Lung Cancer: Translational and Emerging Therapies (Translational Medicine)

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Lung Cancer Translational and Emerging Therapies

Edited by

Kishan J. Pandya University of Rochester, Rochester, New York, USA

Julie R. Brahmer Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

Manuel Hidalgo Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

Informa Healthcare USA, Inc. 52 Vanderbilt Avenue New York, NY 10017 © 2007 by Informa Healthcare USA, Inc. Informa Healthcare is an Informa business No claim to original U.S. Government works Printed in the United States of America on acid-free paper 10 9 8 7 6 5 4 3 2 1 International Standard Book Number-10: 0-8493-9021-4 (Hardcover) International Standard Book Number-13: 978-0-8493-9021-0 (Hardcover) This book contains information obtained from authentic and highly regarded sources. Reprinted material is quoted with permission, and sources are indicated. A wide variety of references are listed. Reasonable efforts have been made to publish reliable data and information, but the author and the publisher cannot assume responsibility for the validity of all materials or for the consequence of their use. No part of this book may be reprinted, reproduced, transmitted, or utilized in any form by any electronic, mechanical, or other means, now known or hereafter invented, including photocopying, microfilming, and recording, or in any information storage or retrieval system, without written permission from the publishers For permission to photocopy or use material electronically from this work, please access www. copyright.com (http://www.copyright.com/) or contact the Copyright Clearance Center, Inc. (CCC) 222 Rosewood Drive, Danvers, MA 01923, 978-750-8400. CCC is a not-for-profit organization that provides licenses and registration for a variety of users. For organizations that have been granted a photocopy license by the CCC, a separate system of payment has been arranged. Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation without intent to infringe.

Library of Congress Cataloging-in-Publication Data Lung cancer: translational and emerging therapies / [edited by] Kishan J. Pandya, Julie R. Brahmer, Manuel Hidalgo. p. ; cm. -- (Translational medicine series ; 3) Includes bibliographical references. ISBN-13: 978-0-8493-9021-0 (hb : alk. paper) ISBN-10: 0-8493-9021-4 (hb : alk. paper) 1. Lung--Cancer--Chemotherapy. 2. Lungs--Cancer--Treatment--Technological innovations. 3. Lungs--Cancer-Molecular aspects. I. Pandya, Kishan J. II. Brahmer, Julie R. III. Hidalgo, Manuel, MD. IV. Series. [DNLM: 1. Lung Neoplasms--drug therapy. 2. Antineoplastic Agents--therapeutic use. WF 658 L9637 2007] RC280.L8L827 2007 616.99’42406--dc22

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Preface

Lung cancer is the most common cancer worldwide, affecting over a million people every year, and it is the leading cause of death. Despite modest improvements in therapy, the five-year survival of this disease is less than 15%. The mainstay of treatment is surgery and adjuvant chemotherapy for early stage disease, concurrent chemoradiotherapy for locally advanced disease, and chemotherapy for metastatic disease. Molecularly targeted treatments are now coming to the fore, and epidermal growth factor receptor tyrosine kinase inhibitors such as erlotinib (Tarceva®) are now approved for use as second-line or third-line treatment of metastatic disease. Although not yet established as standard therapy, there are an ever increasing number of novel and targeted therapies being assessed in the treatment of lung cancer. These therapies are in varied stages of development and include antiangiogenesis inhibitors, epidermal growth factor receptor inhibitors, tumor vaccines, monoclonal antibodies, and endothelial receptor antagonists, to name just a few. Also in development are combination therapies of established treatments with targeted therapies. These emerging therapies reflect our expanding understanding of mechanisms of tumorogenesis and cell growth. This book provides the state-of-the-art information on evolving translational therapies in lung cancer. Currently, there is no text on this topic that assembles, reviews, and synthesizes this material in one volume. It is appropriate that Drs. Gandara and Gummerlock and their colleagues set the stage and describe the molecular biology of lung cancer as the basis for targeted therapy in their chapter. Dr. Janet Dancey describes some of the more challenging aspects of clinical trial design issues related to clinical evaluation of these novel agents. Some agents that have shown promise include angiogenesis inhibitors, antibody to vascular endothelial growth factor receptor, small molecule tyrosine kinase, and other multi-targeted agents. Drs. Ramnath and Adjei describe the basis of antiangiogenic therapy as well as provide a comprehensive review of small iii

