Paclitaxel Plus Bevacizumab in Patients with Chemosensitive Relapsed Small Cell Lung Cancer: A Safety, Feasibility, and Efficacy Study from the Hoosier Oncology Group BRIEF REPORT Paclitaxel Plus Bevacizumab in Patients with Chemosensitive Relapsed Small Cell Lung Cancer A Safety, Feasibility, and Efficacy Study from the Hoosier Oncology Group Shadia Jalal, MD,* Pablo Bedano, MD,† Lawrence Einhorn, MD,* Sumeet Bhatia, MD,‡ Rafat Ansari, MD,§ Naftali Bechar, MD,§� Karuna Koneru, MD,¶ Ramaswamy Govindan, MD,# Jingwei Wu, MS,** Menggang Yu, PhD,** Bryan Schneider, MD,* and Nasser Hanna,MD* Introduction: Bevacizumab when combined with carboplatin and paclitaxel improves response rates (RRs) and overall survival in patients with advanced non-small cell lung cancer. Paclitaxel has single-agent activity in relapsed small cell lung cancer (SCLC). Angiogenesis seems to play an important role in the pathogenesis of SCLC. This study evaluated the safety and efficacy of paclitaxel plus bevacizumab in patients with chemosensitive relapsed SCLC. Methods: Patients with relapsed chemosensitive SCLC with an Eastern Cooperative Oncology Group performance status of 0 to 1 were eligible. They received paclitaxel 90 mg/m2 intravenously on days 1, 8, and 15. Bevacizumab was administered at 10 mg/kg intravenously on days 1 and 15. Cycles were every 28 days. The primary endpoint was progression-free survival (PFS). Secondary endpoints included RRs, toxicity, and overall survival. Correlative studies evaluated vascular endothelial growth factor polymorphisms. Results: Thirty-four patients were enrolled in the study. Median age was 66.5 (range, 38 – 88) years, male:female: 61.8%:38.2%, Eastern Cooperative Oncology Group performance status 0:1 47.1%:52.9%. Median progression-free survival was 14.7 weeks (equivalent to historical controls). Median survival time was 30 weeks. The overall RR was 18.1%. Stable disease rate was 39.3%, and 45.4% of patients had progressive disease. No unexpected toxicities were noted, and grade 3/4 toxicities were limited to neutropenia, fatigue, and dyspnea. None of the vascular endothelial growth factor poly- morphisms evaluated were significantly associated with response. Conclusions: The addition of bevacizumab to paclitaxel does not improve outcomes in relapsed chemosensitive SCLC. Key Words: Relapsed small cell, Paclitaxel, Bevacizumab. (J Thorac Oncol. 2010;5: 2008–2011) Small cell lung cancer (SCLC) accounts for 13 to 15% oflung cancers with the majority of patients ultimately succumbing to their disease.1 The majority of patients are diagnosed with extensive disease at presentation and are treated with platinum-based therapy. Depending on the dura- tion of response to platinum-based therapy, patients are described as having chemosensitive or chemorefractory dis- ease. Those with chemosensitive disease, typically defined as relapsing more than 60 to 90 days after completion of platinum-based therapy, frequently benefit from further che- motherapy at the time of disease progression. Multiple agents have activity in the second-line setting, but responses are typically brief (2– 4 months), and survival times are short (median, 6 months). Paclitaxel also has single-agent activity in chemotherapy-naive patients with SCLC with a response rate (RR) of 30 to 50%.2,3 In addition, paclitaxel is active in a chemorefractory population with SCLC.4 Bevacizumab (Avastin, Genentech, South San Fran- cisco, CA) is a recombinant vascular endothelial growth factor (VEGF) monoclonal antibody that was included in the first-line treatment paradigm of advanced non-small cell lung cancer after its combination with carboplatin/paclitaxel in the Eastern Cooperative Oncology Group (ECOG) 4599 study. This trial showed an improvement in RR and overall survival (OS) compared with chemotherapy alone.5 SCLC is a tumor with early