VACCINES mmunotherapy in oncology

BIOLOGICS • VACCINES • BIOTHERAPIES • PRECISION

MARCH 2015 Volume 2 • Number 2

Immunotherapyin oncology TM

SUPPLEMENT TO PERSONALIZED MEDICINE IN ONCOLOGY ™

From the Publishers of Personalized Medicine in Oncology ™

GLIOBLASTOMA Immunotherapy in Glioblastoma, the Most Lethal Form of Brain Cancer............................................0Targeting EGFRvIII in Glioblastoma .......................Page 16

VACCINESVaccines for Glioblastoma ....................................Page 22

IMMUNE CHECKPOINT BLOCKADE Exploring Immune Checkpoint Blockade for Glioblastoma...................................................Page 26

GASTROINTESTINAL CANCERPD-L1 Inhibitor Pembrolizumab Produces Good Responses in Advanced Gastric Cancer ...............Page 28

IMMUNO-ONCOLOGY PIPELINEBristol-Myers Squibb to Expand Its Immuno- Oncology Pipeline with Agreement to Acquire Flexus Biosciences, Inc.........................................Page 30

SAVE THE DATE JULY 22-25, 2015THE WESTIN SEATTLE • SEATTLE, WASHINGTON

CONFERENCE CO-CHAIRS

Sanjiv S. Agarwala, MDProfessor of MedicineTemple University School of MedicineChief, Medical Oncology & HematologySt. Luke’s Cancer Center Bethlehem, PA

Jorge E. Cortes, MDChair, CML and AML SectionsD.B. Lane Cancer Research Distinguished Professor for Leukemia ResearchDepartment of Leukemia, Division of Cancer MedicineThe University of Texas MD Anderson Cancer CenterHouston, TX

Hope S. Rugo, MDProfessor of MedicineDirector, Breast Oncology and Clinical Trials EducationUCSF Helen Diller Family Comprehensive Cancer CenterSan Francisco, CA

Hope S. Rugo, M.D.Professor of MedicineDirector, Breast Oncology and Clinical Trials EducationUniversity of California San Francisco Helen Diller Family ComprehensiveCancer Center San Francisco, CA

Hope S. Rugo, MD, is a Professor of Medicine in the Division of Hematology and Oncology at the University of California San Francisco, Helen Diller Family Comprehensive Cancer Center, where she directs Breast Cancer and Clinical Trial Education. Her research interests include novel therapies for advanced breast cancer, immune modulation to restore chemotherapy sensitivity, evaluation of circulating cells as novel markers of response and resistance to therapy, neoadjuvant therapy and supportive care.

Dr. Rugo is an investigator in the Bay Area Spore at the UCSF Breast Cancer Center, the national multi-center ISPY2 trial, and is the principal investigator of a number of clinical trials. She is one of three recipients of a Komen Promise Award, receives funding from the Breast Cancer Research Foundation, and serves on a number of steering committees for national and international trials. Dr. Rugo is a member of the ALLIANCE Breast Core Committee and the Translational Breast Cancer Research Consortium, is the UCSF representative to the NCCN Guidelines Committee, and serves on several committees for the American Society of Clinical Oncology. She has published many peer-reviewed papers and has given presentations on a variety of cancer related topics.

With a summa cum laude undergraduate degree from Tufts University. Dr. Rugo received her MD from the University of Pennsylvania School of Medicine and completed both a residency in internal medicine and fellowship in hematology and oncology at the UCSF. Additionally, she completed a two-year post-doctoral fellowship in immunology at Stanford University. She received the Cancer Care Physician of the year award in 2010.

www.pmo-live.com

The Global Biomarkers Consortium (GBC) and World Cutaneous Malignancies Congress (WCMC)

will be holding their fourth annual joint meeting focused on personalized and precision medicine in oncology (PMO)

on July 22-25, 2015, in Seattle, Washington.

July 22-24A Focus on the Application of Molecular Biomarkers in Clinical Practice Across Multiple Tumor Types

July 24-25Spotlight on Cutaneous Malignancies, Including Melanoma, Cutaneous T-Cell Lymphoma, and Basal Cell Carcinoma

SCHEDULE OF EVENTS (subject to change)

PMOLive2015_112114

3 www.PersonalizedMedOnc.com l Immunotherapy in Oncology lVol 2, No 2 l March 2015

MARCH 2015 VOLUME 2, NUMBER 2

TABLE OF CONTENTS

PUBLISHING STAFFVice President/Group Publisher

Russell Hennessy [email protected]

Manager, Client Services Travis Sullivan

[email protected] Director Kristin Siyahian

[email protected] Editor Robert E. Henry

Senior Copyeditor BJ HansenCopyeditor

Rosemary HansenProduction Manager

Marie RS BorrelliThe Lynx Group President/CEO Brian Tyburski

Chief Operating Officer Pam Rattananont Ferris

Vice President of Finance Andrea Kelly

Human Resources Jennine Leale

Director, Strategy & Program Development John Welz

Director, Quality Control Barbara Marino

Quality Control Assistant Theresa Salerno

Director, Production & Manufacturing Alaina Pede

Director, Creative & Design Robyn Jacobs

Creative & Design Assistants Lora LaRocca

Wayne WilliamsDirector, Digital Media

Anthony RomanoJr Digital Media Specialist

Charles Easton IVWeb Content Manager

Anthony TreveanDigital Programmer Michael Amundsen

Meeting & Events Planner Linda MezzacappaProject Manager Deanna Martinez

Project Coordinator Rachael Baranoski

IT Manager Kashif Javaid

Administrative Team Leader Allison Ingram

Administrative Assistant Amanda Hedman

Office Coordinator Robert Sorensen

Green Hill Healthcare Communications, LLC 1249 South River Road - Ste 202A

Cranbury, NJ 08512 phone: 732-656-7935

fax: 732-656-7938

OUR MISSIONPersonalized Medicine in Oncology provides the bridge between academic research and practicing clinicians by demon-strating the immediate implications of precision medicine – including advancements in molecular sequencing, targeted therapies, and new diagnostic modalities – to the management of patients with cancer, offering oncologists, oncology nurses, payers, researchers, drug developers, policymakers, and all oncology stakeholders the relevant practical informa-tion they need to improve cancer outcomes. This journal translates the new understanding of the biology of cancer into the day-to-day management of the individual patient with cancer, using a patient’s unique genetic makeup to select the best available therapy.

OUR VISION Our vision is to transform the current medical model into a new model of personalized care, where decisions and practices are tailored for the individual – beginning with an incremental integration of personalized techniques into the conventional practice paradigm currently in place.

Immunotherapyin oncology TM


GLIOBLASTOMA

10 Immunotherapy in Glioblastoma, the Most Lethal Form of Brain Cancer ITO reviews the background of this disease and current treatment strategies as well as the unmet need for novel treatments and the emerging immunotherapeutic approach to treatment.

16 Targeting EGFRvIII in Glioblastoma ITO explores a mutation of the epidermal growth factor receptor (EGFR), known as EGFR variant 3 (EGFRvIII), that is expressed in a significant proportion of glioblastoma tumors and is linked to poor long-term survival. Unlike unmutated EGFR, EGFRvIII has not been detected at a significant level in normal tissues; therefore, targeting of this tumor-specific molecule is not likely to impact healthy tissues. A number of immunotherapeutic approaches are in development that target EGFRvIII in glioblastoma.

VACCINES

22 Vaccines for Glioblastoma A presentation of cancer vaccines that have the potential for eliciting a widespread and durable response. Today, a number of vaccines are under investigation for the treatment of patients with glioblastoma.

IMMUNE CHECKPOINT BLOCKADE

26 Exploring Immune Checkpoint Blockade for Glioblastoma The approvals by the Food and Drug Administration of the CTLA-4–blocking antibody, ipilimumab (in 2011), and the PD-1–blocking antibody, pembrolizumab (in 2014), for the treatment of advanced melanoma demonstrate that checkpoint-blocking antibodies have a promising role in immunotherapy.

Immunotherapyin oncology

INNOVANOVANO TORVATORVAOF THE YEAR

2015

In partnership with

WORLD CUTANEOUSMALIGNANCIES CONGRESS™

GLOBAL BIOMARKERS CONSORTIUM™

Clinical Approaches to Targeted Technologies




The offi cial publication of

www.PersonalizedMedOnc.com

PMOinnovatorAsize 020515

The world of personalized medicine is a rapidly changing, ever-evolving state involving many stakeholders on the front- lines of its creation: physicians, industry, researchers, patient advocates, and payers. The publishers of PMO have the dis-tinct honor of interviewing leaders in these sectors to bring you their game-changing strategies, missions, and impact on personalized oncology care.

Each year, we select the innovator whose contribution to the fi eld of oncology represents the most profound impact on patient care. For 2015, it is our pleasure to award the distinc-

tion of Innovator of the Year to James Allison, PhD, of The University of Texas MD Anderson Cancer Center.

Dr Allison is the chairman of the Immunology Department and executive director of the immunology platform for the Moon Shots Program at MD Anderson in Houston. He is the recipient of numerous honors for biomedical research, including the inaugural AACR-CRI Lloyd J. Old Award in Cancer Immunology, the 2013 Innovations Award for Bioscience from The Economist, and a 2014 Breakthrough Prize in Life Sciences. He also coleads a Stand Up to Cancer Dream Team research project in immunotherapy.

Dr Allison is on a quest to train the immune system to attack cancer cells, eliminate tumors, and protect against recurrence. The strategy being employed is a new para-digm for cancer treatment called immune checkpoint targeting. This approach has proved effective in treating many different types of cancer and is now a standard of care for metastatic melanoma. To see our interview with Dr Allison, please visit us at www.PersonalizedMedOnc.com.

It is our pleasure to congratulate Dr Allison on his work to date and the profound impact it has had on the lives of patients. We wish him continued success in his quest to harness the power of the immune system to combat cancer.

M O P

TM

Personalized Medicine in OncologyBIOMARKERS • IMMUNOTHERAPY • TARGETED THERAPIES • DIAGNOSTICS

YEAR AWARDINNOVATOROF THE

Interview with the Innovators

James Allison, PhDThe University of Texas

MD Anderson Cancer Center


MARCH 2015 VOLUME 2, NUMBER 2

TABLE OF CONTENTS (Continued)

Personalized Medicine in Oncology, ISSN 2166-0166 (print); ISSN applied for (online) is published 8 times a year by Green Hill Healthcare Communications, LLC, 1249 South River Road, Suite 202A, Cranbury, NJ 08512. Telephone: 732.656.7935. Fax: 732.656.7938. Copy right © 2015 by Green Hill Health care Com muni cations, LLC. All rights reserved. Personalized Medicine in Oncology logo is a trademark of Green Hill Healthcare Communications, LLC. No part of this publication may be reproduced or transmitted in any form or by any means now or hereafter known, electronic or mechanical, including photocopy, recording, or any informational storage and retrieval system, without written permission from the publisher. Printed in the United States of America.

EDITORIAL CORRESPONDENCE should be ad dressed to EDITORIAL DIRECTOR, Personalized Medicine in Oncology (PMO), 1249 South River Road, Suite 202A, Cranbury, NJ 08512. YEARLY SUBSCRIPTION RATES: United States and possessions: individuals, $50.00; institutions, $90.00; single issues, $5.00. Orders will be billed at individual rate until proof of status is confirmed. Prices are subject to change without notice. Correspondence regarding permission to reprint all or part of any article published in this journal should be addressed to REPRINT PERMISSIONS DEPART MENT, Green Hill Healthcare Communications, LLC, 1249 South River Road, Suite 202A, Cranbury, NJ 08512. The ideas and opinions expressed in PMO do not necessarily reflect those of the editorial board, the editorial director, or the publishers. Publication of an advertisement or other product mentioned in PMO should not be construed as an endorsement of the product or the manufacturer’s claims. Readers are encouraged to contact the manufacturer with questions about the features or limitations of the products mentioned. Neither the editorial board nor the publishers assume any responsibility for any injury and/or damage to persons or property arising out of or related to any use of the material contained in this periodical. The reader is advised to check the appropriate medical literature and the product information currently provided by the manufacturer of each drug to be administered to verify the dosage, the method and duration of administration, or contraindications. It is the responsibility of the treating physician or other healthcare professional, relying on independent experience and knowledge of the patient, to determine drug dosages and the best treatment for the patient. Every effort has been made to check generic and trade names, and to verify dosages. The ultimate responsibility, however, lies with the prescribing physician. Please convey any errors to the editorial director.

Personalized Medicine in Oncology is included in the following indexing and database services: Cumulative Index to Nursing and Allied Health Literature (CINAHL) EBSCO research databases

Immunotherapyin oncology TM SAVE the

DATEJULY 22-25, 2015




The Westin SeattleSeattle, Washington

ANNUAL CONFERENCE

www.pmo-live.com

GASTROINTESTINAL CANCER

28 PD-L1 Inhibitor Pembrolizumab Produces Good Responses in Advanced Gastric Cancer In patients with advanced gastric cancer who express programmed cell death (PD)-1 ligand 1 (PD-L1), the humanized monoclonal antibody pembrolizumab demonstrated robust antitumor activity and an acceptable safety profile, according to updated results presented at the 2015 Gastrointestinal Cancers Symposium.

