Buparlisib plus fulvestrant versus placebo plus fulvestrant in postmenopausal, hormone receptor-positive, HER2-negative, advanced breast cancer (BELLE-2): a randomised, double-blind, placebo-controlled, phase 3 trial

Abstract

Summary Background Phosphatidylinositol 3-kinase (PI3K) pathway activation is a hallmark of endocrine therapy-resistant, hormone receptor-positive breast cancer. This phase 3 study assessed the efficacy of the pan-PI3K inhibitor buparlisib plus fulvestrant in patients with advanced breast cancer, including an evaluation of the PI3K pathway activation status as a biomarker for clinical benefit. Methods The BELLE-2 trial was a randomised, double-blind, placebo-controlled, multicentre study. 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 were included. Eligible patients were randomly assigned (1:1) using interactive voice response technology (block size of 6) on day 15 of cycle 1 to receive oral buparlisib (100 mg/day) or matching placebo, starting on day 15 of cycle 1, plus intramuscular fulvestrant (500 mg) on days 1 and 15 of cycle 1, and on day 1 of subsequent 28-day cycles. Patients were assigned randomisation numbers with a validated interactive response technology; these numbers were linked to different treatment groups which in turn were linked to treatment numbers. PI3K status in tumour tissue was determined via central laboratory during a 14-day run-in phase. Randomisation was stratified by PI3K pathway activation status (activated vs non-activated vs and unknown) and visceral disease status (present vs absent). Patients, investigators, local radiologists, study team, and anyone involved in the study were masked to the identity of the treatment until unblinding. The primary endpoints were progression-free survival by local investigator assessment per Response Evaluation Criteria In Solid Tumors (version 1.1) in the total population, in patients with known (activated or non-activated) PI3K pathway status, and in PI3K pathway-activated patients. Efficacy analyses were done in the intention-to-treat population. Safety was analysed in all patients who received at least one dose of study drug and had at least one post-baseline safety assessment according to the treatment they received. This trial is registered with ClinicalTrials.gov, number NCT01610284, and is currently ongoing but not recruiting participants. Findings Between Sept 7, 2012, and Sept 10, 2014, 1147 patients from 267 centres in 29 countries were randomly assigned to receive buparlisib (n=576) or placebo plus fulvestrant (n=571). In the total patient population (n=1147), median progression-free survival was 6·9 months (95% CI 6·8–7·8) in the buparlisib group versus 5·0 months (4·0–5·2) in the placebo group (hazard ratio [HR] 0·78 [95% CI 0·67–0·89]; one-sided p=0·00021). In patients with known PI3K status (n=851), median progression-free survival was 6·8 months (95% CI 5·0–7·0) in the buparlisib group vs 4·5 months (3·3–5·0) in the place...

PI3K/mTOR Inhibitors in the Treatment of Luminal Breast Cancer. Why, When and to Whom

“…In the overall population, median PFS was significantly improved by the addition of buparlisib to ET (6.9 vs. 5.0 months; hazard ratio 0.78, p = 0.00021) [25]. Importantly, the benefit associated with buparlisib was limited to patients with PIK3CA mutations detectable in their circulating tumor DNA (ctDNA) [25]. The most common grade 3-4 adverse events in the buparlisib group versus the placebo group were hepatotoxicity with increased ALT (25% vs. 1%) and AST (18% vs. 3%), hyperglycemia (15% vs. < 1%) and rash (8% vs. none).…”

“…More recently, the BELLE-2 trial evaluated another pan-PI3K inhibitor, named buparlisib, in association with fulvestrant in 1,147 patients with luminal HER2 -MBC pretreated with AI. In the overall population, median PFS was significantly improved by the addition of buparlisib to ET (6.9 vs. 5.0 months; hazard ratio 0.78, p = 0.00021) [25]. Importantly, the benefit associated with buparlisib was limited to patients with PIK3CA mutations detectable in their circulating tumor DNA (ctDNA) [25].…”

“…These findings should be validated in larger prospective clinical trials. The scenario is different for PI3K inhibitors, as PIK3CA mutations, identified at the level of ctDNA, were predictive of response to buparlisib in both the BELLE-2 and BELLE-3 studies [25,26]. Considering the noninvasive nature of the liquid biopsy approach, the findings of BELLE studies could represent a milestone in the development of personalized cancer therapies.…”

The PI3K Pathway in Human Disease

“…The BELLE series of clinical trials assessed the efficacy and safety of various drug combinations with the pan-PI3K inhibitor buparlisib (BKM120; Table S1) in patients with ER+, HER2- breast cancer. Patients who had progressed on aromatase inhibitor monotherapy received fulvestrant plus either buparlisib or placebo in the Belle-2 phase 3 trial (Baselga et al, 2017). Although the primary endpoint of extended progression-free survival (PFS) was met, the overall response rate (ORR, equals PFS plus stable disease) was disappointingly low.…”

Blood-based biomarkers in breast cancer: From proteins to circulating tumor cells to circulating tumor DNA

“…In a phase III randomized clinical trial in patients with advanced breast cancer, combined treatment with the PI3K inhibitor, buparlisib and fulvestrant, resulted in increased PFS and OS compared to fulvestrant alone in patients with ctDNA PIK3CA mutations but not in those with ctDNA wild-type PIK3CA. 75 Provided these results can be confirmed, the mutational status of PIK3CA might be useful in identifying patients who are likely to benefit from combined treatment with buparlisib and fulvestrant. …”