Journal of Clinical Oncology

August 20, 2013

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VOLUME 31 ⅐ NUMBER 24 ⅐ AUGUST 20 2013 JOURNAL OF CLINICAL ONCOLOGY O R I G I N A L R E P O R T Randomized Phase III Trial of Maintenance Bevacizumab With or Without Pemetrexed After First-Line Induction With Bevacizumab, Cisplatin, and Pemetrexed in Advanced Nonsquamous Non–Small-Cell Lung Cancer: AVAPERL (MO22089) Fabrice Barlesi, Aix Marseille University– Assistance Publique Ho ˆpitaux de Marseille and Centre d'Investigation Clinique, Marseille; Arnaud Scherpereel, Ho ˆpital Calmette, Centre Hospitalier Re ´gional Universitaire de Lille, Lille, France; Achim Rittmeyer, Lungenfachklinik Immenhausen, Immenhausen, Germany; Antonio Pazzola, Ospedale Civile Santissima, Annunziata, Sassari, Italy; Neus Ferrer Tur, Hospital Son Lla `tzer, Palma de Majorca, Spain; Joo-Hang Kim, Yonsei University College of Medicine; Myung-Ju Ahn, Sungkyunkwan University School of Medicine, Seoul, South Korea; Joachim G.J.V. Aerts, Amphia Hospital, Breda, and Erasmus Medical Center, Rotterdam; Harry J.M. Groen, University Medical Center Groningen, Groningen, the Netherlands; Vera Gorbunova, N.N. Blokhin Cancer Research Centre of Russia, Moscow, Russia; Anders Vikstro Lungkliniken, Linko ¨m, ¨ping, Sweden; and Elaine K. Wong, Pablo Perez-Moreno, and Lada Mitchell, F. Hoffmann-La Roche, Basel, Switzerland. Published online ahead of print at on July 8, 2013. Written on behalf of AVAPERL study investigators. Support for this study and for third-party writing assistance was provided by F. Hoffmann-La Roche. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article. Clinical trial information: NCT00961415. Corresponding author: Fabrice Barlesi, MD, PhD, Sce Oncologie Multidisciplinaire et Innovations The ´rapeutiques, Ho ˆpital Nord– Chemin des Bourrely, 13915 Marseille Cedex 20, France; e-mail: fabrice.barlesi@ © 2013 by American Society of Clinical Oncology 0732-183X/13/3124-3004/$20.00 DOI: 10.1200/JCO.2012.42.3749 3004 Fabrice Barlesi, Arnaud Scherpereel, Achim Rittmeyer, Antonio Pazzola, Neus Ferrer Tur, Joo-Hang Kim, Myung-Ju Ahn, Joachim G.J.V. Aerts, Vera Gorbunova, Anders Vikstrom, Elaine K. Wong, ¨ Pablo Perez-Moreno, Lada Mitchell, and Harry J.M. Groen See accompanying article on page 2983; listen to the podcast by Dr West at A B S T R A C T Purpose Maintenance therapy is associated with improved survival in patients with non–small-cell lung cancer (NSCLC), but few studies have compared active agents in this setting. AVAPERL evaluated the safety and efficacy of bevacizumab with or without pemetrexed as continuation maintenance treatment. Patients and Methods Patients with advanced nonsquamous NSCLC received first-line bevacizumab 7.5 mg/kg, cisplatin 75 mg/m2, and pemetrexed 500 mg/m2 once every 3 weeks for four cycles. Those achieving response or stable disease were randomly assigned at a ratio of 1:1 to maintenance bevacizumab 7.5 mg/kg or bevacizumab 7.5 mg/kg plus pemetrexed 500 mg/m2 once every 3 weeks until disease progression or unacceptable toxicity. The primary end point was progression-free survival (PFS) after random assignment. Results In total, 376 patients received induction treatment, 71.9% achieved disease control, and 67.3% were randomly assigned to maintenance therapy, with 125 and 128 receiving single-agent bevacizumab and bevacizumab plus pemetrexed treatment, respectively. At a median follow-up of 8.1 months, PFS from random assignment was significantly improved in the bevacizumab plus pemetrexed arm (median, 3.7 v 7.4 months; hazard ratio, 0.48; 95% CI, 0.35 to 0.66; P Ͻ .001) per a stratified model. The PFS benefit extended across age, performance status, smoking history, and induction response (stable disease v partial response) subgroups. Any grade, grade Ն 3, and serious adverse events occurred more often with bevacizumab plus pemetrexed maintenance. No new safety signals were observed. Conclusion In an unselected population of patients with nonsquamous NSCLC who had achieved disease control with platinum-based chemotherapy plus bevacizumab, bevacizumab plus pemetrexed maintenance was associated with a significant PFS benefit compared with bevacizumab alone. The combination was well tolerated. J Clin Oncol 31:3004-3011. © 2013 by American Society of Clinical Oncology INTRODUCTION For patients with advanced or metastatic non– small-cell lung cancer (NSCLC), prognosis is poor, and 1-year survival rates are 30% to 40%.1 Therapy is palliative, and tumor response rates are between 25% and 35%.1 First-line cytotoxic combinations reached an apparent efficacy plateau more than a © 2013 by American Society of Clinical Oncology decade ago.2,3 Antiangiogenic therapy, which targets tumor vasculature rather than cancer cells,4 was anticipated to prolong survival in NSCLC. The phase III ECOG (Eastern Cooperative Oncology Group) 4599 study established bevacizumab, a monoclonal antibody against vascular endothelial growth factor A, with carboplatin plus paclitaxel induction followed by bevacizumab continuation maintenance

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