IMMUNO-ONCOLOGY PIPELINE

30 Bristol-Myers Squibb to Expand Its Immuno-Oncology Pipeline with Agreement to Acquire Flexus Biosciences, Inc Bristol-Myers Squibb Company and Flexus Biosciences, Inc announced that the companies have signed a definitive agreement under which Bristol-Myers Squibb will acquire all of the outstanding capital stock of Flexus, a privately held biotechnology company focused on the discovery and development of novel anticancer therapeutics.


Visit our NEW website www.lynxcme.com to learn more!

CONTINUING EDUCATION

CONSIDERATIONS in

Multiple Myeloma™

6th Annual

ASK THE EXPERTS: Maintenance Settings

Kenneth C. Anderson, MDDirector, Jerome Lipper Multiple Myeloma Center and LeBow Institute for Myeloma TherapeuticsKraft Family Professor of Medicine Harvard Medical SchoolDana-Farber Cancer Institute, Boston, MA

Tina Flaherty, ANP-BC, AOCNNurse PractitionerDivision of Hematologic MalignanciesDana-Farber Cancer InstituteBoston, MA

Houry Leblebjian, PharmD, BCOPClinical Pharmacy Specialist in Hematology/OncologyDana-Farber Cancer InstituteBoston, MA

Supported by educational grants from Onyx Pharmaceuticals and

Millennium: The Takeda Oncology Company.

PUBLISHING STAFF

Group Director, Sales & MarketingJohn W. Hennessy

[email protected]

Editorial DirectorSusan A. Berry

[email protected]

Senior Copy EditorBJ Hansen

Copy EditorsDana Delibovi

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� e Lynx GroupPresident/CEOBrian Tyburski

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Director, Quality ControlBarbara Marino

Director, Production & ManufacturingAlaina Pede

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LETTER FROM THE EDITOR-IN-CHIEF

Over the past decade, signifi cant progress has been made in the management of multiple myeloma, including new standards of care and the development and approval of several novel, effective agents. Despite this progress, more work needs to be done and numerous questions remain regarding the application and interpretation of recent clinical advances.

In this sixth annual “Considerations in Multiple Myeloma” newsletter series, we continue to explore unre-solved issues related to the management of the disease and new directions in treatment. To ensure an inter-professional perspective, our faculty is comprised of physicians, nurses, and pharmacists from leading cancer institutions, who provide their insight, knowledge, and clinical experience related to the topic at hand. In this second issue, experts from Dana-Farber Cancer Institute answer questions related to the management of patients in the maintenance setting.

Sincerely,

Sagar Lonial, MDProfessorVice Chair of Clinical AffairsDepartment of Hematology and Medical OncologyWinship Cancer InstituteEmory University School of MedicineAtlanta, GA

This activity is jointly sponsored by Medical Learning Institute Inc and Center of Excellence Media, LLC.

FACULTY

MAY 2013 • VOLUME 6 • NUMBER 2

Kenneth C. Anderson, MDDirector, Jerome Lipper Multiple Myeloma Center and LeBow Institute for Myeloma TherapeuticsKraft Family Professor of Medicine Harvard Medical SchoolDana-Farber Cancer Institute, Boston, MA

Tina Flaherty, ANP-BC, AOCNNurse PractitionerDivision of Hematologic MalignanciesDana-Farber Cancer InstituteBoston, MA

Houry Leblebjian, PharmD, BCOPClinical Pharmacy Specialist in Hematology/OncologyDana-Farber Cancer InstituteBoston, MA

Supported by educational grants from Onyx Pharmaceuticals and

Millennium: The Takeda Oncology Company.


FACULTYFACULTYF

CONTRIBUTING FACULTY

Discussions in Personalized Treatment for Lymphoma: Do We Have Consensus?

Supported by an educational grant from Celgene Corporation


© 2013 Green Hill Healthcare Communications, LLC

ChairStephanie A. Gregory, MD

The Elodia Kehm Chair of HematologyProfessor of Medicine

Director, Lymphoma ProgramRush University Medical Center/Rush University

Chicago, IL

Sonali M. Smith, MDAssociate Professor

Section of Hematology/OncologyDirector, Lymphoma Program

The University of Chicago Medical CenterChicago, IL

Mitchell R. Smith, MD, PhDDirector of Lymphoid

Malignancies ProgramTaussig Cancer Institute

Cleveland ClinicCleveland, OH

Steve M. Horwitz, MDAssistant AttendingMedical Oncologist

Lymphoma, Cutaneous Lymphomas, T-Cell Lymphoma

Memorial Sloan-Kettering Cancer CenterNew York, NY

MARCH 2013 • VOLUME 4 • NUMBER 2

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YEARANNIVERSARY

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LETTER TO OUR READERS

Dear Colleague,

In the new era of personalized treatment for patients battling cancer, the topic of immuno-therapy is front and center in our discussions. The possibility of harnessing the power of our own immune system to combat cancer has captivated the imagination of researchers, clini-

cians, and the public alike. The science behind it is fascinating, the appeal of empowering the natural mission of the body’s immune response is overwhelmingly positive, and the commercial-ization of products that have the potential to be the new blockbuster drugs excites.

Immunotherapy in Oncology (ITO) exists to explore all of these facets of immunotherapy: the science, the utilization, and the marketplace. We are tremendously excited about the forthcom-ing options immunotherapeutic agents offer our patients, and we realize how challenging it is for clinicians to stay abreast of the tsunami of information coming from these research efforts. To this end, we are devoted to bringing you timely and relevant information in the hope that its dissemination will bring lifesaving information to those who can employ its strategies for the benefit of patients fighting cancer.

In the current issue, we are pleased to offer a special focus on glioblastomas. In a series of 4 articles, we explore the background of this disease to include current therapies and the need for new treatments, a genetic mutation target for immunotherapy, an update on vaccines, and informa-tion about immune checkpoint blockade in glioblastomas.

Of note, ITO, along with our sister publication Person-alized Medicine in Oncology, recently presented our Innovator of the Year Award to immunologist James Allison, PhD, of MD Anderson Cancer Center for his as-tounding work in the field. Our publisher had the pleasure of interviewing Dr Allison about the progress being made in this exciting field. To view the interview, please visit us at www.PersonalizedMedOnc.com.

As always, thank you for your participation in our reading community. It is my great pleasure to serve you as the Editor in Chief.

Sincerely,

Sanjiv S. Agarwala, MDEditor in ChiefImmunotherapy in Oncology

The Reach of Immunotherapy: Focus on Glioblastoma

Sanjiv S. Agarwala, MD

Immunotherapy in Oncology exists to explore all of these facets of immunotherapy: the science, the utilization, and the marketplace.

8 l Immunotherapy in Oncology l www.PersonalizedMedOnc.com March 2015 l Vol 2, No 2

EDITORIAL BOARD

EDITORS IN CHIEF

Sanjiv S. Agarwala, MD St. Luke’s Hospital Bethlehem, Pennsylvania

Al B. Benson III, MD, FACP, FASCONorthwestern University Chicago, Illinois

SECTION EDITORSBiomarkers Pranil K. Chandra, DO PathGroup Brentwood, Tennessee

Darren Sigal, MD Scripps Clinic Medical Group San Diego, California

Breast Cancer Edith Perez, MD Mayo Clinic Jacksonville, Florida

Hematologic Malignancies Gautam Borthakur, MD The University of Texas MD Anderson Cancer Center Houston, Texas

Pathology David L. Rimm, MD, PhD Yale Pathology Tissue Services Yale University School of Medicine New Haven, Connecticut

Drug Development Igor Puzanov, MD Vanderbilt University Vanderbilt-Ingram Cancer Center Nashville, Tennessee

Lung Cancer Vincent A. Miller, MD Foundation Medicine Cambridge, Massachusetts

Predictive Modeling Michael Kattan, PhD Case Western Reserve University Cleveland, Ohio

Gastrointestinal Cancer Eunice Kwak, MD Massachusetts General Hospital Cancer Center Harvard Medical School Boston, Massachusetts

Melanoma Doug Schwartzentruber, MD Indiana University Simon Cancer Center Indianapolis, Indiana

Prostate Cancer Oliver Sartor, MD Tulane University New Orleans, Louisiana

EDITORIAL BOARDGregory D. Ayers, MS Vanderbilt University School of Medicine Nashville, Tennessee

Lyudmila Bazhenova, MD University of California, San Diego San Diego, California

Leif Bergsagel, MD Mayo Clinic Scottsdale, Arizona

Mark S. Boguski, MD, PhD Harvard Medical School Boston, Massachusetts

Gilberto Castro, MD Instituto do Câncer do Estado de São Paulo São Paulo, Brazil

Madeleine Duvic, MD The University of Texas MD Anderson Cancer Center Houston, Texas

Beth Faiman, PhD(c), MSN, APRN-BC, AOCN Cleveland Clinic Taussig Cancer Center Cleveland, Ohio

Steven D. Gore, MD The Johns Hopkins University School of Medicine Baltimore, Maryland

Gregory Kalemkerian, MD University of Michigan Ann Arbor, Michigan

Howard L. Kaufman, MD Cancer Institute of New Jersey New Brunswick, New Jersey

Katie Kelley, MD UCSF School of Medicine San Francisco, California

Minetta Liu, MD Mayo Clinic Cancer Center Rochester, Minnesota

Kim Margolin, MD University of Washington Fred Hutchinson Cancer Research Center Seattle, Washington

Gene Morse, PharmD University at Buffalo Buffalo, New York

Nikhil C. Munshi, MD Dana-Farber Cancer Institute Boston, Massachusetts

Steven O’Day, MD John Wayne Cancer Institute Santa Monica, California

Rafael Rosell, MD, PhD Catalan Institute of Oncology Barcelona, Spain

Steven T. Rosen, MD, FACP Northwestern University Chicago, Illinois

Hope S. Rugo, MD University of California, San Francisco San Francisco, California

Lee Schwartzberg, MD The West Clinic Memphis, Tennessee

John Shaughnessy, PhD University of Arkansas for Medical Sciences Little Rock, Arkansas

Lillie D. Shockney, RN, BS, MAS Johns Hopkins University Baltimore, Maryland

Lawrence N. Shulman, MD Dana-Farber Cancer Institute Boston, Massachusetts

Jamie Shutter, MD South Beach Medical Consultants, LLC Miami Beach, Florida

David Spigel, MD Sarah Cannon Research Institute Nashville, Tennessee

Moshe Talpaz, MD University of Michigan Medical Center Ann Arbor, Michigan

Sheila D. Walcoff, JD Goldbug Strategies, LLC Rockville, Maryland

Anas Younes, MD The University of Texas MD Anderson Cancer Center Houston, Texas

targgeetttgeted thherapy•

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A SUPPLEMENT SERIES TO

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GLIOBLASTOMA

The American Cancer Society estimates that ap-proximately 22,850 malignant tumors of the brain and spinal cord (12,900 in men and 9950 in

women) will be diagnosed in the United States in 2015, and about 15,320 patients (8940 men and 6380 women) will die of these tumors this year.1 Glioblastoma multi-forme, a type of glioma (ie, World Health Organization grade 4 glioma), is the most prevalent and aggressive form of malignant primary brain cancer, accounting for 45.6% of all primary malignant brain tumors.2 In 2015, 10,200 new cases of glioblastoma are predicted to be di-agnosed.2 Glioblastoma has been associated with a par-ticularly poor prognosis, with only one-third of patients surviving for 1 year and less than 5% living beyond 5 years.2-4 The median survival time after diagnosis for pa-tients with glioblastoma is 14.6 months.5

Famous people who have had glioblastoma include Senator Edward Kennedy (survived 15 months after di-agnosis),6 actress Ethel Merman (survived 10 months),7 Chairman of the Republican National Committee Lee Atwater (survived 12 months),8 and Major League Base-ball relief pitcher Frank Edwin “Tug” McGraw Jr (sur-vived 9 months).9

Unmet Need for New Therapies to Treat GlioblastomaThe current standard of care for patients with newly

diagnosed glioblastoma is surgical resection followed by fractionated external beam radiotherapy and systemic temozolomide,4 resulting in a median overall survival (OS) of 14.6 months based on data from a randomized

phase 3 trial.5 Although this treatment can prolong sur-vival, it is not curative, and the vast majority of patients with glioblastoma experience recurrent disease, with a median time to recurrence of 7 months.10 Currently, there is no standard treatment for patients with recurrent glioblastoma, although additional surgery, radiotherapy, chemotherapy (eg, temozolomide), bevacizumab, and low-intensity electric fields are used4 (Table).

