Combination of Buparlisib and Fulvestrant in Postmenopausal Women With Advanced Breast Cancer

Key Points

  • The addition of buparlisib to fulvestrant improved progression-free survival in all patients and in those with PI3K pathway–activated status.
  • The combination of buparlisib and fulvestrant is not being pursued due to associated toxicity.

In the phase III BELLE-2 trial, the addition of the PI3K inhibitor buparlisib to fulvestrant (Faslodex) improved progression-free survival in postmenopausal hormone receptor–positive, HER2-negative advanced breast cancer—but at the cost of excessive toxicity. Results were reported in The Lancet Oncology by Baselga et al.

Study Details

In the double-blind trial, 1,147 patients from 267 sites in 29 countries were randomized between September 2012 and September 2014 to receive oral buparlisib at 100 mg/d (n = 576) or matching placebo (n =571) starting on day 15 of cycle 1 plus intramuscular fulvestrant at 500 mg on days 1 and 15 of cycle 1 and on day 1 of subsequent 28-day cycles. Patients had to have disease progressing on or after aromatase inhibitor treatment and had received up to one previous line of chemotherapy for advanced disease. Tumor PI3K status was determined via central laboratory during a 14-day run-in phase. The primary endpoints were progression-free survival on investigator assessment in the total population, in patients with known PI3K pathway status, and in patients with PI3K pathway–activated status; analyses were performed in the intention-to-treat population.

Progression-Free Survival

Median follow-up for progression-free survival was 13.7 months in the buparlisib group and 14.3 months in the placebo group. Median progression-free survival was 6.9 months in the buparlisib group vs 5.0 months in the placebo group among all patients (hazard ratio [HR] = 0.78, P = .00021), 6.8 months vs 4.5 months among 851 patients with a known PI3K status (HR = 0.80, P = .0033), and 6.8 months vs 4.0 months among 372 patients with PI3K pathway activation (HR = 0.76, P = .014). Among all patients, overall response rates were 11.8% vs 7.7%. Overall survival data were immature.

Adverse Events

The buparlisib group experienced higher rates of any grade hyperglycemia (43% vs 8%), elevated aspartate transaminase (AST; 37% vs 9%), elevated alanine transaminase (ALA; 41% vs 7%), nausea (39% vs 23%), diarrhea (37% vs 15%), rash (32% vs 6%), fatigue (32% vs 24%), stomatitis (22% vs 7%), and mood disorders (anxiety in 22% vs 8% and depression in 27% vs 9%). The most common grade 3 or 4 adverse events in the buparlisib group vs the placebo group were increased ALT (25% vs 1%), increased AST (18% vs3%), hyperglycemia (15% vs < 1%), and rash (8% vs 0%). Serious adverse events occurred in 23% vs 16%, with the most common being increased ALT (3% vs < 1%) and increased AST (2% vs < 1%).

Adverse events led to treatment interruption in 51% vs 14%, dose reductions in 45% vs 6%, and treatment discontinuation in 39% vs 5%; the most common adverse events leading to discontinuation in the buparlisib group were increased ALT (10%), increased AST (7%), hyperglycemia (3%), depression (3%), and rash (3%). No treatment-related deaths were observed.

The investigators concluded: “The results from this study show that PI3K inhibition combined with endocrine therapy is effective in postmenopausal women with endocrine-resistant, hormone receptor–positive and HER2-negative advanced breast cancer. Use of more selective PI3K inhibitors, such as α-specific PI3K inhibitor, is warranted to further improve safety and benefit in this setting. No further studies are being pursued because of the toxicity associated with this combination.”

The study was supported by Novartis Pharmaceuticals Corporation.

José Baselga, MD, of Memorial Sloan Kettering Cancer Center, 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®.




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