hematogenous spread. Tumor microvessel count and VEGF expression were prog- *Indiana University Melvin and Bren Simon Cancer Center, Indianapolis; †Clarian Hematology/Oncology, Indianapolis; ‡Community Regional Cancer Center, Indianapolis; §Northern Indiana Cancer Research Con- sortium, South Bend; �Community Oncology Center, Kokomo; ¶Cancer Care Center of Southern Indiana, Bloomington, Indiana; #Washington University Medical Center, Siteman Cancer Center, St. Louis, Missouri; and Division of Biostatistics, Indiana University School of Medicine, Indianapolis, Indiana. Disclosure: Dr. Einhorn holds stock in Amgen and GlaxoSmith Kline. Dr. Bhatia was paid to be on the advisory board of Genentech. Dr. Govindan has served as an advisor to Genentech, Lilly Oncology, Astrazeneca, GSK, and Boehringer Ingelheim Pharma. Dr. Schneider is on the advi- sory board for Genentech, has previously received research grant for biomarker discovery from Genentech, and has a US patent for VEGF single nucleotide polymorphisms the rights of which belong to Genen- tech. Dr. Hanna has disclosed that his institution and the Hoosier Oncology Group received a grant from Genentech to conduct the study. Address for correspondence: Shadia Jalal, MD, IU Simon Cancer Center, 535 Barnhill Drive, RT 473, Indianapolis, IN 46202. E-mail: sjalal@iupui.edu Copyright © 2010 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/10/0512-2008 Journal of Thoracic Oncology • Volume 5, Number 12, December 20102008 nostic factors and correlated with worse survival (p � 0.001 and p � 0.0008, respectively) in patients with SCLC who underwent pneumonectomies or lobectomies.6 VEGF was also reported to be expressed in 81% of patients with SCLC.7 Therefore, we initiated this study evaluating the safety and efficacy of the combination of paclitaxel and bevaci- zumab in relapsed chemosensitive SCLC. We used the dosing schedule evaluated as initial treatment in patients with met- astatic breast cancer in which the combination resulted in an improvement in RR (36.9% versus 21.2%, p � 0.001) and progression-free survival (PFS; 11.8 versus 5.9 months, haz- ard ratio � 0.6, p � 0.001) over paclitaxel alone.8 PATIENTS AND METHODS Eligibility criteria included age �18 years, histo- logic or cytologic diagnosis of SCLC, prior treatment with at least one platinum-containing regimen, ECOG perfor- mance status 0 to 1, and measurable disease by Response Evaluation Criteria in Solid Tumor (RECIST) Group re- sponse criteria. All patients had chemosensitive disease defined as relapse more than 60 days after completing initial treatment. Adequate hematologic, renal, and liver function at baseline were required. No therapies were allowed within 3 weeks of registration. Patients were excluded if they had evidence of brain metastases within 42 days of registration. All patients provided written informed consent before enrolling in the study. Local institutional review boards approved the protocol. Treatment Plan Patients received 90 mg/m2 of paclitaxel as a 1-hour intravenous infusion on days 1, 8, and 15 and bevacizumab at 10 mg/kg intravenously on days 1 and 15. Cycles were repeated every 28 days. Patients were premedicated before paclitaxel per package insert. Bevacizumab was administered after the completion of paclitaxel on day 1 of cycle 1. After 4 to 6 cycles of treatment with the combination, patients were allowed to continue with bevacizumab alone as maintenance therapy until disease progression or intolerable side effects. Statistical Analysis The primary endpoint of the study was PFS defined as the interval from the start of therapy until disease progression or death. Secondary endpoints included RR as defined by the Response Evaluation Criteria in Solid Tumor criteria and OS time defined as time from initiation of first cycle to death. Other secondary endpoints