1. World Cancer Research Fund International. Cancer statistics: worldwide. http://www.wcrf.org/cancer_statistics/world_cancer_statistics.php.

Accessed February 25, 2013.

2. World Health Organization. Cancer fact sheet 297. Reviewed January 2013. http://www.who.int/mediacentre/factsheets/fs297/en/.

Accessed February 25, 2013.

3. English R, Lebovitz Y, Griffin R. Forum on Drug Discovery, Development, and Translation; Institute of Medicine. Transforming Clinical Research in the United States: Challenges and Opportunities: Workshop Summary.

Washington, DC: National Academies Press; 2010. http://www.ncbi. nlm.nih.gov/books/NBK50895/. Accessed February 25, 2013.

4. Mills EJ, Seely D, Rachlis B, et al. Barriers to participation in clinical trials of cancer: a meta-analysis and systematic review of patient-reported factors. Lancet Oncol. 2006;7(2):141-148.

5. Unger JM, Hershman DL, Albain KS, et al. Patient income level and cancer clinical trial participation. J Clin Oncol. 2013;31(5):536-542.

6. DeNavas-Walt C, Proctor BD, Smith JC; US Census Bureau, Current Population Reports, P60-243. Income, Poverty, and Health Insurance Coverage in the United States: 2011. Washington, DC: US Government Printing Office; September 2012.

7. Nass SJ, Moses HL, Mendelsohn J, eds. Physician and patient participation in cancer clinical trials. In: A National Cancer Clinical Trials System for the 21st Century: Reinvigorating the NCI Cooperative Group Program. Washington, DC: National Academies Press; 2010. http:// www.nap.edu/openbook.php?record_id=12879&page=191 Accessed February 4, 2013.

The International Journal of Targeted Therapies in Cancer

The Gold Standard in Physician-Led Education

www.AJHO.com A great American tradition is now backed by the oncology CME leader.

The American Journal of Hematology/Oncology, a peer-reviewed resource for accredited oncology education, harnesses the breadth and depth of the educational programs and renowned faculty in the Physicians’ Education Resource stable of legacy meetings. Each issue features original research and concise reviews of the current treatment trends in specific disease states, and provides practicing oncologists with the tools and the science they need to improve outcomes and the delivery of care.

In 2013, The American Journal of Hematology/Oncology —the gold standard in physician-led education—joins the OncLive family of publications.

Advancing Cancer Care Through Professional Education®

F e at u r e

Clinical Trial Profile

BELLE-2 and -3: BKM120 With Fulvestrant in Postmenopausal Patients With Hormone Receptor-Positive, HER2-Negative Locally Advanced or Metastatic Breast Cancer

By Tracey Regan

The effectiveness of treating women with hormone receptor–positive advanced breast cancer with a combination of BKM120, an investigational targeted therapy, and fulvestrant is being evaluated in two multicenter, phase III clinical trials.

BKM120, developed by Novartis Pharmaceuticals, is an oral pan-phosphatidylinositol-3-kinase (PI3K) inhibitor designed to block the PI3K-AKT-mTOR pathway, thereby reverting the cellular metabolism, proliferation, and survival processes back to normal (see article page 30). Mutations in the PI3K pathway occur in more than a third of hormone receptor–positive tumors,1 while research suggests that PI3K mutations may confer resistance to hormone therapy. By targeting the PI3K-AKT-mTOR pathway primarily at the level of a part of the PIK3CA gene, BKM120 has been designed to both arrest tumor growth and induce cell death in cancers that are resistant to currently available therapies. Investigators say that it may also boost the effectiveness of antiestrogen medications.

“The underlying problem is enormous. The most common breast cancer is hormone receptor-positive, and more women die of this subtype annually than any other.”

– Sara Hurvitz, MD

“The underlying problem is enormous. The most common breast cancer is hormone receptor-positive, and more women die of this subtype annually than any other. While there are a lot of therapies to combat it, resistance to endocrine therapy is guaranteed in metastatic disease, which can be difficult to treat. There needs to be better options,” said Sara Hurvitz, MD, director of the Breast Oncology Program at UCLA and a principal investigator for both trials, known as BELLE-2 and BELLE-3. “The hope is to improve outcomes by hitting the PI3K pathway while continuing to 22

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hold the brakes on the hormonal pathway,” Hurvitz said.

Participants in the BELLE-2 trial (Table 1) are postmenopausal women with locally advanced or metastatic HER2-negative cancer whose disease has progressed on or after aromatase inhibitor (AI) therapy. In the related BELLE-3 trial (Table 2), patients have been treated with AIs and an mTOR inhibitor, which blocks aberrant signaling in another part of the larger PI3K-AKT-mTOR pathway and is designed to reverse endocrine resistance.

The trials, both of which are randomized and doubleblind, are designed to test whether it is more effective to add BKM120 to fulvestrant or to take fulvestrant alone.

The primary endpoint in both trials is progression-free survival (PFS). Secondary outcome measures include overall survival and clinical benefit rate.

The BELLE-2 trial, which began in February 2012, will enroll about 842 participants and has an estimated study completion date of March 2017. BELLE-3, which began in October 2012, will enroll about 615 participants and has an estimated completion date of October 2016. Women seeking to participate must first submit tumor samples to assess PI3K activation status.

BELLE-2 excludes prior mTOR therapy, and BELLE-3 requires prior mTOR therapy. “Thus, the question as to whether or not inhibiting the PI3K pathway is beneficial in patients whose disease has progressed on an mTOR inhibitor will be addressed,” Hurvitz said. “We’re trying to learn if inhibiting PI3K in combination with an estrogenreceptor blockade helps reverse endocrine resistance in patients whose disease has progressed on or shortly after an aromatase inhibitor and to test whether inhibiting PI3K after a patient’s tumor has been treated with an mTOR inhibitor is able to reverse treatment resistance.”

In BELLE-2, half of participants will take daily doses of The International Journal of Targeted Therapies in Cancer

F e at u r e

Clinical Trial Profile

the investigational therapy and injections of fulvestrant (500 mg, during cycle 1 on days 1 and 15, and once every cycle thereafter), while the other half will take a placebo in combination with fulvestrant. In BELLE-3, two-thirds of patients will take BKM120 with fulvestrant and one-third will take the placebo. The combination therapy will also be evaluated for safety in both trials.

“It is important to make sure toxicity levels are tolerable in the treatment of a chronic, incurable disease,” said Hurvitz, who described the trial participants as middle-aged and otherwise generally healthy, with measurable disease progression or nonmeasurable disease bone lesions. “It is important that patients know there needs to be an open door of communication [about adverse effects] for their own safety and well-being. If this isn’t discussed with patients, they may stop taking their medication at home without telling the physician, or may not disclose side effects they are experiencing in order to avoid having the physician lower the dose or stop the medicine. Both these outcomes are potentially harmful to patients,” she noted.

Fulvestrant is a “well tolerated anti-estrogen therapy,” Hurvitz said. The FDA recently approved a higher dosage of fulvestrant, following studies that found that 500 mg was more effective than 250 mg, the standard dosage for nearly a decade.

“As a treatment for estrogen receptor–positive breast cancer, it is an active compound that would be a reasonable single-agent choice for the women participating in these trials,” Hurvitz said, noting that patients with metastatic estrogen receptor–positive, postmenopausal breast cancer take it in the first-line setting or, more commonly, after progression on an AI. Hurvitz said there have been few published data so far on the effectiveness of BKM120. The results from a phase I dose-escalation study that enrolled 35 heavily pretreated patients with a range of advanced solid tumors including colorectal and breast cancers, among others,2 were deemed sufficiently promising to move ahead with the BELLE trials, as well as others in which the drug is being tested alone and in combination with other therapies.

In the phase I trial, investigators described the drug as safe and well tolerated, while presenting clear evidence of target inhibition and preliminary antitumor activity.2 The maximum tolerated dose was 100 mg per day. One patient with triple-negative breast cancer demonstrated a confirmed partial response, while in several others the disease stabilized. The principal adverse events were mood alterations, hypoglycemia, rash, and fatigue.

“We saw little toxicity in terms of rashes, gastrointestinal problems, and hematologic toxicities. Glucose levels were also easy to manage. The pharmacokinetic profile was excellent,” said Howard Burris III, MD, executive diTargetedHC.com

“We saw little toxicity in terms of rashes, gastrointestinal problems, and hematologic toxicities. Glucose levels were also easy to manage.

The pharmacokinetic profile was excellent.”

– H o w a rd B u rr i s III , M D

rector of the Drug Development Program at Sarah Cannon Research Institute, Nashville, Tennessee, and an investigator in the phase I trial. “Interestingly, some participants reported a change in mental status, mostly anxiety. While it may sound unusual, for an oncologist this effect is not necessarily negative. It means the drug crossed the bloodbrain barrier, and in one patient we saw a substantial decrease of lesions in the brain. We didn’t have to drop the dose much to diminish this side effect.”

For patients whose disease has progressed, such as patients enrolling in the BELLE trials, options include trying another AI, or an AI plus an mTOR inhibitor (everolimus) or fulvestrant, Hurvitz said.

“Or they could switch to chemotherapy such as singleagent taxane or oral capecitabine,” Hurvitz said, adding, however, “Chemotherapy is usually associated with a lot more toxicity so it is usually put off as long as possible with estrogen receptor–positive disease.”

Generally, patients who receive mTOR therapies are postmenopausal women with estrogen receptor–positive metastatic breast cancer whose disease has progressed on or after an AI, Hurvitz said.

Everolimus received FDA approval in 2012 for endocrine-resistant, hormone receptor–positive metastatic breast cancer in combination with an AI, based on the results from a study that showed everolimus in combination with exemestane significantly improved PFS compared with exemestane alone. For now, only postmenopausal women with hormone receptor–positive breast cancer that has progressed on prior AIs are eligible to take it.

Burris said there is much interest among clinicians and drug companies in testing therapies that inhibit the PI3KAKT-mTOR pathway in cancer. “It is known that the PI3KAKT-mTOR signaling pathway is dysregulated in many solid tumors. We see mutations, amplifications, and other abnormalities, so it makes sense to try to block aberrant signaling at the PI3K and mTOR levels,” he said. “There is a high level of PI3K aberrations in breast and gynecologic cancers, and specifically in hormone-positive subtypes.”

Burris called the approval of everolimus “clinical proof V.2

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A Phase III Study of BKM120 With Fulvestrant in Postmenopausal Patients With Hormone Receptor–Positive, HER2-Negative, Locally Advanced or Metastatic Breast Cancer Refractory to Aromatase Inhibitors (BELLE-2)

ta b l e 1.

C l i n i c a l T r i a l s . g o v Ident i f i er : N C T 01 61 0 2 8 4

Primary outcome measure: Secondary outcome measures:

progression-free survival overall survival; overall response rate; clinical benefit rate; type, frequency and severity of adverse events

Study start date:

February 2012

Estimated study completion date:

March 2017

Estimated enrollment: Patients:

842 Women 18 years and older

S e l ected i nc l u s i o n C r i ter i a : Postmenopausal Locally advanced or metastatic breast cancer Progression or recurrence of breast cancer while on or after aromatase inhibitor treatment HER2-negative and hormone receptor–positive status Tumor sample has been shipped to a Novartis-designated laboratory for identification of biomarkers indicating PI3K activation status Measurable disease or nonmeasurable disease bone lesions in the absence of measurable disease as per RECIST 1.1 Adequate bone marrow and organ function defined by laboratory values No previous treatment with PI3K inhibitors, AKT inhibitors, mTOR inhibitor, or fulvestrant Not more than one prior chemotherapy line for metastatic disease No symptomatic brain metastases No increasing or chronic treatment (> 5 days) with corticosteroids or another immunosuppressive agent No active cardiac disease as defined in the protocol Patients with certain scores on an anxiety and depression mood questionnaire are excluded.

D o s a g es : Arm A:

BKM120 tablet (100 mg) taken orally once a day and fulvestrant (500 mg) given intramuscularly at cycle 1 day 1, cycle 1 day 15, and at day 1 at each cycle thereafter. Treatment will be given until disease progression or as described in the protocol.

Arm B:

Placebo tablet taken orally once a day and fulvestrant (500 mg) given intramuscularly at cycle 1 day 1, cycle 1 day 15, and at day 1 at each cycle thereafter. Treatment will be given until disease progression or as described in the protocol.

Adverse Effects:

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The principal adverse events observed in the phase I dose-escalation study of BKM120 in patients with advanced solid tumors were mood alterations, hypoglycemia, rash, and fatigue.

that blocking this pathway can be effective. We also see that this class of drug can be used in combination with other drugs. Often, it’s hard to combine biologic therapies with other agents,” he said.

While noting that the second generation of PI3K inhibitors such as BKM120 block further upstream in the signaling pathway than mTOR inhibitors, Burris said they may prove more effective “to ‘nip this in the bud’ earlier on in the process. It may potentially lessen a patient’s chance of developing resistance via other pathways.”

Abnormal activation of the PI3K-AKT-mTOR pathway plays a role in the initiation and maintenance of human tumors and is a key regulator of angiogenesis and increased metabolic activities in tumor cells, said Alessandro Riva, MD, global head of Oncology Development and Medical Affairs at Novartis Oncology.

“The PI3K pathway may become dysregulated by several means, Alessandro Riva, MD including mutations in the genes involved in the pathway such as the PIK3CA gene, the PTEN gene, or higher than usual expression of receptors such as the HER2 receptor in breast cancer or EGFR receptor in head and neck and lung cancer,” he said.

“This dysregulation of the pathway can lead to unchecked growth of the cells, leading to tumors and survival of the cells longer than usual, which leads to tumor growth.”

In another phase Ib study, BKM120 was combined with letrozole to explore the safety and activity of the combination to treat patients with hormone receptor–positive metastatic breast cancer.3 “In this exploratory early-phase trial, the combination was well tolerated at full doses of both drugs. Several patients experienced longer term disease control,” Riva said.

BKM120 is also being investigated as single-agent therapy in a number of other therapeutic areas, including non-small cell lung cancer, prostate cancer, glioblastoma multiforme, gastrointestinal stromal tumors, and myelofibrosis, as well as in combination with other standard-of-care therapies.

REFERENCES 1. Baselga J. Targeting the phosphoinositide-3 (PI3) kinase pathway in breast cancer. Oncologist. 2011;16(suppl 1):12-19.

2. Bendell JC, Rodon J, Burris HA, et al. Phase I, dose-escalation study of BKM120, an oral pan-class I PI3K inhibitor, in patients with advanced solid tumors. J Clin Oncol. 2012;30(3):282-290.

3. Mayer IA, Balko JM, Kuba MG, et al. PD09-05: SU2C phase Ib study of pan-PI3K inhibitor BKM120 plus aromatase inhibitor letrozole in ER+/ HER2– metastatic breast cancer (MBC). Cancer Res. 2011;71(24; suppl 3). Presented at the 2011 San Antonio Breast Cancer Symposium; December 6-10, 2011; San Antonio, TX. Abstract PD09-05.

The International Journal of Targeted Therapies in Cancer

Clinical Trial Profile

F e at u r e

A Phase III Study of BKM120 With Fulvestrant in Patients With Hormone Receptor-Positive, HER2-Negative, Aromatase InhibitorTreated, Locally Advanced or Metastatic Breast Cancer Who Progressed on or After mTOR Inhibitor Based Treatment (BELLE-3)

ta b l e 2 .

C l i n i c a l T r i a l s . g o v Ident i f i er : N C T 01 6 3 3 0 6 0

Primary outcome measure: Secondary outcome measures:

progression-free survival overall survival; overall response rate; clinical benefit rate; type, frequency and severity of adverse events

Study start date:

October 2012

Estimated study completion date:

October 2016

Estimated enrollment: Patients:

615 Women 18 years and older

S e l ected i nc l u s i o n C r i ter i a :

Callfor Papers As targeted therapies for cancer emerge on the market at a record-breaking pace, oncologists on the front lines of clinical practice are challenged to stay up to date on clinical trial evidence and on emerging strategies for successfully applying targeted therapies to patient care.

The International Journal of Targeted Therapies in Cancer seeks to bridge this gap between bench science and bedside care on the use of targeted therapies in cancer. To that end, the editors are issuing a call for papers on topics that help community oncologists integrate information about targeted therapies into patient care.

Postmenopausal Locally advanced or metastatic breast cancer Prior treatment with aromatase inhibitors Evidence of progression to the combination of mTOR inhibitor and endocrine therapy given as the last therapy prior to study entry HER2-negative and hormone receptor–positive status Tumor sample has been shipped to a central laboratory for identification of biomarkers indicating PI3K activation status Adequate bone marrow and organ function Not more than 1 prior chemotherapy treatment for locally advanced or metastatic disease No previous treatment with PI3K inhibitors, AKT inhibitors, or fulvestrant No symptomatic central nervous system metastases No increasing or chronic treatment (> 5 days) with corticosteroids or another immunosuppressive agent No concurrent malignancy or malignancy within 3 years prior to start of study treatment No active cardiac disease or a history of cardiac dysfunction as defined in the protocol

In order to ensure that papers fit with the goals and scope of the journal, authors are encouraged to first contact the journal’s editors with either an outline or abstract of the proposed submission. Papers should aid oncology healthcare professionals in gaining a greater understanding of new therapies and diagnostics, and should focus on the application of these to clinical practice and optimal patient care. Topics of interest include, but are not limited to: • Molecular targets, pathways, and vaccines in development in cancer therapy • New and emerging targeted therapies and personalized medicine in oncology • Diagnostic and genetic testing in oncology • Management of adverse events in cancer targeted therapies

No hypersensitivity to fulvestrant treatment excipients No treatment with certain drugs or by radiation within 2-4 weeks of enrollment Patients with certain scores on an anxiety and depression mood questionnaire are excluded D o s a g es : Arm A:

Arm B:

Adverse Effects:

BKM120 tablet (100 mg) taken orally once a day and fulvestrant (500 mg) given intramuscularly at cycle 1 day 1, cycle 1 day 15, and at day 1 at each cycle thereafter. Treatment will be given until disease progression or as described in the protocol.

