Abstract PD5-12: Buparlisib (BUP) or placebo (PBO) plus fulvestrant (FUL) in postmenopausal patients (pts) with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) advanced breast cancer (ABC): Overall survival (OS) results from BELLE-2, a randomized, phase III study
Authors: Campone M , Im S-A , Iwata H , Clemons M , Ito Y , Awada A , Chia S , Jagiełło-Gruszfeld A , Pistilli B , Tseng L-M , Hurvitz S , Masuda N , Cortés J , De Laurentiis M , Arteaga CL , Jiang Z , Jonat W , Sellami D , El-Hashimy M , Le Mouhaër S , Sankaran B , Bourdeau L , Baselga J 
Published: February 2018

Abstract
Background: BELLE-2 (NCT01610284) met its primary endpoint of a statistically significant improvement in progression-free survival (PFS) with the pan-phosphoinositide 3-kinase (PI3K) inhibitor BUP+FUL compared with PBO+FUL in postmenopausal pts with HR+, HER2– ABC (Baselga et al. Lancet Oncol 2017). Here, we report the final results for OS.
Methods: Postmenopausal women with HR+, HER2– ABC refractory to aromatase inhibitors were enrolled in this randomized, double-blind, placebo-controlled, Phase III study. Pts were randomized (1:1) to receive either oral BUP (100 mg/day) or PBO plus intramuscular FUL (500 mg per standard of care). Randomization was stratified by PI3K pathway status in archival tumor tissue (activated [PIK3CA mutation or loss of phosphatase and tensin homolog expression], non-activated or unknown) and visceral disease status (present or absent). Baseline PIK3CA mutation status in circulating tumor (ct) DNA was assessed in a subset of pts. The key secondary endpoint was OS, defined as time from randomization to date of death due to any cause, in the full population (PI3K pathway activated, non-activated and unknown), main study cohort (PI3K pathway activated and non-activated) and PI3K pathway-activated subpopulation. Other secondary endpoints included safety. OS by PIK3CA status in ctDNA was also investigated.
Results: 1147 pts received BUP+FUL or PBO+FUL. In the full population and main cohort, OS results trended in favor of BUP+FUL vs PBO+FUL, but were not statistically significant (Table). Post-treatment use of antineoplastic medications was balanced between both arms. In pts with PI3K pathway-activated status, OS improved by approximately 6 months (Table). In pts with mutant PIK3CA ctDNA status, there was a slight trend in favor of BUP+FUL vs PBO+FUL (Table).
Median OS, monthsHR (95% CI)P valueFull population N=1147BUP+FUL n=57633.20.87 (0.74–1.02)0.045* PBO+FUL n=57130.4 Main cohort n=851BUP+FUL n=42730.90.91 (0.75–1.09)0.144* PBO+FUL n=42428.9 PI3K pathway activated n=372BUP+FUL n=18833.60.81 (0.61–1.08)0.075** PBO+FUL n=18427.5 ctDNA PIK3CA mutant n=200BUP+FUL n=8726.00.81 (0.56–1.17)0.127** PBO+FUL n=11324.8 ctDNA PIK3CA non-mutant n=387BUP+FUL n=19931.41.12 (0.83–1.50)0.774** PBO+FUL n=18836.8 *One-sided P value. **Nominal P value.
The safety profile of BUP+FUL was consistent with that previously reported, with no new safety concerns. Grade 3/4 adverse events with at least 5% difference between BUP+FUL vs PBO+FUL, respectively, were increased alanine aminotransferase (25.7% vs 1.1%), increased aspartate aminotransferase (18.0% vs 2.8%), hyperglycemia (15.4% vs 0.2%) and rash (8.0% vs 0.0%).
Conclusions: The BELLE-2 OS results showed a trend in favor of BUP+FUL, but did not meet statistical significance. More selective PI3K inhibition may improve treatment benefit and safety compared with pan-PI3K inhibition. Further assessment of the predictive benefit of ctDNA-confirmed PIK3CA mutations in this setting is required.
Citation Format: Campone M, Im S-A, Iwata H, Clemons M, Ito Y, Awada A, Chia S, Jagiełło-Gruszfeld A, Pistilli B, Tseng L-M, Hurvitz S, Masuda N, Cortés J, De Laurentiis M, Arteaga CL, Jiang Z, Jonat W, Sellami D, El-Hashimy M, Le Mouhaër S, Sankaran B, Bourdeau L, Baselga J. Buparlisib (BUP) or placebo (PBO) plus fulvestrant (FUL) in postmenopausal patients (pts) with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) advanced breast cancer (ABC): Overall survival (OS) results from BELLE-2, a randomized, phase III study [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD5-12.