TemozolomideTemozolomide, an alkylating (methylating) agent, is

the current standard of care in conjunction with post-operative radiotherapy for patients with newly diag-nosed glioblastoma.4 Temozolomide was approved by the Food and Drug Administration (FDA) in 2005 to treat newly diagnosed adult patients with glioblastoma based on results from a randomized phase 3 clinical study (N = 573) in which temozolomide added 2.5 months to the median OS (median survival was 14.6 months for the group receiving temozolomide plus ra-diotherapy vs 12.1 months for the group receiving ra-diotherapy alone) and 1.9 months to the median pro-gression-free survival (PFS) time (median PFS was 6.9 months for the group receiving temozolomide plus ra-diotherapy vs 5.0 months for the group receiving radio-therapy alone).5 However, resistance to temozolomide is modulated by the DNA repair enzyme O6-methyl-guanine-DNA methyltransferase (MGMT).11 MGMT status has been demonstrated to be predictive of re-sponse to radiation or chemotherapy. The MGMT gene is responsible for a DNA repair mechanism in cells. Methylation of MGMT impedes the DNA repair mechanism in cancer cells, making them susceptible to radiation or chemotherapy such as temozolomide. The DNA repair mechanism in cancer cells with unmethyl-ated MGMT is intact, enabling them to survive and proliferate. Thus, in a significant subset of glioblastoma tumors, expression of MGMT is silenced by promoter methylation, causing resistance to the drug.11 Over 40% of patients undergoing chemotherapy and 55% of

Immunotherapy in Glioblastoma, the Most Lethal Form of Brain CancerGlioblastoma is one of the major cancer types for which new immune-based cancer treatments are currently in development

The current standard of care for patients with newly diagnosed glioblastoma is surgical resection followed by fractionated external beam radiotherapy and systemic temozolomide.


GLIOBLASTOMA

newly diagnosed cases do not benefit at all from the addition of temozolomide to their treatment.12,13

Chemotherapy-Impregnated Implantable WafersIn 1996, the FDA approved an implantable biode-

gradable wafer (known as polifeprosan 20 with carmus-tine implant) as an adjunct to surgery in patients with recurrent glioblastoma based on the results from a dou-ble-blind, placebo-controlled, phase 3 study in which the implantation increased survival at 6 months by more than 50% in the subset of patients with glioblastoma (from 36% in the placebo group to 56% in those who received the implantable wafer).18,19 Similar to temozolo-mide, carmustine is a DNA alkylating agent. The dime-sized wafer is made up of a biocompatible polymer that contains the cancer chemotherapeutic drug carmustine (BCNU). Following removal of the tumor by a neurosur-geon, up to 8 wafers (depending on anatomic limita-tions) can be implanted in the cavity where the tumor resided. Once implanted, the wafers slowly dissolve, re-leasing high concentrations of BCNU directly into the tumor site. The specificity of this treatment minimizes drug exposure to other areas of the body.18,20,21 However,

the National Comprehensive Cancer Network guide-lines warn that BCNU wafers can potentially interact with other agents, resulting in increased toxicity, and implantation of the wafers may preclude future participa-tion in clinical trials of adjuvant therapy.4 In clinical trials, carmustine wafers used in combination with radia-tion and temozolomide have been shown to modestly

prolong survival in subsets of patients. However, because there are complications associated with the use of wafers, including infection, swelling, need for removal, and im-pairment of wound healing,22-24 they are not used rou-tinely at most centers.25 In addition, BCNU wafers have not been proved to confer a significant advantage in

Table Limitations of Current Treatments for Glioblastoma4,14-17

Therapy Description Limitations/Concerns

Temozolomide Chemotherapeutic alkylating (methyl-ating) agent

• High rate of resistance

Chemotherapy-impregnated implantable wafers

Chemotherapeutic agent (carmustine [BCNU])

• May interact with other agents, resulting in increased toxicity

• Implantation of the wafers may preclude future participation in clinical trials of adjuvant therapy

• No proven significant advantage in survival for patients with grade 3 tumors

• No survival advantage for patients with grade 4 tumors, and no increase in progres-sion-free survival

• Anatomic limitations

Bevacizumab Antiangiogenic agent • Increase in rates of hypertension, thrombo-embolic events, intestinal perforation, and neutropenia

• Over time, an increased symptom burden, a worse quality of life, and a decline in neuro-cognitive function

• May promote the emergence of a more aggressive phenotype tumor

• May aid metastasis• May inhibit wound healing• May promote infection

Tumor Treating Fields Medical device that generates low- intensity electric fields

• Lacks improved efficacy

Similar to temozolomide, carmustine is a DNA alkylating agent. The dime-sized waferis made up of a biocompatible polymer thatcontains the cancer chemotherapeutic drugcarmustine (BCNU).


survival for patients with grade 3 tumors when treated with the drug, compared with placebo; there does not appear to be a survival advantage for patients with grade 4 tumors, and no increase in PFS has been shown.14

BevacizumabAntiangiogenic strategies are a promising approach

for glioblastomas due to the highly vascular nature of these tumors, and preclinical data have demonstrated that their growth is dependent on angiogenesis.26,27 In 2009, the FDA granted accelerated approval to beva-cizumab, a vascular endothelial growth factor A–specific angiogenesis inhibitor, as a single agent for the treatment of patients with recurrent glioblastoma based on results

from 2 open-label phase 2 studies.28-30 In the first study, which randomized 167 patients to bevacizumab with or without irinotecan, MRI-defined objective response was achieved in 28% of patients who received bevacizumab alone and in 38% of patients who received both beva-cizumab and irinotecan.29 Median survival was approxi-mately 9 months, similar to that found in a previous phase 2 trial.31 In the other pivotal study, 48 heavily pretreated patients with recurrent glioblastoma treated with single-agent bevacizumab had a median OS of 31 weeks, and 6-month OS was 57%.30

In the frontline setting, bevacizumab failed to in-crease OS or statistically significant PFS for newly diag-nosed patients with glioblastoma in the RTOG 0825 study.15 In this randomized, double-blind, placebo-con-trolled phase 3 study, 637 patients with glioblastoma were treated with radiotherapy and temozolomide. Pa-tients received either bevacizumab or placebo beginning during week 4 of radiotherapy and continued for up to 12 cycles of maintenance chemotherapy. There was no sig-nificant difference in the duration of OS between the bevacizumab group and the placebo group (median, 15.7 and 16.1 months, respectively; hazard ratio [HR] for death in the bevacizumab group, 1.13). PFS was longer in the bevacizumab group (10.7 months vs 7.3 months; HR for progression or death, 0.79). Increases in rates of hypertension, thromboembolic events, intestinal perfo-ration, and neutropenia were seen in the bevacizumab group. Over time, an increased symptom burden, a worse quality of life, and a decline in neurocognitive function were more frequent in the bevacizumab group.15

In a similar randomized, double-blind, placebo-con-trolled phase 3 study (the AVAglio study) of bevacizu-mab in the frontline setting, 921 patients with glioblas-toma treated with radiotherapy and temozolomide received either bevacizumab or placebo (458 patients were assigned to the bevacizumab group and 463 patients to the placebo group).32 In this study, as in the RTOG 0825 study, median PFS was longer in the bevacizumab group than in the placebo group (10.6 months vs 6.2 months; HR for progression or death, 0.64; 95% CI, 0.55-0.74; P <.001), and OS did not differ significantly between groups (HR for death, 0.88; 95% CI, 0.76-1.02; P = .10). The respective OS rates with bevacizumab and placebo were 72.4% and 66.3% at 1 year (P = .049) and 33.9% and 30.1% at 2 years (P = .24). In contrast to the RTOG 0825 study, baseline quality of life and perfor-mance status were maintained longer in the bevacizu-mab group in the AVAglio study; however, the rate of adverse events was higher with bevacizumab than with placebo. More patients in the bevacizumab group than in the placebo group had grade ≥3 adverse events (66.8% vs 51.3%) and grade ≥3 adverse events often associated

GLIOBLASTOMA

Facts About Glioblastoma• Approximately 3.13 cases of glioblastoma occur per

100,000 individuals• Glioblastoma accounts for 15.4% of all primary brain

tumors and 45.6% of primary malignant brain tumors• Incidence of glioblastoma increases with age (median

age 64 years), with rates highest in those 75 to 84 years of age

• Because of the increasing segment of the population that is aged ≥65 years, the incidence rates of glioblasto-ma are rising over time; it is estimated that the inci-dence in 2050 will be 72% higher than it was in 2010

• Glioblastoma is 1.6 times more common in men than in women

• Glioblastoma is about 2 times more common in whites than in blacks

• Relative survival estimates for glioblastoma are quite low; ≤5.0% of patients survive 5 years after diagnosis. The survival estimates are somewhat higher for the small number of patients who are diagnosed when younger than age 20 years.

Sources: Ostrom QT, Gittleman H, Liao P, et al. CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2007-2011. Neuro Oncol. 2014;16(suppl 4):iv1-iv63. Dobes M, Khurana VG, Shadbolt B, et al. Increasing incidence of glioblastoma multiforme and menin-gioma, and decreasing incidence of Schwannoma (2000-2008): findings of a multicenter Australian study. Surg Neurol Int. 2011;2:176. Johnson DR. Rising incidence of glioblastoma and meningioma in the United States: projections through 2050. J Clin Oncol. 2012;30(suppl). Abstract 2065.

In the frontline setting, bevacizumab failedto increase OS or statistically significant PFS for newly diagnosed patients with glioblastoma in the RTOG 0825 study.


with bevacizumab (32.5% vs 15.8%).32

Overall concerns regarding the use of antiangiogenic therapies such as bevacizumab include that they may promote the emergence of a more aggressive phenotype tumor and aid metastasis, as well as inhibit wound healing and pro-mote infection.16,17

Tumor Treating FieldsIn 2011, the FDA approved a

portable medical device that generates low-intensity electric fields termed Tumor Treating Fields (TTF) for the treatment of recurrent glioblastoma. Approv-al was based on results from a clinical trial that randomized 237 patients to TTF or chemo-therapy.33 Although TTF thera-py was associated with lower tox-icity than chemotherapy, as well as improved quality of life, it lacked improved efficacy; similar survival was observed in the 2 groups in the study.33

Emerging Immunotherapeutic ApproachesBecause of the limited treatment options for patients

with glioblastoma, there is an urgent need for new target-ed treatment options. However, the brain has been characterized as one of the “immunologically privileged” sites that are able to tolerate the introduction of an anti-gen without eliciting an inflammatory immune re-sponse.34 Therefore, it might seem that immunotherapy would not be effective in treating brain tumors. Howev-er, it is now known that an immune response can be generated against antigens in the brain, making immu-notherapeutic approaches for glioblastoma possible.35,36

Many promising immunotherapies for glioblastoma are in development, including passive, active, and adop-tive immunotherapeutic approaches. Passive immuno-therapy involves administering antibodies or toxins to patients without specifically inducing or expanding a host antitumor response. Active immunotherapy in-volves immunizing the tumor-bearing host with a “vac-cine” to expand an antitumor immune response in vivo. Adoptive immunotherapy, on the other hand, employs the ex vivo expansion of effector cells and return of these cells to the tumor-bearing host. Examples of active im-munotherapies include autologous tumor cell vaccines, heat shock protein peptide-based vaccines, and rindope-

pimut (CDX-110; an epidermal growth factor receptor variant III [EGFRvIII]-specific peptide conjugated to a nonspecific immunomodulator). Adoptive immunother-apy strategies include various dendritic cell vaccines in which autologous dendritic cells are isolated from pa-tients, pulsed with tumor-specific molecules (eg, tu-mor-specific peptides such as EGFRvIII), expanded ex vivo, and then reintroduced to the patient.

Immunotherapies such as dendritic cell vaccines, heat shock protein vaccines, and EGFRvIII vaccines have shown encouraging results in clinical trials and have demonstrated synergistic effects with convention-al therapeutics resulting in ongoing phase 3 trials. The future of glioblastoma therapeutics will involve focus-ing on developing strategies and finding the place for these emerging immunotherapies in the multimodal treatment regimen.37 u

References1. American Cancer Society. Brain and Spinal Cord Tumors in Adults. What are the key statistics about brain and spinal cord tumors? www.cancer.org/cancer/braincnstu morsinadults/detailedguide/brain-and-spinal-cord-tumors-in-adults-key-statistics. Accessed January 20, 2015.2. Ostrom QT, Gittleman H, Liao P, et al. CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2007-2011. Neuro Oncol. 2014;16(suppl 4):iv1-iv63.3. American Cancer Society. Brain and Spinal Cord Tumors in Adults. Survival rates for selected adult brain and spinal cord tumors. www.cancer.org/cancer/braincns tumorsinadults/detailedguide/brain-and-spinal-cord-tumors-in-adults-survival-rates. Accessed January 20, 2015.4. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Central Nervous System Cancers. Version 2.2014. www.

GLIOBLASTOMA

85+ years

Annual rate of new diagnoses

75 to 84 years

8.95

15.03 13.09

Prevalence

Source: Ostrom QT, Gi:leman H, Liao P, et al. CBTRUS staEsEcal report: primary brain and central nervous system tumors diagnosed in the United States in 2007-‐2011. Neuro Oncol. 2014;16(Suppl 4):iv1-‐63.