Placebo tablet taken orally once a day and fulvestrant (500 mg) given intramuscularly at cycle 1 day 1, cycle 1 day 15, and at day 1 at each cycle thereafter. Treatment will be given until disease progression or as described in the protocol.

The principal adverse events observed in the phase I doseescalation study of BKM120 in patients with advanced solid tumors were mood alterations, hypoglycemia, rash, and fatigue.

The journal editors will review all proposed outlines or abstracts and assign full papers according to those that best meet the journal’s goals. All assigned papers will undergo peer review. To submit an abstract or outline, or if you have questions or wish to speak to an editor, please email Devera Pine at dpine@onclive.com.

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Clinical Articles Peer Reviewed Thyroid Cancer

Cabozantinib in Medullary Thyroid Cancer Daniel W. Bowles, MD, and Antonio Jimeno, MD, PhD

Background

abstr act

Cabozantinib is a novel, small-molecule, multitargeted receptor tyrosine kinase inhibitor with particular activity against MET, VEGFR-2, and RET. There is ample evidence of MET, VEGFR-2, and RET signaling in several tumor types. Preclinical data suggest that cabozantinib has activity in tumors derived from both epithelial and mesenchymal origins. Phase I and II clinical studies support significant antitumor activity, particularly in medullary thyroid cancer (MTC) and cancers metastatic to the bone. A positive phase III trial in MTC recently led to its FDA approval for this indication. This review will evaluate cabozantinibâ&#x20AC;&#x2122;s preclinical pharmacology, pharmacokinetics, and clinical activity in MTC in phase I and phase III studies.

Daniel W. Bowles, MD Assistant Professor, Division of Medical Oncology, University of Colorado, Aurora, CO

corresponding author Antonio Jimeno, MD, PhD Associate Professor, Division of Medical Oncology, University of Colorado, Aurora, CO; antonio.jimeno@ucdenver.edu

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Cabozantinib is a novel receptor tyrosine kinase inhibitor (TKI) that targets hepatocyte growth factor receptor (MET, or HGFR), VEGFR-2, and the proto-oncogene rearranged during transfection (RET).

MET MET is the cellular receptor for hepatocyte growth factor (HGF). HGF is a secreted single-chain precursor protein expressed predominantly by mesenchymal cells that interacts with adjacent epithelial cells.1 Upon HGF binding, MET forms homodimers that in turn allow for trans-phosphorylation of two tyrosine residues. The principal MET-activated signaling cascades are the mitogenactivated protein kinases (MAPK), phosphotidylinositol 3-kinase (PI3K)/AKT, and signal transducer and activator of transcription protein (STAT) pathways.2,3 The end result of these MET-activated signaling cascades is increased cell mobility, enhanced growth, and decreased apoptosis.3 Under normal conditions, HGF and MET signaling are part of normal tissue development and response to injury.4-6 HGF and MET were identified as potent oncogenes7,8 and are upregulated in breast, colorectal, oral squamous cell, pancreatic, prostate, renal, and thyroid carcinomas, among others.9-15 MET gene amplification has been described in colorectal, esophageal, gastric, and non-small cell lung carcinomas, and malignant peripheral nerve sheath tumors. Germline or somatic MET mutations have been described in gastric, head and neck squamous cell, and renal cell carcinomas.10, 16-21

VEGFR-2 The vascular endothelial growth factor (VEGF) family of ligands (VEGF-A, VEGF-B, VEGF-C) and receptors (VEGFR-1, -2, -3) have been strongly implicated in the development and growth of many different tumors types and are reviewed elsewhere.22-24 VEGFR-2 expression has been associated with worse prognosis in several cancers, including breast, non-small cell lung, and prostate cancers.25-28

RET RET is a proto-oncogene receptor tyrosine kinase originally described in papillary thyroid cancer.29 RET is The International Journal of Targeted Therapies in Cancer

Clinical Articles Peer Reviewed Thyroid Cancer Clinical Pearls

composed of an extracellular region with four cadherinlike repeats, a transmembrane region, and a cytoplasmic tyrosine kinase domain.30 The glial cell line–derived neurotrophic factor (GNDF) family of proteins are the ligands for RET, and include GNDF, neurturin, artemin, and persephin. Activation of RET is complex and requires binding of both GNDF family ligands and glycosylphosphatidylinositol-anchored GDNF-family receptor-α proteins.31 Once this complex forms, RET can homodimerize and phosphorylate several intracellular tyrosine residues. As with MET and VEGFR-2, activation of RET can lead to the activation of multiple cell signaling pathways, including PI3K/AKT, MAPK, Ras/ERK, and Rac/-c-Jun NH2 terminal kinase (JNK).32-34 In normal human development, RET plays an important role in the development of the parasympathetic and sympathetic nervous systems.35 Germline mutations in RET are responsible for the development of Hirschsprung’s disease.36,37 RET mutations are common in medullary thyroid cancers (MTCs). Virtually all MTCs that are associated with multiple endocrine neoplasia type 2 (MEN 2) syndromes, as well as familial MTC, are due to mutations in RET.38,39 Approximately 50% of sporadic MTC are associated with RET mutations.39,40 In addition, RET mutations are clearly associated with pheochromocytomas, but they have also been described in pancreatic and nonmedullary thyroid cancer.41-43

• Cabozantinib is an active agent in MTC. • Cabozantinib may have unique activity against diseases with bone metastases.

Kinase Inhibition Potency of Cabozantinib (IC50: dose that inhibits by 50% the enzyme activity)44

ta b l e 1.

Target Protein

IC50 (nmol/L)

VEGFR-2

0.035

MET

1.3

FGFR1

5294

PDGFR-β

234

KIT

4.6

FLT1

12

FLT4

6.0

FLT3

11.3

Tie2

14.3

AXL

7.0

RON

124

Clinical Studies Preclinical Pharmacology and Proof-of-Concept Studies Cabozantinib is a potent small-molecule TKI targeting several kinases important in tumor growth and metastasis at nmol/L concentrations (Table 1).44 For example, cabozantinib treatment decreases MET phosphorylation, inhibits cell migration and invasion, and shows in vivo efficacy in MET-amplified malignant peripheral nerve sheath tumor STS26T and MPNST724 cells in culture and mouse xenografts.45 Tumors from cabozantinib-treated animals showed decreased MET phosphorylation and blood vessel density, and lung metastases.

Cabozantinib has been studied in numerous phase I, phase II, and phase III trials as a single agent or in combination with other drugs (Table 2).

Pharmacokinetics and Metabolism The pharmacokinetics and metabolism of cabozantinib have been examined at length in a single-agent phase I clinical trial.46 The peak plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) were proportional to drug dose. The terminal half-life (t½) was 91.3 ± 33.3 hours. Steady-state drug clearance was 4.2 ± 1.5 L/h for the 175-mg dosage, and steady-state drug levels were achieved after 15 days. Metabolism is thought to occur via the liver and the cytochrome P450 system, including the CYP2C8 enzyme.

TargetedHC.com

Antonio Jimeno, MD, PhD, and Daniel W. Bowles, MD, in the Division of Medical Oncology laboratory at the University of Colorado, Aurora, CO.

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Clinical Articles Peer Reviewed Thyroid Cancer

ta b l e 2 .

Selected List of Current Trials of Cabozantinib

Therapies

Phase

Target Cancers

Status

Cabozantinib (NCT01709435)

I

Solid tumors in children

Recruiting

Cabozantinib (NCT01688999)

II

Urothelial carcinoma

Recruiting

Cabozantinib (NCT01582295)

II

Multiple myeloma

Recruiting

Cabozantinib (NCT01755195)

II

Soft-tissue sarcoma

Recruiting

Cabozantinib vs paclitaxel (NCT01716715)

II

Persistent or recurrent epithelial ovarian, fallopian tube, or primary peritoneal cavity cancer

Recruiting

Cabozantinib + gemcitabine (NCT01663272)

II

Pancreatic cancer

Recruiting

Cabozantinib vs prednisone (NCT01605227)

III

Castration-resistant prostate cancer

Recruiting

Cabozantinib vs mitoxantrone (NCT01522443)

III

Castration-resistant prostate cancer

Recruiting

Phase I Trial, Including Medullary Thyroid Cancer Expansion A phase I dose-escalation study (NCT00215605) examining the tolerability, safety, and dosage for cabozantinib was conducted using a 3 + 3 design; adult patients with advanced incurable malignancies received intermittent or continuous dosing.46 Patients in the intermittent arm received 0.08 to 11.52 mg/kg daily for 5 days followed by 9 days off of drug. Patients in the continuous-dosing arms received either cabozantinib 175 mg or 265 mg oral suspension daily or 175-mg or 250-mg capsules daily. A preplanned expansion for patients with MTC was performed at the maximum tolerated dose (MTD). In this trial, 43% of all adverse events were grade 1 or 2, with 20% of patients experiencing diarrhea, fatigue, anorexia, nausea, hand-foot syndrome (HFS), rash, increased AST, vomiting, or mucositis. Adverse events were more severe in the continuous-dosing regimen. Grade 3 hypertension occurred in 2% of patients with MTC, with hypertension of any grade occurring in 16% of patients in the trial.

Dose-limiting toxicities included elevations in transaminases, lipase elevation, and mucositis. The MTD was 175 mg. The MTC cohort had excellent response, with 29% having an objective response and 68% with stable disease. The non-MTC subset had 38% of patients with stable disease for at least 3 months.

Phase III Trial in Medullary Thyroid Cancer In the expanded MTC cohort in the phase I trial, there 28

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was evidence of significant anticancer activity.46 Based on these data, Exelixis launched a multinational, randomized, placebo-controlled, double blind, phase III trial of cabozantinib in patients with relapsed, unresectable, or metastatic MTC (NCT00704730). The trial was known as EXAM and included 330 patients with progressive, metastatic MTC.47 All patients were required to have evidence of actively progressing disease prior to study entry.

Patients were randomized (2:1) to receive either cabozantinib 140 mg (n = 219) or placebo (n = 111) once daily until disease progression or intolerable toxicity.

The randomization was stratified by age (â&#x2030;¤ 65 years vs > 65 years) and previous exposure to a TKI, and the main efficacy outcome measures were progression-free survival (PFS), objective response, and response duration. No crossover was allowed upon progression. A highly statistically significant PFS prolongation was seen with cabozantinib compared with placebo (11.2 vs 4.0 months; P < .0001).

Partial responses were observed only in the active treatment arm (27% vs 0%; P < .0001), and median duration of response was 14.7 months. More patients in the cabozantinib group were progression-free at 1 year (47% vs 7%).

The most common adverse drug reactions were diarrhea, stomatitis, HFS, decreased weight, decreased appetite, nausea, fatigue, oral pain, hair color changes, dysgeusia, hypertension, abdominal pain, and constipation. Common laboratory abnormalities included increased AST, increased ALT, lymphopenia, increased alkaline phosphatase, hypocalcemia, neutropenia, thrombocytopenia, hypophosphatemia, and hyperbilirubinemia.

The FDA approved cabozantinib (Cometriq) on November 29, 2012, for the treatment of metastatic MTC. The package insert includes a boxed warning alerting that severe and fatal perforations and fistulae in the colon have occurred in some patients.

Conclusions Cabozantinib is a novel, small-molecule TKI targeting MET, VEGFR-2, and RET. It has significant preclinical activity in a number of different epithelial and mesenchymal malignancies. A phase III trial of single-agent cabozantinib in patients with MTC met its primary efficacy endpoints, and the FDA approved cabozantinib for patients with metastatic MTC. Currently, there is another FDA-approved therapy for MTC, vandetinib. How to best integrate cabozantinib with vandetinib is a question that remains unanswered, and we have thus far no molecular rationale to make this determination. Cabozantinib is under evaluation in several additional diseases, and the effects on bone disease are quite striking, although they might be more relevant to diseases other than MTC. The International Journal of Targeted Therapies in Cancer

Clinical Articles Peer Reviewed Thyroid Cancer

RE F ERENCES 1. Sonnenberg E, Meyer D, Weidner KM, Birchmeier C. Scatter factor/ hepatocyte growth factor and its receptor, the c-met tyrosine kinase, can mediate a signal exchange between mesenchyme and epithelia during mouse development. J Cell Biol. 1993;123(1):223-235.

2. Baselga J, De Jonge MJ, Rodon J, et al. A first-in-human phase I study of BKM120, an oral pan-class I PI3K inhibitor, in patients (pts) with advanced solid tumors. J Clin Oncol. 2010;28(15S; abstr 3003).

3. Trusolino L, Bertotti A, Comoglio PM. MET signalling: principles and functions in development, organ regeneration and cancer. Nat Rev Mol Cell Biol. 2010;11(12):834-848.

4. Birchmeier C, Birchmeier W, Gherardi E, Vande Woude GF. Met, metastasis, motility and more. Nat Rev Mol Cell Biol. 2003;4(12):915-925.

5. Birchmeier C, Gherardi E. Developmental roles of HGF/SF and its receptor, the c-Met tyrosine kinase. Trends Cell Biol. 1998;8(10):404-410.

6. Michalopoulos GK, DeFrances MC. Liver regeneration. Science.

1997;276(5309):60-66.

7. Bottaro DP, Rubin JS, Faletto DL, et al. Identification of the hepatocyte growth factor receptor as the c-met proto-oncogene product. Science.

1991;251(4995):802-804.

8. Nakamura T, Nishizawa T, Hagiya M, et al. Molecular cloning and expression of human hepatocyte growth factor. Nature. 1989;342(6248):440-443.

9. Camp RL, Rimm EB, Rimm DL. Met expression is associated with poor outcome in patients with axillary lymph node negative breast carcinoma.

Cancer. 1999;86(11):2259-2265.

10. Di Renzo MF, Olivero M, Giacomini A, et al. Overexpression and amplification of the met/HGF receptor gene during the progression of colorectal cancer. Clin Cancer Res. 1995;1(2):147-154.

11. Morello S, Olivero M, Aimetti M, et al. MET receptor is overexpressed but not mutated in oral squamous cell carcinomas. J Cell Physiol.

2001;189(3):285-290.

12. Di Renzo MF, Poulsom R, Olivero M, Comoglio PM, Lemoine NR. Expression of the Met/hepatocyte growth factor receptor in human pancreatic cancer. Cancer Res. 1995;55(5):1129-1138.

13. Humphrey PA, Zhu X, Zarnegar R, et al. Hepatocyte growth factor and its receptor (c-MET) in prostatic carcinoma. Am J Pathol. 1995;147(2):386-396.

14. Natali PG, Prat M, Nicotra MR, et al. Overexpression of the met/HGF receptor in renal cell carcinomas. Int J Cancer. 1996;69(3):212-217.

15. Ruco LP, Ranalli T, Marzullo A, et al. Expression of Met protein in thyroid tumours. J Pathol. 1996;180(3):266-270.

16. Miller CT, Lin L, Casper AM, et al. Genomic amplification of MET with boundaries within fragile site FRA7G and upregulation of MET pathways in esophageal adenocarcinoma. Oncogene. 2006;25(3):409-418.

17. Hara T, Ooi A, Kobayashi M, Mai M, Yanagihara K, Nakanishi I. Amplification of c-myc, K-sam, and c-met in gastric cancers: detection by fluorescence in situ hybridization. Lab Invest. 1998;78(9):1143-1153.

18. Bean J, Brennan C, Shih JY, et al. MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib. Proc Natl Acad Sci USA. 2007;104(52):20932-20937.

19. Di Renzo MF, Olivero M, Martone T, et al. Somatic mutations of the MET oncogene are selected during metastatic spread of human HNSC carcinomas. Oncogene. 2000;19(12):1547-1555.

20. Schmidt L, Duh FM, Chen F, et al. Germline and somatic mutations in the tyrosine kinase domain of the MET proto-oncogene in papillary renal carcinomas. Nat Genet. 1997;16(1):68-73.

21. Mantripragada KK, Spurlock G, Kluwe L, et al. High-resolution DNA copy number profiling of malignant peripheral nerve sheath tumors using targeted microarray-based comparative genomic hybridization. Clin Cancer Res. 2008;14(4):1015-1024.

22. Carmeliet P, Jain RK. Principles and mechanisms of vessel normalization for cancer and other angiogenic diseases. Nat Rev Drug Discov. 2011;10(6):417-427.

23. Carmeliet P, Jain RK. Molecular mechanisms and clinical applications of angiogenesis. Nature. 2011;473(7347):298-307.

24. De Bock K, Mazzone M, Carmeliet P. Antiangiogenic therapy, hypoxia, and metastasis: risky liaisons, or not? Nat Rev Clin Oncol. 2011;8(7):393-404.

25. Charpidou A, Gkiozos I, Konstantinou M, et al. Bronchial washing levels of vascular endothelial growth factor receptor-2 (VEGFR2) correlate with overall survival in NSCLC patients. Cancer Lett. 2011;304(2):144-153.

26. Farace F, Gross-Goupil M, Tournay E, et al. Levels of circulating CD45(dim)CD34(+)VEGFR2(+) progenitor cells correlate with outcome in metastatic renal cell carcinoma patients treated with tyrosine kinase inhibitors. Br J Cancer. 2011;104(7):1144-1150.

27. Linderholm BK, Hellborg H, Johansson U, Skoog L, Lehtiö J. Vascular endothelial growth factor receptor 2 and downstream p38 mitogenactivated protein kinase are possible candidate markers of intrinsic resistance to adjuvant endocrine treatment in steroid receptor positive breast cancer. Breast Cancer Res Treat. 2011;125(2):457-465.

