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
Authors: Di Leo A , Seok Lee K , Ciruelos E , Lønning P , Janni W , O'Regan 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 
Published: March 2017

Abstract
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: &gt;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&lt;0.001). Median PFS (mPFS) in the BUP vs PBO arm was 3.9 vs 1.8 months. The 6-month PFS rate was 30.6% vs 20.1%. PFS per central assessment was consistent with these findings (HR 0.57; 95% CI: 0.44–0.74; p&lt;0.001). PIK3CA status in ctDNA was available for 349 pts; 147 (42.1%) pts had PIK3CA-mutant (mut) status and 202 (57.9%) had PIK3CA-wildtype (wt) status. PFS improvement in the BUP vs PBO arm was greater in the PIK3CA-mut (mPFS 4.7 vs 1.6 months; HR 0.50; 95% CI: 0.33–0.76) than the PIK3CA-wt group (mPFS 3.7 vs 2.7 months; HR 0.73; 95% CI: 0.52–1.01). A similar treatment effect was seen in 321 pts with PIK3CA status based on PCR in tissue samples (PIK3CA-mut HR 0.39; 95% CI: 0.23–0.65. PIK3CA-wt HR 0.83; 95% CI: 0.60–1.14). ORR was 7.6% (95% CI: 4.8–11.3) vs 2.1% (95% CI: 0.4–6.0) in the BUP vs PBO arm, and CBR at 24 weeks was 24.6% (95% CI: 19.7–29.9) vs 15.4% (95% CI: 9.9–22.4). Most common (&gt;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, Lønning P, Janni W, O'Regan 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.