65 to 74 years

55 to 64 years

45 to 54 years

35 to 44 years

20 to 34 years

0 to 19 years

8.03 3.59

1.23 0.41 0.15

Of all primary malignant brain tumors are glioblastomas

45.6%

More common in men than in women 1.6 ×

More common in whites than in blacks 2 ×

75+ years 0.9 2.0 65 to 74 years

55 to 64 years

45 to 54 years

35 to 44 years

20 to 34 years

0 to 19 years

4.1

6.5 1.23

5-‐year relaGve survival rates

17.6 18.2


GLIOBLASTOMA

nccn.org/professionals/physician_gls/f_guidelines.asp#site. Accessed January 20, 2015.5. Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352:987-996.6. Kolata G, Altman LK. Weighing hope and reality in Kennedy’s cancer battle. The New York Times. www.nytimes.com/2009/08/28/health/28brain.html?scp=1&sq=t ed%20kennedy%20gbm&st=cse&_r=1&. August 27, 2009. Accessed January 20, 2015.7. Kenrick J. Ethel Merman biography - part III. Musicals101.com. www.musicals101.com/mermbio3.htm. 2003. Accessed January 20, 2015.8. Brady J. I’m still Lee Atwater. The Washington Post. www.washingtonpost.com/wp-srv/style/longterm/books/bckgrnd/atwater.htm. December 1, 1996. Accessed Jan-uary 20, 2015.9. ESPN. Former relief pitcher Tug McGraw dead at 59. http://sports.espn.go.com/espn/wire?section=mlb&id=1701250. January 6, 2004. Accessed January 20, 2015.10. Wen PY, DeAngelis LM. Chemotherapy for low-grade gliomas: emerging con-sensus on its benefits. Neurology. 2007;68:1762-1763.11. Sengupta S, Marrinan J, Frishman C, et al. Impact of temozolomide on immune response during malignant glioma chemotherapy. Clin Dev Immunol. 2012; 2012:831090.12. Mrugala MM, Chamberlain MC. Mechanisms of disease: temozolomide and glioblastoma – look to the future. Nat Clin Pract Oncol. 2008;5:476-486.13. Mirimanoff RO, Gorlia T, Mason W, et al. Radiotherapy and temozolomide for newly diagnosed glioblastoma: recursive partitioning analysis of the EORTC 26981/22981-NCIC CE3 phase III randomized trial. J Clin Oncol. 2006;24:2563-2569.14. Garside R, Pitt M, Anderson R, et al. The effectiveness and cost-effectiveness of carmustine implants and temozolomide for the treatment of newly diagnosed high-grade glioma: a systematic review and economic evaluation. Health Technol Assess. 2007;11(45):iii-iv, ix-221.15. Gilbert MR, Dignam JJ, Armstrong TS, et al. A randomized trial of bevacizumab for newly diagnosed glioblastoma. N Engl J Med. 2014;370:699-708.16. Roukos DH, Tzakos A, Zografos G. Current concerns and challenges regarding tailored anti-angiogenic therapy in cancer. Expert Rev Anticancer Ther. 2009;9:1413-1416.17. Hayden EC. Cutting off cancer’s supply lines. Nature. 2009;458:686-687.18. Gliadel Wafer (carmustine implant) for intracranial use [package insert]. Atlanta, GA: Arbor Pharmaceuticals, LLC; 2013.19. Brem H, Piantadosi S, Burger PC, et al. Placebo-controlled trial of safety and efficacy of intraoperative controlled delivery by biodegradable polymers of chemo-therapy for recurrent gliomas. The Polymer-brain Tumor Treatment Group. Lancet. 1995;345:1008-1012.20. CenterWatch. Gliadel wafer (polifeprosan 20 with carmustine implant). www.

centerwatch.com/drug-information/fda-approved-drugs/drug/237/gliadel-wafer-po lifeprosan-20-with-carmustine-implant. Accessed January 20, 2015.21. Reithmeier T, Graf E, Piroth T, et al. BCNU for recurrent glioblastoma multi-forme: efficacy, toxicity and prognostic factors. BMC Cancer. 2010;10:30.22. Hart MG, Grant R, Garside R, et al. Chemotherapeutic wafers for high grade glioma. Cochrane Database Syst Rev. 2008;3:CD007294. 23. McGirt MJ, Than KD, Weingart JD, et al. Gliadel (BCNU) wafer plus concom-itant temozolomide therapy after primary resection of glioblastoma multiforme. J Neurosurg. 2009;110:583-588.24. Westphal M, Hilt DC, Bortey E, et al. A phase 3 trial of local chemotherapy with biodegradable carmustine (BCNU) wafers (Gliadel wafers) in patients with primary malignant glioma. Neuro Oncol. 2003;5:79-88.25. Wilson TA, Karajannis MA, Harter DH. Glioblastoma multiforme: state of the art and future therapeutics. Surg Neurol Int. 2014;5:64.26. Takahashi JA, Fukumoto M, Igarashi K, et al. Correlation of basic fibroblast growth factor expression levels with the degree of malignancy and vascularity in human gliomas. J Neurosurg. 1992;76:792-798.27. Maxwell M, Naber SP, Wolfe HJ, et al. Expression of angiogenic growth factor genes in primary human astrocytomas may contribute to their growth and progres-sion. Cancer Res. 1991;51:1345-1351.28. National Cancer Institute. FDA Approval for Bevacizumab. www.cancer.gov/cancertopics/druginfo/fda-bevacizumab#Anchor-Glioblastoma. Accessed January 23, 2015.29. Friedman HS, Prados MD, Wen PY, et al. Bevacizumab alone and in combina-tion with irinotecan in recurrent glioblastoma. J Clin Oncol. 2009;27:4733-4740. 30. Kreisl TN, Kim L, Moore K, et al. Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblasto-ma. J Clin Oncol. 2009;27:740-745.31. Vredenburgh JJ, Desjardins A, Herndon JE II, et al. Bevacizumab plus irinotecan in recurrent glioblastoma multiforme. J Clin Oncol. 2007;25:4722-4729.32. Chinot OL, Wick W, Mason W, et al. Bevacizumab plus radiotherapy-temozolo-mide for newly diagnosed glioblastoma. N Engl J Med. 2014;370:709-722.33. Stupp R, Wong ET, Kanner AA, et al. NovoTTF-100A versus physician’s choice chemotherapy in recurrent glioblastoma: a randomised phase III trial of a novel treatment modality. Eur J Cancer. 2012;48:2192-2202.34. Hong S, Van Kaer L. Immune privilege: keeping an eye on natural killer T cells. J Exp Med. 1999;190:1197-1200.35. Kanaly CW, Ding D, Heimberger AB, et al. Clinical applications of a pep-tide-based vaccine for glioblastoma. Neurosurg Clin N Am. 2010;21:95-109.36. Walker PR, Calzascia T, Dietrich PY. All in the head: obstacles for immune re-jection of brain tumours. Immunology. 2002;107:28-38.37. Patel MA, Kim JE, Ruzevick J, et al. The future of glioblastoma therapy: syner-gism of standard of care and immunotherapy. Cancers (Basel). 2014;6:1953-1985.

REGISTERTODAY

M AY 3-6, 2015

AVBCConline.org/conference

ANNIVERSARY

TH

ANNUAL CONFERENCE

Omni Shoreham HotelWashington, DC

mothersister

grandmother

uncle

nephew

brother

AONNonline.org/community/aonn-faces-of-hopeShare Your StorY With uS!

FACES HopE ™

of

best friend

The Academy of Oncology Nurse & Patient Navigators (AONN+) invites you to share your story of how cancer has affected you or a loved one. These stories will serve as a forum to build awareness and be a source of inspiration and reassurance to others. Select stories will be featured on the AONN+ website and in future issues of the Journal of Oncology Navigation & Survivorship ®.

AONNFacesofHopeAsize_10715


EGFRvIII IN GLIOBLASTOMA

A mutation of the epidermal growth factor receptor (EGFR), known as EGFR variant III (EGFRvIII), is expressed in a significant propor-

tion of glioblastoma tumors and is linked to poor long-term survival. Unlike unmutated EGFR, EGFRvIII has not been detected at a significant level in normal tissues; therefore, targeting of this tumor-specific molecule is not likely to impact healthy tissues. A number of immuno-

therapeutic approaches are in development that target EGFRvIII in glioblastoma.

The EGFR plays a role in cellular processes such as migration, differentiation, and apoptosis.1

The EGFR is often amplified in glioblastomas and provides a potential therapeutic target; however, nor-mal tissues also express EGFR, and targeting all EGFRs can lead to unintended damage to normal tissue.2 One

Targeting EGFRvIII in Glioblastoma

EGFRvIII: A Target for ImmunotherapyThe epidermal growth factor receptor (EGFR) variant III mutation (EGFRvIII) is characterized by an in-frame deletion of 801 base pairs from the extracellular domain of EGFR resulting in the fusion of 2 distant portions of the molecule, and produces a novel glycine at the fusion junction of the protein.

This mutant of the wild-type receptor is exclusively expressed on the cell surface of glioblastomas and other neoplasms but is absent on normal tissues. This mutation encodes a protein with a constitutively active tyrosine kinase that enhanc-es tumorigenicity and confers radiation and chemotherapeutic resistance to tumor cells.

Sources: Babu R, Adamson DC. Rindopepimut: an evidence-based review of its therapeutic potential in the treatment of EGFRvIII-positive glioblastoma. Core Evid. 2012;7:93-103. Wikstrand CJ, Hale LP, Batra SK, et al. Monoclonal antibodies against EGFRvIII are tumor specific and react with breast and lung carcinomas and malignant gliomas. Cancer Res. 1995;55:3140-3148. Chu CT, Everiss KD, Wikstrand CJ, et al. Receptor dimerization is not a factor in the signalling activity of a transforming variant epidermal growth factor recep-tor (EGFRvIII). Biochem J. 1997;324(Pt 3):855-861. Lal A, Glazer CA, Martinson HM, et al. Mutant epidermal growth factor receptor up-regulates molecular effectors of tumor in-vasion. Cancer Res. 2002;62:3335-3339. Lammering G, Valerie K, Lin PS, et al. Radiation-induced activation of a common variant of EGFR confers enhanced radioresistance. Radio-ther Oncol. 2004;72:267-273. Montgomery RB, Guzman J, O’Rourke DM, et al. Expression of oncogenic epidermal growth factor receptor family kinases induces paclitaxel resistance and alters beta-tubulin isotype expression. J Biol Chem. 2000;275:17358-17363.

Wild-‐type EGFR

Extracellular Domain (Amino Acids 1 to 621)

Intracellular Domain (Amino Acids 645 to 1186)

Transmembrane Domain (Amino Acids 622 to 644)

Ligand Binding Domain

EGFR vIII

DeleEon of Amino Acids 6 to 273

Novel Glycine Residue

EGFRvIII



specific, spontaneously occurring EGFR mutation, EGFRvIII, is found in approximately 30% of glioblasto-mas but is rarely found in normal brain tissue, so target-ing of EGFRvIII is not likely to impact normal tissue.3-5 This constitutively active mutant receptor leads to un-regulated growth, survival, invasion, and angiogenesis in cells that express it.6-10 For the small subset of pa-tients with glioblastoma who survive 1 year or longer after diagnosis, the expression of EGFRvIII is also an independent negative prognostic indicator of surviv-al.11 Because of this, targeting EGFRvIII represents a very promising therapeutic strategy for patients with glioblastoma, and a number of potential immunothera-pies are in development (Table 1).

Rindopepimut Rindopepimut (CDX-110) is a cancer vaccine with

potential antineoplastic activity consisting of an EGFRvIII-specific peptide conjugated to the nonspecific immunomodulator keyhole limpet hemocyanin (KLH). Vaccination with rindopepimut may elicit a cytotoxic T-lymphocyte immune response against tumor cells ex-pressing EGFRvIII.