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28. Carrillo de Santa Pau E, Arias FC, Caso Peláez E, et al. Prognostic significance of the expression of vascular endothelial growth factors A, B, C, and D and their receptors R1, R2, and R3 in patients with nonsmall cell lung cancer. Cancer. 2009;115(8):1701-1712.

29. Fusco A, Grieco M, Santoro M, et al. A new oncogene in human thyroid papillary carcinomas and their lymph-nodal metastases. Nature.

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30. Wells SA, Jr., Santoro M. Targeting the RET pathway in thyroid cancer.

Clin Cancer Res. 2009;15(23):7119-7123.

31. Phay JE, Shah MH. Targeting RET receptor tyrosine kinase activation in cancer. Clin Cancer Res. 2010;16(24):5936-5941.

32. Hasegawa T, Enomoto A, Kato T, et al. Roles of induced expression of MAPK phosphatase-2 in tumor development in RET-MEN2A transgenic mice. Oncogene. 2008;27(43):5684-5695.

33. Besset V, Scott RP, Ibanez CF. Signaling complexes and proteinprotein interactions involved in the activation of the Ras and phosphatidylinositol 3-kinase pathways by the c-Ret receptor tyrosine kinase. J Biol Chem. 2000;275(50):39159-39166.

34. Panta GR, Du L, Nwariaku FE, Kim LT. Direct phosphorylation of proliferative and survival pathway proteins by RET. Surgery.

2005;138(2):269-274.

35. Arighi E, Borrello MG, Sariola H. RET tyrosine kinase signaling in development and cancer. Cytokine Growth Factor Rev. 2005;16(4-5):441-467.

36. Edery P, Lyonnet S, Mulligan LM, et al. Mutations of the RET protooncogene in Hirschsprung’s disease. Nature. 1994;367(6461):378-380.

37. Romeo G, Ronchetto P, Luo Y, et al. Point mutations affecting the tyrosine kinase domain of the RET proto-oncogene in Hirschsprung’s disease. Nature. 1994;367(6461):377-378.

38. Mulligan LM, Kwok JB, Healey CS, et al. Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A. Nature.

1993;363(6428):458-460.

39. Hofstra RM, Landsvater RM, Ceccherini I, et al. A mutation in the RET proto-oncogene associated with multiple endocrine neoplasia type 2B and sporadic medullary thyroid carcinoma. Nature. 1994;367(6461):375-376.

40. Papotti M, Olivero M, Volante M, et al. Expression of hepatocyte growth factor (HGF) and its receptor (MET) in medullary carcinoma of the thyroid. Endocr Pathol. 2000;11(1):19-30.

41. Komminoth P, Roth J, Muletta-Feurer S, Saremaslani P, Seelentag WK, Heitz PU. RET proto-oncogene point mutations in sporadic neuroendocrine tumors. J Clin Endocrinol Metab. 1996;81(6):2041-2046.

42. Sawai H, Okada Y, Kazanjian K, et al. The G691S RET polymorphism increases glial cell line-derived neurotrophic factor-induced pancreatic cancer cell invasion by amplifying mitogen-activated protein kinase signaling. Cancer Res. 2005;65(24):11536-11544.

43. Moses W, Weng J, Kebebew E. Prevalence, clinicopathologic features, and somatic genetic mutation profile in familial versus sporadic nonmedullary thyroid cancer. Thyroid. 2011;21(4):367-371.

44. You WK, Sennino B, Williamson CW, et al. VEGF and c-Met blockade amplify angiogenesis inhibition in pancreatic islet cancer. Cancer Res. 2011;71(14):4758-4768.

45. Torres KE, Zhu QS, Bill K, et al. Activated MET is a molecular prognosticator and potential therapeutic target for malignant peripheral nerve sheath tumors. Clin Cancer Res. 2011;17(12):3943-3955.

46. Kurzrock R, Sherman SI, Ball DW, et al. Activity of XL184 (Cabozantinib), an oral tyrosine kinase inhibitor, in patients with medullary thyroid cancer. J Clin Oncol. 2011;29(19):2660-2666.

47. Schoffski P, Rosella E, Müller S, et al; EXAM Study Group. An international, double-blind, randomized, placebo-controlled phase III trial (EXAM) of cabozantinib (XL184) in medullary thyroid carcinoma (MTC) patients (pts) with documented RECIST progression at baseline.

J Clin Oncol. 2012;30(suppl; abstr 5508).

Author DisclosureS Dr. Jimeno has no conflicts of interest to report.

Dr. Bowles has no conflicts of interest to report.

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PI3K Inhibitors in Breast Cancer Treatment Jose M. Pacheco, MD, and Cynthia X. Ma, MD, PhD

The PI3K Signaling Pathway

abstr act

Aberrant activation of the PI3K pathway occurs frequently in breast cancer and contributes to treatment resistance to standard therapy. There has been a significant interest in developing inhibitors against components of the PI3K pathway, including PI3K, AKT, and mTOR, for the treatment of breast cancer. The success of the mTOR inhibitor everolimus in improving the activity of exemestane in metastatic estrogen receptor–positive breast cancer further supports the biological relevance of this pathway in this tumor type.

Although PI3K-specific inhibitors are in the early stages of clinical development, promising antitumor activity has been observed in phase I studies. However, combination therapies are likely required for the most effective use of these agents. In addition, the development of predictors of response remains a challenge.

Jose M. Pacheco, MD Department of Internal Medicine, Washington University, Saint Louis, MO

corresponding author Cynthia X. Ma, MD, PhD Section of Breast Oncology, Division of Oncology, Department of Medicine, Washington University School of Medicine; and Siteman Cancer Center, St. Louis, MO; CMa@dom.wustl.edu

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Class I phosphatidylinositide 3-kinases (PI3Ks) are lipid kinases that function immediately downstream of the signaling of receptor tyrosine kinases (RTKs; eg, HER2, EGFR, IGF-1R) (Figure).1 They are heterodimers of a p110 catalytic subunit (p110α, p110β, or p110δ) and a regulatory subunit (p85α, p55α, p50α, p85β, or p55γ). The p110α and the p110β catalytic subunits are encoded by PIK3CA and PIK3CB, respectively, and are expressed in all tissues.

The p110δ catalytic subunit is encoded by PIK3CD and is expressed primarily in leukocytes. Ligand binding to the corresponding RTK triggers its intracellular association with the regulatory subunit of PI3K, either directly or indirectly via an intermediate adaptor molecule such as insulin receptor substrate 1 (IRS1). This releases the inhibitory effect of p85 on p110 and activates the kinase activity of PI3K. PI3K converts phosphatidylinositol bisphosphate, PI(4,5)P2, to phosphatidylinositol triphosphate, PI(3,4,5) P3, which interacts with the PH domain of phosphoinositide-dependent kinase 1 (PDK1) and AKT, leading to membrane localization and phosphorylation of AKT at threonine 308. Mammalian target of rapamycin complex 2 (mTORC2) phosphorylates AKT at serine 473, leading to full activation of AKT. The activated AKT in turn phosphorylates the downstream signaling components of the PI3K pathway to promote cell growth, proliferation, and survival. The AKT-induced phosphorylation and inhibition of tuberous sclerosis 2 (TSC2), which is in complex with TSC1, causes accumulation of Rheb GTP and activation of mammalian target of rapamycin complex 1 (mTORC1), leading to activation of S6 kinase (S6K1) and eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1), which are important to protein synthesis. In addition, AKT phosphorylates glycogen synthase 3β (GSK3β), Bcl-2-associated agonist of cell death (BAD), the forkhead transcription factors (FOXO), and other molecules that are important in regulating metabolism, cell proliferation, and survival. Opposing the activity of PI3K, phosphatase and tensin homologue deleted on chromosome 10 (PTEN) dephosphorylates PI(3,4,5)P3 to the inactive diphosphate form, while inositol polyphosphate 4-phosphatase type II (INPP4B) removes the phosphate group at position 4 of the inositol ring from the inositol 3,4-bisphosphate, thus negatively regulating the PI3K pathway. In addition, a negative The International Journal of Targeted Therapies in Cancer

Clinical Articles Peer Reviewed BREAST C a n c e r Clinical Pearls

Clinical Development of PI3K Inhibitors in Breast Cancer Rapalogues, which inhibit mTORC1, were the first agents targeting the PI3K pathway available in clinical trials, and everolimus is now in clinical use for the treatment of nonsteroidal aromatase inhibitor (AI)-resistant metastatic ER+ breast cancer. However, inhibition of mTORC1 activates AKT via the negative feedback loop mediated by IRS1 and the unopposed mTORC2 activity, leading to treatment resistance.10-14 Therefore, inhibitors against upstream components of the pathway, such as AKT and PI3K, may be more efficacious, as suggested in preclinical studies.15,16 Inhibitors against the class 1 PI3Ks are broadly classified into three groups based on the selectivity to PI3K isoforms and mTOR: the pan-PI3K isoform inhibitors (eg, XL147, BKM120, GDC-0941, BAY 80-9646, PX-866); the dual PI3K and mTOR inhibitors (eg, XL765, BEZ235, TargetedHC.com

GSK2126458, GDC-0980, SF-1126, PF-04691502, PF05212384, BGT-226); and isoform-specific inhibitors (eg, p110α-specific inhibitors, BYL719, INK-1114, GDC-0032).

Note that, unlike the rapalogues, the dual PI3K and mTOR inhibitors are effective against both mTORC1 and mTORC2, and therefore have the advantage of preventing the feedback activation of AKT.

figure.

PI3K Pathway

PI(4,5)P2

RTK IRS1

PI(3,4,5)P3

PI(3,4)P2

PI(3)P

p85 PI3K

p110

PTEN

mTORC2

SHIP-1/2

mTORC2 TSC2

GSK3β Proliferation and metabolism

INPP4B

TSC1

BA D

Mutation in PIK3CA, the gene encoding p110α, is one of the most frequent genetic events in breast cancer. It is observed in 30% to 40% of ER+ or HER2+ disease, and in approximately 7% of triple-negative breast cancer (TNBC; negative for ER, PR, and HER2 gene amplification).3-5 These mutations occur most frequently in the evolutionarily conserved helical domain and kinase domain of the protein.5 In laboratory studies, these mutations, including the three hot spot mutations E542K, E545K, and H1047R, have been shown to activate downstream signaling and transform human mammary epithelial cells.6,7 Importantly, cells with PIK3CA mutations are sensitive to the growth inhibitory effect of PI3K pathway inhibitors.7 In addition to PIK3CA, mutations or copy number changes in other components of the PI3K pathway have been identified. For example, PIK3R1, the gene that encodes the regulatory subunit 1 (alpha), is mutated in 2% to 4% of ER+ or HER2+ breast cancer and clustered in the p110 interaction domain.3 Similarly, activating mutations in AKT1 have been observed in 2% to 4% of ER+ or HER2+ breast cancer.3,8,9 Mutation in PTEN or INPP4B, the two negative regulators of the PI3K pathway, are rare, but loss of gene copy number is frequent, particularly in TNBC, in which the occurrence is over 30% and is associated with increased AKT phosphorylation and PI3K pathway signaling activation.3,9 In an analysis of studies of breast cancer

by The Cancer Genome Atlas Network, a statistically significant exclusion pattern was observed among PIK3R1, PIK3CA, PTEN, and AKT1 mutations (P = .025).3

FO XO

PI3K Pathway Abnormalities in Breast Cancer

• Genetic alterations in components of the PI3K pathway are common in breast cancer. These include mutations in PIK3CA, loss of PTEN, or INPP4B, and, less commonly, mutations in PTEN, AKT1 or PIK3R1.

• Direct inhibitors of PI3K are promising agents that are in early stages of clinical development for the treatment of cancers including breast cancer.

• Skin rashes, gastrointestinal symptoms, and hyperglycemia are common side effects and are likely on-target effects from these drugs

ras

feedback loop exists between mTORC1 and AKT, as activation of S6K1 suppresses PI3K signaling by phosphorylation and proteasome-mediated degradation of IRS1.2

Rheb

Apoptosis mTORC1 S6K1

4EBP1

Growth and protein synthesis RTK, receptor tyrosine kinase; PI3K, phosphatidylinositide 3-kinases; PI(4,5) P2, phosphatidylinositol 4,5-bisphosphate; PI(3,4)P2, phosphatidylinositol 3,4-bisphosphate; PI(3,4,5)P3, phosphatidylinositol 3,4,5-trisphosphate; IRS1, insulin receptor substrate 1; PTEN, phosphatase and tensin homolog; PI(3)P, phosphatidylinositol 3-phosphate; INPP4B, inositol polyphosphate 4-phosphatase type II; TSC, tuberous sclerosis; Rheb, Ras homologue enriched in brain: 4E-BP1, eukaryotic translation initiation factor 4E-binding protein 1; mTORC1, mammalian target of rapamycin complex 1; mTORC2, mammalian target of rapamycin complex 2; GSK3β, glycogen synthase 3β; FOXO, forkhead transcription factors; S6K1, ribosomal protein S6 kinase 1; BAD, Bcl-2-associated agonist of cell death.

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ta b l e .

Clinical Trials of PI3K Inhibitors in Breast Cancer Trial Design

Regimen

Breast Cancer Population

I/II

XL147 + trastuzumab or XL147 + paclitaxel + trastuzumab

HER2+ MBC, prior progression on a trastuzumab-based regimen

I/II

XL147 + letrozole

Nonsteroidal AI-resistant ER+ HER2- MBC

II

BKM120

Metastatic TNBC

Ib/II

BKM120 + trastuzumab

HER2+, trastuzumab-resistant MBC

Ib

BKM120 + capecitabine

MBC

Ib

BKM120 + endocrine therapy

ER+ MBC

Ib

BKM120 + paclitaxel; BKM120 + paclitaxel + trastuzumab

MBC

II, randomized, doubleblind, placebo-controlled

BKM120 + paclitaxel

HER2- MBC

I

BKM120 + olaparib

TNBC

Ib/II

BKM120 + lapatinib

HER2+/PI3K-activated, trastuzumab-resistant MBC HER2+ breast cancer

Ib

BKM120 + fulvestrant

ER+ MBC

III, randomized, doubleblind, placebo-controlled

BKM120 + fulvestrant

ER+ HER2-, AI-resistant MBC

III, randomized, doubleblind, placebo-controlled

BKM120 + fulvestrant

ER+ HER2-, AI-resistant MBC progressed on prior everolimus

Ib

GDC-0941 + paclitaxel with/without bevacizumab or trastuzumab

MBC

Ib

GDC-0941 + trastuzumab or T-DM1

HER2+, trastuzumab-resistant MBC

II

GDC-0941 + paclitaxel

MBC

II, randomized, doubleblind, placebo-controlled

GDC-0941 + fulvestrant

ER+, AI-resistant MBC

I

BAY80-6946 + paclitaxel

Expansion cohort in breast cancer

BYL719 + endocrine therapy

ER+ MBC

Ib/II

BEZ235 + trastuzumab vs lapatinib + capecitabine

HER2+, trastuzumab-resistant MBC

II

BEZ235 + paclitaxel

HER2- MBC

Ib

BEZ235 + capecitabine

MBC

Ib

BEZ235 + endocrine therapy

ER+ MBC

Ib

BEZ235 + paclitaxel BEZ235 + paclitaxel + trastuzumab

MBC

XL765 (Sanofi)

I/II

XL765 + letrozole

ER+, AI-resistant MBC

GDC-0980 (Genentech)

II, randomized, doubleblind, placebo-controlled

GDC-0980 + fulvestrant

ER+, AI-resistant MBC

Ib

GDC-0980 + paclitaxel with/without bevacizumab

MBC

I/II

BGT226

MBC

Pan-isoform Inhibitor of PI3K XL147 (Sanofi)

BKM120 (Novartis)

GDC-0941 (Genentech)

BAY 80-6946 (Bayer)

PI3KÎą Selective Inhibitor Ib

BYL719 (Novartis)

Dual PI3K/mTOR inhibitor BEZ235 (Novartis)

BGT226 (Novartis)

MBC, metastatic breast cancer; TNBC, triple-negative breast cancer.

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The International Journal of Targeted Therapies in Cancer

Clinical Articles Peer Reviewed BREAST C a n c e r

PI3K inhibitors from all three groups have demonstrated single-agent activity against breast cancer in phase I studies conducted in patients with solid tumor malignancies. In a dose-escalation study of BKM120 that included nine patients with metastatic breast cancer, one patient with TNBC exhibited a partial response (PR) and two patients had stable disease (SD) ≥ 8 months.17 Partial responses (most were ER+ cases) have also been observed in preliminary reports of phase I studies of single-agent GDC-0941,18 BAY 80-6946,19 and BEZ 235.20 In addition, in the preliminary report of a phase I study of the α-specific inhibitor BYL719 that enrolled 20 patients (15 ER+ HER2-, 5 HER2+) with PIK3CA-mutant metastatic breast cancer,21 six of 18 patients (33%) achieved tumor shrinkage > 20%, and among them, two achieved a PR. However, the activity of a single-agent PI3K inhibitor is likely limited due to the compensatory activation of extracellular signal-regulated kinases or upstream RTKs, as observed in preclinical studies,22-26 supporting combination strategies with inhibitors against these pathways.

The combination of PI3K inhibitors with endocrine agents is supported by preclinical findings that combined targeting of the estrogen receptor, and PI3K is often required to achieve apoptotic effect on cancer cells.15,16 Since activation of the PI3K pathway has been associated with chemotherapy resistance,27 PI3K inhibitors are also being tested for their ability to improve chemotherapy efficacy.

