Overall survival with cisplatin-gemcitabine and bevacizumab or placebo as first-line therapy for nonsquamous non-small-cell lung cancer: results from a randomised phase III trial (AVAiL)

M Reck, J von Pawel, P Zatloukal, R Ramlau, V Gorbounova, V Hirsh, N Leighl, J Mezger, V Archer, N Moore, C Manegold, BO17704 Study Group, M Reck, J von Pawel, P Zatloukal, R Ramlau, V Gorbounova, V Hirsh, N Leighl, J Mezger, V Archer, N Moore, C Manegold, BO17704 Study Group

Abstract

Background: Bevacizumab, the anti-vascular endothelial growth factor agent, provides clinical benefit when combined with platinum-based chemotherapy in first-line advanced non-small-cell lung cancer. We report the final overall survival (OS) analysis from the phase III AVAiL trial.

Patients and methods: Patients (n = 1043) received cisplatin 80 mg/m(2) and gemcitabine 1250 mg/m(2) for up to six cycles plus bevacizumab 7.5 mg/kg (n = 345), bevacizumab 15 mg/kg (n = 351) or placebo (n = 347) every 3 weeks until progression. Primary end point was progression-free survival (PFS); OS was a secondary end point.

Results: Significant PFS prolongation with bevacizumab compared with placebo was maintained with longer follow-up {hazard ratio (HR) [95% confidence interval (CI)] 0.75 (0.64-0.87), P = 0.0003 and 0.85 (0.73-1.00), P = 0.0456} for the 7.5 and 15 mg/kg groups, respectively. Median OS was >13 months in all treatment groups; nevertheless, OS was not significantly increased with bevacizumab [HR (95% CI) 0.93 (0.78-1.11), P = 0.420 and 1.03 (0.86-1.23), P = 0.761] for the 7.5 and 15 mg/kg groups, respectively, versus placebo. Most patients ( approximately 62%) received multiple lines of poststudy treatment. Updated safety results are consistent with those previously reported.

Conclusions: Final analysis of AVAiL confirms the efficacy of bevacizumab when combined with cisplatin-gemcitabine. The PFS benefit did not translate into a significant OS benefit, possibly due to high use of efficacious second-line therapies.

Trial registration: ClinicalTrials.gov NCT00806923.

Figures

Figure 1.
Figure 1.
Plots of Kaplan–Meier estimates for OS (ITT population) for the bevacizumab 7.5 mg/kg group and the bevacizumab 15 mg/kg group relative to placebo, together with time to event data for the OS analysis in the ITT and PP populations (A) and for the subgroup of patients who did not receive poststudy therapy (B). In panel b, data from the two bevacizumab groups have been pooled. CG, cisplatin–gemcitabine; CI, confidence interval; HR, hazard ratio; ITT, intent-to-treat; OS, overall survival; PP, per protocol.
Figure 2.
Figure 2.
Forest plots of HRs for OS by subgroup for each bevacizumab group relative to placebo (ITT population). CG, cisplatin–gemcitabine; ECOG, Eastern Cooperative Oncology Group.

References

    1. Smit EF, van Meerbeeck JP, Lianes P, et al. Three-arm randomized study of two cisplatin-based regimens and paclitaxel plus gemcitabine in advanced non-small-cell lung cancer: a phase III trial of the European Organization for Research and Treatment of Cancer Lung Cancer Group—EORTC 08975. J Clin Oncol. 2003;21:3909–3917.
    1. Le Chevalier T, Scagliotti G, Natale R, et al. Efficacy of gemcitabine plus platinum chemotherapy compared with other platinum containing regimens in advanced non-small-cell lung cancer: a meta-analysis of survival outcomes. Lung Cancer. 2005;47:69–80.
    1. Ferrara N, Hillan KJ, Gerber HP, et al. Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nat Rev Drug Discov. 2004;3:391–400.
    1. Presta LG, Chen H, O'Connor SJ, et al. Humanization of an anti-vascular endothelial growth factor monoclonal antibody for the therapy of solid tumors and other disorders. Cancer Res. 1997;57:4593–4599.
    1. Hurwitz H, Fehrenbacher L, Novotny W. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350:2335–2342.
    1. Giantonio BJ, Catalano PJ, Meropol NJ, et al. Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol. 2007;25:1539–1544.
    1. Miller KD, Wang M, Gralow J, et al. A randomized phase III trial of paclitaxel versus paclitaxel plus bevacizumab as first-line therapy for locally recurrent or metastatic breast cancer: a trial coordinated by the Eastern Cooperative Oncology Group (E2100) Breast Cancer Res Treat. 2005;94:S6. (Abstr 3)
    1. Hainsworth JD, Sosman JA, Spigel DR, et al. Treatment of metastatic renal cell carcinoma with a combination of bevacizumab and erlotinib. J Clin Oncol. 2005;23:7889–7896.
    1. 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.
    1. Reck M, von Pawel J, Zatloukal P, et al. Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non-small cell lung cancer: AVAiL. J Clin Oncol. 2009;27:1227–1234.
    1. Manegold C, von Pawel J, Zatloukal P, et al. BO17704 (AVAiL): a phase III randomised study of first-line bevacizumab combined with cisplatin/gemcitabine (CG) in patients (pts) with advanced or recurrent non-squamous, non-small cell lung cancer (NSCLC) Ann Oncol. 2008;19(Suppl 8):viii1. (Abstr LBA1)
    1. Scagliotti GV, Parikh P, von Pawel J, et al. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol. 2008;26:3543–3551.
    1. Eberhardt W, von Pawel J, Vynnychenko I, et al. FLEX: cetuximab in combination with platinum-based chemotherapy (CT) vs CT alone improves survival in 1st-line treatment of patients with advanced non-small cell lung cancer (NSCLC) Ann Oncol. 2008;19(Suppl 8):viii45. (Abstr 73O)
    1. Shaked Y, Henke E, Roodhart JM, et al. Rapid chemotherapy-induced acute endothelial progenitor cell mobilization: implications for antiangiogenic drugs as chemosensitizing agents. Cancer Cell. 2008;14:263–273.
    1. Hainsworth J, Lin M, O'Connor P, et al. A phase III, multicenter, placebo-controlled, double-blind, randomized, clinical trial to evaluate the efficacy of bevacizumab (Avastin) in combination with erlotinib (Tarceva) compared with erlotinib alone for treatment of advanced non-small cell lung cancer (NSCLC) after failure of standard first line chemotherapy (BETA) J Thorac Oncol. 2008;3(Suppl 4):S302.
    1. US Department of Health and Human Services. Food and Drug Administration. Guidance for Industry: Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics. (1 February 2010, date last accessed)
    1. European Agency for the Evaluation of Medicinal Products. Guideline on the Evaluation of Anticancer Medicinal Products in Man. (1 February 2010, date last accessed)

Source: PubMed

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