Three phase 2 trials of rindopepimut (ACTIVATE, ACT II, and ACT III) have been completed in newly diagnosed EGFRvIII-positive glioblastoma and have shown consistent improvement in overall survival (Figure 1).12 These long-term results represent a substantial sur-vival benefit in comparison with independent control data sets, suggesting that rindopepimut is providing survival beyond what is historically seen in EGFRvIII-expressing glioblastoma patients—a group that typically has more aggressive disease associated with a worse prognosis than the general glioblastoma patient population.12

Table 1 Current Clinical Trials of Immunotherapies Targeting EGFRvIII

Agent Description Stage of Development Comments

Rindopepimut (CDX-110) Autologous dendritic cell vaccine that targets the tumor-specific oncogene EGFRvIII

Phase 3 study (ACT IV) of rindopepimut plus GM-CSF in patients with newly diagnosed EGFRvIII-positive glioblastoma (NCT01480479)

Estimated completion for primary outcome measure: November 2016

Rindopepimut (CDX-110) Autologous dendritic cell vaccine that targets the tumor-specific oncogene EGFRvIII

Phase 2 study (ReACT) of rindopepimut plus GM-CSF in patients with relapsed EGFRvIII-positive glioblastoma (NCT01498328)

Estimated completion for primary outcome measure: June 2015

ADU-623 Vaccine expressing the EGFRvIII-NY-ESO-1 antigens

Phase 1 study in patients with treated and recurrent glioblas-toma (NCT01967758)

Estimated study completion: April 2017

Anti-EGFRvIII chimeric antigen receptor T cells

T cells expressing anti- EGFRvIII chimeric antigen receptor

Phase 1/2 study in patients with glioblastomas expressing EGFRvIII (NCT01454596)

Estimated study completion: December 2019

ABT-414 ADC that targets EGFR/EGFRvIII

Phase 2 study of ABT-414 alone or in combination with temozolomide vs lomustine or temozolomide in patients with recurrent glioblastoma (NCT02343406)

Estimated study completion: June 2017

ABT-414 ADC that targets EGFR/EGFRvIII

Phase 1 study of ABT-414 in combination with radiation and temozolomide in patients with glioblastoma (NCT01800695)

Estimated study completion: March 2016

AMG 595 ADC that binds to EGFRvIII Phase 1 study in patients with recurrent glioblastoma express-ing EGFRvIII (NCT01475006)

Estimated study completion: October 2015

ADC indicates antibody-drug conjugate; GM-CFS, granulocyte-macrophage colony-stimulating factor.



In ACTIVATE (N = 18), patients with newly diag-nosed EGFRvIII-expressing glioblastomas having a gross total resection (>95%), Karnofsky performance status ≥80, and not exhibiting radiographic progression follow-ing external beam radiotherapy and concurrent temo-zolomide therapy were treated with rindopepimut vac-cine and granulocyte-macrophage colony-stimulating factor (GM-CSF), which has been shown to enhance immune responses to vaccination.13,14 At the time of tumor recurrence, 82% (95% CI, 48%-97%) of patients had lost EGFRvIII expression after receiving an EGFRvIII-targeted vaccination (P <.001). This suggest-ed that a specific effect of the vaccine was to eliminate

EGFRvIII-expressing tumor cells, which have been associated with a worse prognosis.13

ACT II (N = 22) was designed to assess the efficacy of rindopepimut with standard adjuvant temozolomide 200 mg/m2 for the first 5 days of a 28-day cycle plus GM-CSF versus temozolomide 100 mg/m2 for the first 21 days of a 28-day cycle plus GM-CSF.15 The patients who received the prolonged temozolomide dosing developed more se-vere lymphopenia; however, there was an even more robust serum immunity to EGFRvIII.

In ACT III, rindopepimut and standard adjuvant temozolomide chemotherapy were administered to 65 patients with newly di-agnosed EGFRvIII-expressing glioblastoma after gross total resection and chemoradia-tion, and results confirmed, in a multicenter setting, the preliminary results seen in pre-vious phase 2 studies.16

Ongoing Rindopepimut StudiesRindopepimut is currently being studied

in 2 clinical trials in EGFRvIII-positive glioblastoma: an international phase 3 study called ACT IV (NCT01480479) in newly diagnosed glioblastoma and a phase 2 study called ReACT (NCT01498328) in recurrent glioblastoma.

ACT IV is a randomized, double-blind, controlled phase 3 study investigating the efficacy and safety of the addition of rindo-pepimut plus GM-CSF (given as a vaccine adjuvant) to the current standard of care, temozolomide, in patients with newly di-agnosed EGFRvIII-positive glioblastoma who have had surgery and radiation plus treatment with temozolomide. Patients are randomly assigned to receive rindopepimut

or KLH (used as a control), each along with temozolo-mide. KLH, an immunogenic carrier protein, is one of the ingredients in the rindopepimut vaccine, but it is not expected to have significant anticancer activity when given alone at this low dose. KLH was selected as a con-trol for this study because of its ability to generate an injection site reaction similar to that observed with the rindopepimut vaccine, which improves the blinding of the study. Patients are treated until disease progression, and all patients are followed for survival. This trial is currently ongoing but is not enrolling patients.

ReACT is an ongoing phase 2 study designed to de-

0

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2

3

4

5

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Phase 2 Studies, Pooled (n = 105)

Matched Historical Control(n = 17)

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Figure 1 Pooled Survival Data from 3 Phase 2 Rindopepimut Clinical Studies in EGFRvIII-Positive Glioblastoma12



termine if adding rindopepimut to the standard of care for relapsed glioblastoma, bevacizumab, improves the outcomes for patients with EGFRvIII-positive recurrent glioblastoma.17 The study includes 3 groups:• Group 1 (n = 72): patients with relapsed glioblasto-

ma who have never been treated with bevacizumab. These patients are randomly assigned to receive ei-ther rindopepimut/GM-CSF or KLH (administered as a control), each along with bevacizumab

• Group 2 (n = 25): patients refractory to bevacizu-mab. These patients receive rindopepimut along with bevacizumab in a single treatment arm

• Group 2C (C = confirmatory): this expansion of group 2 will consist of up to 75 patients who will re-ceive rindopepimut plus bevacizumab in a single treatment arm.

The primary end point of the study is progression-free survival at 6 months (ie, the percentage of patients alive without progression at 6 months). All patients will be treated until disease progression and will be followed for survival.

Interim results from the ReACT study were presented in November 2014 at the 4th Quadrennial Meeting of the World Federation of Neuro-Oncology held in con-junction with the 19th Annual Meeting of the Society for Neuro-Oncology. At the time of the meeting, results showed that, among 72 bevacizumab-naive patients who were randomized to receive either rindopepimut plus bevacizumab (n = 35) or control plus bevacizumab (n = 37), a statistically significant benefit in overall sur-vival (OS) was seen in favor of the patients treated with rindopepimut (hazard ratio 0.47; P = .0208). Median OS was 12.0 months for the rindopepimut plus bevacizumab group and 8.8 months for the control group (Table 2). At the time of the meeting, 27% of patients treated with rindopepimut were progression free compared with 11% of the control patients (P = .048). Seven of 29 patients (24%) evaluable for response in the rindopepimut group experienced a confirmed objective response versus 5 of 30 patients (17%) evaluable for response in the control

group. In addition, 74% of patients in the rindopepimut group had stable disease or better for >2 months versus 57% in the control group.17

Results were also presented for 53 patients (25 pa-tients in group 2; 28 patients in group 2C) refractory to bevacizumab who were receiving rindopepimut along with bevacizumab in the study. The median OS was 5.1 months (95% CI, 3.2-6.5) in these heavily pretreated, refractory EGFRvIII-positive patients (Table 2). In com-parison, a review of the literature assessing survival in recurrent bevacizumab-experienced patients across 8 in-dependent studies suggests a weighted average survival of 3.6 months (range, 2.6-5.8 months) in all-comers. For-ty-six percent of patients in group 2/2C were alive at 6 months. Nineteen percent of patients had stable disease or better for >2 months (range, 2.8-16.5 months).17

ADU-623The ADU-623 vaccine is a live-attenuated, double-

deleted strain of the Gram-positive bacterium Listeria monocytogenes that targets dendritic cells and expresses 2 cancer-specific antigens, EGFRvIII and NY-ESO-1 (a cancer/testis antigen). The vaccine promotes a potent innate immune response as well as an adaptive immune response and targets not only EGFRvIII-expressing tumor cells but also those expressing NY-ESO-1.18 ADU-623 is being investigated in a phase 1 study that will enroll up to 38 patients with high-grade gliomas (includ-ing glioblastomas) who have previously been treated with standard-of-care therapy. The study will evaluate 3 dose levels of ADU-623 with the primary goal of estab-lishing the safety of the immunotherapy and to deter-mine the optimal dose. The trial will also evaluate the patients’ tumor responses and immune responses to the ADU-623 immunotherapy.19

Anti-EGFRvIII Chimeric Antigen Receptor T CellsChimeric antigen receptors (CARs) represent an

emerging technology that combines the variable region of an antibody with T-cell signaling moieties and can be

Table 2 Interim Median Overall Survival in the ReACT Study

Treatment Group Description nOverall Survival

(Months)

Group 1 Bevacizumab-naive patients receiving rindopepimut plus bevacizumab

35 12.0

Group 1 Bevacizumab-naive patients receiving control plus bevacizumab

37 8.8

Group 2/2C Bevacizumab-refractory patients receiving rindopepimut plus bevacizumab

53 5.1



genetically expressed in T cells to mediate potent anti-gen-specific activation.20 CAR T cells have the potential to eradicate neoplasms by recognizing tumor cells regard-less of major histocompatibility complex (MHC) presen-tation of target antigen or MHC downregulation in tu-mors, factors that prevent the success of other anticancer treatments.20 Clinical trials using CARs in other types of cancer have demonstrated the potential efficacy of this strategy.20 However, severe adverse events, including patient deaths, have occurred from administration of CAR T cells when directed against tumor antigens si-multaneously expressed on normal tissues.21,22 Unlike previous CAR T cells, anti-EGFRvIII CAR T cells have the potential to eliminate tumor cells without damaging normal tissue due to the tumor specificity of its target antigen.20

A phase 1/2 clinical study (NCT01454596) is being conducted by the National Cancer Institute to test the safety and feasibility of administering T cells expressing the anti-EGFRvIII chimeric antigen receptor to patients with malignant gliomas expressing EGFRvIII.23

Antibody-Drug ConjugatesTwo therapeutic approaches to cancer therapy are

antibodies that specifically bind tumor surface antigens and cytotoxic chemotherapies. Unfortunately, many antibodies lack therapeutic activity, and toxic chemo-therapeutic drugs do not selectively localize to tumors, so their systemic drug distribution may result in damage to healthy tissues, and drug dose escalation to therapeuti-cally active levels may be impossible. Because antibodies bind specifically to cells expressing their antigen, they represent ideal “vehicles” or “guided missiles” to deliver cytotoxic drugs directly to the tumor.24 Antibody-drug conjugates (ADCs) combine the potency of cytotoxic agents with the target selectivity of antibodies by chem-ically linking a cytotoxic payload to an antibody, poten-tially creating a synthetic molecule that will deliver tar-geted antitumor therapy that is both safe and efficacious.25

ABT-414ABT-414 is an ADC consisting of an antibody target-

ing active EGFR or EGFRvIII conjugated to the cyto-toxic agent monomethyl auristatin F. A phase 1 clinical

trial (NCT01800695) is being conducted to evaluate the safety and pharmacokinetics of ABT-414 in patients with glioblastoma. There are 3 groups in this study: • Group A: patients with newly diagnosed glioblasto-

ma and prior surgical resection receive ABT-414 with concurrent radiotherapy and temozolomide

• Group B: patients with newly diagnosed glioblasto-ma who have completed adjuvant radiation and/or temozolomide therapy or patients with recurrent glioblastoma receive ABT-414 with temozolomide

• Group C: patients with recurrent glioblastoma re-ceive ABT-414 as monotherapy.

Interim results from this phase 1 trial, reported at the 2014 meeting of the Society for Neuro-Oncology, showed that 4 of 12 patients (33%) with measurable disease and EGFR amplification achieved an objective response, including 2 patients who achieved a complete response.26,27 Of the 2 patients who achieved a complete response, one was enrolled in group B and the other in group C. These patients each had disease that recurred after radiation and chemotherapy, a patient population for which effective therapies are very limited. Common adverse events in groups A, B, and C included fatigue, blurred vision, nausea, photophobia, constipation, in-creased aspartate aminotransferase levels, increased ala-nine aminotransferase levels, keratitis, thrombocytope-nia, dry eye, eye pain, and foreign body sensation in the eye. Grade 3/4 adverse events included keratitis, lymphopenia, and thrombocytopenia. Dose-limiting toxicities occurred at multiple doses and affected the eye (keratitis) and liver.

Based on these results, ABT-414, which was granted orphan drug designation by the Food and Drug Admin-istration and the European Medicines Agency earlier this year, will soon advance to a randomized phase 2 study (NCT02343406) in patients with recurrent glio-blastoma.28 There will be 3 groups in this study:• Group 1 (Experimental): patients with recurrent

glioblastoma will receive ABT-414 in combination with temozolomide

• Group 2 (Experimental): patients with recurrent glioblastoma will receive ABT-414 monotherapy

• Group 3A (Active comparator): patients who re-lapse during treatment with temozolomide or within 16 weeks after the first day of the last cycle of treat-ment with temozolomide will receive lomustine

• Group 3B (Active comparator): patients who re-lapse 16 weeks or more after the first day of the last cycle of treatment with temozolomide will receive retreatment with temozolomide.

