Adding Bevacizumab to Letrozole Improves Progression-Free Survival but Increases Toxicity in Metastatic Breast Cancer


Key Points

  • The addition of bevacizumab to first-line letrozole was associated with improved progression-free survival among postmenopausal women with hormone receptor–positive metastatic breast cancer.
  • The incidence of grade 3 or 4 adverse events was higher in patients receiving bevacizumab.

The addition of bevacizumab (Avastin) to first-line endocrine therapy with letrozole improved progression-free survival but increased toxicity among postmenopausal women with hormone receptor–positive metastatic breast cancer, according to the results of the phase III CALGB 40503/Alliance trial reported by Dickler et al in the Journal of Clinical Oncology.

Study Details

In this open-label trial, 343 women with hormone receptor–positive metastatic breast cancer were randomized between May 2008 and November 2011 to receive letrozole at 2.5 mg orally per day with or without bevacizumab at 15 mg/kg intravenously (IV) once every 3 weeks, with stratification for measurable disease and disease-free interval. The primary endpoint was investigator-assessed progression-free survival.

For the bevacizumab/letrozole vs letrozole groups, median age was 56 vs 59 years; 61% vs 63% had measurable disease; 89% vs 91% were white; 43% vs 48% had de novo metastatic disease and 43% vs 45% had a disease-free interval of more than 2 years; metastatic sites were bone only in 24% vs 25%, visceral only in 24% vs 24%, and both in 51% vs 49%; 88% vs 84% had one to three metastatic sites and 10% vs 13% had at least four metastatic sites; 92% vs 89% had a HER2-negative status; 47% vs 49% had prior endocrine therapy (tamoxifen in 35% vs 36%, an aromatase inhibitor in 21% vs 25%); and 42% vs 38% had prior chemotherapy.

Progression-Free Survival

At median follow-up of 39 months, median progression-free survival was 20.2 months (95% confidence interval [CI] = 17.0–24.1 months) in the bevacizumab/letrozole group vs 15.6 months (95% CI = 12.9–19.7 months) in the letrozole group (hazard ratio [HR] = 0.75, P = .016). The proportions of patients who were progression-free were 87% vs 77% at 6 months and 73% vs 61% at 12 months. Subgroup analyses suggested consistent effects with bevacizumab/letrozole according to age, de novo vs recurrent disease, bone only vs other sites of metastases, and number of metastatic sites.

Among patients with measureable disease, objective response rates were 69% vs 49% (P = .004).  At a median follow-up of 42 months, median overall survival was 47.2 vs 43.9 months (HR = 0.87, P = .188).

Adverse Events

Overall, grade ≥ 3 treatment-related adverse events were more common with bevacizumab/letrozole (47% vs 14%), including nonhematologic adverse events (46% vs 14%). The bevacizumab/letrozole group had higher rates of grade 3 or 4 hypertension (24% vs 2%), proteinuria (11% vs 0%), joint pain (10% vs 0%), and head pain/headache (5% vs 1%). Left ventricular systolic dysfunction was observed in 2% vs 0% and thrombosis/embolism in 2% vs 1%. One death in the bevacizumab/letrozole group (due to central nervous system hemorrhage) and one death in the letrozole group (due to pneumonia) were considered related to study treatment.

The investigators concluded: “The addition of bevacizumab to letrozole improved [progression-free survival] in hormone receptor–positive [metastatic breast cancer], but this benefit was associated with a markedly increased risk of grade 3 to 4 toxicities. Research on predictive markers will be required to clarify the role of bevacizumab in this setting.”

The study was supported by the National Cancer Institute, Genentech (research funding and bevacizumab), Novartis (letrozole), and a core grant from the Memorial Sloan Kettering Cancer Center.

Maura N. Dickler, MD, of the Memorial Sloan Kettering Cancer Center in New York, is the corresponding author of the Journal of Clinical Oncology article.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.