JTO_5(9)1414-1423 - (Page 1)

For non-US Physicians only ORIGINAL ARTICLE Treatment Outcomes by Tumor Histology in Eastern Cooperative Group Study E4599 of Bevacizumab with Paclitaxel/Carboplatin for Advanced Non-small Cell Lung Cancer Alan Sandler, MD,* Jing Yi, PhD,† Suzanne Dahlberg, PhD,‡ Margaret M. Kolb, DrPH,† Lisa Wang, PhD,† Julie Hambleton, MD,† Joan Schiller, MD,§ and David H. Johnson, MD Introduction: The combination of paclitaxel/carboplatin (PC) and bevacizumab (B) was previously shown to extend overall survival (OS) in patients with advanced nonsquamous non-small cell lung cancer (NSCLC). An analysis of survival and safety outcomes based on histology is presented here. Methods: Patients with cytologically or histologically confirmed metastatic NSCLC were treated with PC B (PCB) or PC. Median OS for all patients was determined using Kaplan-Meier methodology. Hazard ratios (HRs) and 95% confidence intervals (CIs) were obtained using an unstratified Cox proportional hazards model. Histology-by-treatment interaction was tested with an unstratified multivariate Cox regression model. Results: A total of 444 patients were randomized to PC, and 434 patients were randomized to PCB (the intent-to-treat population). Median OS times were 10.3 and 12.3 months for PC and PCB, respectively, with an HR for PCB of 0.80 (95% CI: 0.69 – 0.93). A total of 68.8% of patients had adenocarcinoma histology; 18.9% had “not otherwise specified”; 5.5% had large cell undifferentiated; 2.6% had bronchoalveolar carcinoma; and 3.9% “other.” For ade*Division of Hematology/Oncology, Department of Medicine, Oregon Health & Science University, Portland, Oregon; †Genentech Inc., South San Francisco, California; ‡Department of Biostatistics, Dana-Farber Cancer Institute, Boston, Massachusetts; §Division of Hematology/Oncology, Department of Medicine, University of Texas Southwestern Medical Center, Dallas, Texas; and Division of Hematology/Oncology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Nashville, Tennessee. Disclosure: Alan Sandler, MD, received a grant for this study and serves as a consultant and on the advisory board for Genentech. Jing Yi, PhD, and her husband are employed by Genentech. Margaret M. Kolb, DrPH, serves as a paid consultant to Genentech. Lisa Wang, PhD, and Julie Hambleton, MD, are employed by and hold stock in Genentech. Joan Schiller, MD, serves on the advisory board for Genentech. The other authors declare no conflicts of interest. Address for correspondence: Alan Sandler, MD, Division of Hematology and Medical Oncology, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Mail Code: L586, Portland, OR 97239-3098. E-mail: sandlera@ohsu.edu Presented as an abstract (a portion of the tumor histology analysis described in this article) at the International Association of Lung Cancer Annual Meeting in Chicago, IL, 2008. Copyright © 2010 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/10/0509-1416 nocarcinoma, median OS was 10.3 months for PC treatment (n 302) and 14.2 months for PCB (n 300), HR 0.69 (95%CI: 0.58 – 0.83). Sample sizes for other specific histologic subtypes were too small for meaningful comparisons. Safety profiles among histologies were consistent with the overall safety profile, and there were no unexpected adverse event trends. Conclusions: Addition of B to PC is associated with increased survival in previously untreated patients with nonsquamous NSCLC. Adenocarcinoma was associated with an increased survival benefit of PCB treatment. Data for other histologies are inconclusive, primarily because of small patient sample sizes and large CIs. Key Words: Non-small cell lung cancer, Bevacizumab, Nonsquamous, Histology, Adenocarcinoma. (J Thorac Oncol. 2010;5: 1416–1423) t is estimated that 215,020 cases of lung cancer were newly diagnosed in 2008 and that more than 160,000 men and women died of the disease.1 Non-small cell lung cancer (NSCLC) accounts for more than 85% of all lung cancers.2 The recombinant, humanized monoclonal antibody bevacizumab (B; Avastin; Genentech, South San Francisco, CA) in combination with paclitaxel (P) and carboplatin (C) is approved by Food and Drug Administration for first-line treatment of patients with unresectable, locally advanced, recurrent or metastatic nonsquamous NSCLC.3– 6 B binds to a vascular endothelial growth factor, an essential endothelial cell mitogen and survival factor, and a key factor in tumorassociated angiogenesis. In a phase III randomized control trial conducted by Eastern Cooperative Oncology Group (ECOG), the median overall survival (OS) for patients with NSCLC receiving PC B (PCB) was 12.3 months, compared with 10.3 months for patients who received paclitaxel/ carboplatin (PC) alone.3 The median progression-free survival (PFS) time was 6.2 months for patients who received PCB, compared with 4.5 months for patients who received PC alone. The diagnosis of NSCLC comprises a number of histologies based primarily on pathologic or cytologic review of surgical specimens. The most common histologies are ade- I 1416 Journal of Thoracic Oncology • Volume 5, Number 9, September 2010

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JTO_5(9)1414-1423

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