AMG 595AMG 595, an ADC consisting of a human monoclo-

Severe adverse events, including patient deaths, have occurred from administrationof CAR T cells when directed against tumorantigens simultaneously expressed on normal tissues.



nal antibody directed against EGFRvIII, conjugated to the cytotoxic agent mertansine, is in a phase 1, first-in-human, open-label, dose-finding study enrolling pa-tients with recurrent gliomas, including glioblastomas (NCT01475006).29 An immunohistochemical assay developed using a novel EGFRvIII antibody is current-ly being employed for prospective patient selection in this study.30 u

References1. Hynes NE, Lane HA. ERBB receptors and cancer: the complexity of targeted in-hibitors. Nat Rev Cancer. 2005;5:341-354.2. Del Vecchio CA, Li G, Wong AJ. Targeting EGF receptor variant III: tumor-specif-ic peptide vaccination for malignant gliomas. Expert Rev Vaccines. 2012;11:133-144.3. Wikstrand CJ, Hale LP, Batra SK, et al. Monoclonal antibodies against EGFRvIII are tumor specific and react with breast and lung carcinomas and malignant gliomas. Cancer Res. 1995;55:3140-3148.4. Humphrey PA, Wong AJ, Vogelstein B, et al. Anti-synthetic peptide antibody reacting at the fusion junction of deletion-mutant epidermal growth factor receptors in human glioblastoma. Proc Natl Acad Sci U S A. 1990;87:4207-4211.5. Wong AJ, Ruppert JM, Bigner SH, et al. Structural alterations of the epidermal growth factor receptor gene in human gliomas. Proc Natl Acad Sci U S A. 1992;89:2965-2969.6. Antonyak MA, Moscatello DK, Wong AJ. Constitutive activation of c-Jun N- terminal kinase by a mutant epidermal growth factor receptor. J Biol Chem. 1998;273:2817-2822.7. Moscatello DK, Holgado-Madruga M, Emlet DR, et al. Constitutive activation of phosphatidylinositol 3-kinase by a naturally occurring mutant epidermal growth fac-tor receptor. J Biol Chem. 1998;273:200-206.8. Moscatello DK, Ramirez G, Wong AJ. A naturally occurring mutant human epi-dermal growth factor receptor as a target for peptide vaccine immunotherapy of tu-mors. Cancer Res. 1997;57:1419-1424.9. Li G, Mitra S, Wong AJ. The epidermal growth factor variant III peptide vaccine for treatment of malignant gliomas. Neurosurg Clin N Am. 2010;21:87-93.10. Heimberger AB, Sampson JH. The PEPvIII-KLH (CDX-110) vaccine in glioblas-toma multiforme patients. Expert Opin Biol Ther. 2009;9:1087-1098.11. Heimberger AB, Hlatky R, Suki D, et al. Prognostic effect of epidermal growth factor receptor and EGFRvIII in glioblastoma multiforme patients. Clin Cancer Res. 2005;11:1462-1466.12. Celldex Therapeutics. Celldex Therapeutics’ rindopepimut demonstrates prom-ising clinical activity in patients with EGFRvIII-positive recurrent glioblastoma at SNO [press release]. http://ir.celldex.com/releasedetail.cfm?ReleaseID=809242. No-vember 24, 2013. Accessed January 30, 2015.13. Sampson JH, Heimberger AB, Archer GE, et al. Immunologic escape after pro-longed progression-free survival with epidermal growth factor receptor variant III peptide vaccination in patients with newly diagnosed glioblastoma. J Clin Oncol. 2010;28:4722-4729.14. Babu R, Adamson DC. Rindopepimut: an evidence-based review of its therapeu-tic potential in the treatment of EGFRvIII-positive glioblastoma. Core Evid.

2012;7:93-103.15. Sampson JH, Aldape KD, Archer GE, et al. Greater chemotherapy-induced lymphopenia enhances tumor-specific immune responses that eliminate EGFRvIII-expressing tumor cells in patients with glioblastoma. Neuro Oncol. 2011;13:324-333.16. Schuster J, Lai RK, Recht LD. A phase II, multicenter trial of rindopepimut (CDX-110) in newly diagnosed glioblastoma: the ACT III study [published online January 13, 2015]. Neuro Oncol.17. Celldex Therapeutics. Interim update from randomized phase 2 ReACT study of rindopepimut in recurrent bevacizumab-naive glioblastoma demonstrates statistically significant survival benefit [press release]. http://ir.celldex.com/releasedetail.cfm?Re leaseID=883150. November 15, 2014. Accessed January 30, 2015.18. Aduro BioTech. Aduro BioTech announces initation of a clinical trial of its novel immunotherapy in patients with brain cancer at Providence Cancer Center [press release]. www.aduro.com/news/press-releases/2014/05-05-2014/. May 5, 2014. Accessed February 1, 2015.19. ClinicalTrials.gov. Phase I study of safety and immunogenicity of ADU-623. https://clinicaltrials.gov/ct2/show/NCT01967758. Accessed February 1, 2015.20. Miao H, Choi BD, Suryadevara CM, et al. EGFRvIII-specific chimeric antigen receptor T cells migrate to and kill tumor deposits infiltrating the brain parenchyma in an invasive xenograft model of glioblastoma. PLoS One. 2014;9:e94281.21. Morgan RA, Yang JC, Kitano M, et al. Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing ERBB2. Mol Ther. 2010;18:843-851.22. Brentjens R, Yeh R, Bernal Y, et al. Treatment of chronic lymphocytic leukemia with genetically targeted autologous T cells: case report of an unforeseen adverse event in a phase I clinical trial. Mol Ther. 2010;18:666-668.23. ClinicalTrials.gov. CAR T cell receptor immunotherapy targeting EGFRvIII for patients with malignant gliomas expressing EGFRvIII. https://clinicaltrials.gov/ct2/show/NCT01454596. Accessed February 1, 2015.24. Panowski S, Bhakta S, Raab H, et al. Site-specific antibody drug conjugates for cancer therapy. MAbs. 2014;6:34-45.25. Leal M, Sapra P, Hurvitz SA, et al. Antibody-drug conjugates: an emerging mo-dality for the treatment of cancer. Ann N Y Acad Sci. 2014;1321:41-54.26. AbbVie. AbbVie presents results from study of ABT-414 in patients with glio-blastoma multiforme at the 19th Annual Scientific Meeting and Education Day of the Society for Neuro-Oncology [press release]. http://abbvie.mediaroom.com/2014-11-14-AbbVie-Presents-Results-from-Study-of-ABT-414-in-Patients-with-Glioblas toma-Multiforme-at-the-19th-Annual-Scientific-Meeting-and-Educa tion-Day-of-the-Society-for-Neuro-Oncology. November 14, 2014. Accessed Febru-ary 2, 2015.27. Gan HK, Fichtel L, Lassman AB, et al. A phase 1 study evaluating ABT-414 with temozolomide (TMZ) or concurrent radiotherapy (RT) and TMZ in glioblastoma (GBM). Presented at: 19th Annual Scientific Meeting and Education Day of the Society for Neuro-Oncology (SNO); November 13-16, 2014; Miami, Florida. Ab-stract ET-19.28. ClinicalTrials.gov. ABT-414 alone or ABT-414 plus temozolomide vs. lomustine or temozolomide for recurrent glioblastoma. https://clinicaltrials.gov/ct2/show/NCT02343406?term=NCT02343406&rank=1. Accessed February 1, 2015.29. ClinicalTrials.gov. AMG 595 first-in-human in recurrent gliomas. https://clini-caltrials.gov/ct2/show/NCT01475006. Accessed February 1, 2015.30. Damore MA, Coberly SK, Wakamiya K, et al. An EGFRvIII-specific IHC IUO test for patient selection in AMG 595 phase I trial. J Clin Oncol. 2013;31(suppl). Abstract 2071.

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VACCINES

More than a century ago, researchers began using vaccination to fight cancer. They injected pa-tients with cells and extracts from their own

tumors, or tumors of the same type from different indi-viduals, in an attempt to stimulate a tumor-specific, therapeutic immune response to tumors.1 Today, a num-ber of vaccines are under investigation for the treatment of patients with glioblastoma (Table).

Cancer vaccines harness the potent antigen-present-ing capabilities of dendritic cells, which have the abili-ty to stimulate primary T-cell antitumor immune re-sponses. Dendritic cells, part of the innate immune system, incorporate antigens and subsequently present them to the cells of the adaptive immune system to initiate an immune response. Dendritic cells can be removed from the body and modified ex vivo to en-hance specific antigen presentation or can be activated in vivo to the same end.2

ICT-107ICT-107 is an autologous vaccine consisting of the

patient’s dendritic cells pulsed with 6 synthetic tumor- associated antigens (AIM-2, MAGE-1, TRP-2, gp100, HER2, IL-13Rα2) that are commonly expressed by glioblastoma stem cells or glioblastoma tumors.2 Results from a small, single-institution, phase 1 study of ICT-107 in 16 newly diagnosed patients with glioblastoma showed that median progression-free survival (PFS) was 16.9 months, and the 5-year rate of PFS was 37.5%; median overall survival (OS) was 38.4 months, and the 5-year rate of OS was 50%.3

Based on the results from this phase 1 study, a mul-ticenter, randomized, double-blind, placebo-controlled, phase 2 study (NCT01280552) of the safety and effica-cy of ICT-107 was conducted in 124 patients newly diagnosed with glioblastoma following resection and chemoradiation. The study included patients with human leukocyte antigen-A1 (HLA-A1)-positive or HLA-A2–positive glioblastoma. All patients received standard-of-care temozolomide, and 81 patients were randomized to receive the ICT-107 vaccine and 43 patients to receive placebo (their own dendritic cells not exposed to antigen). The primary end point of the study was OS.4

Updated results from this study, which were pre-sented in November 2014 at the 19th Annual Scien-tific Meeting and Education Day of the Society for Neuro-Oncology, failed to demonstrate a statistically significant improvement in OS. In the intent-to-treat (ITT) population, median OS was 18.3 months for the ICT-107 group and 16.7 for the control group, representing a numeric, but not statistically signifi-cant, advantage for the treatment group (age-stratified hazard ratio [HR] 0.854 [0.547-1.334]; P = .487; (Fig-ure 1).5 However, a statistically significant improve-ment was seen in PFS among those patients who re-ceived the vaccine. Median PFS in the ITT population was 11.4 months for the ICT-107 group and 10.1 months for the control group, representing a statisti-cally significant benefit in the ICT-107 group (age-stratified HR 0.64 [0.42-0.97]; P = .033).

The methylation status of the O6-methylgua-nine-DNA methyltransferase (MGMT) gene promot-er (which is thought to contribute to cellular DNA repair) is an important molecular factor in glioblasto-ma tumors. Methylation of the gene promoter in the tumor tissue silences the expression of MGMT and has been found to be a prognostic and potentially predictive marker for benefit from temozolomide treatment in patients with newly diagnosed glioblas-toma. Because of this, subgroup analyses, including

Vaccines for GlioblastomaCancer vaccines, which depend on activation of the patient’s immune system to recognize and destroy the tumor, have the potential for eliciting a widespread and durable response

Dendritic cells, part of the innate immune system, incorporate antigens and subsequently present them to the cells of the adaptive immune system to initiate an immune response.


VACCINES

HLA-A2 patients within each of the 2 major MGMT subgroups (unmethylated and methylated), were con-ducted in the phase 2 ICT-107 study. When survival was assessed in these prespecified patient subgroups, results favored treatment with ICT-107 over control in HLA-A2 patients within both the unmethylated and methylated HLA-A2 MGMT subgroups.5 Median PFS for the HLA-A2 unmethylated MGMT per-pro-tocol (PP) population was 10.5 months for the ICT-107 group and 6.0 months for the control group, rep-resenting a 4.5-month median PFS benefit for the ICT-107 group (age-stratified HR 0.72 [0.35-1.47]; P = .364). Median PFS for the HLA-A2 methylated MGMT PP population was 24.1 months for the ICT-107 group and 8.5 months for the control group, rep-resenting a statistically significant 15.6-month PFS benefit for the ICT-107 group (age-stratified HR 0.257 [0.095-0.697]; P = .004). No differences in ad-verse events were seen between the 2 groups.5

DCVax-LDCVax-L (also known as DCVax-Brain or DCVax)

is a dendritic cell vaccine derived from autologous den-dritic cells pulsed with a patient-specific tumor lysate.

