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

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 placebo group (HR 0·80 [95% CI 0·68-0·94]; one-sided p=0·0033). In PI3K pathway-activated patients (n=372), median progression-free survival was 6·8 months (95% CI 4·9-7·1) in the buparlisib group versus 4·0 months (3·1-5·2) in the placebo group (HR 0·76 [0·60-0·97], one-sided p=0·014). The most common grade 3-4 adverse events in the buparlisib group versus the placebo group were increased alanine aminotransferase (146 [25%] of 573 patients vs six [1%] of 570), increased aspartate aminotransferase (103 [18%] vs 16 [3%]), hyperglycaemia (88 [15%] vs one [<1%]), and rash (45 [8%] vs none). Serious adverse events were reported in 134 (23%) of 573 patients in the buparlisib group compared with 90 [16%] of 570 patients in the placebo group; the most common serious adverse events (affecting ≥2% of patients) were increased alanine aminotransferase (17 [3%] of 573 vs one [<1%] of 570) and increased aspartate aminotransferase (14 [2%] vs one [<1%]). No treatment-related deaths occurred.

Interpretation: 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.

Funding: Novartis Pharmaceuticals Corporation.

Conflict of interest statement

Declaration of interests

JB reports financial support for medical editorial assistance from Novartis during the conduct of the study. S-AI reports grant support from AstraZeneca and advisory consultant role Novartis, Roche/Genentech and Spectrum, outside the submitted work. HI reports grant support and personal fees from Novartis during the conduct of the study; grant support from GlaxoSmithKline, Eli Lilly, Merck Sharp & Dohme, Nippon Kayaku, and Bayer; grant support and personal fees from Chugai, Daiichi-Sankyo, Eisai, AstraZeneca, Pfizer, and Kyowa Hakko Kirin; and personal fees from Taiho and Takeda, outside the submitted work. JC reports personal fees from Novartis, Roche, Celgene, Eisai, AstraZeneca, Pfizer, and Cellestia, outside the submitted work. MDLs reports personal fees in the form of speaker’s honoraria and advisory board honoraria from Novartis, Roche, AstraZeneca, Amgen, and Celgene, outside the submitted work. WJ reports personal fees from Novartis for the roles of lecturer and advisory board member, outside the submitted work. MC reports funding from Novartis to attend the IMPAKT meeting, outside the submitted work. YI reports grant support from Chugai, Novartis, Parexel, and EPS during the conduct of the study. AA reports honorarium for advisory board from Novartis, Roche, Pfizer, and Puma, outside the submitted work. SC reports personal fees in the form of honorarium for advisory board and financial support from Novartis during the conduct of the study. SH reports payment from Novartis to UCLA during the conduct of this study. She also reports grant support from Amgen, GlaxoSmithKline, Genentech/Roche, and Medivation, and grant support and travel reimbursement from Eli Lilly, Novartis, Boehringer Ingelheim, OBI Pharma, PUMA, and Merrimack, outside the submitted work. BD, S, PU, and CM are employees of Novartis. EDiT reports personal fees as an employee of Novartis Pharmaceutical Corporation at the time of the study conduct and when the first draft of the manuscript was developed. MC reports grant support, personal fees and non-financial support from Novartis during the conduct of this study. He also reports grant support and personal fees from Roche and Pfizer, grant support from TESSARO, and personal fees from AstraZeneca, outside the submitted work. All other authors declare no competing interests.

Copyright © 2017 Elsevier Ltd. All rights reserved.

Figures

Figure 1. Trial profile

The safety analysis set is defined as patients who received at least one dose of study treatment and had one post-baseline safety assessment. Four patients (two from the buparlisib plus fulvestrant group and two from the placebo plus fulvestrant group) did not receive study treatment and were therefore excluded from the safety analysis. One patient was randomly assigned to the buparlisib plus fulvestrant group, but actually received treatment with placebo plus fulvestrant, so this patient was analysed as part of the placebo plus fulvestrant group for the safety analysis. ctDNA=circulating tumour DNA. PIK3=phospahtidylinositol 3-kinase. *587 of these patients submitted ctDNA for PIK3CA analysis.

Figure 2. Progression-free survival

(A) Progression-free survival in the total population. (B) Progression-free survival in PI3K pathway-activated patients. HR=hazard ratio.

Figure 3. Progression-free survival by ctDNA PIK3CA mutant status

(A) Progression-free survival in ctDNA-mutant patients. (B) Progression-free survival in ctDNA wild-type patients. ctDNA=circulating tumour DNA. HR=hazard ratio.