included determination of adverse events, their severity, and all grade 3 and grade 4 toxicities. The median PFS with historical controls (topotecan) is 14 weeks. With a total number of 34 patients, this study had 91% power and � � 5%, to detect an improvement in PFS to 24 weeks. Laboratory Correlates Correlative studies involved evaluation of VEGF polymorphisms and their correlation with RR. Fisher’s exact test was used to correlate VEGF polymorphisms with response data. Blood samples were collected in 6-mL lavender-top tubes from patients agreeable to laboratory correlatives. The following VEGF polymorphisms were evaluated: �936 C/T, �634 G/C, �2578 C/A, �1154 G/A, and �460 C/T. These specific polymorphisms were selected because of their known impact on modulating angiogenesis. Polymorphisms were assessed using standard polymerase chain-restriction frag- ment length polymorphism methods that are previously es- tablished and Taqman-based assays.9 RESULTS Between April 26, 2006, and January 11, 2007, 34 patients were enrolled in the study. Baseline characteristics are summarized in Table 1. Treatment Administered (n � 33) The median number of cycles received on trial was 3 (range, 1–9). Approximately 60% of patients were able to receive the study regimen without dose modifications. Fifty percent of the patients required no dose delays. Only two patients continued on the maintenance bevacizumab phase after six cycles of paclitaxel plus bevacizumab. Efficacy Response results are available for 33 patients because one patient never received treatment. One complete response (CR) was observed, five patients achieved a partial response (PR) (15.1%) for an overall RR of 18.1%. Fifteen patients progressed (45.4%), and stable disease was noted in 13 patients (39.3%). The median PFS was 14.7 weeks (95% confidence interval � 7–15.7), and the median survival time (MST) was 30 weeks (95% confidence interval � 18 – 48). TABLE 1. Baseline Characteristics (n � 34) Characteristics n � 34 Age (yr) Median 66.5 Range 38–88 Sex, n (%) Male 21 (61.8) Female 13 (38.2) ECOG PS 0 16 (47.1) 1 18 (52.9) Smoking history, n (%) Current 12 (35.3) Former 20 (58.8) Never 2 (5.9) Prior treatment, n (%) 1. Chemotherapy 29 (85.3) 2. Chemotherapy 5 (14.7) Radiotherapy 18 (31) Median number of days from previous regimen to registration (range) 142 (35–557) ECOG PS, Eastern cooperative oncology group performance status. Journal of Thoracic Oncology • Volume 5, Number 12, December 2010 Paclitaxel Plus Bevacizumab in Patients with SCLC Copyright © 2010 by the International Association for the Study of Lung Cancer 2009 Safety/Toxicity Toxicities noted in �10% of patients (n � 34) are presented in Tables 2 and 3. No unexpected toxicities were observed with the combination. Grade 1 pulmonary hemor- rhage was noted in one patient. Three patients had grade 1 to grade 2 proteinuria. There were no febrile neutropenia epi- sodes and no treatment-related deaths. Laboratory Correlative Results Data were available for 30 patients to assess VEGF polymorphisms and association with response. The frequen- cies of the various VEGF polymorphisms in different patient response groups are presented in Table 4. No associations were statistically significant, although the association of VEGF 1154GA with response approached statistical signifi- cance (p � 0.0677). DISCUSSION The addition of bevacizumab to paclitaxel does not seem to improve PFS in patients with chemosensitive re- lapsed SCLC. The median PFS reported with this combina- tion is similar to that reported with topotecan. In addition, the RR of 18.1% is similar to that of other regimens, and the MST was 7.5 months. The regimen seems safe, and no unexpected toxicities were observed. Our study yielded comparable results with another phase II study, which combined topotecan with bevaci- zumab.10 That trial