DCVax-L has been studied in 2 small, completed, sin-gle-arm, phase 1 studies.6 In the first single-arm, phase 1 study (N = 12), 7 patients with newly diagnosed glioblas-toma and 5 with recurrent glioblastoma received DCVax-L in addition to standard-of-care treatment

Table Clinical Trials of Glioblastoma Vaccines

Agent Description Stage of Development Comments

ICT-107 Vaccine derived from autolo-gous dendritic cells pulsed with immunogenic peptides from tumor antigens targeting 6 tumor antigens that are commonly expressed on glioblastoma

Phase 2 study in patients with newly diagnosed glioblastoma (NCT01280552)

Estimated study completion: December 2015

DCVax-L (dendritic cell-autologous lung tumor vaccine)

Vaccine derived from autolo-gous dendritic cells pulsed with glioblastoma lysates

Phase 3 placebo-controlled study in patients with newly diagnosed glioblastoma (NCT00045968)

Estimated completion for primary outcome measure: September 2015

Tumor lysate-pulsed dendritic cell vaccine

Vaccine derived from autolo-gous dendritic cells pulsed with tumor lysate antigen ± toll-like receptor agonists (adjuvant imiquimod or poly interstitial Cajal-like cell [ICLC])

Phase 2 study in patients with newly diagnosed or recurrent glioblastoma (NCT01204684)

Estimated completion for primary outcome measure: September 2015

Tumor lysate-pulsed dendritic cell vaccine

Vaccine derived from autolo-gous dendritic cells pulsed with tumor lysate antigen + adjuvant imiquimod

Open-label, phase 1 study in patients with malignant gliomas (NCT01792505)

Estimated study completion: October 2016

HSPPC-96 (heat shock protein-peptide complex-96)

HSPPC-96 vaccine + bevaci-zumab vs bevacizumab alone

Phase 2 study comparing the efficacy of HSPPC-96 vac-cine + bevacizumab vs beva-cizumab alone in patients with surgically resectable recurrent glioblastoma (NCT01814813)

Estimated completion for primary outcome measure: April 2016

The methylation status of the O6-methyl- guanine-DNA methyltransferase gene promoter (which is thought to contribute to cellular DNA repair) is an important molecular factor in glioblastoma tumors.


VACCINES

(which included reoperation, temozolomide, and/or other medications).7 The median time to progression for these 12 patients was 15.5 months (vs 8.2 months for a matched control group), and the median OS time was 23.4 months (vs 18.3 months for a matched control group). In the second single-arm phase 1 study (NCT00068510; N = 23), 15 patients with newly diag-nosed glioblastoma and 8 with recurrent glioblastoma

received DCVax-L in conjunction with toll-like receptor agonists (ie, either 5% imiquimod cream or intramuscular injec-tions of poly interstitial Cajal-like cell [ICLC] adjuvant) until tumor progression.8 The median time to progression was report-ed as 15.9 months and median OS as 31.4 months. Among the 15 newly diagnosed patients, the median OS was 35.9 months.

Based on these results, an international, multicenter, double-blind, randomized, placebo-controlled phase 3 study (NCT00045968) is being conducted in 348 patients with newly diagnosed glio-blastoma.6,9 Patients will receive the stan-dard-of-care treatment (including radia-tion and temozolomide), and one group will receive DCVax-L whereas the other group will receive a placebo. The primary end point of the study is PFS.

Also based on the results from the above-mentioned phase 1 study (NCT00068510) in which patients re-ceived DCVax-L in conjunction with toll-like receptor agonists, a placebo-con-trolled phase 2 study (NCT01204684) is under way at Jonsson Comprehensive Cancer Center in Los Angeles by the same investigators to evaluate the vaccine in combination with either 0.2% imiquimod cream, a single intramuscular injection of poly ICLC, or placebo.10

An open-label, phase 1 study (NCT01792505) is also under way at Ce-dars-Sinai Medical Center in Los Angeles in which patients undergo surgical resec-tion followed by vaccination with dendritic cells pulsed with tumor lysate in combina-tion with imiquimod cream application.11

Heat Shock Protein Peptide-Based Vaccines

The expression of heat shock proteins (HSPs), a group of ubiquitous soluble intra-cellular proteins, is increased when cells are

exposed to elevated temperatures or other stresses.12 HSP-peptide complexes (HSPPCs) found in cancer cells carry tumor-specific antigenic proteins and can facilitate adaptive and innate immune responses.12,13 An HSPPC vaccine based on tumor-derived glycoprotein 96 (HSPPC-96) has been studied as a single agent in a phase 2 study in recurrent glioblastoma.13 Results from this multicenter, open-label study (N = 41) showed that,

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Hazard ratio 0.854 P = .487

Figure 1 Median Overall Survival Data from the Phase 2 ICT-107 Study in Newly Diagnosed Patients with Glioblastoma (ITT Population)

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Figure 2 Median Survival Data from the Phase 2 HSPPC-96 Study in Patients with Recurrent Glioblastoma (ITT Population)

HSPPC-96 indicates heat shock proteins–peptide complex vaccine based on tumor-derived glycoprotein 96; ITT, intent-to-treat.

ITT indicates intent-to-treat.


VACCINES

in the ITT population, the median PFS was 19.1 weeks (95% CI, 14.1-24.1), with a 6-month PFS of 29.3% (95% CI, 16.6-45.7); the median OS was 42.6 weeks (95% CI, 34.7-50.5), with a 6-month OS of 90.2% (95% CI, 75.9-96.8) and a 12-month OS of 29.3% (95% CI, 16.6-45.7; (Figure 2).14

A phase 2 study of HSPPC-96 has also been completed in patients with newly diagnosed glioblastoma in combination with radiation therapy and temozolomide chemotherapy (NCT00905060). Prelimi-nary results from this study showed that patients treated with HSPPC-96 plus the standard of care (radiation and temozolo-mide) had a median OS of approximately 24 months, and 33% of patients remained alive at 2 years and continue to be fol-lowed for survival.15 In addition to the long-term survival data, patients treated with HSPPC-96 had a median PFS of nearly 18 months, 2 to 3 times longer than patients treated with radiation and temo-zolomide alone.15,16 Furthermore, 22% of patients were alive and without progression at 24 months and contin-ue to be followed for survival (Figure 3).15

A large-scale phase 2, randomized 3-group study (NCT01814813) of HSPPC-96 in combination with bevacizumab (given concomitantly or at the point of progression) versus bevacizumab alone in recurrent glio-blastoma is being conducted by the National Cancer Institute.17 u

References1. Myc LA, Gamian A, Myc A. Cancer vaccines. Any future? Arch Immunol Ther Exp (Warsz). 2011;59:249-259.2. Xu LW, Chow KK, Lim M, et al. Current vaccine trials in glioblastoma: a review. J Immunol Res. 2014;2014:796856.3. Phuphanich S, Wheeler CJ, Rudnick JD, et al. Phase I trial of a multi-epitope-pulsed dendritic cell vaccine for patients with newly diagnosed glioblastoma. Cancer Immunol Immunother. 2013;62:125-135.4. Wen PY, Reardon DA, Phuphanich S, et al. A randomized, double-blind, place-bo-controlled phase 2 trial of dendritic cell (DC) vaccination with ICT-107 in newly diagnosed glioblastoma (GBM) patients. J Clin Oncol. 2014;32(suppl). Abstract 2005.5. ImmunoCellular Therapeutics. ICT-107. www.imuc.com/pipeline/ict-107. Ac-cessed February 4, 2015.6. Northwest Biotherapeutics. DCVax® – L phase III for GBM brain cancer. www.nwbio.com/clinical-trials/dcvax-l-phase-iii-for-gbm-brain-cancer/. Accessed February 4, 2015.

7. Liau LM, Prins RM, Kiertscher SM, et al. Dendritic cell vaccination in glioblasto-ma patients induces systemic and intracranial T-cell responses modulated by the local central nervous system tumor microenvironment. Clin Cancer Res. 2005;11:5515-5525.8. Prins RM, Soto H, Konkankit V, et al. Gene expression profile correlates with T-cell infiltration and relative survival in glioblastoma patients vaccinated with dendritic cell immunotherapy. Clin Cancer Res. 2011;17:1603-1615.9. ClinicalTrials.gov. Study of a drug [DCVax®-L] to treat newly diagnosed GBM brain cancer. www.clinicaltrials.gov/ct2/show/study/NCT00045968. Accessed Febru-ary 4, 2015.10. ClinicalTrials.gov. Dendritic cell vaccine for patients with brain tumors. https://clinicaltrials.gov/ct2/show/NCT01204684. Accessed February 4, 2015.11. ClinicalTrials.gov. Dendritic cell vaccine with imiquimod for patients with malig-nant glioma. https://clinicaltrials.gov/show/NCT01792505. Accessed February 4, 2015.12. Amato RJ. Heat-shock protein-peptide complex-96 for the treatment of cancer. Expert Opin Biol Ther. 2007;7:1267-1273.13. Crane CA, Han SJ, Ahn B, et al. Individual patient-specific immunity against high-grade glioma after vaccination with autologous tumor derived peptides bound to the 96 KD chaperone protein. Clin Cancer Res. 2013;19:205-214.14. Bloch O, Crane CA, Fuks Y, et al. Heat-shock protein peptide complex-96 vac-cination for recurrent glioblastoma: a phase II, single-arm trial. Neuro Oncol. 2014;16:274-279.15. Agenus. Agenus brain cancer vaccine shows extended survival in phase 2 final data analysis [press release]. www.agenusbio.com/docs/press-releases/2014/agenus-brain-cancer-vaccine-shows-extended-survival-in-phase-2-final-data-analysis.php. July 1, 2014. Accessed February 10, 2015.16. Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352:987-996.17. ClinicalTrials.gov. Vaccine therapy with bevacizumab versus bevacizumab alone in treating patients with recurrent glioblastoma multiforme that can be removed by surgery. https://clinicaltrials.gov/ct2/show/NCT01814813?term=NCT01814813&ra nk=1. Accessed February 4, 2015.

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Figure 3 Median Survival Data from the Phase 2 Study of HSPPC-96 Plus

Standard of Care (Radiation and Temozolomide) in Newly Diagnosed Patients with Glioblastoma (Preliminary Results)

HSPPC-96 indicates heat shock proteins–peptide complex vaccine based on tumor-derived glycoprotein 96.



Immune “checkpoints” refer to the numerous negative immunologic regulators (inhibitory pathways) that are crucial for maintaining self-tolerance (ie, the pre-

vention of autoimmunity) and modulating the immune responses in peripheral tissues.1

Cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) and programmed death 1 (PD-1) receptor are 2 important cellular targets that play nonredundant roles in regulating adaptive immunity.2 Whereas CTLA-4 at-tenuates the early activation of naive and memory T cells, the major role of PD-1 is to limit the activity of T cells in peripheral tissues at the time of an inflammatory response to infection and to limit autoimmunity.1,3,4 The approvals by the Food and Drug Administration (FDA) of the CTLA-4–blocking antibody, ipilimumab (in 2011), and the PD-1–blocking antibody, pembrolizumab (in 2014), for the treatment of patients with advanced melanoma demonstrate that checkpoint-blocking anti-bodies have a promising role in immunotherapy.

NivolumabNivolumab is a fully human monoclonal immuno-

globulin (Ig) G4 immune checkpoint inhibitor antibody that binds to the PD-1 receptor and selectively prevents its interaction with its ligands PD-L1 and PD-L2, there-by blocking the ability of PD-1 to suppress T-cell antitu-mor function.5,6 PD-1 pathway blocking agents, such as nivolumab, are therefore capable of reversing T-cell suppression and ultimately inducing antitumor respons-

es.7 Results from a phase 1/2 study indicate that nivolu-mab is active in multiple tumor types, and nivolumab monotherapy is currently being studied in phase 3 clini-cal trials in advanced melanoma, renal cell carcinoma, and non–small cell lung carcinoma.7

IpilimumabIpilimumab is a fully humanized IgG1 monoclonal

antibody that binds to CTLA-4 and prevents CTLA-4–mediated negative regulation of T cells, thus promoting antitumor immunity.1 Ipilimumab is FDA approved as a treatment for metastatic melanoma and has demonstrat-ed clinical activity against brain metastases in patients with advanced melanoma.8

Dual Blockade of CTLA-4 and PD-1 with Nivolumab and Ipilimumab

Although single-agent CTLA-4 or PD-1 pathway blockade has demonstrated clear antitumor activity across multiple tumor types, combined blockade of PD-1 and CTLA-4 appears to achieve more pronounced anti-tumor activity than blockade of either pathway alone.2,9

Preclinical data suggest that combining CTLA-4 and PD-1 blockade may improve antitumor activity achieved over blocking either receptor alone.10,11

The first clinical study of combined checkpoint block-ade was a phase 1 dose-escalation study (NCT01024231) in 53 patients with advanced melanoma.12,13 In this study, a dose of ipilimumab 3 mg/kg plus nivolumab 1 mg/kg every 3 weeks was established for the treatment of advanced melanoma. At these doses, 53% of patients had an objective response, all with tumor reduction of ≥80%. This regimen is currently being investigated in a phase 3 study (NCT01844505) in advanced melanoma.

Nivolumab and Ipilimumab in GlioblastomaPreclinical data in murine glioblastoma models

strongly support the evaluation of immune checkpoint inhibitors among patients with glioblastoma.14

Exploring Immune Checkpoint Blockade for GlioblastomaThe blockade of immune checkpoints is among the most promising approaches to activating therapeutic antitumor immunity

Ipilimumab is a fully humanized IgG1 monoclonal antibody that binds to CTLA-4 and prevents CTLA-4–mediated negative regulation of T cells, thus promotingantitumor immunity.



