BELLE-3 Trial: Combination Therapy in Resistant Advanced Breast Cancer


Key Points

  • In women with hormone receptor–positive, HER2-negative advanced breast cancer progressing on or after mTOR inhibition, buparlisib plus fulvestrant was associated with prolonged progression-free survival.
  • The combination was associated with a worse safety profile.

The phase III BELLE-3 trial has shown prolonged progression-free survival but a worse safety profile with the addition of the pan-phosphoinositide 3-kinase inhibitor buparlisib to fulvestrant (Faslodex) in postmenopausal women with hormone receptor–positive, HER2-negative advanced breast cancer progressing on or after mTOR inhibition. These findings were reported in The Lancet Oncology by Di Leo et al.

Study Details

In the double-blind trial, 432 patients whose disease had relapsed on or after endocrine therapy and mTOR inhibitor therapy from 200 sites in 22 countries were randomized 2:1 between January 2013 and March 2016 to receive oral buparlisib at 100 mg/d plus intramuscular fulvestrant at 500 mg on days 1 and 15 of cycle 1 and on day 1 of subsequent 28-day cycles (n = 289) or placebo plus fulvestrant (n = 143).

Randomization was stratified by visceral disease status. The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population.

Progression-Free Survival

Median progression-free survival was 3.9 months in the buparlisib group vs 1.8 months in the placebo group (hazard ratio [HR] = 0.67, P = .00030). Progression-free survival at 6 months was 31% vs 20%. A subgroup analysis showed an enhanced benefit with buparlisib in patients with visceral disease (HR = 0.56, 95% confidence interval [CI] = 0.43–0.74) and those with PIK3CA mutation on circulating tumor DNA analysis (HR = 0.46, 95% CI = 0.29–0.73).

Adverse Events

Grade 3 or 4 adverse events occurred in 61% of the buparlisib group and 34% of the placebo group, with the most common in the buparlisib group including elevated alanine transaminase (22% vs 3%), elevated aspartate transaminase (AST; 18% vs 3%), hyperglycemia (12% vs 0%), hypertension (6% vs 4%), and fatigue (3% vs 1%). Serious adverse events occurred in 22% vs 16% and included elevated AST (2% vs 0%), dyspnea (2% vs 1%), and pleural effusion (2% vs 0%).

The investigators concluded: “The safety profile of buparlisib plus fulvestrant does not support its further development in this setting. Nonetheless, the efficacy of buparlisib supports the rationale for the use of PI3K inhibitors plus endocrine therapy in patients with PIK3CA mutations.”

The study was funded by Novartis Pharmaceuticals Corporation.

Angelo Di Leo, MD, of Nuovo Ospedale di Prato Santo Stefano, is the corresponding author of The Lancet 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®.