The Table lists clinical trials of PI3K inhibitors in breast cancer, most of which are ongoing. A phase Ib study of BKM120 in combination with letrozole in postmenopausal women with ER+, HER2- metastatic breast cancer was reported in abstract form.28 Although the majority of patients enrolled in the study had disease progression with prior AI treatment, among the 51 patients evaluated, one had a complete response (CR), one had a PR, and 13 had SD for ≥4 months.

In the preliminary report of a phase I/Ib study of BEZ235 in combination with trastuzumab in HER2+, trastuzumab-resistant metastatic breast cancer that carried a molecular alteration in PIK3CA and/or PTEN, one PR and four SD for ≥ 4 cycles (1 patient had SD for > 84 weeks) were observed in the 15 patients evaluated.29 These results are encouraging.

Overall, the PI3K inhibitors have demonstrated a tolerable toxicity profile, with hyperglycemia, maculopapular rash, gastrointestinal side effects, and stomatitis as common dose-limiting toxicities. Although the spectrum of side effects seems to be similar between the α-specific and the pan-isoform inhibitors, a head-to-head comparison of their efficacy and tolerability has not been performed. In preclinical studies, breast cancers carrying

TargetedHC.com

PIK3CA mutations were found to be highly dependent on p110α for cell survival, while PTEN-deficient tumors were more dependent on p110β.30 Therefore, it is rational to test the p110α-specific inhibitors in PIK3CA-mutant tumors, while pan-isoform or p110 β-specific PI3K inhibitors may be necessary for PTEN-deficient tumors.

Predicting Response to PI3K Inhibitors To date, there have been no established biomarkers that predict treatment efficacy for PI3K inhibitors. In preclinical models, cell lines harboring aberrations in the PI3K pathways, such as mutations in PIK3CA or loss of PTEN, were shown to be sensitive to PI3K pathway inhibitors,31-33 and mutations in RAS were associated with resistance.33,34 However, a partial response was observed in a patient with metastatic TNBC with KRAS mutation in the phase I study of BKM120,17 indicating the complexity of the issue. Prospective clinical trials are ongoing to evaluate the role of PI3K pathway aberrations in response to PI3K inhibitors.

Conclusions PI3K inhibitors are among the most promising agents being evaluated for the treatment of breast cancer. Although single-agent activity has been observed in phase I trials, combination therapy is likely to be most effective. Randomized clinical trials are ongoing to evaluate their activities in combination with endocrine agents, chemotherapy, and HER2-targeted agents. In addition, there is continued effort to identify predictors of response to these agents.

We look forward to the results of these important studies.

RE F ERENCES 1. Engelman JA. Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nat Rev Cancer. 2009;9(8):550-562.

2. Haruta T, Uno T, Kawahara J, et al. A rapamycin-sensitive pathway down-regulates insulin signaling via phosphorylation and proteasomal degradation of insulin receptor substrate-1. Molecular Endocrinology.

2000;14(6):783-794.

3. The Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumours. Nature. 2012;490(7418):61-70.

4. Ellis MJ, Lin L, Crowder R, et al. Phosphatidyl-inositol-3-kinase alpha catalytic subunit mutation and response to neoadjuvant endocrine therapy for estrogen receptor positive breast cancer. Breast Cancer Res Treat. 2010;119(2):379-390.

5. Samuels Y, Wang Z, Bardelli A, et al. High frequency of mutations of the PIK3CA gene in human cancers. Science. 2004;304(5670):554.

6. Zhao JJ. The oncogenic properties of mutant p110[agr] and p110[bgr] phosphatidylinositol 3-kinases in human mammary epithelial cells. Proc.

Natl Acad. Sci. USA. 2005;102:18443-18448.

7. Zhang H, Liu G, Dziubinski M, Yang Z, Ethier SP, Wu G. Comprehensive analysis of oncogenic effects of PIK3CA mutations in human mammary epithelial cells. Breast Cancer Res Treat. 2008;112(2):217-227.

8. Carpten JD, Faber AL, Horn C, et al. A transforming mutation in the pleckstrin homology domain of AKT1 in cancer. Nature.

2007;448(7152):439-444.

9. Stemke-Hale K, Gonzalez-Angulo AM, Lluch A, et al. An integrative genomic and proteomic analysis of PIK3CA, PTEN, and AKT mutations in breast cancer. Cancer Res. 2008;68(15):6084-6091.

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10. Sun S-Y, Rosenberg LM, Wang X, et al. Activation of Akt and eIF4E survival pathways by rapamycin-mediated mammalian target of rapamycin inhibition. Cancer Res. 2005;65(16):7052-7058.

11. O’Reilly KE, Rojo F, She QB, et al. mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res. 2006;66(3):1500-1508.

12. Wan X, Harkavy B, Shen N, Grohar P, Helman LJ. Rapamycin induces feedback activation of Akt signaling through an IGF-1R-dependent mechanism. Oncogene. 2007;26(13):1932-1940.

13. Tabernero J, Rojo F, Calvo E, et al. Dose- and schedule-dependent inhibition of the mammalian target of rapamycin pathway with everolimus: a phase I tumor pharmacodynamic study in patients with advanced solid tumors. J Clin Oncol. 2008;26(10):1603-1610.

14. Cho DC. Low expression of surrogates for mTOR pathway activation predicts resistance to CCI-779 in patients with advanced renal cell carcinoma (RCC). Presented at: AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics: Discovery, Biology, and Clinical Applications; November 14-18, 2005; Philadelphia, PA. 15. Sanchez CG, Ma CX, Crowder RJ, et al. Preclinical modeling of combined phosphatidylinositol-3-kinase inhibition with endocrine therapy for estrogen receptor-positive breast cancer. Breast Cancer Res. 2011;13(2):R21.

16. Crowder RJ, Phommaly C, Tao Y, et al. PIK3CA and PIK3CB inhibition produce synthetic lethality when combined with estrogen deprivation in estrogen receptor-positive breast cancer. Cancer Res. 2009;69(9):3955-3962.

17. Bendell JC, Rodon J, Burris HA, et al. Phase I, dose-escalation study of BKM120, an oral pan-Class I PI3K inhibitor, in patients with advanced solid tumors. J Clin Oncol. 2012;30(3):282-290.

18. Von Hoff DD, LoRusso P, Tibes R, et al. A first-in-human phase I study to evaluate the pan-PI3K inhibitor GDC-0941 administered QD or BID in patients with advanced solid tumors. J Clin Oncol. 2010;28(suppl 15; abstr 2541).

19. Lotze MT, Appleman LJ, Ramanathan RK, et al. Phase I study of intravenous PI3K inhibitor BAY 80-6946: activity in patients (pts) with advanced solid tumors and non-Hodgkin lymphoma treated in MTD expansion cohorts. J Clin Oncol. 2012;30(suppl; abstr 3019).

20. Burris H, Rodon J, Sharma S, et al. First-in-human phase I study of the oral PI3K inhibitor BEZ235 in patients (pts) with advanced solid tumors.

J Clin Oncol. 2010;28(suppl 15; abstr 3005).

21. Juric D, Argiles G, Burris HA, et al. Phase I study of BYL719, an alphaspecific PI3K inhibitor, in patients with PIK3CA mutant advanced solid tumors: preliminary efficacy and safety in patients with PIK3CA mutant ER-positive (ER+) metastatic breast cancer (MBC) Cancer Res. 2012;72(24 suppl; abstr P6-10-07).

22. Ibrahim YH, Garcia-Garcia C, Serra V, et al. PI3K Inhibition impairs BRCA1/2 expression and sensitizes BRCA-proficient triple-negative breast cancer to PARP inhibition. Cancer Discov. 2012;2(11):1036-1047.

23. Serra V, Scaltriti M, Prudkin L, et al. PI3K inhibition results in enhanced HER signaling and acquired ERK dependency in HER2-overexpressing breast cancer. Oncogene. 2011;30(22):2547-2557.

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24. Chandarlapaty S, Sawai A, Scaltriti M, et al. AKT inhibition relieves feedback suppression of receptor tyrosine kinase expression and activity.

Cancer Cell. 2011;19(1):58-71.

25. Chakrabarty A, Sanchez V, Kuba MG, Rinehart C, Arteaga CL. Feedback upregulation of HER3 (ErbB3) expression and activity attenuates antitumor effect of PI3K inhibitors. Proc Natl Acad Sci USA. 2012;109(8):2718-2723.

26. Chaturvedi D, Gao X, Cohen MS, Taunton J, Patel TB. Rapamycin induces transactivation of the EGFR and increases cell survival. Oncogene.

2009;28(9):1187-1196.

27. West KA, Sianna Castillo S, Dennis PA. Activation of the PI3K/Akt pathway and chemotherapeutic resistance. Drug Resistance Updates.

2002;5(6):234-248.

28. Mayer IA, Abramson VG, Balko JM, et al. A phase Ib study of pan-PI3K inhibitor BKM120 with letrozole in ER+/HER2- metastatic breast cancer (MBC). J Clin Oncol. 2012;30(suppl; abstr 510).

29. Krop IE, Saura C, Ahnert JR, et al. A phase I/IB dose-escalation study of BEZ235 in combination with trastuzumab in patients with PI3kinase or PTEN altered HER2+ metastatic breast cancer. J Clin Oncol.

2012;30(suppl; abstr 508).

30. Wee S, Wiederschain D, Maira SM, et al. PTEN-deficient cancers depend on PIK3CB. Proc Natl Acad Sci USA. 2008;105(35):13057-13062.

31. Brachmann SM, Hofmann I, Schnell C, et al. Specific apoptosis induction by the dual PI3K/mTor inhibitor NVP-BEZ235 in HER2 amplified and PIK3CA mutant breast cancer cells. Proc Natl Acad Sci USA. 2009;106(52):22299-22304.

32. O’Brien C, Wallin JJ, Sampath D, et al. Predictive biomarkers of sensitivity to the phosphatidylinositol 3’ kinase inhibitor GDC-0941 in breast cancer preclinical models. Clin Cancer Res. 2010;16(14):3670-3683.

33. Di Nicolantonio F, Arena S, Tabernero J, et al. Deregulation of the PI3K and KRAS signaling pathways in human cancer cells determines their response to everolimus. J Clin Invest. 2010;120(8):2858-2866.

34. Maira SM, Pecchi S, Huang A, et al. Identification and characterization of NVP-BKM120, an orally available pan-class I PI3-kinase inhibitor. Mol Cancer Ther. 2012;11(2):317-328.

Author Disclosures Dr. Pacheco has no conflicts of interest to report.

Dr. Ma has been a consultant/advisory board member and received honoraria from Novartis Pharmaceuticals and has received clinical trial funding from Novartis and Pfizer Inc.

The International Journal of Targeted Therapies in Cancer

In the newly metastatic CRPC patient who is asymptomatic or minimally symptomatic

STARTS THE FIGHT

AND HELPS HIS IMMUNE SYSTEM SUSTAIN* IT 1

• Targets and attacks prostate cancer cells • Statistically significant overall survival advantage1,2 • Sustained* immune response *A sustained immune response was seen out to 26 weeks in the pivotal study (the last time point measured).1 INDICATION: PROVENGE® (sipuleucel-T) is an autologous cellular immunotherapy indicated for the treatment of asymptomatic or minimally symptomatic metastatic castrate resistant (hormone refractory) prostate cancer.

IMPORTANT SAFETY INFORMATION: PROVENGE is intended solely for autologous use and is not routinely tested for transmissible infectious diseases.

In controlled clinical trials, serious adverse events reported in the PROVENGE group included acute infusion reactions (occurring within 1 day of infusion) and cerebrovascular events. Severe (Grade 3) acute infusion reactions were reported in 3.5% of patients in the PROVENGE group. Reactions included chills, fever, fatigue, asthenia, dyspnea, hypoxia, bronchospasm, dizziness, headache, hypertension, muscle ache, nausea, and vomiting. No Grade 4 or 5 acute infusion reactions were reported in patients in the PROVENGE group.

The most common adverse events (incidence ≥15%) reported in the PROVENGE group were chills, fatigue, fever, back pain, nausea, joint ache, and headache.

For more information on PROVENGE, please see Brief Summary of Prescribing Information on adjacent pages. www.PROVENGEHCP.com

PROVENGE® (sipuleucel-T) Suspension for Intravenous Infusion

Rx Only

BRIEF SUMMARY — See full Prescribing Information for complete product information

INDICATIONS AND USAGE: PROVENGE® (sipuleucel-T) is an autologous cellular immunotherapy indicated for the treatment of asymptomatic or minimally symptomatic metastatic castrate resistant (hormone refractory) prostate cancer.

DOSAGE AND ADMINISTRATION • For Autologous Use Only.

• The recommended course of therapy for PROVENGE is 3 complete doses, given at approximately 2-week intervals.

• Premedicate patients with oral acetaminophen and an antihistamine such as diphenhydramine.

• Before infusion, confirm that the patient’s identity matches the patient identifiers on the infusion bag.

• Do Not Initiate Infusion of Expired Product.

• Infuse PROVENGE intravenously over a period of approximately 60 minutes.

Do Not Use a Cell Filter.

• Interrupt or slow infusion as necessary for acute infusion reactions, depending on the severity of the reaction.

(See Dosage and Administration [2] of full Prescribing Information.)

CONTRAINDICATIONS: None.

WARNINGS AND PRECAUTIONS • PROVENGE is intended solely for autologous use.

• Acute infusion reactions (reported within 1 day of infusion) included, but were not limited to, fever, chills, respiratory events (dyspnea, hypoxia, and bronchospasm), nausea, vomiting, fatigue, hypertension, and tachycardia. In controlled clinical trials, 71.2% of patients in the PROVENGE group developed an acute infusion reaction.

In controlled clinical trials, severe (Grade 3) acute infusion reactions were reported in 3.5% of patients in the PROVENGE group. Reactions included chills, fever, fatigue, asthenia, dyspnea, hypoxia, bronchospasm, dizziness, headache, hypertension, muscle ache, nausea, and vomiting. The incidence of severe events was greater following the second infusion (2.1% vs 0.8% following the first infusion), and decreased to 1.3% following the third infusion. Some (1.2%) patients in the PROVENGE group were hospitalized within 1 day of infusion for management of acute infusion reactions.

No Grade 4 or 5 acute infusion reactions were reported in patients in the PROVENGE group.

Closely monitor patients with cardiac or pulmonary conditions. In the event of an acute infusion reaction, the infusion rate may be decreased, or the infusion stopped, depending on the severity of the reaction. Appropriate medical therapy should be administered as needed.

• Handling Precautions for Control of Infectious Disease. PROVENGE is not routinely tested for transmissible infectious diseases. Therefore, patient leukapheresis material and PROVENGE may carry the risk of transmitting infectious diseases to health care professionals handling the product. Universal precautions should be followed.

• Concomitant Chemotherapy or Immunosuppressive Therapy. Use of either chemotherapy or immunosuppressive agents (such as systemic corticosteroids) given concurrently with the leukapheresis procedure or PROVENGE has not been studied. PROVENGE is designed to stimulate the immune system, and concurrent use of immunosuppressive agents may alter the efficacy and/or safety of PROVENGE. Therefore, patients should be carefully evaluated to determine whether it is medically appropriate to reduce or discontinue immunosuppressive agents prior to treatment with PROVENGE. • Product Safety Testing. PROVENGE is released for infusion based on the microbial and sterility results from several tests: microbial contamination determination by Gram stain, endotoxin content, and in-process sterility with a 2-day incubation to determine absence of microbial growth. The final (7-day incubation) sterility test results are not available at the time of infusion. If the sterility results become positive for microbial contamination after PROVENGE has been approved for infusion, Dendreon will notify the treating physician. Dendreon will attempt to identify the microorganism, perform antibiotic sensitivity testing on recovered microorganisms, and communicate the results to the treating physician. Dendreon may request additional information from the physician in order to determine the source of contamination.

(See Warnings and Precautions [5] of full Prescribing Information.)

ADVERSE REACTIONS Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety evaluation of PROVENGE is based on 601 prostate cancer patients in the PROVENGE group who underwent at least 1 leukapheresis procedure in four randomized, controlled clinical trials. The control was non-activated autologous peripheral blood mononuclear cells.

The most common adverse events, reported in patients in the PROVENGE group at a rate ≥15%, were chills, fatigue, fever, back pain, nausea, joint ache, and headache. Severe (Grade 3) and life-threatening (Grade 4) adverse events were reported in 23.6% and 4.0% of patients in the PROVENGE group compared with 25.1% and 3.3% of patients in the control group. Fatal (Grade 5) adverse events were reported in 3.3% of patients in the PROVENGE group compared with 3.6% of patients in the control group.

Serious adverse events were reported in 24.0% of patients in the PROVENGE group and 25.1% of patients in the control group. Serious adverse events in the PROVENGE group included acute infusion reactions (see Warnings and Precautions), cerebrovascular events, and single case reports of eosinophilia, rhabdomyolysis, myasthenia gravis, myositis, and tumor flare.

PROVENGE was discontinued in 1.5% of patients in Study 1 (PROVENGE group n=341; Control group n=171) due to adverse events. Some patients who required central venous catheters for treatment with PROVENGE developed infections, including sepsis. A small number of these patients discontinued treatment as a result. Monitoring for infectious sequelae in patients with central venous catheters is recommended.

Each dose of PROVENGE requires a standard leukapheresis procedure approximately 3 days prior to the infusion. Adverse events that were reported ≤1 day following a leukapheresis procedure in ≥5% of patients in controlled clinical trials included citrate toxicity (14.2%), oral paresthesia (12.6%), paresthesia (11.4%), and fatigue (8.3%).

Table 1 provides the frequency and severity of adverse events reported in ≥5% of patients in the PROVENGE group of randomized, controlled trials of men with prostate cancer.

