Abstract S1-7: Phase III trial evaluating the addition of bevacizumab to endocrine therapy as first-line treatment for advanced breast cancer – First efficacy results from the LEA study.

Abstract

Abstract Background: Preclinical data (de la Haba J, AACR 2011) and retrospective clinical data (Mander P, Cancer 2003; Linderhol B, JCO 2000) suggest that high vascular endothelial growth factor (VEGF) levels in breast tumors are associated with a decreased response to endocrine therapy. We designed the randomized phase III LEA study of first-line bevacizumab in combination with hormone therapy in endocrine responsive advanced breast cancer patients to address the hypothesis that anti-VEGF treatment can prevent resistance to hormone therapy in these patients. Methods: A multicenter, bi-national, randomized, open label, phase III study investigated the addition of Bevacizumab (B) 15mg/kg every 3 weeks to an endocrine therapy (ET) with letrozole (2.5 mg/day) or fulvestrant (250mg/4 weeks) as first-line therapy in advanced breast cancer. Postmenopausal patients with HER2-negative and hormone-receptor-positive breast cancer were eligible and randomized in a 1:1 ratio after being stratified for prior adjuvant therapy with an aromatase inhibitor (AI); number of involved sites (one/multiple); measurable lesions (yes/no) and participating country (Spain/Germany). The primary objective was to compare progression-free survival (PFS) between treatment arms. Secondary objectives were overall survival, time to treatment failure, overall response rate, response duration, clinical benefit rate, and safety. In total, 344 patients (172 in each treatment arm) were needed to detect a hazard ratio of 0.69 (corresponding to a median PFS of 9 months in the ET arm and 13 months in the ET+B arm) with α=0.05 and β=0.2. With an expected drop-out rate of 10%, 378 patients were to be included. The efficacy analysis is pre-planned after 270 events. Results: From 11/2007 to 8/2011, 380 patients were randomized in Spain and Germany to ET (n = 189) or ET+B (n = 191), 342 patients received letrozole and 38 fulvestrant. Baseline characteristics were well balanced. Median age was 65 years (38–86) and 72% of patients had ECOG PS 0. Twelve patients (4%) entered the trial with locally advanced disease, 65% had measurable lesions, 63% had bone and 45% visceral metastasis. 76% of patients had both hormone receptor positive. 44% had adjuvant chemotherapy and 51% adjuvant endocrine therapy from which 36% of patients received adjuvant AI. Full safety data will be presented at ESMO this year. The main side effects (any grade, per patient, ET+B vs ET) were anemia 76% vs 44%, p < 0.001; fatigue 50% vs 31%, p = 0.001; hemorrhage 19% vs 2%, p < 0.001; hypertension 55% vs 12%, p < 0.001; proteinuria 21%vs 3%, p < 0.001; and thrombosis grade 3–4, 2.3% vs 0%, p = 0.057. Until June 2012, 226 PFS events have been observed. The current event rate holds out the expectation to have the 270 necessary events by August-2012. Conclusions: LEA is the first phase III study to explore the use of an anti-angiogenic drug in combination with endocrine therapy. The efficacy results will be presented at the meeting. First and second authors have contributed equally to this study Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr S1-7.