Abstract CT010: Efficacy results based on PIK3CA status in BELLE-3: A Phase 3 study of buparlisib (BKM120) + fulvestrant in postmenopausal women with aromatase inhibitor-treated, HR+/HER2- ABC after progression on an mTOR inhibitor
Authors: O'Regan Ruth , Arteaga Carlos L. , Bachelot Thomas , Ciruelos Eva , Lønning Per E. , Sankaran Banu , Wang Ying A. , Scheuer Nicolas , Sellami Dalila , Hirawat Samit , Leo Angelo Di 
Published: July 2017

Abstract
Introduction
The phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway is often activated in endocrine therapy (ET)-resistant, hormone receptor-positive (HR+) breast cancer (BC). Adding a PI3K inhibitor (PI3Ki) to ET may overcome ET or mTOR inhibitor (mTORi) resistance. In the Phase 3 BELLE-2 study, the pan-PI3Ki buparlisib (BUP) + fulvestrant (FULV) prolonged progression-free survival (PFS) in patients (pts) with HR+, human epidermal growth factor receptor 2-negative (HER2–) advanced BC (ABC), particularly in pts with PIK3CA mutations in circulating tumor DNA (ctDNA). Here, we report biomarker results from BELLE-3 (NCT01633060).
Methods
In total, 432 postmenopausal women with HR+/HER2– ABC who previously received an aromatase inhibitor and progressed on/within 30 days of ET + mTORi treatment were enrolled. Pts must not have received &gt;1 chemotherapy regimen for ABC, or any prior PI3Ki, protein kinase B (AKT) inhibitor, or FULV. Pts were randomized 2:1 to receive BUP (100 mg/day) + FULV (500 mg) or placebo (PBO) + FULV, stratified by visceral disease status. PIK3CA status was assessed by BEAMing (exons 9 and 20 only) in plasma ctDNA collected at baseline, and in archival tumor samples by polymerase chain reaction (PCR) and next-generation sequencing (NGS). The primary endpoint was locally assessed PFS (RECIST v1.1). Secondary endpoints included overall survival, overall response rate, PFS by ctDNA PIK3CA status, quality of life, and safety; with exploratory PFS analyses by PIK3CA status in tumor tissue.
Results
BELLE-3 met its primary objective: PFS was significantly prolonged for BUP vs PBO, with hazard ratio (HR) 0.67 (95% confidence interval [CI]: 0.53–0.84; p&lt;0.001) and median PFS 3.9 vs 1.8 months. PIK3CA mutations were present in 135/348 (39%) available ctDNA samples, 109/321 (34%) tumor samples (by PCR), and 76/185 (41%) tumor samples (by NGS). PFS benefit for BUP vs PBO was higher in the PIK3CA-mutant ctDNA group (HR 0.46 [95% CI: 0.29–0.73]; median PFS 4.2 vs 1.6 months) than the PIK3CA-wild-type (WT) group (HR 0.73 [95% CI: 0.53–1.00]; median PFS 3.9 vs 2.7 months). PFS benefit was also higher in the PIK3CA-mutant tumor tissue group by PCR (HR 0.39 [95% CI: 0.23–0.65]) than the PIK3CA-WT group (HR 0.83 [95% CI: 0.60–1.14]), and in the PIK3CA-mutant tumor tissue group by NGS (HR 0.46 [95% CI: 0.26–0.82]) than the PIK3CA-WT group (HR 0.62 [95% CI: 0.40–0.97]). PIK3CA status in ctDNA and archival tissue by PCR had an overall concordance of 83%, with a sensitivity of 79% and specificity of 85%.
Conclusions
BELLE-3 met its primary endpoint in the full population. PFS benefit for BUP vs PBO was higher in pts with PIK3CA mutations detected in ctDNA or archival tissue (by PCR or NGS). Ongoing Phase 3 studies with PI3Kα-selective inhibitors will confirm the predictive value of PIK3CA mutations in ctDNA and tumor tissue on efficacy.
Citation Format: Ruth O'Regan, Carlos L. Arteaga, Thomas Bachelot, Eva Ciruelos, Per E. Lønning, Banu Sankaran, Ying A. Wang, Nicolas Scheuer, Dalila Sellami, Samit Hirawat, Angelo Di Leo. Efficacy results based on PIK3CA status in BELLE-3: A Phase 3 study of buparlisib (BKM120) + fulvestrant in postmenopausal women with aromatase inhibitor-treated, HR+/HER2- ABC after progression on an mTOR inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT010. doi:10.1158/1538-7445.AM2017-CT010