The population included 485 patients with metastatic castrate resistant prostate cancer and 116 patients with non-metastatic androgen dependent prostate cancer who were scheduled to receive 3 infusions of PROVENGE at approximately 2-week intervals. The population was age 40 to 91 years (median 70 years), and 90.6% of patients were Caucasian.

Table 1 Incidence of Adverse Events Occurring in ≥5% of Patients Randomized to PROVENGE PROVENGE (N = 601)

Any Adverse Event Chills Fatigue Fever Back pain Nausea Joint ache Headache Citrate toxicity Paresthesia Vomiting Anemia Constipation Pain Paresthesia oral Pain in extremity Dizziness Muscle ache Asthenia Diarrhea Influenza-like illness Musculoskeletal pain Dyspnea Edema peripheral Hot flush Hematuria Muscle spasms

Control* (N = 303)

All Grades n (%)

Grade 3-5 n (%)

All Grades n (%)

591 (98.3) 319 (53.1) 247 (41.1) 188 (31.3) 178 (29.6) 129 (21.5) 118 (19.6) 109 (18.1) 89 (14.8) 85 (14.1) 80 (13.3) 75 (12.5) 74 (12.3) 74 (12.3) 74 (12.3) 73 (12.1) 71 (11.8) 71 (11.8) 65 (10.8) 60 (10.0) 58 (9.7) 54 (9.0) 52 (8.7) 50 (8.3) 49 (8.2) 46 (7.7) 46 (7.7)

186 (30.9) 13 (2.2) 6 (1.0) 6 (1.0) 18 (3.0) 3 (0.5) 11 (1.8) 4 (0.7) 0 (0.0) 1 (0.2) 2 (0.3) 11 (1.8) 1 (0.2) 7 (1.2) 0 (0.0) 5 (0.8) 2 (0.3) 3 (0.5) 6 (1.0) 1 (0.2) 0 (0.0) 3 (0.5) 11 (1.8) 1 (0.2) 2 (0.3) 6 (1.0) 2 (0.3)

291 (96.0) 33 (10.9) 105 (34.7) 29 (9.6) 87 (28.7) 45 (14.9) 62 (20.5) 20 (6.6) 43 (14.2) 43 (14.2) 23 (7.6) 34 (11.2) 40 (13.2) 20 (6.6) 43 (14.2) 40 (13.2) 34 (11.2) 17 (5.6) 20 (6.6) 34 (11.2) 11 (3.6) 31 (10.2) 14 (4.6) 31 (10.2) 29 (9.6) 18 (5.9) 17 (5.6)

Grade 3-5 n (%) 97 (32.0) 0 (0.0) 4 (1.3) 3 (1.0) 9 (3.0) 0 (0.0) 5 (1.7) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 7 (2.3) 3 (1.0) 3 (1.0) 0 (0.0) 1 (0.3) 0 (0.0) 0 (0.0) 2 (0.7) 3 (1.0) 0 (0.0) 3 (1.0) 3 (1.0) 1 (0.3) 1 (0.3) 3 (1.0) 0 (0.0)

(Table 1 continued on next page.)

Table 1 Incidence of Adverse Events Occurring in ≥5% of Patients Randomized to PROVENGE PROVENGE (N = 601)

Hypertension Anorexia Bone pain Upper respiratory tract infection Insomnia Musculoskeletal chest pain Cough Neck pain Weight decreased Urinary tract infection Rash Sweating Tremor

Control* (N = 303)

All Grades n (%)

Grade 3-5 n (%)

All Grades n (%)

Grade 3-5 n (%)

45 (7.5) 39 (6.5) 38 (6.3) 38 (6.3)

3 (0.5) 1 (0.2) 4 (0.7) 0 (0.0)

14 (4.6) 33 (10.9) 22 (7.3) 18 (5.9)

0 (0.0) 3 (1.0) 3 (1.0) 0 (0.0)

37 (6.2) 36 (6.0)

0 (0.0) 2 (0.3)

22 (7.3) 23 (7.6)

1 (0.3) 2 (0.7)

35 (5.8) 34 (5.7) 34 (5.7) 33 (5.5) 31 (5.2) 30 (5.0) 30 (5.0)

0 (0.0) 3 (0.5) 2 (0.3) 1 (0.2) 0 (0.0) 1 (0.2) 0 (0.0)

17 (5.6) 14 (4.6) 24 (7.9) 18 (5.9) 10 (3.3) 3 (1.0) 9 (3.0)

0 (0.0) 2 (0.7) 1 (0.3) 2 (0.7) 0 (0.0) 0 (0.0) 0 (0.0)

*Control was non-activated autologous peripheral blood mononuclear cells.

Cerebrovascular Events. In controlled clinical trials, cerebrovascular events, including hemorrhagic and ischemic strokes, were reported in 3.5% of patients in the PROVENGE group compared with 2.6% of patients in the control group.

(See Adverse Reactions [6] of full Prescribing Information.)

To report SUSPECTED ADVERSE REACTIONS, contact Dendreon Corporation at 1-877-336-3736 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Dendreon Corporation Seattle, Washington 98101

REFERENCES: 1. PROVENGE [package insert]. Dendreon Corporation; June 2011.

2. Kantoff PW, Higano CS, Shore ND, et al; for the IMPACT Study Investigators. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363:411-422.

©2013 Dendreon Corporation.

All rights reserved. January 2013.

Printed in the U.S.A. Dendreon, the Dendreon logo, and PROVENGE are registered trademarks of Dendreon Corporation.

P-A-01.13-002.00

Clinical Articles Peer Reviewed N o n – Sm a l l C e l l L u n g C a n c e r

Turning Concept Into Reality: Modulating the Immune System to Treat Non–Small Cell Lung Cancer Patrick M. Forde, MD, and Julie R. Brahmer, MD, MSc

abstr act

For many years non–small cell lung cancer (NSCLC), unlike melanoma and renal cell carcinoma, was thought to be a nonimmunogenic tumor unlikely to benefit from therapies aimed at augmenting endogenous antitumor immunity. Recent early-phase trial data with several agents that target immune checkpoint molecules responsible for suppression of T-cell– mediated immunity have challenged this perception. Antibodies targeting cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed death-1 (PD-1) are currently undergoing phase III investigation for advanced NSCLC. Vaccines targeting molecules expressed on NSCLC tumors have shown promise in earlyphase trials, and phase III studies are ongoing. In this article, we summarize early-phase trial results in NSCLC with immune checkpoint inhibitors and vaccines, and look forward to future developments in this rapidly expanding field.

Therapy for advanced non–small cell lung cancer (NSCLC) has shown incremental improvement over the past two decades with median overall survival (OS) in phase III trials now typically exceeding 12 months for patients with nonsquamous disease, and approaching 15 months in the most recently reported studies.1-3 In addition, OS for the 10% to 15% of patients who have a targetable driver mutation in the epidermal growth factor receptor (EGFR) and are treated with EGFR tyrosine kinase inhibitor (TKI) therapy has ranged from 22.9 to 27.7 months in recent studies.4,5 Results from trials enrolling patients with squamous NSCLC, which rarely has driver mutations that can be targeted with current FDA-approved agents, have been less encouraging, with typical median survival figures of 9 to 12 months.6,7 For earlier-stage disease, approximately 50% to 75% of patients will eventually relapse and die from lung cancer despite apparently curative resection.8 In this setting, novel treatments such as immunotherapy are of great interest, particularly if new biomarkers of response can be developed, allowing their use to cross the boundaries of histology and mutational status.

Vaccines Vaccine-based strategies currently in phase III development in NSCLC are summarized in Table 1.9-18

Melanoma-Associated Antigen A3 Vaccine

Pat r i c k M . F o r d e , M D Fellow in the Thoracic Oncology Research Program, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD

corresponding author Julie R. Brahmer, MD, MSc Associate Professor of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD; brahmju@jhmi.edu

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Melanoma-associated antigen A3 (MAGE-A3) is a tumorspecific gene product that is recognized by cytotoxic T cells and frequently upregulated in the early development of NSCLC.19,20 MAGE-A3 is expressed in 30% to 50% of NSCLC tumors and at a higher frequency in squamous tumors, poorly differentiated tumors, and advanced disease.21,22 Expression has also been associated with poorer disease-free survival (DFS) for resected NSCLC.23 Given the specificity of MAGE-A3 expression for tumor cells, MAGE-A3 vaccine has been created containing MAGE-A3 recombinant protein combined with a ASO2B immunologic adjuvant system, which appears to potentiate the immunologic effect. This vaccine has shown preliminary efficacy in metastatic melanoma, with five responses from 26 patients in a phase I/II study.23 Initial studies in patients post-resection of early-stage NSCLC demonstrated that seven of eight vaccinated paThe International Journal of Targeted Therapies in Cancer

Clinical Articles Peer Reviewed N o n – Sm a l l C e l l L u n g C a n c e r Clinical Pearls

tients attained a rise in serum anti-MAGE-A3 antibodies, and repeated vaccination augmented this response.24 In a double-blind phase II study, 182 patients with resected stage IB or II NSCLC, expressing MAGE-A3 by quantitative reverse transcriptase–polymerase chain reaction, were randomized 2:1 to receive adjuvant MAGE-A3 vaccine intramuscular injections or placebo.9 Analysis showed a positive trend favoring the MAGE-A3 vaccine with hazard ratios of 0.76 (95% CI, 0.48-1.21) for DFS and 0.81 (95% CI, 0.47-1.40) for OS; however, these figures did not reach statistical significance. The investigators developed a gene signature from this study, of immune-related genes that appeared to predict benefit from the vaccine, and indeed may be predictive of response to immune-based therapeutics in general.25 The MAGE-A3 vaccine is currently being investigated in a large phase III trial, NCT00480025, that has enrolled over 3000 patients with stage IB-IIIA resected NSCLC (MAGRIT study) and includes patients who receive adjuvant chemotherapy.10 The primary endpoint for this study is DFS, and initial efficacy data are expected in mid-2013.

Liposomal BLP25 Mucin glycoprotein 1 (MUC 1) is a membrane-associated glycoprotein that is overexpressed in human cancers

ta b l e 1.

• Immunotherapy is showing unexpected promise in NSCLC, with numerous large phase III trials under way or planned.

• Results from vaccine trials in both the adjuvant and advanceddisease settings are awaited. Important vaccines in development include the MAGE-A3 vaccine, liposomal BLP25 targeting MUC1, an allogeneic vaccine, belagenpumatucel-L, and a vaccine targeting epidermal growth factor.

• Agents modulating immune checkpoint molecules are entering phase III investigation in NSCLC, including ipilimumab targeting CTLA-4 and nivolumab (BMS-936558) targeting PD-1.

including NSCLC, and has been associated with a poor prognosis.26 Liposomal BLP25 (Stimuvax) is a peptide vaccine that targets MUC 1 and has elicited T-cell responses in phase I studies.27 In a phase IIb study, 171 patients with advanced NSCLC were randomized to receive either a single dose of low-dose cyclophosphamide followed by 8 weekly doses of liposomal BLP25 vaccine or best supportive care.11 Results showed a nonsignificant trend toward improved survival for patients who received liposomal BLP25 (17.2 vs 13.0 months; hazard ratio [HR] = 0·745; 95% CI, 0.533-1.042). Adverse events included flu-like symptoms and injection site reaction, and were generally grade 1-2.

Vaccines in Phase III Clinical Development for NSCLC

Vaccine

Antigen/ Formulation

Phase II

Phase III

Post-surgical resection of early-stage NSCLC MAGE-A3

Full protein ASO2B/AS15

Trend for increased DFS vs placebo (HR = 0.74; P = .107)9

MAGRIT study, stage IB-IIIA, MAGEA3-positive, vaccine or placebo after surgery alone/surgery + adjuvant chemo; completed accrual 201210

Post-CRT for unresectable stage III NSCLC Liposomal-BLP25 (Stimuvax)

MUC1 peptide, liposomal

Trend for increased OS vs BSC (HR = 0.75; P = .112)11

START study, stage IIIA/B, after definitive CRT, reportedly negative for OS12; formal results awaited

Belagenpumatucel-L (Lucanix)

Allogeneic cell vaccine transfected with TGF-β2 antisense gene

Response in 15%, higher dose correlated with survival13

STOP study, stage III/IV, vaccine vs placebo after first-line platinum doublet chemo; completed accrual 201214

rHu-EGF (CIMAvax-EGF)

EGF fused to carrier protein

Trend for increased OS in patients developing antibody response15

Stage III/IV, vaccine vs BSC16

TG4010

MUC1, recombinant viral vector coding human MUC1 and hIL-2

Chemo + TG4010 vs chemo alone, trend for improved RR for vaccine, no difference in OS17

First-line MUC1-positive stage III/IV, chemo + vaccine vs chemo alone18

Advanced NSCLC

MAGE-A3, melanoma-associated antigen-A3; DFS, disease-free survival; OS, overall survival; BSC, best supportive care; chemo, chemotherapy; CRT, chemoradiation; TGF- β2, transforming growth factor-β2; rHu-EGF, recombinant human epidermal growth factor; MUC1, mucin glycoprotein 1; hIL-2, recombinant human interleukin-2; RR, response rate by RECIST 1.0.

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Clinical Articles Peer Reviewed N o n – Sm a l l C e l l L u n g C a n c e r

ta b l e 2 .

Immune Checkpoint Blockade in NSCLC

Target

Agent

Early-Phase Results

Phase III

CTLA-4

Ipilimumab

Phase II study, phased schedule with chemotherapy showed prolonged irPFS vs chemo alone31

First-line, advanced squamous NSCLC, chemo +/- phased ipilimumab32 Second-line, advanced NSCLC, single-agent chemo vs nivolumab

PD-1

Nivolumab (BMS936558)

Phase I study included 121 evaluable, pretreated patients with advanced NSCLC; RR, 16%33,34

PD-L1

BMS936559

Phase I study included 49 evaluable, pretreated patients with advanced NSCLC; RR, 10%35

NSCLC, non–small cell lung cancer; chemo, chemotherapy; CTLA-4, cytotoxic T-lymphocyte antigen-4; irPFS, progression-free-survival by immune response; PD-1, programmed death-1; RR, response rate by RECIST 1.0; PD-L1, programmed death-ligand 1.

Two international phase III studies of liposomal BLP25 are ongoing.28,29 The START study (Stimulating Targeted Antigenic Responses to NSCLC), NCT00409188, in Europe and the United States, randomized 1300 patients with stage IIIA/B NSCLC to vaccine or placebo after definitive chemoradiation,28 while a similar study in Asia has commenced enrollment.29 Merck Serono, the pharmaceutical company responsible for liposomal BLP25, recently announced that START did not meet its primary endpoint of improving OS; however, detailed results of this study are awaited.12

Belagenpumatucel-L Belagenpumatucel-L is an allogeneic cell vaccine consisting of four NSCLC lines (2 adenocarcinoma, 1 squamous, and 1 large cell). Allogeneic vaccines do not have the logistical concerns associated with manufacture that are seen with autologous agents such as the prostate cancer vaccine, sipuleucel-T30; however, more uncertainty exists with allogeneic vaccines regarding the degree of true antitumor activity elicited. Belagenpumatucel-L downregulates transforming growth factor-β2 (TGF-β2) by transfecting cells with a TGF-β2 antisense gene, thus enhancing tumor antigen recognition.13 In a phase II dose-variable study of 75 patients with stage II-IV NSCLC, a response rate of 15% was noted in 61 patients with stage III-IV disease.13 OS appeared to be prolonged in patients who received higher doses of the vaccine (OS, 47% at 2 years vs 18% for lower dose), and patients who had a humoral and cellular response to the vaccine had improved OS (32.5 months vs 11.6 months; P = .011). The phase III STOP trial, NCT00676507, is comparing belagenpumatucel-L with placebo for patients with advanced NSCLC who have stable disease or a response after first-line platinum doublet chemotherapy.

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The primary endpoint of this study is OS.14 This study completed enrollment of over 700 patients in 2012.

Epidermal Growth Factor Cimavax-EGF is a therapeutic cancer vaccine comprising human recombinant epidermal growth factor (EGF) conjugated to a carrier protein, P64K from Neisseria Meningitides.15 After promising phase II results in advanced NSCLC, enrollment was completed on a phase III study, NCT01444118, with results expected within the next year.16

Immune Checkpoints To date, agents targeting two immune checkpoint molecules, CTLA-4 and PD-1, have entered phase III clinical trial investigation in NSCLC. In addition, early-phase studies of an antibody targeting the ligand of PD-1, programmed death-ligand 1 (PD-L1), have also shown promising results in NSCLC. Studies to date incorporating these agents are summarized in Table 2.31-35

CTLA-4 CTLA-4 is a transmembrane receptor whose expression is induced by T cell activation, leading to downregulation of T cell responses and suppression of the innate immune response to tumor.36 Ipilimumab is a fully human monoclonal antibody that blocks CTLA-4, thus releasing innate antitumor immunity.37 In a phase II study, 204 patients with advanced NSCLC were randomized to firstline platinum doublet chemotherapy with placebo versus chemotherapy with concurrent or phased-schedule ipilimumab.31 The phased schedule of two induction chemotherapy cycles followed by four cycles of chemotherapy concurrent with ipilimumab met the primary endpoint of improved progression-free survival by immune response (irPFS),38 (5.7 months vs 4.6 months; P = .05), whereas the concurrent schedule did not. The benefit of ipilimumab in this study appeared to be confined to patients with squamous histology, leading to activation of an ongoing phase III study, NCT01285609, in this cohort.32

PD-1 PD-1 is a coinhibitory molecule, widely expressed on immune cells after antigen exposure, that acts to dampen the T-cell–mediated immune response to tumors and other antigens.39 In a large phase I study incorporating 296 patients with melanoma, renal cell carcinoma, and advanced NSCLC (76 patients evaluable for response at the time of report), single-agent anti-PD-1 (nivolumab [BMS-936558]) was responsible for a 16% response rate by RECIST 1.0 in patients with heavily pretreated NSCLC.33,34 In addition, 33% of patients with NSCLC were free from tumor progression at 6 months. Responses The International Journal of Targeted Therapies in Cancer

Clinical Articles Peer Reviewed N o n – Sm a l l C e l l L u n g C a n c e r

were noted in nine of 48 patients with squamous NSCLC and 11 of 73 patients with nonsquamous NSCLC, suggesting activity in both subsets. Immunohistochemical expression of PD-L1 on tumor cells appeared to correlate with response to anti-PD-1, with no responses seen in tumors lacking PD-L1 expression; however, only 10 patients with NSCLC were included in this analysis.