included both chemosensitive and che- morefractory patients, was associated with more grade 3 to grade 4 toxicities, and reported a MST and PFS of only 32 and 18.4 weeks, respectively. Other studies have evaluated bevacizumab combined with chemotherapy in previously untreated patients with SCLC. ECOG conducted a phase II trial that evaluated the addition of bevacizumab to cisplatin and etoposide. The combination was tolerable with no unexpected toxicities, but efficacy was not substantially different than expected with cisplatin plus etoposide alone.11 The Cancer and Leukemia Group B evaluated the combination of cisplatin and irinote- can plus bevacizumab in 68 untreated patients with extensive stage SCLC.12 Median PFS was 7.1 months, and MST was 11.7 months. These results compared favorably with out- comes from other trials, but the study failed to reach its primary endpoint of improving survival times compared with historical controls.13 The Sara Cannon group evaluated bev- acizumab combined with carboplatin and irinotecan in a similar patient population. The median time to disease pro- gression was 9.1 months, and MST was 12.1 months.14 Nevertheless, this regimen was associated with a significant incidence of grade 3 or more diarrhea and fatigue. Collectively, this data suggest that bevacizumab is unlikely to substantially improve outcomes in unselected patients with SCLC. Our study also investigated whether subgroups of patients with certain VEGF polymorphisms may preferentially benefit from bevacizumab. Schneider et al.15 were the first to describe VEGF polymorphisms that correlate with efficacy and toxicity with bevacizumab in patients with metastatic breast cancer. In their analysis, TABLE 2. Hematologic Toxicities (n � 34) Toxicity Any Grade, n (%) Grades 3–4, n (%) Hematologic Neutropenia 9 (26) 6 (17.6) Febrile neutropenia 0 0 Anemia 12 (35) 0 Thrombocytopenia 6 (17.6) 0 TABLE 3. Nonhematologic Toxicities (n � 34) Toxicity Any Grade, n (%) Grades 3–4, n (%) Fatigue 29 (85) 9 (26) Dyspnea 20 (58.8) 5 (14.7) Hypertension 9 (26.4) 0 Neuropathy 15 (44) 0 Nausea 17 (50) 0 Vomiting 4 (11.7) 0 Liver enzyme abnormalities Elevation in alkaline phosphatase 5 (14.7) 0 Elevation in AST 5 (14.7) 0 Diarrhea 12 (35) 0 Constipation 17 (50) 0 Anorexia 19 (55.8) 0 Mucositis 6 (17.6) 0 Hyperglycemia 5 (14.7) 0 Headache 11 (32.3) 0 AST, aspartate aminotransferase. TABLE 4. Frequencies of VEGF Polymorphisms and Correlation with Responses (n � 30) VEGF Polymorphism CR/PR (%) PD (%) SD (%) VEGF-2578 AA 2 (6.6) 3 (10) 1 (3.3) CA 3 (10) 5 (16.7) 5 (16.7) CC 0 (0) 2 (6.6) 6 (20) VEGF-1154 AA 0 (0) 1 (3.3) 0 (0) GA 5 (16.7) 6 (20) 4 (13.3) GG 0 (0) 6 (20) 8 (26.6) VEGF 936 CC 3 (10) 10 (33.3) 10 (33.3) CT 1 (3.3) 3 (10) 1 (3.3) TT 1 (3.3) 0 (0) 1 (3.3) VEGF-634 CC 0 (0) 4 (13.3) 2 (6.6) GC 3 (10) 2 (6.6) 4 (13.3) GG 2 (6.6) 7 (23.3) 6 (20) VEGF-1498 CC 2 (6.6) 3 (10) 1 (3.3) CT 3 (10) 6 (20) 5 (16.7) TT 0 (0) 4 (13.3) 6 (20) VEGF, vascular endothelial growth factor; SD, stable disease; PD, progressive disease; CR, complete response; PR, partial response. Jalal et al. Journal of Thoracic Oncology • Volume 5, Number 12, December 2010 Copyright © 2010 by the International Association for the Study of Lung Cancer2010 VEGF-2578 AA and VEGF-1154 AA genotypes correlated with a superior median OS with a bevacizumab-containing regimen in advanced breast cancer. In this analysis, VEGF- 634 CC and VEGF-1498 TT genotypes were associated with a decreased risk of significant hypertension with bevaci- zumab. This study is the first to evaluate VEGF polymor- phisms in SCLC. We were unable to identify a VEGF polymorphism that was associated with response. Neverthe- less, interpretation of VEGF polymorphisms and their impact on response in our study should be viewed with caution due to the small patient number, the even smaller patient number