Buparlisib, a pan-PI3K inhibitor, plus fulvestrant improved efficacy but also increased toxicity compared with fulvestrant and placebo among women with hormone receptor (HR)-positive, HER2-negative, advanced breast cancer, according to a study published in The Lancet Oncology.1

Activating PIK3CA mutations are frequently found among women with HR-positive breast cancer and are associated with endocrine therapy resistance and progression. The purpose of this trial was to evaluate the efficacy and safety of the addition of a pan-PI3K inhibitor to standard therapy for HR-positive breast cancer.

The multicenter, double-blind phase 3 BELLE-2 trial (ClinicalTrials.gov Identifier: NCT01610284) randomly assigned 1147 postmenopausal patients with HR-positive, HER2-negative, inoperable, locally advanced or metastatic breast cancer to receive fulvestrant plus buparlisib or placebo. Patients had progressed during or after aromatase inhibitor therapy or with chemotherapy. Randomization was based on PI3K pathway activation status.

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The mean age at baseline was 61.5 and the Eastern Cooperative Oncology Group (ECOG) performance status was 0 in 59% and 1 in 38.5%. Activating PI3K pathway mutations were present in 32.5% and unknown among 26%.

The overall response to buparlisib was 11.8% (95% CI, 9.3-14.7%) and 7.7% (95% CI, 5.7-10.2%) with placebo, which remained similar in the cohort with PI3K pathway activating mutations.

Buparlisib prolonged progression-free survival (PFS) with a median PFS of 6.9 months (95% CI, 6.8-7.8 months) compared with 5.0 months (95% CI, 4.0-5.2 months) with placebo. The PFS outcomes were similar among patients with PI3K activating mutations.

The overall survival data are immature and estimates were not reported.

Serious AEs occurred in 23% of patients treated with buparlisib compared with 16% of patients who received placebo, with the most frequent including elevated liver enzymes. There were no treatment-related deaths.

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The buparlisib and fulvestrant combination will not be pursued further due to increased toxicity.

The authors wrote, however, that “use of more selective PI3K inhibitors, such as α-specific PI3K inhibitor, is warranted to further improve safety and benefit in this setting.”


  1. Baselga J, Im SA, Iwata H, et al. 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. Lancet Oncol. 2017 May 30. doi: 10.1016/S1470-2045(17)30376-5 [Epub ahead of print]