Pneumonitis was noted as a potential immune-related serious toxicity associated with anti-PD-1 therapy, occurring in 3% of the overall study population, with cessation of therapy and early institution of steroids leading to the resolution of several cases. Currently, a phase III study, NCT01642004, of single-agent nivolumab compared with second-line, single-agent chemotherapy in advanced NSCLC is ongoing.

Several other agents targeting PD-1 are currently either undergoing or in the planning stages of early clinical development, including MK-3475 (Merck), MEDI4736 (Medimmune), MPDL-3280A (Genentech), AMP-224 (Amplimmune/GSK), and AUR-012 (Aurigene).

PD-L1 In a phase I study of anti-PD-L1 (BMS-936559) that included 75 heavily pretreated patients with advanced NSCLC, anti-PD-L1 induced a 10% response rate in the 49 patients evaluable for response; an additional 12% of patients had stable disease lasting more than 6 months.35

Conclusion Strategies aimed at augmenting endogenous antitumor immunity have shown significant promise in earlyphase studies in NSCLC. Results are awaited from large phase III studies of vaccine-based therapies. Immune checkpoint inhibition has led to responses and prolonged remissions for some patients with advanced NSCLC, and phase III studies of anti-CTLA-4 and anti-PD-1 therapies are planned or in progress. Challenges remain, in particular validating biomarkers of response to immunotherapy in order to maximize benefit. Elucidating the optimal sequence and combinations of immune-based treatments with traditional cytotoxic chemotherapy and other targeted agents will be the next step in the development of these exciting new therapies.

TargetedHC.com

RE F ERENCES 1. Kabbinavar FF, Miller VA, Johnson BE, et al. Overall survival (OS) in ATLAS, a phase IIIb trial comparing bevacizumab (B) therapy with or without erlotinib (E) after completion of chemotherapy (chemo) with B for firstline treatment of locally advanced, recurrent, or metastatic non-small cell lung cancer (NSCLC). J Clin Oncol. 2010;28(15 suppl; abstr 7526).

2. Lara PN Jr, Douillard JY, Nakagawa K, et al. Randomized phase III placebo-controlled trial of carboplatin and paclitaxel with or without the vascular disrupting agent vadimezan (ASA404) in advanced non-smallcell lung cancer J Clin Oncol. 2011;29(22):2965-2971.

3. Cancergrace.org. My Four Key Points from the PointBreak Trial. Available at: http://cancergrace.org/lung/2012/09/07/4-key-points-frompointbreak-trial/. Accessed March 22, 2013.

4. Rosell R, Carcereny E, Gervais R, et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol.

2012;13(3):239-246.

5. Inoue A, Kobayashi K, Maemondo M, et al. Updated overall survival results from a randomized phase III trial comparing gefitinib with carboplatin-paclitaxel for chemo-naïve non-small cell lung cancer with sensitive EGFR gene mutations (NEJ002). Ann Oncol. 2013;24(1):54-59.

6. Pirker R, Pereira JR, Szczesna A, et al. Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an openlabel randomised phase III trial. Lancet. 2009;373(9674):1525-1531.

7. 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 nonsmall-cell lung cancer: final results of a phase III trial. J Clin Oncol.

2012;30(17):2055-2062.

8. Chansky K, Sculier JP, Crowley JJ, et al. The International Association for the Study of Lung Cancer Staging Project: prognostic factors and pathologic TNM stage in surgically managed non-small cell lung cancer. J Thorac Oncol. 2009;4(7):792-801.

9. Vansteenkiste J, Zielinski M, Linder A, et al. Final results of a multicenter, double-blind, randomized, placebo-controlled phase II study to assess the efficacy of MAGE-A3 immunotherapeutic as adjuvant therapy in stage IB/II non-small cell lung cancer. Presented at: 2007 ASCO Annual Meeting; June 1-5, 2007; Chicago, IL. 10. Clinicaltrials.gov identifier: NCT00480025.

11. Butts C, Murray N, Maksymiuk A, et al. Randomized phase IIB trial of BLP25 liposome vaccine in stage IIIB and IV non-small-cell lung cancer.

J Clin Oncol. 2005;23(27):6674-6681.

12. EMD Serono. Available at: http://www.emdserono.com/.

13. Nemunaitis J, Dillman RO, Schwarzenberger PO, et al. Phase II study of belagenpumatucel-L, a transforming growth factor beta-2 antisense gene-modified allogeneic tumor cell vaccine in non-small cell lung cancer. J Clin Oncol. 2006;24(29):4721-4730.

14. Clinicaltrials.gov identifier: NCT00676507.

15. Neninger Vinageras E, de la Torre A, Osorio Rodríguez M, et al. Phase II randomized controlled trial of an epidermal growth factor vaccine in advanced non-small-cell lung cancer. J Clin Oncol. 2008;26(9):1452-1458.

16. Clinicaltrials.gov identifier: NCT01444118.

17. Quoix E, Ramlau R, Westeel V, et al. Therapeutic vaccination with TG4010 and first-line chemotherapy in advanced non-small-cell lung cancer: a controlled phase 2B trial. Lancet Oncol. 2011;12(12):1125-1133.

18. Clinicaltrials.gov identifier: NCT01383148.

19. Kobayashi H, Song Y, Hoon DS, et al. Tumor-reactive T helper lymphocytes recognize a promiscuous MAGE-A3 epitope presented by various major histocompatibility complex class II alleles. Cancer Res. 2001;61(12):4773-4778.

20. Jang SJ, Soria JC, Wang L, et al. Activation of melanoma antigen tumor antigens occurs early in lung carcinogenesis. Cancer Res. 2001;61(21):7959-7963.

21. Bolli M, Kocher T, Adamina M, et al. Tissue microarray evaluation of Melanoma antigen E (MAGE) tumor-associated antigen expression: potential indications for specific immunotherapy and prognostic relevance in squamous cell lung carcinoma. Ann Surg. 2002;236(6):785-793.

22. Gure AO, Chua R, Williamson B, et al. Cancer-testis genes are coordinately expressed and are markers of poor outcome in non-small cell lung cancer. Clin Cancer Res. 2005;11(22):8055-8062.

23. Kruit WH, van Ojik HH, Brichard VG, et al. Phase 1/2 study of subcutaneous and intradermal immunization with a recombinant MAGE3 protein in patients with detectable metastatic melanoma. Int J Cancer.

2005;117(4):596-604.

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MOA Spotlight Exploring the Ruxolitinib Mechanism of Action: This mechanism of action (MOA) video about ruxolitinib describes myelofibrosis, the JAK pathway, JAK2 mutations, and the role of ruxolitinib (Jakafi) in treating intermediate or high-risk myelofibrosis.

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Clinical Articles

Safety:2.6875"

Peer Reviewed N o n – Sm a l l C e l l L u n g C a n c e r

Author DisclosureS Dr. Forde has no conflicts of interest to report.

Dr. Brahmer has been an advisory board member for Bristol-Myers Squibb Company and Merck & Co., Inc.

WARNING: GASTROINTESTINAL PERFORATIONS, SURGERY AND WOUND HEALING COMPLICATIONS, and HEMORRHAGE Gastrointestinal Perforations The incidence of gastrointestinal perforation, some fatal, in Avastin‑treated patients ranges from 0.3 to 2.4%. Discontinue Avastin in patients with gastrointestinal perforation. [See Dosage and Administration (2.4), Warnings and Precautions (5.1).]

Surgery and Wound Healing Complications The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Avastin‑treated patients.

Discontinue Avastin in patients with wound dehiscence. The appropriate interval between termination of Avastin and subsequent elective surgery required to reduce the risks of impaired wound healing/wound dehiscence has not been determined. Discontinue at least 28 days prior to elective surgery. Do not initiate Avastin for at least 28 days after surgery and until the surgical wound is fully healed. [See Dosage and Administration (2.4), Warnings and Precautions (5.2), Adverse Reactions (6.1).]

Hemorrhage Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, central nervous systems (CNS) hemorrhage, epistaxis, and vaginal bleeding occurred up to five‑fold more frequently in patients receiving Avastin. Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis. [See Dosage and Administration (2.4), Warnings and Precautions (5.3), Adverse Reactions (6.1).]

1 INDICATIONS AND USAGE 1.1 Metastatic Colorectal Cancer (mCRC) Avastin is indicated for the first‑ or second‑line treatment of patients with metastatic carcinoma of the colon or rectum in combination with intravenous 5‑fluorouracil– based chemotherapy.

Avastin in combination with fluoropyrimidine‑irinotecan or fluoropyrimidine‑ oxaliplatin based chemotherapy is indicated for the second‑line treatment of patients with metastatic colorectal cancer who have progressed on a first‑line Avastin‑ containing regimen.

Limitation of Use: Avastin is not indicated for adjuvant treatment of colon cancer.

[See Clinical Studies (14.2).]

1.2 Non‑Squamous Non–Small Cell Lung Cancer (NSCLC) Avastin is indicated for the first‑line treatment of unresectable, locally advanced, recurrent or metastatic non–squamous non–small cell lung cancer in combination with carboplatin and paclitaxel.

1.3 Glioblastoma Avastin is indicated for the treatment of glioblastoma with progressive disease in adult patients following prior therapy as a single agent.

The effectiveness of Avastin in glioblastoma is based on an improvement in objective response rate. There are no data demonstrating an improvement in disease‑related symptoms or increased survival with Avastin. [See Clinical Studies (14.4).]

1.4 Metastatic Renal Cell Carcinoma (mRCC) Avastin is indicated for the treatment of metastatic renal cell carcinoma in combination with interferon alfa.

4 CONTRAINDICATIONS None.

5 WARNINGS AND PRECAUTIONS 5.1 Gastrointestinal Perforations Serious and sometimes fatal gastrointestinal perforation occurs at a higher incidence in Avastin treated patients compared to controls. The incidence of gastrointestinal perforation ranged from 0.3 to 2.4% across clinical studies. [See Adverse Reactions (6.1).]

The typical presentation may include abdominal pain, nausea, emesis, constipation, and fever. Perforation can be complicated by intra‑abdominal abscess and fistula formation.

The majority of cases occurred within the first 50 days of initiation of Avastin.

Discontinue Avastin in patients with gastrointestinal perforation. [See Boxed Warning, Dosage and Administration (2.4).]

5.2 Surgery and Wound Healing Complications Avastin impairs wound healing in animal models. [See Nonclinical Toxicology (13.2).] In clinical trials, administration of Avastin was not allowed until at least 28 days after surgery. In a controlled clinical trial, the incidence of wound healing complications, including serious and fatal complications, in patients with mCRC who underwent surgery during the course of Avastin treatment was 15% and in patients who did not receive Avastin, was 4%. [See Adverse Reactions (6.1).]

Avastin should not be initiated for at least 28 days following surgery and until the surgical wound is fully healed. Discontinue Avastin in patients with wound healing complications requiring medical intervention.

The appropriate interval between the last dose of Avastin and elective surgery is unknown; however, the half‑life of Avastin is estimated to be 20 days. Suspend Avastin for at least 28 days prior to elective surgery. Do not administer Avastin until the wound is fully healed. [See Boxed Warning, Dosage and Administration (2.4).]

5.3 Hemorrhage Avastin can result in two distinct patterns of bleeding: minor hemorrhage, most commonly Grade 1 epistaxis; and serious, and in some cases fatal, hemorrhagic events. Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, hematemesis, CNS hemorrhage, epistaxis, and vaginal bleeding occurred up to five‑fold more frequently in patients receiving Avastin compared to patients receiving only chemotherapy. Across indications, the incidence of Grade ≥ 3 hemorrhagic events among patients receiving

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24. Atanackovic D, Altorki NK, Stockert E, et al. Vaccine-induced CD4+ T cell responses to MAGE-3 protein in lung cancer patients. J Immunol.

2004;172(5):3289-3296.

25. Vansteenkiste JF, Zielinski M, Dahabreh IJ, et al. Association of gene expression signature and clinical efficacy of MAGE-A3 antigen-specific cancer immunotherapeutic as adjuvant therapy in resected stage IB/II non-small cell lung cancer. J Clin Oncol. 2008;26(15S). Abstract 7501.

26. Kelly RJ, Giaccone G. Lung cancer vaccines. Cancer J. 2011;17(5):302-308.

27. Butts C, Murray RN, Smith CJ, et al. A multicenter open-label study to assess the safety of a new formulation of BLP25 liposome vaccine in patients with unresectable stage III non-small-cell lung cancer. Clin Lung Cancer. 2010;11(6):391-395.

28. Clinicaltrials.gov identifier: NCT00409188.

29. Clinicaltrials.gov identifier: NCT01015443.

30. Di Lorenzo G, Ferro M, Buonerba C. Sipuleucel-T (Provenge®) for castration-resistant prostate cancer. BJU Int. 2012;110(2 Pt 2):E99-E104.

31. Lynch TJ, Bondarenko I, Luft A, et al. Ipilimumab in combination with paclitaxel and carboplatin as first-line treatment in stage IIIB/IV non-small-cell lung cancer: results from a randomized, double-blind, multicenter phase II study. J Clin Oncol. 2012;30(17):2046-2054.

32. ClinicalTrials.gov Identifier: NCT01285609.

33. Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer N Engl J Med. 2012;28;366(26):2443-2454.

34. Topalian SL, Brahmer JR, Hodi, FS, et al. Anti-programmed death-1 (PD-1) (BMS-936558/MDX-1106/ONO in patients (pts) with advanced solid tumors: clinical activity, safety, and molecular markers.

Presented at the 2012 European Society for Medical Oncology Annual Meeting; September 28-October 2, 2012; Vienna, Austria. Abstract 1391. Available at: http://abstracts.webges.com/viewing/view. php?congress=esmo2012&congress_id=370&publication_id=1391.

Accessed April 12, 2013.

35. Brahmer JR, Tykodi SS, Chow LQ, et al. Safety and activity of antiPD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366:2455-2465.

36. Krummel MF, Allison JP. CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation. J Exp Med. 1995;182(2):459-465.

37. Wolchok J. How recent advances in immunotherapy are changing the standard of care for patients with metastatic melanoma. Ann Oncol.

2012;23(suppl 8):viii15-21.

38. Wolchok JD, Hoos A, O’Day S, et al. Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria Clin Cancer Res. 2009;15(23):7412-7420.

39. Dong H, Strome SE, Salomao DR, et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion Nat Med. 2002;8(8):793-800.

AVASTIN® (bevacizumab) Solution for intravenous infusion Initial U.S. Approval: 2004 This is a brief summary of information about AVASTIN. Before prescribing, please see full Prescribing Information.

AVASTIN® (bevacizumab)

AVASTIN® (bevacizumab)

AVASTIN® (bevacizumab)

Avastin ranged from 1.2 to 4.6%. [See Adverse Reactions (6.1).]

Serious or fatal pulmonary hemorrhage occurred in four of 13 (31%) patients with squamous cell histology and two of 53 (4%) patients with non‑squamous non‑small cell lung cancer receiving Avastin and chemotherapy compared to none of the 32 (0%) patients receiving chemotherapy alone.

In clinical studies in non–small cell lung cancer where patients with CNS metastases who completed radiation and surgery more than 4 weeks prior to the start of Avastin were evaluated with serial CNS imaging, symptomatic Grade 2 CNS hemorrhage was documented in one of 83 Avastin‑treated patients (rate 1.2%, 95% CI 0.06%–5.93%).

Intracranial hemorrhage occurred in 8 of 163 patients with previously treated glioblastoma; two patients had Grade 3–4 hemorrhage.

Do not administer Avastin to patients with recent history of hemoptysis of ≥ 1/2 teaspoon of red blood. Discontinue Avastin in patients with hemorrhage. [See Boxed Warning, Dosage and Administration (2.4).]

6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the label: • Gastrointestinal Perforations [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.1).]

• Surgery and Wound Healing Complications [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.2).]

• Hemorrhage [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.3).]

• Non‑Gastrointestinal Fistula Formation [See Dosage and Administration (2.4), Warnings and Precautions (5.4).]

• Arterial Thromboembolic Events [See Dosage and Administration (2.4), Warnings and Precautions (5.5).]

• Hypertensive Crisis [See Dosage and Administration (2.4), Warnings and Precautions (5.6).]

• Reversible Posterior Leukoencephalopathy Syndrome [See Dosage and Administration (2.4), Warnings and Precautions (5.7).]

• Proteinuria [See Dosage and Administration (2.4), Warnings and Precautions (5.8).]

• Ovarian Failure [See Warnings and Precautions (5.10), Use in Specific Populations (8.6).]

The most common adverse reactions observed in Avastin patients at a rate > 10% and at least twice the control arm rate, are epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain and exfoliative dermatitis.

Across all studies, Avastin was discontinued in 8.4 to 21% of patients because of adverse reactions.

the incidence of Grade 3 or 4 neutropenia was increased in mCRC patients receiving IFL plus Avastin (21%) compared to patients receiving IFL alone (14%).

