Buparlisib + Fulvestrant Assessed in Postmenopausal, HER-2 negative, Advanced Breast CA

Title: Buparlisib plus fulvestrant versus placebo plus fulvestrant in postmenopausal, hormone receptor-positive, HER-2 negative, advanced breast cancer (BELLE-2): a randomised, double-blind, placebo-controlled, phase 3 trial

Baselga, J. et al.


What You Need to Know:

In postmenopausal women with endocrine-resistant, hormone receptor-positive and human epidermal growth factor (HER2)-negative advanced breast cancer, treatment combining buparlisib, a phosphatidylinositol 3-kinase (PI3K) inhibitor, with fulvestrant has proven to be effective.

Trial Design:

  • Randomized, double-blind, placebo-controlled, phase 3 trial (BELLE-2) evaluated the efficacy of buparlisib + fulvestrant and the possibility of the activation of the PI3K pathway as a biomarker for disease
  • Patients included “postmenopausal women aged 18 years or older with histologically confirmed, hormone receptor-positive and human epidermal growth factor (HER2)-negative inoperable locally advanced or metastatic breast cancer whose disease had progressed on or after aromatase inhibitor treatment and had received up to one previous line of chemotherapy for advanced disease”
  • 1147 patients randomly assigned (1:1) to receive 100mg/day of oral bupralisib (n=576) or placebo (n=571) on day 15 of cycle 1 + 500mg fulvestrant administered intramuscularly on days 1 and 15 of cycle 1, followed by day 1 of following 28-day cycles
  • Randomization stratified by status of PI3K pathway activation (activated vs non-activated vs unknown) and status of visceral disease (present vs absent)
  • Primary endpoints: progression-free survival assessed by Response Evaluation Criteria in Solid Tumors
  • Efficacy analyses completed in intention-to-treat population
  • Safety analyses: included all patients who received 1 study drug dose and 1 safety assessment completed post-baseline

Key Outcomes:

  • Median progression-free survival: 6.9 months (95% CI: 6.8, 7.8) in buparlisib patients vs 5.0 months (95% CI: 4.0, 5.2) in placebo patients (HR: 0.78; 95% CI: 0.67, 0.89; one-sided p=0.00021)
  • Median progression-free survival in known PI3K status (n=851): 6.8 months (95% CI: 5.0, 7.0) in buparlisib patients vs 4.5 months (3.3, 5.0) in placebo patients (HR: 0.80; 95% CI: 0.68, 0.94; one-sided p=0.0033)
  • Median progression-free survival in PI3K pathway-activated patients (n=372): 6.8 months (95% CI: 4.9, 7.1) in buparlisib patients vs 4.0 months (95% CI: 3.1, 5.2) in placebo patients (HR: 0.76; 95% CI: 0.60, 0.97; one-sided p=0.014)
  • Most frequent grade 3-4 adverse events for buparlisib vs placebo patients, respectively: alanine aminotransferase elevations (25% vs 1%), aspartate aminotransferase elevations (18% vs 3%), hyperglycemia (15% vs <1%), rash (8% vs 0%)
  • 23% of buparlisib patients reported serious adverse events vs 16% of placebo patients
  • Zero treatment-related deaths reported