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molecule inhibitors of angiogenesis, followed by a chapter on inhibition of angiogenesis using monoclonal antibodies by Drs. Dubey and Salgia. Drs. Jimeno and Hidalgo discuss the targeting of the epidermal growth factor receptor in the treatment of lung cancer, and Dr. Fred Hirsch and his colleagues discuss the markers of sensitivity and response to treatment with these agents. Drs. Papadopoulos and Tolcher complete the discussion with their chapter on other novel targeted therapies, including such targets as Bcl, tumor necrosis factor–related apoptosis-inducing ligand receptors, inhibitor of apoptosis proteins family, and proteosome. Vaccine therapy remains a promising area of research, and Dr. Davies and her colleagues update us on cancer immunology and the exciting data on several novel vaccine approaches and other new methods to modify the immune response. Technological advances in the delivery of radiation as well as newer chemotherapeutic agents have produced improvements in combining these modalities for the treatment of locally advanced disease, as discussed by Drs. Milano and Chen, and also in the treatment of brain metastases, as discussed by Drs. Siker and Mehta. Technological advances in radiological imaging is making it possible to delineate the size and the location of tumors more precisely, as well as detect the presence of metastatic disease, allowing for more accurate staging of the disease as reviewed by Drs. Bhatt and Dogra. Compared to a decade ago, we have made significant progress in understanding the molecular biology of lung cancer and the potential therapeutic targets in this disease, none of which would be possible without the untiring efforts of researchers and cooperation of the patients and their families. Kishan J. Pandya Julie R. Brahmer Manuel Hidalgo

Contents

Preface . . . . iii Contributors . . . . vii 1. Molecular Biology of Lung Cancer as the Basis for Targeted Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 Oliver Gautschi, Philip C. Mack, Jim Heighway, Paul H. Gumerlock, and David R. Gandara 2. Early Clinical Trial Design Issues: Patient Populations, End Points, and Barriers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25 Janet E. Dancey 3. Antiangiogenic Therapy for Lung Cancer: Small-Molecule Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45 Nithya Ramnath and Alex A. Adjei 4. Antiangiogenic Therapy for Lung Cancer: Antibodies and Other Novel Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73 Sarita Dubey and Ravi Salgia 5. Epidermal Growth Factor Receptor Inhibition in Non–Small Cell Lung Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81 Antonio Jimeno and Manuel Hidalgo 6. Epidermal Growth Factor Receptor Targeted Therapy— Markers of Sensitivity and Response . . . . . . . . . . . . . . . . . . . . . . . . 97 Rafal Dziadziuszko, Barbara Szostakiewicz, and Fred R. Hirsch v

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Contents

7. Other Novel Targeted Therapies in Lung Cancer . . . . . . . . . . . . . 123 Kyriakos P. Papadopoulos and Anthony W. Tolcher 8. Lung Cancer Vaccines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149 Cheryl Ho, Oliver Gautschi, Primo N. Lara, David R. Gandara, and Angela M. Davies 9. Advances in Chemoradiation Treatment of Locoregionally Advanced Non–Small Cell Lung Cancer . . . . . . . . . . . . . . . . . . . . 175 Michael T. Milano and Yuhchyau Chen 10. Advances in the Treatment of Brain Metastases . . . . . . . . . . . . . . 207 Malika L. Siker and Minesh P. Mehta 11. Recent Advances in Imaging for Lung Cancer . . . . . . . . . . . . . . . 231 Shweta Bhatt, Kristopher M. Skwarski, and Vikram S. Dogra Index . . . . 257

Contributors

Alex A. Adjei

Roswell Park Cancer Institute, Buffalo, New York, U.S.A.

Shweta Bhatt Department of Imaging Sciences, University of Rochester School of Medicine and Dentistry, Rochester, New York, U.S.A. Yuhchyau Chen Department of Radiation Oncology, University of Rochester School of Medicine and Dentistry, Rochester, New York, U.S.A. Janet E. Dancey Division of Cancer Treatment and Diagnosis, National Cancer Institute, Rockville, Maryland, U.S.A. Angela M. Davies California, U.S.A.

University of California Davis Cancer Center, Sacramento,

Vikram S. Dogra Department of Imaging Sciences, University of Rochester School of Medicine and Dentistry, Rochester, New York, U.S.A. Sarita Dubey Division of Hematology/Oncology, University of California– San Francisco, San Francisco, California, U.S.A. Rafal Dziadziuszko Division of Medical Oncology, Department of Medicine, University of Colorado Health Sciences and Cancer Center, Aurora, Colorado, U.S.A., and Department of Oncology and Radiotherapy, Medical University of Gdan´sk, Gdan´sk, Poland David R. Gandara California, U.S.A.

University of California Davis Cancer Center, Sacramento,

Oliver Gautschi University of California Davis Cancer Center, Sacramento, California, U.S.A. Paul H. Gumerlock University of California Davis Cancer Center, Sacramento, California, U.S.A. vii

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Contributors

Jim Heighway Cancer Communications, Northwich, U.K. Manuel Hidalgo Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University School of Medicine, Baltimore, Maryland, U.S.A. Fred R. Hirsch Division of Medical Oncology, Department of Medicine, University of Colorado Health Sciences and Cancer Center, Aurora, Colorado, U.S.A. Cheryl Ho Division of Medical Oncology, British Columbia Cancer Agency, Vancouver, British Columbia, Canada Antonio Jimeno Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University School of Medicine, Baltimore, Maryland, U.S.A. Primo N. Lara University of California Davis Cancer Center, Sacramento, California, U.S.A. Philip C. Mack University of California Davis Cancer Center, Sacramento, California, U.S.A. Minesh P. Mehta Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, U.S.A. Michael T. Milano Department of Radiation Oncology, University of Rochester School of Medicine and Dentistry, Rochester, New York, U.S.A. Kyriakos P. Papadopoulos South Texas Accelerated Research Therapeutics, Division of Medical Oncology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, U.S.A. Nithya Ramnath Roswell Park Cancer Institute, Buffalo, New York, U.S.A. Ravi Salgia Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, Illinois, U.S.A. Malika L. Siker Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, U.S.A. Kristopher M. Skwarski Department of Respiratory Medicine, Royal Infirmary of Edinburgh, Edinburgh, Scotland, U.K. Barbara Szostakiewicz Department of Oncology and Radiotherapy, Medical University of Gdan´sk, Gdan´sk, Poland Anthony W. Tolcher South Texas Accelerated Research Therapeutics, Division of Medical Oncology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, U.S.A.