In Study 5, the incidence of Grade 4 neutropenia was increased in NSCLC patients receiving paclitaxel/carboplatin (PC) plus Avastin (26.2%) compared with patients receiving PC alone (17.2%). Febrile neutropenia was also increased (5.4% for PC plus Avastin vs. 1.8% for PC alone). There were 19 (4.5%) infections with Grade 3 or 4 neutropenia in the PC plus Avastin arm of which 3 were fatal compared to 9 (2%) neutropenic infections in patients receiving PC alone, of which none were fatal. During the first 6 cycles of treatment, the incidence of serious infections including pneumonia, febrile neutropenia, catheter infections and wound infections was increased in the PC plus Avastin arm [58 patients (13.6%)] compared to the PC alone arm [29 patients (6.6%)].

In Study 6, one fatal event of neutropenic infection occurred in a patient with previously treated glioblastoma receiving Avastin alone. The incidence of any grade of infection in patients receiving Avastin alone was 55% and the incidence of Grade 3–5 infection was 10%.

5.4 Non‑Gastrointestinal Fistula Formation Serious and sometimes fatal non‑gastrointestinal fistula formation involving tracheo‑esophageal, bronchopleural, biliary, vaginal, renal and bladder sites occurs at a higher incidence in Avastin‑treated patients compared to controls. The incidence of non‑gastrointestinal perforation was ≤ 0.3% in clinical studies. Most events occurred within the first 6 months of Avastin therapy.

Discontinue Avastin in patients with fistula formation involving an internal organ. [See Dosage and Administration (2.4).]

5.5 Arterial Thromboembolic Events Serious, sometimes fatal, arterial thromboembolic events (ATE) including cerebral infarction, transient ischemic attacks, myocardial infarction, angina, and a variety of other ATE occurred at a higher incidence in patients receiving Avastin compared to those in the control arm. Across indications, the incidence of Grade ≥ 3 ATE in the Avastin containing arms was 2.6% compared to 0.8% in the control arms. Among patients receiving Avastin in combination with chemotherapy, the risk of developing ATE during therapy was increased in patients with a history of arterial thromboembolism, or age greater than 65 years. [See Use in Specific Populations (8.5).]

The safety of resumption of Avastin therapy after resolution of an ATE has not been studied. Discontinue Avastin in patients who experience a severe ATE. [See Dosage and Administration (2.4).]

5.6 Hypertension The incidence of severe hypertension is increased in patients receiving Avastin as compared to controls. Across clinical studies the incidence of Grade 3 or 4 hypertension ranged from 5‑18%.

Monitor blood pressure every two to three weeks during treatment with Avastin. Treat with appropriate anti‑hypertensive therapy and monitor blood pressure regularly. Continue to monitor blood pressure at regular intervals in patients with Avastin‑induced or ‑exacerbated hypertension after discontinuation of Avastin.

Temporarily suspend Avastin in patients with severe hypertension that is not controlled with medical management. Discontinue Avastin in patients with hypertensive crisis or hypertensive encephalopathy. [See Dosage and Administration (2.4).]

5.7 Reversible Posterior Leukoencephalopathy Syndrome (RPLS) RPLS has been reported with an incidence of < 0.1% in clinical studies. The onset of symptoms occurred from 16 hours to 1 year after initiation of Avastin. RPLS is a neurological disorder which can present with headache, seizure, lethargy, confusion, blindness and other visual and neurologic disturbances. Mild to severe hypertension may be present. Magnetic resonance imaging (MRI) is necessary to confirm the diagnosis of RPLS. Discontinue Avastin in patients developing RPLS. Symptoms usually resolve or improve within days, although some patients have experienced ongoing neurologic sequelae. The safety of reinitiating Avastin therapy in patients previously experiencing RPLS is not known. [See Dosage and Administration (2.4).]

5.8 Proteinuria The incidence and severity of proteinuria is increased in patients receiving Avastin as compared to controls. Nephrotic syndrome occurred in < 1% of patients receiving Avastin in clinical trials, in some instances with fatal outcome. [See Adverse Reactions (6.1).] In a published case series, kidney biopsy of six patients with proteinuria showed findings consistent with thrombotic microangiopathy.

Monitor proteinuria by dipstick urine analysis for the development or worsening of proteinuria with serial urinalyses during Avastin therapy.

Patients with a 2 + or greater urine dipstick reading should undergo further assessment with a 24‑hour urine collection.

Suspend Avastin administration for ≥ 2 grams of proteinuria/24 hours and resume when proteinuria is < 2 gm/24 hours. Discontinue Avastin in patients with nephrotic syndrome. Data from a postmarketing safety study showed poor correlation between UPCR (Urine Protein/Creatinine Ratio) and 24 hour urine protein (Pearson Correlation 0.39 (95% CI 0.17, 0.57).

[See Use in Specific Populations (8.5).] The safety of continued Avastin treatment in patients with moderate to severe proteinuria has not been evaluated. [See Dosage and Administration (2.4).]

5.9 Infusion Reactions Infusion reactions reported in the clinical trials and post‑marketing experience include hypertension, hypertensive crises associated with neurologic signs and symptoms, wheezing, oxygen desaturation, Grade 3 hypersensitivity, chest pain, headaches, rigors, and diaphoresis. In clinical studies, infusion reactions with the first dose of Avastin were uncommon (< 3%) and severe reactions occurred in 0.2% of patients.

Stop infusion if a severe infusion reaction occurs and administer appropriate medical therapy. [See Dosage and Administration (2.4).]

5.10 Ovarian Failure The incidence of ovarian failure was higher (34% vs. 2%) in premenopausal women receiving Avastin in combination with mFOLFOX chemotherapy as compared to those receiving mFOLFOX chemotherapy alone for adjuvant treatment for colorectal cancer, a use for which Avastin is not approved. Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin. [See Adverse Reactions (6.1), Use in Specific Populations (8.6).]

6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data below reflect exposure to Avastin in 4599 patients with CRC, non‑squamous NSCLC, glioblastoma, or mRCC trials including controlled (Studies 1, 2, 4, 5 and 8) or uncontrolled, single arm (Study 6) treated at the recommended dose and schedule for a median of 8 to 23 doses of Avastin.

[See Clinical Studies (14).] The population was aged 18‑89 years (median 60 years), 45.4% male and 85.8% (3729/4345) White. The population included 2184 first‑ and second‑line mCRC patients who received a median of 10 doses of Avastin, 480 first‑line metastatic NSCLC patients who received a median of 8 doses of Avastin, 163 glioblastoma patients who received a median of 9 doses of Avastin, and 337 mRCC patients who received a median of 16 doses of Avastin. These data also reflect exposure to Avastin in 363 patients with metastatic breast cancer (MBC) who received a median of 9.5 doses of Avastin, 669 female adjuvant CRC patients who received a median of 23 doses of Avastin and exposure to Avastin in 403 previously untreated patients with diffuse large B‑cell lymphoma (DLBCL) who received a median of 8 doses of Avastin. Avastin is not approved for use in MBC, adjuvant CRC, or DLBCL. Surgery and Wound Healing Complications The incidence of post‑operative wound healing and/or bleeding complications was increased in patients with mCRC receiving Avastin as compared to patients receiving only chemotherapy. Among patients requiring surgery on or within 60 days of receiving study treatment, wound healing and/or bleeding complications occurred in 15% (6/39) of patients receiving bolus‑IFL plus Avastin as compared to 4% (1/25) of patients who received bolus‑IFL alone.

In Study 6, events of post‑operative wound healing complications (craniotomy site wound dehiscence and cerebrospinal fluid leak) occurred in patients with previously treated glioblastoma: 3/84 patients in the Avastin alone arm and 1/79 patients in the Avastin plus irinotecan arm. [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.2).]

Hemorrhage The incidence of epistaxis was higher (35% vs. 10%) in patients with mCRC receiving bolus‑IFL plus Avastin compared with patients receiving bolus‑IFL plus placebo. All but one of these events were Grade 1 in severity and resolved without medical intervention. Grade 1 or 2 hemorrhagic events were more frequent in patients receiving bolus‑IFL plus Avastin when compared to those receiving bolus‑IFL plus placebo and included gastrointestinal hemorrhage (24% vs. 6%), minor gum bleeding (2% vs. 0), and vaginal hemorrhage (4% vs. 2%). [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.3).]

Venous Thromboembolic Events The overall incidence of Grade 3–4 venous thromboembolic events in Study 1 was 15.1% in patients receiving bolus‑IFL plus Avastin and 13.6% in patients receiving bolus‑IFL plus placebo. In Study 1, more patients in the Avastin containing arm experienced deep venous thrombosis (34 vs. 19 patients ) and intra‑abdominal venous thrombosis (10 vs. 5 patients).

The risk of developing a second thromboembolic event while on Avastin and oral anticoagulants was evaluated in two randomized studies. In Study 1, 53 patients (14%) on the bolus‑IFL plus Avastin arm and 30 patients (8%) on the bolus‑IFL plus placebo arm received full dose warfarin following a venous thromboembolic event (VTE). Among these patients, an additional thromboembolic event occurred in 21% (11/53) of patients receiving bolus‑IFL plus Avastin and 3% (1/30) of patients receiving bolus‑IFL alone.

In a second, randomized, 4‑arm study in 1401 patients with mCRC, prospectively evaluating the incidence of VTE (all grades), the overall incidence of first VTE was higher in the Avastin containing arms (13.5%) than the chemotherapy alone arms (9.6%). Among the 116 patients treated with anticoagulants following an initial VTE event (73 in the Avastin plus chemotherapy arms and 43 in the chemotherapy alone arms), the overall incidence of subsequent VTEs was also higher among the Avastin treated patients (31.5% vs. 25.6%). In this subgroup of patients treated with anticoagulants, the overall incidence of bleeding, the majority of which were Grade 1, was higher in the Avastin treated arms than the chemotherapy arms (27.4% vs. 20.9%). [See Dosage and Administration (2.4).]

Neutropenia and Infection The incidences of neutropenia and febrile neutropenia are increased in patients receiving Avastin plus chemotherapy compared to chemotherapy alone. In Study 1,

Proteinuria Grade 3–4 proteinuria ranged from 0.7 to 7.4% in Studies 1, 2, 4, 5 and 8. The overall incidence of proteinuria (all grades) was only adequately assessed in Study 8, in which the incidence was 20%. Median onset of proteinuria was 5.6 months (range 15 days to 37 months) after initiation of Avastin. Median time to resolution was 6.1 months (95% CI 2.8 months, 11.3 months). Proteinuria did not resolve in 40% of patients after median follow up of 11.2 months and required permanent discontinuation of Avastin in 30% of the patients who developed proteinuria (Study 8). [See Warnings and Precautions (5.8).]

Congestive Heart Failure (CHF) The incidence of Grade ≥ 3 left ventricular dysfunction was 1.0% in patients receiving Avastin compared to 0.6% in the control arm across indications. In patients with metastatic breast cancer (MBC), an indication for which Avastin is not approved, the incidence of Grade 3–4 CHF was increased in patients in the Avastin plus paclitaxel arm (2.2%) as compared to the control arm (0.3%). Among patients receiving prior anthracyclines for MBC, the rate of CHF was 3.8% for patients receiving Avastin as compared to 0.6% for patients receiving paclitaxel alone.

The safety of continuation or resumption of Avastin in patients with cardiac dysfunction has not been studied.

In previously untreated patients with diffuse large B‑cell lymphoma (DLBCL), an indication for which Avastin is not approved, the incidence of CHF and decline in left‑ventricular ejection fraction (LVEF) were significantly increased in the Avastin plus R‑CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) arm (n=403) compared to the placebo plus R‑CHOP arm (n=379); both regimens were given for 6 to 8 cycles. At the completion of R‑CHOP therapy, the incidence of CHF was 10.9% in the Avastin plus R‑CHOP arm compared to 5.0% in the R‑CHOP alone arm [relative risk (95% CI) of 2.2 (1.3, 3.7)]. The incidence of a LVEF event, defined as a decline from baseline of 20% or more in LVEF or a decline from baseline of 10% or more to a LVEF value of less than 50%, was also increased in the Avastin plus R‑CHOP arm (10.4%) compared to the R‑CHOP alone arm (5.0%).

Time to onset of left‑ventricular dysfunction or CHF was 1‑6 months after initiation of therapy in at least 85% of the patients and was resolved in 62% of the patients experiencing CHF in the Avastin arm compared to 82% in the control arm.

Ovarian Failure The incidence of new cases of ovarian failure (defined as amenorrhoea lasting 3 or more months, FSH level ≥ 30 mIU/mL and a negative serum β‑HCG pregnancy test) was prospectively evaluated in a subset of 179 women receiving mFOLFOX chemotherapy alone (n = 84) or with Avastin (n = 95). New cases of ovarian failure were identified in 34% (32/95) of women receiving Avastin in combination with chemotherapy compared with 2% (2/84) of women receiving chemotherapy alone [relative risk of 14 (95% CI 4, 53)]. After discontinuation of Avastin treatment, recovery of ovarian function at all time points during the post‑treatment period was demonstrated in 22% (7/32) of the Avastin‑treated women. Recovery of ovarian function is defined as resumption of menses, a positive serum β‑HCG pregnancy test, or a FSH level < 30 mIU/mL during the post‑treatment period. Long term effects of Avastin exposure on fertility are unknown. [See Warnings and Precautions (5.10), Use in Specific Populations (8.6).]

Metastatic Colorectal Cancer (mCRC) The data in Table 1 and Table 2 were obtained in Study 1, a randomized, double‑blind, controlled trial comparing chemotherapy plus Avastin with chemotherapy plus placebo. Avastin was administered at 5 mg/kg every 2 weeks.

All Grade 3–4 adverse events and selected Grade 1–2 adverse events (hypertension, proteinuria, thromboembolic events) were collected in the entire study population. Severe and life‑threatening (Grade 3–4) adverse events, which occurred at a higher incidence ( ≥ 2%) in patients receiving bolus‑IFL plus Avastin as compared to bolus‑IFL plus placebo, are presented in Table 1.

Table 1 NCI‑CTC Grade 3−4 Adverse Events in Study 1 (Occurring at Higher Incidence [ ≥ 2 %] Avastin vs. Control)

NCI‑CTC Grade 3‑4 Events Body as a Whole Asthenia Abdominal Pain Pain Cardiovascular Hypertension Deep Vein Thrombosis Intra‑Abdominal Thrombosis Syncope Digestive Diarrhea Constipation Hemic/Lymphatic Leukopenia Neutropeniaa a

Arm 1 IFL+ + Placebo (n = 396) 74%

Arm 2 IFL+ + Avastin (n = 392) 87%

7% 5% 5%

10% 8% 8%

2% 5% 1% 1%

12% 9% 3% 3%

25% 2%

34% 4%

31% 14%

37% 21%

Central laboratories were collected on Days 1 and 21 of each cycle.

Neutrophil counts are available in 303 patients in Arm 1 and 276 in Arm 2.

AVASTIN® (bevacizumab)

AVASTIN® (bevacizumab)

AVASTIN® (bevacizumab)

Grade 1–4 adverse events which occurred at a higher incidence ( ≥ 5%) in patients receiving bolus‑IFL plus Avastin as compared to the bolus‑IFL plus placebo arm are presented in Table 2. Grade 1–4 adverse events were collected for the first approximately 100 patients in each of the three treatment arms who were enrolled until enrollment in Arm 3 (5‑FU/LV + Avastin) was discontinued.

Table 2 NCI‑CTC Grade 1‑4 Adverse Events in Study 1 (Occurring at Higher Incidence [≥ 5%] in IFL + Avastin vs. IFL)

and hypertensive crisis), and hemorrhage (3% vs. 0.3%; including epistaxis, small intestinal hemorrhage, aneurysm ruptured, gastric ulcer hemorrhage, gingival bleeding, haemoptysis, hemorrhage intracranial, large intestinal hemorrhage, respiratory tract hemorrhage, and traumatic hematoma).

Grade 1–5 adverse events occurring at a higher incidence ( ≥ 5%) in patients receiving IFN‑α plus Avastin compared to the IFN‑α plus placebo arm are presented in Table 3.

Table 3 NCI‑CTC Grades 1−5 Adverse Events in Study 8 (Occurring at Higher Incidence [≥ 5%] in IFN‑α + Avastin vs. IFN‑α + Placebo)

approximately 1 to 12 times the recommended human dose of bevacizumab demonstrated teratogenicity, including an increased incidence of specific gross and skeletal fetal alterations. Adverse fetal outcomes were observed at all doses tested. Other observed effects included decreases in maternal and fetal body weights and an increased number of fetal resorptions. [See Nonclinical Toxicology (13.3).]

Because of the observed teratogenic effects of bevacizumab in animals and of other inhibitors of angiogenesis in humans, bevacizumab should be used during pregnancy only if the potential benefit to the pregnant woman justifies the potential risk to the fetus.

8.3 Nursing Mothers It is not known whether Avastin is secreted in human milk. Human IgG is excreted in human milk, but published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are secreted in human milk and because of the potential for serious adverse reactions in nursing infants from bevacizumab, a decision should be made whether to discontinue nursing or discontinue drug, taking into account the half‑life of the bevacizumab (approximately 20 days [range 11–50 days]) and the importance of the drug to the mother. [See Clinical Pharmacology (12.3).]

