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

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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.
— Maura N. Dickler, MD, and colleagues

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In a phase III trial (CALGB 40503/Alliance) reported in the Journal of Clinical Oncology, Maura N. ­Dickler, MD, of Memorial Sloan Kettering Cancer Center, and colleagues found that the addition of bevacizumab (Avastin) to first-line endocrine therapy with letrozole improved progression-free survival among postmenopausal women with hormone receptor–positive metastatic breast cancer.1 However, the benefit was accompanied by an increased risk of grade 3 or 4 toxicities.

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 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-plus-letrozole vs letrozole groups: the 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 > 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 1 to 3 metastatic sites and 10% vs 13% had at least 4 metastatic sites; 92% vs 89% had HER2-negative status; 47% vs 49% had prior endocrine therapy (tamoxifen in 35% vs 36%, aromatase inhibitor in 21% vs 25%); and 42% vs 38% had prior ­chemotherapy.

Combination Therapy in Metastatic Breast Cancer

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

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-plus-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 plus 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 median follow-up of 42 months, median overall survival was 47.2 months for the bevacizumab-plus-letrozole group vs 43.9 months for the letrozole-alone group (HR = 0.87, P = .188)—a trend that favors the bevacizumab-plus-letrozole arm.

Adverse Events

Overall, grade ≥ 3 treatment-related adverse events were more common with bevacizumab plus letrozole (47% vs 14%), including nonhematologic adverse events (46% vs 14%). The bevacizumab-plus-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-plus-letrozole group (due to central nervous system hemorrhage) and one 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. ■

Disclosure: The study was supported by the National Cancer Institute, Genentech (research funding and bevacizumab), Novartis (letrozole), and a core grant from Memorial Sloan Kettering Cancer Center. For full disclosures of the study authors, visit


1. Dickler MN, Barry WT, Cirrincione CT, et al: Phase III trial evaluating letrozole as first-line endocrine therapy with or without bevacizumab for the treatment of postmenopausal women with hormone receptor-positive advanced-stage breast cancer: CALGB 40503 (Alliance). J Clin Oncol 34:2602-2609, 2016.




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