The first clinical study (NCT02017717) to examine the safety and efficacy of nivolumab (alone or in combi-nation with ipilimumab) versus bevacizumab in an esti-mated 260 patients with recurrent glioblastoma is under way at 64 sites in 13 countries.15 It is an open-label, randomized, phase 2b study in patients with grade 4 malignant gliomas (glioblastomas or gliosarcomas) and documented first recurrence of glioblastoma after treat-ment with radiation and temozolomide. After a safety lead-in phase, patients will be randomized to receive ei-ther nivolumab alone or nivolumab plus ipilimumab or bevacizumab alone. The estimated study completion date is January 2018. u

References1. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12:252-264.2. Callahan MK, Postow MA, Wolchok JD. CTLA-4 and PD-1 pathway blockade: combinations in the clinic. Front Oncol. 2015;4:385.3. Kyi C, Postow MA. Checkpoint blocking antibodies in cancer immunotherapy. FEBS Lett. 2014;588:368-376.4. Momtaz P, Postow MA. Immunologic checkpoints in cancer therapy: focus on the programmed death-1 (PD-1) receptor pathway. Pharmgenomics Pers Med. 2014;7:357-365.

5. Brahmer JR, Drake CG, Wollner I, et al. Phase I study of single-agent anti-pro-grammed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol. 2010;28:3167-3175.6. Wang C, Thudium KB, Han M, et al. In vitro characterization of the anti-PD-1 antibody nivolumab, BMS-936558, and in vivo toxicology in non-human primates. Cancer Immunol Res. 2014;2:846-856.7. Gunturi A, McDermott DF. Nivolumab for the treatment of cancer. Expert Opin Investig Drugs. 2015;24:253-260.8. Margolin K, Ernstoff MS, Hamid O, et al. Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial. Lancet Oncol. 2012;13:459-465.9. Postow MA, Callahan MK, Wolchok JD. Immune checkpoint blockade in cancer therapy [published online January 20, 2015]. J Clin Oncol.10. Curran MA, Montalvo W, Yagita H, et al. PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors. Proc Natl Acad Sci U S A. 2010;107:4275-4280.11. Duraiswamy J, Kaluza KM, Freeman GJ, et al. Dual blockade of PD-1 and CTLA-4 combined with tumor vaccine effectively restores T-cell rejection function in tu-mors. Cancer Res. 2013;73:3591-3603.12. Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in ad-vanced melanoma. N Engl J Med. 2013;369:122-133.13. Sznol M, Kluger HM, Callahan MK, et al. Survival, response duration, and ac-tivity by BRAF mutation (MT) status of nivolumab (NIVO, anti-PD-1, BMS-936558, ONO-4538) and ipilimumab (IPI) concurrent therapy in advanced melano-ma (MEL). J Clin Oncol. 2014;32(suppl). Abstract LBA9003.14. Reardon DA, Gokhale PC, Hodi FS, et al. Immune checkpoint blockade for glioblastoma: preclinical activity of single agent and combinatorial therapy. J Clin Oncol. 2014;32(suppl). Abstract 2084.15. Sampson JH, Vlahovic G, Desjardins A, et al. Randomized phase IIb study of nivolumab (anti-PD-1; BMS-936558, ONO-4538) alone or in combination with ipilimumab versus bevacizumab in patients (pts) with recurrent glioblastoma (GBM). J Clin Oncol. 2014;32(suppl). Abstract TPS2101.

REGISTER TODAY JULY 22-25, 2015THE WESTIN SEATTLE • SEATTLE, WASHINGTON

CONFERENCE CO-CHAIRS




Hope S. Rugo, M.D.Professor of MedicineDirector, Breast Oncology and Clinical Trials EducationUniversity of California San Francisco Helen Diller Family ComprehensiveCancer Center San Francisco, CA

Hope S. Rugo, MD, is a Professor of Medicine in the Division of Hematology and Oncology at the University of California San Francisco, Helen Diller Family Comprehensive Cancer Center, where she directs Breast Cancer and Clinical Trial Education. Her research interests include novel therapies for advanced breast cancer, immune modulation to restore chemotherapy sensitivity, evaluation of circulating cells as novel markers of response and resistance to therapy, neoadjuvant therapy and supportive care.

Dr. Rugo is an investigator in the Bay Area Spore at the UCSF Breast Cancer Center, the national multi-center ISPY2 trial, and is the principal investigator of a number of clinical trials. She is one of three recipients of a Komen Promise Award, receives funding from the Breast Cancer Research Foundation, and serves on a number of steering committees for national and international trials. Dr. Rugo is a member of the ALLIANCE Breast Core Committee and the Translational Breast Cancer Research Consortium, is the UCSF representative to the NCCN Guidelines Committee, and serves on several committees for the American Society of Clinical Oncology. She has published many peer-reviewed papers and has given presentations on a variety of cancer related topics.

With a summa cum laude undergraduate degree from Tufts University. Dr. Rugo received her MD from the University of Pennsylvania School of Medicine and completed both a residency in internal medicine and fellowship in hematology and oncology at the UCSF. Additionally, she completed a two-year post-doctoral fellowship in immunology at Stanford University. She received the Cancer Care Physician of the year award in 2010.

PMOLive_fi ll030415


2015 GASTROINTESTINAL CANCERS SYMPOSIUM

Add gastric cancer to the list of cancers that re-spond to immunotherapy. In patients with ad-vanced gastric cancer who express programmed

cell death (PD)-1 ligand 1 (PD-L1), the humanized monoclonal antibody pembrolizumab demonstrated robust antitumor activity and an acceptable safety pro-file, according to updated results presented at the 2015 Gastrointestinal Cancers Symposium.

In the phase 1b KEYNOTE-012 trial in patients with previously treated advanced gastric cancer, 22.2% achieved an objective response with pembrolizumab, said Kei Muro, MD, of the Aichi Cancer Center Hospital, Nagoya, Japan, and lead investigator of the KEYNOTE-012 trial.

“Overall, these findings support the importance of the PD-L1 pathway in gastric cancer and the further development of pembrolizumab as a treatment option for patients with advanced gastric cancer,” said Muro.

“PD-1 is a negative costimulatory receptor expressed on the surface of the activated T cell and plays an im-portant role in suppressing immune surveillance,” he said. “Binding of PD-1 to its ligands, PD-L1 and PD-L2, inhibits effector T-cell function, which dampens the immune response and leads to neoplastic growth.” The expression of PD-L1 in tumors correlates with poor prognosis.

Pembrolizumab is a selective, humanized monoclo-nal antibody designed to block the interaction between PD-1 and its ligands, thereby reactivating the immune system to eradicate the host tumor.

The administration of 10-mg/kg pembrolizumab

monotherapy every 2 weeks was evaluated in KEY-NOTE-012 in patients with recurrent or metastatic stomach or gastroesophageal cancer with PD-L1 expres-sion. Of the 162 evaluable patients, 65 (40%) had PD-L1 expression. Of these 65 patients, 39 were enrolled in the trial and received pembrolizumab intravenously.

Overall, 51.3% of the patients had a previous gas-trectomy; 66.7% had received ≥2 previous therapies for advanced disease.

After a median follow-up of 8.8 months, “pembroliz-umab demonstrated strong evidence of anticancer ac-tivity,” said Muro. The response rate was 22.2% by central review (33.3% by investigator review); all were partial responses. Stable disease was recorded in 13.9% of patients by central review (12.8% by investigator).

“Overall, 53.1% experienced a decrease from base-line in the size of their target lesions,” Muro said.

The median time to response was 8 weeks, and the median duration of response was 24 weeks. “Response to pembrolizumab was durable, with 6 of the 8 respond-ers maintaining response,” said Muro.

The 6-month rate of progression-free survival (PFS) was 24%, and the median PFS was 1.9 months. The overall survival (OS) rate at 6 months was 69%, and the median OS had not been reached at the time of the analysis.

“There was a trend toward an association between higher levels of PD-L1 expression and response, PFS, and OS,” Muro said. “Further analysis of these prelimi-nary data is ongoing to help determine the relationship between PD-L1 expression and antitumor activity in gastric cancer.”

The safety profile of pembrolizumab was acceptable. Most adverse events were grade 1 or 2. The most com-mon adverse events were fatigue (17.9%), decreased appetite (12.8%), hypothyroidism (12.8%), and ar-thralgia (10.3%). Four patients had severe adverse events (peripheral sensory neuropathy, fatigue, de-creased appetite, and pneumonitis); 1 patient died from treatment-associated hypoxia. u

PD-L1 Inhibitor Pembrolizumab Produces Good Responses in Advanced Gastric Cancer

Pembrolizumab is a selective, humanizedmonoclonal antibody designed to block theinteraction between PD-1 and its ligands,thereby reactivating the immune system toeradicate the host tumor.


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IMMUNO-ONCOLOGY PIPELINE

Bristol-Myers Squibb Company and Flexus Biosci-ences, Inc announced today the companies have signed a definitive agreement under which Bris-

tol-Myers Squibb will acquire all of the outstanding capital stock of Flexus, a privately held biotechnology company focused on the discovery and development of novel anticancer therapeutics. The transaction has a potential total consideration of $1.25 billion, including $800 million up front and development milestones that, upon achievement, could total up to $450 million. The transaction has been approved by the boards of directors of both companies and by the stockholders of Flexus.

The acquisition will give Bristol-Myers Squibb full rights to F001287, Flexus’ lead preclinical small-molecule IDO1 inhibitor targeted for IND filing in the second half of 2015. In addition, Bristol-Myers Squibb will acquire Flexus’ IDO/TDO discovery program, which includes its IDO-selective, IDO/TDO dual and TDO-selective com-pound libraries. A newly formed entity established by the current shareholders of Flexus will retain, from and after the closing, all non-IDO/TDO assets of Flexus, including those related to Flexus’ phase 1 FLT3 and CDK4/6 inhib-itor, its earlier stage small-molecule Treg cancer immuno-therapy programs, and its current personnel and facilities.

“Bristol-Myers Squibb is committed to leading scien-tific advances in immuno-oncology, and our acquisition of Flexus will expand our innovative pipeline with an important approach to enhancing immune responses in cancer,” said Francis Cuss, MB BChir, FRCP, executive vice president and chief scientific officer, Bristol-Myers Squibb. “With the addition of a potentially best-in-class IDO1 inhibitor and the broad IDO/TDO programs, Bris-tol-Myers Squibb will accelerate its ability to explore numerous immunotherapeutic approaches across tumor types, including combinations with our biologic check-point and costimulatory agents that target different and complementary pathways.”

“Bristol-Myers Squibb is a recognized leader in the cancer immunotherapy field, and we are delighted with the opportunity to have their organization advance the

development of our potentially best-in-class IDO/TDO inhibitors and to bring more innovative cancer immuno-therapies to patients,” said Terry Rosen, PhD, chief ex-ecutive officer of Flexus Biosciences. “With the consum-mation of this acquisition, we will continue to advance our oncology and immuno-oncology pipeline of Agents for Reversal of Tumor Immunosuppression (ARTIS) in the newly created spin-off, with the strong support of our committed group of investors.”

Bristol-Myers Squibb and Flexus anticipate the trans-action will close during the first quarter of 2015. Closing of the transaction is subject to customary closing condi-tions, including clearance under the Hart-Scott-Rodino Antitrust Improvements Act.

Citi acted as exclusive advisor to Flexus on the trans-action and Gunderson Dettmer acted as legal counsel. Kirkland & Ellis LLP is serving as legal advisor to Bris-tol-Myers Squibb in connection with the transaction.

About IDO/TDO IDO and TDO are enzymes expressed by many tumor

cells and cells in the surrounding microenvironment that suppress T-cell function by producing a potent immuno-suppressive factor, kynurenine, thus inhibiting the im-mune system from identifying and destroying certain types of tumors. IDO/TDO inhibitors reduce kynurenine production, enabling the immune system to attack tu-mors more effectively. Given the immunomodulatory effects of IDO/TDO inhibitors, strong scientific rationale supports exploring combination regimens with immuno-therapies where synergistic activity may enhance long-term survival benefits for patients. u

Bristol-Myers Squibb to Expand Its Immuno-Oncology Pipeline with Agreement to Acquire Flexus Biosciences, Inc

Bristol-Myers Squibb press release, February 23, 2015.

KEY POINTS

➤ Bristol-Myers Squibb gains full rights to Flexus’ lead preclinical IDO1 inhibitor F001287 and the company’s broad IDO/TDO discovery program

➤ Enables Bristol-Myers Squibb to fully explore the potential of IDO/TDO-targeted immunotherapies in combination with its immuno-oncology portfolio

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Tumor-derived antigens (TDAs) set the immune system in motion by priming and activating T cells. Once released, TDAs are processed by dendritic cells and subsequently presented to T cells, initiating an adaptive immune response.1-3

Learn more at MelanomaAntigens.com

References: 1. Kaufman HL, Disis ML. J Clin Invest. 2004;113:664-667. 2. Klebanoff CA, Gattinoni L, Restifo NP. Immunol Rev. 2006;211:214-224. 3. den Boer AT, van Mierlo GJD, Fransen MF, Melief CJM, Offringa R, Toes REM. J Immunol. 2004;172:6074-6079.

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Dendritic cell

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