Feasibility Trial of Letrozole in Combination With Bevacizumab in Patients With Metastatic Breast Cancer

Abstract

Purpose Preclinical models suggest that the use of anti–vascular endothelial growth factor (anti-VEGF) therapy with antiestrogens may prevent or delay the development of endocrine therapy resistance. We therefore performed a feasibility study to evaluate the safety of letrozole plus bevacizumab in patients with hormone receptor–positive metastatic breast cancer (MBC). Methods Patients with locally advanced breast cancer or MBC were treated with the aromatase inhibitor (AI) letrozole (2.5 mg orally daily) and the anti-VEGF antibody bevacizumab (15 mg/kg intravenously every 3 weeks). The primary end point was safety, defined by grade 4 toxicity using the National Cancer Institute Common Toxicity Criteria, version 3.0. Secondary end points included response rate, clinical benefit rate, and progression-free survival (PFS). Prior nonsteroidal AIs (NSAIs) were permitted in the absence of progressive disease. Results Forty-three patients were treated. After a median of 13 cycles (range, 1 to 71 cycles), select treatment-related toxicities included hypertension (58%; grades 2 and 3 in 19% and 26%), proteinuria (67%; grades 2 and 3 in 14% and 19%), headache (51%; grades 2 and 3 in 16% and 7%), fatigue (74%; grades 2 and 3 in 19% and 2%), and joint pain (63%; grades 2 and 3 in 19% and 0%). Eighty-four percent of patients had at least stable disease on an NSAI, confounding efficacy results. Partial responses were seen in 9% of patients and stable disease ≥ 24 weeks was noted in 67%. Median PFS was 17.1 months. Conclusion Combination letrozole and bevacizumab was feasible with expected bevacizumab-related events of hypertension, headache, and proteinuria. Phase III proof-of-efficacy trials of endocrine therapy plus bevacizumab are in progress (Cancer and Leukemia Group B 40503).

Final overall survival results and effect of prolonged (≥1 year) first-line bevacizumab-containing therapy for metastatic breast cancer in the ATHENA trial

“…However, some investigators adopted this approach and it was considered by some to be a minor violation. The feasibility and efficacy of administering bevacizumab in combination with letrozole, anastrozole, or fulvestrant were recently reported [14,15], and concomitant endocrine therapy with bevacizumab could plausibly have influenced efficacy outcomes in ATHENA. The ongoing randomized phase III LEA trial in Spain and Germany is comparing letrozole or fulvestrant alone or in combination with bevacizumab in post-menopausal women with previously untreated HER2-negative LR/mBC (ML19802; NCT00545077).…”

Antiangiogenesis Therapy in Breast Cancer

“…Of the 43 patients evaluated, four patients had a partial response (PR) and 29 patients had stable disease (SD) for more than 24 weeks. Although the most common grade 3 side effects were hypertension and proteinuria (seen in 11 and 8 patients, respectively), overall the combination therapy of letrozole and bevacizumab appeared to be well tolerated [29]. Currently, a randomized, double-blind, placebo-controlled phase 3 trial of endocrine therapy alone or endocrine therapy plus bevacizumab (NSC 704865; IND 7921) is ongoing in patients with stage IIIB or IV hormone receptor-positive breast cancer to evaluate whether anti-VEGF therapy with bevacizumab can delay Ongoing the development of endocrine resistance and prolong PFS when added to first-line endocrine therapy.…”

Clinical Trials Combining Aromatase Inhibitors with Other Targeted Treatments

“…As several phase II studies had suggested the feasibility and activity of the combination of bevacizumab with endocrine agents [50,51], a randomized phase III study (LEA) was conducted to test the hypothesis that anti-VEGF treatment with bevacizumab could prevent primary resistance to hormone therapy (either letrozole 2.5 mg/day or fulvestrant 250 mg/4 weeks) given as first-line therapy in endocrine responsive advanced breast cancer [52]. The PFS was better with the combination of bevacizumab plus endocrine therapy than with endocrine monotherapy (18.4 vs. 13.8 months), but this was not statistically significant.…”