Arm 1 Arm 2 Arm 3 IFL + Placebo IFL + Avastin 5‑FU/LV + Avastin (n = 98) (n = 102) (n = 109) Body as a Whole Pain Abdominal Pain Headache Cardiovascular Hypertension Hypotension Deep Vein Thrombosis Digestive Vomiting Anorexia Constipation Stomatitis Dyspepsia GI Hemorrhage Weight Loss Dry Mouth Colitis Hemic/Lymphatic Thrombocytopenia Nervous Dizziness Respiratory Upper Respiratory Infection Epistaxis Dyspnea Voice Alteration Skin/Appendages Alopecia Skin Ulcer Special Senses Taste Disorder Urogenital Proteinuria

55% 55% 19%

61% 61% 26%

62% 50% 26%

14% 7% 3%

23% 15% 9%

34% 7% 6%

47% 30% 29% 18% 15% 6% 10% 2% 1%

52% 43% 40% 32% 24% 24% 15% 7% 6%

47% 35% 29% 30% 17% 19% 16% 4% 1%

0%

5%

5%

20%

26%

19%

39% 10% 15% 2%

47% 35% 26% 9%

40% 32% 25% 6%

26% 1%

32% 6%

6% 6%

9%

14%

21%

24%

36%

36%

Avastin in Combination with FOLFOX4 in Second‑line mCRC Only Grade 3‑5 non‑hematologic and Grade 4–5 hematologic adverse events related to treatment were collected in Study 2. The most frequent adverse events (selected Grade 3–5 non‑hematologic and Grade 4–5 hematologic adverse events) occurring at a higher incidence (≥2%) in 287 patients receiving FOLFOX4 plus Avastin compared to 285 patients receiving FOLFOX4 alone were fatigue (19% vs. 13%), diarrhea (18% vs.

13%), sensory neuropathy (17% vs. 9%), nausea (12% vs. 5%), vomiting (11% vs. 4%), dehydration (10% vs. 5%), hypertension (9% vs. 2%), abdominal pain (8% vs. 5%), hemorrhage (5% vs. 1%), other neurological (5% vs. 3%), ileus (4% vs. 1%) and headache (3% vs. 0%). These data are likely to under‑estimate the true adverse event rates due to the reporting mechanisms used in Study 2.

Avastin in Combination with Fluoropyrimidine‑Irinotecan or Fluoropyrimidine‑ Oxaliplatin Based Chemotherapy in Second‑line mCRC Patients who have Progressed on an Avastin Containing Regimen in First‑line mCRC: No new safety signals were observed in Study 4 when Avastin was administered in second line mCRC patients who progressed on an Avastin containing regimen in first line mCRC. The safety data was consistent with the known safety profile established in first and second line mCRC. Unresectable Non‑Squamous Non‑Small Cell Lung Cancer (NSCLC) Only Grade 3‑5 non‑hematologic and Grade 4‑5 hematologic adverse events were collected in Study 5. Grade 3–5 non‑hematologic and Grade 4–5 hematologic adverse events (occurring at a higher incidence (≥2%) in 427 patients receiving PC plus Avastin compared with 441 patients receiving PC alone were neutropenia (27% vs. 17%), fatigue (16% vs. 13%), hypertension (8% vs. 0.7%), infection without neutropenia (7% vs. 3%), venous thrombus/embolism (5% vs. 3%), febrile neutropenia (5% vs. 2%), pneumonitis/ pulmonary infiltrates (5% vs. 3%), infection with Grade 3 or 4 neutropenia (4% vs. 2%), hyponatremia (4% vs. 1%), headache (3% vs. 1%) and proteinuria (3% vs. 0%).

Glioblastoma All adverse events were collected in 163 patients enrolled in Study 6 who either received Avastin alone or Avastin plus irinotecan. All patients received prior radiotherapy and temozolomide. Avastin was administered at 10 mg/kg every 2 weeks alone or in combination with irinotecan. Avastin was discontinued due to adverse events in 4.8% of patients treated with Avastin alone.

In patients receiving Avastin alone (N = 84), the most frequently reported adverse events of any grade were infection (55%), fatigue (45%), headache (37%), hypertension (30%), epistaxis (19%) and diarrhea (21%). Of these, the incidence of Grade ≥ 3 adverse events was infection (10%), fatigue (4%), headache (4%), hypertension (8%) and diarrhea (1%). Two deaths on study were possibly related to Avastin: one retroperitoneal hemorrhage and one neutropenic infection.

In patients receiving Avastin alone or Avastin plus irinotecan (N = 163), the incidence of Avastin‑related adverse events (Grade 1–4) were bleeding/ hemorrhage (40%), epistaxis (26%), CNS hemorrhage (5%), hypertension (32%), venous thromboembolic event (8%), arterial thromboembolic event (6%), wound‑healing complications (6%), proteinuria (4%), gastrointestinal perforation (2%), and RPLS (1%). The incidence of Grade 3–5 events in these 163 patients were bleeding/hemorrhage (2%), CNS hemorrhage (1%), hypertension (5%), venous thromboembolic event (7%), arterial thromboembolic event (3%), wound‑healing complications (3%), proteinuria (1%), and gastrointestinal perforation (2%).

Metastatic Renal Cell Carcinoma (mRCC) All grade adverse events were collected in Study 8. Grade 3–5 adverse events occurring at a higher incidence ( ≥ 2%) in 337 patients receiving interferon alfa (IFN‑α) plus Avastin compared to 304 patients receiving IFN‑α plus placebo arm were fatigue (13% vs. 8%), asthenia (10% vs. 7%), proteinuria (7% vs. 0%), hypertension (6% vs. 1%; including hypertension

System Organ Class/ IFN‑α + Placebo (n = 304) Preferred terma Gastrointestinal disorders Diarrhea 16% General disorders and administration site conditions Fatigue 27% Investigations Weight decreased 15% Metabolism and nutrition disorders Anorexia 31% Musculoskeletal and connective tissue disorders Myalgia 14% Back pain 6% Nervous system disorders Headache 16% Renal and urinary disorders Proteinuria 3% Respiratory, thoracic and mediastinal disorders Epistaxis 4% Dysphonia 0% Vascular disorders Hypertension 9%

IFN‑α + Avastin (n = 337) 21% 33% 20% 36% 19% 12% 24% 20% 27% 5% 28%

Adverse events were encoded using MedDRA, Version 10.1.

a

The following adverse events were reported at a 5‑fold greater incidence in the IFN‑α plus Avastin arm compared to IFN‑α alone and not represented in Table 3: gingival bleeding (13 patients vs. 1 patient); rhinitis (9 vs.0 ); blurred vision (8 vs. 0); gingivitis (8 vs. 1); gastroesophageal reflux disease (8 vs.1 ); tinnitus (7 vs. 1); tooth abscess (7 vs.0); mouth ulceration (6 vs. 0); acne (5 vs. 0); deafness (5 vs. 0); gastritis (5 vs. 0); gingival pain (5 vs. 0) and pulmonary embolism (5 vs. 1).

6.2 Immunogenicity As with all therapeutic proteins, there is a potential for an immune response to Avastin. In clinical trials of adjuvant colon carcinoma, 14 of 2233 evaluable patients (0.63%) tested positive for treatment‑emergent anti‑bevacizumab antibodies detected by an electrochemiluminescent (ECL) based assay. Among these 14 patients, three tested positive for neutralizing antibodies against bevacizumab using an enzyme‑linked immunosorbent assay (ELISA). The clinical significance of these anti‑product antibody responses to bevacizumab is unknown.

Immunogenicity assay results are highly dependent on the sensitivity and specificity of the test method and may be influenced by several factors, including sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Avastin with the incidence of antibodies to other products may be misleading.

6.3 Postmarketing Experience The following adverse reactions have been identified during post‑approval use of Avastin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Body as a Whole: Polyserositis Cardiovascular: Pulmonary hypertension, RPLS, Mesenteric venous occlusion Eye disorders (from unapproved intravitreal use for treatment of various ocular disorders): Permanent loss of vision; Endophthalmitis (infectious and sterile); Intraocular inflammation; Retinal detachment; Increased intraocular pressure; Hemorrhage including conjunctival, vitreous hemorrhage or retinal hemorrhage; Vitreous floaters; Ocular hyperemia; Ocular pain or discomfort Gastrointestinal: Gastrointestinal ulcer, Intestinal necrosis, Anastomotic ulceration Hemic and lymphatic: Pancytopenia Hepatobiliary disorders: Gallbladder perforation Musculoskeletal: Osteonecrosis of the jaw Renal: Renal thrombotic microangiopathy (manifested as severe proteinuria) Respiratory: Nasal septum perforation, dysphonia Systemic Events (from unapproved intravitreal use for treatment of various ocular disorders): Arterial thromboembolic events, Hypertension, Gastrointestinal perforation, Hemorrhage 7 DRUG INTERACTIONS A drug interaction study was performed in which irinotecan was administered as part of the FOLFIRI regimen with or without Avastin. The results demonstrated no significant effect of bevacizumab on the pharmacokinetics of irinotecan or its active metabolite SN38.

In a randomized study in 99 patients with NSCLC, based on limited data, there did not appear to be a difference in the mean exposure of either carboplatin or paclitaxel when each was administered alone or in combination with Avastin.

However, 3 of the 8 patients receiving Avastin plus paclitaxel/carboplatin had substantially lower paclitaxel exposure after four cycles of treatment (at Day 63) than those at Day 0, while patients receiving paclitaxel/carboplatin without Avastin had a greater paclitaxel exposure at Day 63 than at Day 0.

In Study 8, there was no difference in the mean exposure of interferon alfa administered in combination with Avastin when compared to interferon alfa alone.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C There are no adequate or well controlled studies of bevacizumab in pregnant women.

While it is not known if bevacizumab crosses the placenta, human IgG is known to cross the placenta Reproduction studies in rabbits treated with

8.4 Pediatric Use The safety, effectiveness and pharmacokinetic profile of Avastin in pediatric patients have not been established.

Antitumor activity was not observed among eight children with relapsed glioblastoma treated with bevacizumab and irinotecan. There is insufficient information to determine the safety and efficacy of Avastin in children with glioblastoma.

Juvenile cynomolgus monkeys with open growth plates exhibited physeal dysplasia following 4 to 26 weeks exposure at 0.4 to 20 times the recommended human dose (based on mg/kg and exposure). The incidence and severity of physeal dysplasia were dose‑related and were partially reversible upon cessation of treatment.

8.5 Geriatric Use In Study 1, severe adverse events that occurred at a higher incidence ( ≥ 2%) in patients aged ≥ 65 years as compared to younger patients were asthenia, sepsis, deep thrombophlebitis, hypertension, hypotension, myocardial infarction, congestive heart failure, diarrhea, constipation, anorexia, leukopenia, anemia, dehydration, hypokalemia, and hyponatremia. The effect of Avastin on overall survival was similar in elderly patients as compared to younger patients.

In Study 2, patients aged ≥ 65 years receiving Avastin plus FOLFOX4 had a greater relative risk as compared to younger patients for the following adverse events: nausea, emesis, ileus, and fatigue.

In Study 5, patients aged ≥65 years receiving carboplatin, paclitaxel, and Avastin had a greater relative risk for proteinuria as compared to younger patients. [See Warnings and Precautions (5.8).]

Of the 742 patients enrolled in Genentech‑sponsored clinical studies in which all adverse events were captured, 212 (29%) were age 65 or older and 43 (6%) were age 75 or older. Adverse events of any severity that occurred at a higher incidence in the elderly as compared to younger patients, in addition to those described above, were dyspepsia, gastrointestinal hemorrhage, edema, epistaxis, increased cough, and voice alteration.

In an exploratory, pooled analysis of 1745 patients treated in five randomized, controlled studies, there were 618 (35%) patients aged ≥ 65 years and 1127 patients < 65 years of age. The overall incidence of arterial thromboembolic events was increased in all patients receiving Avastin with chemotherapy as compared to those receiving chemotherapy alone, regardless of age. However, the increase in arterial thromboembolic events incidence was greater in patients aged ≥ 65 years (8.5% vs.

2.9%) as compared to those < 65 years (2.1% vs. 1.4%). [See Warnings and Precautions (5.5).]

8.6 Females of Reproductive Potential Avastin increases the risk of ovarian failure and may impair fertility. Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin. Long term effects of Avastin exposure on fertility are unknown.

In a prospectively designed substudy of 179 premenopausal women randomized to receive chemotherapy with or without Avastin, the incidence of ovarian failure was higher in the Avastin arm (34%) compared to the control arm (2%). After discontinuation of Avastin and chemotherapy, recovery of ovarian function occurred in 22% (7/32) of these Avastin‑treated patients. [See Warnings and Precautions (5.10), Adverse Reactions (6.1).]

10 OVERDOSAGE The highest dose tested in humans (20 mg/kg IV) was associated with headache in nine of 16 patients and with severe headache in three of 16 patients.

Avastin® (bevacizumab) Manufactured by: Genentech, Inc. A Member of the Roche Group 1 DNA Way South San Francisco, CA 94080‑4990

01/13 AVA0000759205 10136665 Initial U.S. Approval: February 2004 Code Revision Date: January 2013 Avastin® is a registered trademark of Genentech, Inc. © 2013 Genentech, Inc.

NOW APPROVED: Avastin continued beyond first progression in MCRC In combination with fluoropyrimidine-based chemotherapy following a first-line Avastin-containing regimen...

Think Avastin

Continuing to deliver proven overall survival The only biologic to prospectively demonstrate significant overall survival (OS) in a Phase III MCRC trial after treatment with a first-line Avastin-containing regimen1 Median OS:

Percentage Surviving

100

11.2 vs 9.8 months

(HR=0.81 [95% CI, 0.69–0.94], P=0.0057)

80 60

Avastin + fluoropyrimidine-based chemotherapy* (n=409) Fluoropyrimidine-based chemotherapy* alone (n=411)

40 20 0

12

24 OS (Months)

36

48

*Chemotherapy combinations included both irinotecan- and oxaliplatin-containing regimens.

At first progression, chemotherapy was switched: oxaliplatin→irinotecan or irinotecan→oxaliplatin.1

1.7-month increase in median PFS beyond first progression with Avastin plus fluoropyrimidine-based chemotherapy*: 5.7 vs 4.0 months with fluoropyrimidine-based chemotherapy* alone (HR=0.68 [95% CI, 0.59–0.78], P<0.0001)1 There was no significant difference in response rate1

MCRC=metastatic colorectal cancer; HR=hazard ratio; CI=confidence interval; PFS=progression-free survival.

Indications

Avastin is indicated for the first- or second-line treatment of patients with metastatic carcinoma of the colon or rectum in combination with intravenous 5-fluorouracil–based chemotherapy.

Avastin, in combination with fluoropyrimidine-irinotecan- or fluoropyrimidineoxaliplatin-based chemotherapy, is indicated for the second-line treatment of patients with metastatic colorectal cancer who have progressed on a first-line Avastin-containing regimen.

Limitation of Use: Avastin is not indicated for adjuvant treatment of colon cancer.

Boxed WARNINGS

Gastrointestinal (GI) perforation — Serious and sometimes fatal GI perforation occurs at a higher incidence in Avastin-treated patients compared to controls — The incidences of GI perforation ranged from 0.3% to 2.4% across clinical studies — Discontinue Avastin in patients with GI perforation Surgery and wound healing complications — The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Avastin-treated patients — Do not initiate Avastin for at least 28 days after surgery and until the surgical wound is fully healed. The appropriate interval between termination of Avastin and subsequent elective surgery required to reduce the risks of impaired wound healing/wound dehiscence has not been determined — Discontinue Avastin at least 28 days prior to elective surgery and in patients with wound healing complications requiring medical intervention Hemorrhage — Severe or fatal hemorrhage, including hemoptysis, GI bleeding, hematemesis, central nervous system hemorrhage, epistaxis, and vaginal bleeding, occurred up to 5-fold more frequently in patients receiving Avastin. Across indications, the incidence of grade ≥3 hemorrhagic events among patients receiving Avastin ranged from 1.2% to 4.6% — Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis (≥1/2 tsp of red blood) — Discontinue Avastin in patients with serious hemorrhage (ie, requiring medical intervention)

Additional serious adverse events

Additional serious and sometimes fatal adverse events with increased incidence in the Avastin-treated arm vs control included — Non-GI fistula formation (≤0.3%) — Arterial thromboembolic events (grade ≥3, 2.6%) — Proteinuria (nephrotic syndrome, <1%)

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Additional serious adverse events with increased incidence in the Avastin-treated arm vs control included — Hypertension (grade 3–4, 5%–18%) — Reversible posterior leukoencephalopathy syndrome (RPLS) (<0.1%) Infusion reactions with the first dose of Avastin were uncommon (<3%), and severe reactions occurred in 0.2% of patients Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin

Most common adverse events

Across all studies, the most common adverse reactions observed in Avastin patients at a rate >10% and at least twice the control arm rate were — Epistaxis — Proteinuria — Lacrimation disorder — Headache — Taste alteration — Back pain — Hypertension — Dry skin — Exfoliative dermatitis — Rhinitis — Rectal hemorrhage Across all studies, Avastin was discontinued in 8.4% to 21% of patients because of adverse reactions

Pregnancy warning

Avastin may impair fertility Based on animal data, Avastin may cause fetal harm Advise patients of the potential risk to the fetus during and following Avastin and the need to continue adequate contraception for at least 6 months following the last dose of Avastin For nursing mothers, discontinue nursing or Avastin, taking into account the importance of Avastin to the mother

Indication-specific adverse events

When continued beyond first progression in MCRC, no new safety signals were observed in Study ML18147 when Avastin was administered in second-line MCRC patients who progressed on an Avastin-containing regimen in first-line MCRC. The safety data was consistent with the known safety profile established in first- and second-line MCRC You may report side effects to the FDA at (800) FDA-1088 or www.fda.gov/medwatch.

You may also report side effects to Genentech at (888) 835-2555.

Please see accompanying brief summary of Prescribing Information, including Boxed WARNINGS, for additional important safety information.

Reference: 1. Avastin Prescribing Information. Genentech, Inc. January 2013.

(01/13)

www.avastin.com