1 Molecular Biology of Lung Cancer as the Basis for Targeted Therapy Oliver Gautschi and Philip C. Mack University of California Davis Cancer Center, Sacramento, California, U.S.A.

Jim Heighway Cancer Communications, Northwich, U.K.

Paul H. Gumerlock and David R. Gandara University of California Davis Cancer Center, Sacramento, California, U.S.A.

INTRODUCTION Here we present recent advances in the molecular biology of lung cancer. This knowledge contributes to our understanding of the mechanisms of carcinogenesis, cancer progression, and metastasis and is essential for the subsequent development of new therapies targeted against disease-relevant genetic pathways. These findings thus provide the background for the following chapters on specific therapeutic approaches. The current state of knowledge regarding the molecular biology of lung cancer at the level of DNA, chromatin, RNA, and protein is summarized, along with the implications of large-scale analysis, biomarker development, and histopathology. Tumor immunology and angiogenesis are discussed in other chapters in this book.

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Gautschi et al.

GENETIC ALTERATIONS IN LUNG CANCER In the beginning of the 20th century, Hansemann and Boveri hypothesized that cancer is the result of genetic lesions (1). Today, we know that the epidemiology of lung cancer is strongly associated with environmental genotoxins, but our understanding of the biological implications of critical genetic alterations is still incomplete. Exposure to cigarette smoke is associated with approximately 90% of lung cancers (2). Cigarette smoke contains more than 50 different carcinogens that induce alterations in a large number of genes controlling the homeostasis of normal alveolar and bronchial cells (3). With the use of cytogenetics, comparative genomic hybridization, and allelotyping, a wide array of genetic changes have been discovered in cancer. As discussed here and as for other cancers, alterations of proto-oncogenes, tumor suppressor genes (TSGs), and chromosome telomeres are particularly important in the etiology and progression of lung cancer. Proto-oncogenes are genes that contribute to malignant transformation when mutationally activated or overexpressed. In 1917, Rous reported that sarcoma in chickens could be caused by a transmissible agent. This observation led to the discovery of the Rous sarcoma virus and the subsequent isolation of v-Src, the transforming component of the viral genome and the first known oncogene. A human gene with homology to v-Src (SRC) was subsequently identified, and in 1980 Hunter and Sefton found that v-Src encodes a mutant kinase, which is constitutively active, thereby transforming cells (4). These and other studies demonstrated that a range of viral oncogenes had related normal counterparts in mammalian genomes. In view of the potential for such sequences to cause malignancy when misregulated, they were termed proto-oncogenes. The human homologue SRC was initially thought to be a relatively weak protooncogene, but recent data indicate that SRC kinase is an important regulator of migration, proliferation, survival, angiogenesis, and inflammation in normal and cancer cells (5). Potential clinical implications of these findings in lung cancer are now being explored in clinical trials with small molecule inhibitors of SRC kinase (6). Proto-oncogenes that have been associated with lung cancer include MYC, KRAS, epidermal growth factor receptor (EGFR), HER2, and cyclin D1 (CCND1) (Table 1) (7). The MYC oncogene was isolated in the early 1980s from a retrovirus causing myelocytomatosis and carcinoma in chickens. Human MYC family genes were subsequently found to be activated in Burkitt lymphoma (MYC, translocation), neuroblastoma (MYCN, amplification), and lung cancer (MYCL, amplification). Amplification of MYC family proto-oncogenes is found in almost all small-cell lung cancers (SCLC) and is reported to confer an aggressive, resistant phenotype (9). MYC genes encode transcription factors, which dimerize with the cofactor Max and induce transcription of genes involved in cell cycle progression. MYC/Max dimers can also repress the transcription of genes that lead to cell cycle arrest following DNA damage such as cyclin-dependent kinase (CDK) inhibitor 2A (CDKN2A). Several strategies are being pursued to target MYC in

Molecular Biology of Lung Cancer Table 1 Gene MYC MYCN MYCL KRAS HRAS NRAS ERBB2 EGFR

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Activated Proto-oncogenes in Lung Cancer Chromosome

Mode of activation

8q24 2p24 1p34 12p12 11p15 1p13 17q12 7p11.2

Amplification Amplification Amplification Mutation Mutation Mutation Amplification Mutation/amplification

Frequency in SCLC (%) 90 25 25