Abstract S4-07: BELLE-3: A phase III study of buparlisib + fulvestrant in postmenopausal women with HR+, HER2–, aromatase inhibitor-treated, locally advanced or metastatic breast cancer, who progressed on or after mTOR inhibitor-based treatment

Background: Phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway activation is a hallmark of hormone receptor-positive (HR+) breast cancer (BC) resistant to endocrine therapy (ET). Preclinical and clinical data suggest that adding a PI3K inhibitor (PI3Ki) to ET may overcome resistance. In BELLE-2, a Phase III randomized study, buparlisib (BUP; BKM120; pan-PI3Ki) + fulvestrant (FULV) demonstrated clinical activity and manageable safety in patients (pts) with HR+, human epidermal growth factor receptor 2-negative advanced BC, with the greatest treatment effect in pts with PIK3CA mutation in circulating tumor DNA (ctDNA). Here, we report results from the final progression-free survival (PFS) analysis of the BELLE-3 study. Methods: Pts (N=432) were randomized 2:1 to BUP (100mg/day) or placebo (PBO) + FULV (500mg per standard of care) and stratified by visceral disease status. Key inclusion criteria: prior aromatase inhibitor therapy; disease progression ≤30 days from combination therapy of ET + mTOR inhibitor as last regimen. Key exclusion criteria: >1 chemotherapy regimen for advanced BC; prior PI3Ki, AKT inhibitor, or FULV; history of/active mood disorders. Primary and key secondary endpoints were PFS (local assessment; Response Evaluation Criteria In Solid Tumors v1.1) and overall survival (OS), respectively. Other secondary endpoints included: overall response rate (ORR); clinical benefit rate (CBR); efficacy by PIK3CA status in ctDNA (BEAMing technology); safety. Results: BELLE-3 met its primary endpoint with a statistically significant improvement in PFS per investigator assessment in favor of BUP + FULV (BUP arm) vs PBO + FULV (PBO arm; hazard ratio [HR] 0.67; 95% confidence interval [CI]: 0.53–0.84; p 10%; BUP vs PBO arm) Grade 3/4 AEs were increased alanine aminotransferase (21.9% vs 2.9%), increased aspartate aminotransferase (17.7% vs 2.9%), and hyperglycemia (12.2% vs 0). Conclusions: BELLE-3 met its primary endpoint in the full population. PFS improvement in the BUP vs PBO arm was greater in pts with PIK3CA-mut than PIK3CA-wt tumors, based on ctDNA and PCR. Secondary endpoints showed improved clinical benefit with BUP + FULV vs PBO + FULV. Safety was in line with that previously seen with the combination. Keywords: Breast cancer; PI3K inhibitor; Fulvestrant; Buparlisib. Citation Format: Di Leo A, Seok Lee K, Ciruelos E, Lonning P, Janni W, O9Regan R, Mouret Reynier M-A, Kalev D, Egle D, Csoszi T, Bordonaro R, Decker T, Tjan-Heijnen VC, Blau S, Schirone A, Weber D, El-Hashimy M, Dharan B, Sellami D, Bachelot T. BELLE-3: A phase III study of buparlisib + fulvestrant in postmenopausal women with HR+, HER2–, aromatase inhibitor-treated, locally advanced or metastatic breast cancer, who progressed on or after mTOR inhibitor-based treatment [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr S4-07.