in different response subgroups, and the lack of grade 3 to grade 4 hypertension, a potential surrogate for benefit with VEGF-directed therapy. Furthermore, multiple association tests were performed; therefore, the traditional p value less than 0.05 for statistical significance may not be valid. Patients with relapsed SCLC continue to be in need of improved therapy options. Continued understanding of the complex biology of this smoking-associated illness confirms the differences between SCLC and non-small cell lung cancer where multiple agents of benefit in the latter are ineffective in SCLC. Chemotherapy remains the cornerstone of therapy for patients with SCLC. Novel therapies and strategies in the treatment of this disease continue to be explored. ACKNOWLEDGMENTS Supported by Genentech. REFERENCES 1. Govindan R, Page N, Morgensztern D, et al. Changing epidemiology of small cell lung cancer in the United States over the last 30 years: analysis of the surveillance, epidemiologic, and end results database. J Clin Oncol 2006;24:4539 – 4544. 2. Ettinger DS, Finkelstein DM, Sarma RP, et al. Phase II study of paclitaxel in patients with extensive-disease small-cell lung cancer: an Eastern Cooperative Oncology Group study. J Clin Oncol 1995;13: 1430 –1435. 3. Kirschling RJ, Grill JP, Marks RS, et al. Paclitaxel and G-CSF in previously untreated patients with extensive stage small-cell lung can- cer: a phase II study of the North Central Cancer Treatment Group. Am J Clin Oncol 1999;22:517–522. 4. Smit EF, Fokkema E, Biesma B, et al. A phase II study of paclitaxel in heavily pretreated patients with small-cell lung cancer. Br J Cancer 1998;77:347–351. 5. Sandler A, Gray R, Perry MC, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small cell lung cancer. N Engl J Med 2006;355: 2542–2550. 6. Lucci M, Mussi A, Fontanini G, et al. Small cell lung carcinoma (SCLC): the angiogenic phenomenon. Eur J Cardiothorac Surg 2002; 21:1105–1110. 7. Dowell JE, Amirkhan RH, Lai WS, et al. Survival in small cell lung cancer is independent of tumor expression of VEGF and COX-2. Anticancer Res 2004;24:2367–2373. 8. Miller K, Wang M, Gralow J, et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med 2007;357: 2666 –2676. 9. Schneider BP, Radovich M, Sledge GW, et al. Association of polymor- phisms of angiogenesis genes with breast cancer. Breast Cancer Res Treat 2008;111:157–163. 10. Waterhouse DM, Morgan SK, Spigel DR, et al. Phase II study of oral topotecan plus bevacizumab (topo-bev) for second line treatment of small cell lung cancer (SCLC). J Clin Oncol 2010:Abstract 7055. 11. Horn L, Dahlberg SE, Sandler AB, et al. Phase II study of cisplatin plus etoposide and bevacizumab for previously untreated, extensive-stage small cell lung cancer: Eastern Cooperative Oncology Group Study E3501. J Clin Oncol 2009;27:6008 – 6011. 12. Ready N, Dudeck AZ, Wan XF, et al. CALGB30306:A phase II study of cisplatin (C),irinotecan (I) and bevacizumab (B) for untreated extensive stage small cell lung cancer (ES-SCLC). J Clin Oncol 2007;25:Abstract 7564. 13. Noda K, Nishiwaki Y, Kawahara M, et al. Irinotecan plus cisplatin compared with etoposide plus cisplatin for extensive small cell lung cancer. 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Journal of Thoracic Oncology • Volume 5, Number 12, December 2010 Paclitaxel Plus Bevacizumab in Patients with SCLC Copyright © 2010 by the International Association for the Study of Lung Cancer 2011 Paclitaxel Plus Bevacizumab in Patients with Chemosensitive Relapsed Small Cell Lung Cancer: A Safety, Feasibility, and Efficacy Study from the Hoosier Oncology Group PATIENTS AND METHODS Treatment Plan Statistical Analysis Laboratory Correlates Laboratory Correlates RESULTS Treatment Administered (n = 33) Efficacy Safety/Toxicity Laboratory Correlative Results DISCUSSION ACKNOWLEDGMENTS REFERENCES