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

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.

Dual Inhibition of PI3K and mTOR Mitigates Compensatory AKT Activation and Improves Tamoxifen Response in Breast Cancer

“…Retrospective clinical data showed that decreasing VEGF level may restore sensitivity and improve efficacy to hormonal therapy (22). Phase III LEA study showed that there was a trend of longer progression-free survival in patients treated with bevacizumab and hormone therapy in HR-positive advanced breast cancer (23). Corroborating the data illustrated in Fig.…”

Targeting breast cancer through its microenvironment: Current status of preclinical and clinical research in finding relevant targets

“…Whether there is truly a benefit with bevacizumab for this subtype in the metastatic setting is currently being investigated (Table 1). Also, no additional value was found when bevacizumab was combined with either anti-HER2 or endocrine therapy in a subset of HER2 positive and ER positive MBC patients (Martin et al, 2012;Gianni et al, 2013). The negative BEATRICE, BETH and E5103 trials do not support a role for bevacizumab in the adjuvant treatment for TNBC, HER2 positive and HER2 negative patients (Miller et al, 2012;Cameron et al, 2013;Slamon et al, 2013).…”

A new era of improving progression-free survival with dual blockade in postmenopausal HR+, HER2− advanced breast cancer

“…Three completed phase 3 studies-Letrozole/Fulvestrant and Avastin (LEA) [19,23], Phase 3 Study of Temsirolimus with Letrozole or Letrozole Alone (HORIZON) [20], and Breast Cancer Trials of Oral Everolimus-2 (BOLERO-2) [21,24]-have evaluated a targeted agent (the anti-vascular endothelial growth factor antibody bevacizumab in LEA; the mTOR inhibitors temsirolimus in HORIZON and everolimus in BOLERO-2) in combination with endocrine therapy in postmenopausal women with HR + advanced breast cancer. Patients enrolled in the LEA study received bevacizumab plus either letrozole or fulvestrant, or letrozole or fulvestrant alone, as first-line therapy for HR + advanced breast cancer (N = 374).…”