Abstract A050: PIK3CA mutation status in tumor tissue and ctDNA as a biomarker for PFS in patients with HR+, HER2- ABC treated with buparlisib or placebo plus fulvestrant: results from the BELLE-2 and BELLE-3 randomized studies
Authors: Baselga José , Sellami Dalila , El-Hashimy Mona , Dharan Bharani , Wang Amanda , Scheuer Nicolas , Sankaran Banu , Di Leo Angelo 
Published: August 2018

Abstract
Background: PIK3CA mutation status is a potential biomarker for treatment response to buparlisib (BUP; pan-phosphatidylinositol 3-kinase [PI3K] inhibitor) plus fulvestrant (FUL) in patients (pts) with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC). Here, we report progression-free survival (PFS) per PIK3CA mutation status (by polymerase chain reaction [PCR] in tumor tissue or BEAMing in circulating tumor [ct]DNA) in two distinct studies: BELLE-2 (NCT01610284) and BELLE-3 (NCT01633060). Methods: The double-blind Phase III BELLE-2 study randomized (1:1) postmenopausal pts with HR+, HER2- ABC who progressed on/after aromatase inhibitor therapy to receive oral (PO) BUP or placebo (PBO) plus intramuscular (IM) FUL. PIK3CA mutation status was determined by PCR in tumor tissue or BEAMing in ctDNA at baseline in a subset of pts with available samples. The double-blind phase III BELLE-3 study randomized (2:1) postmenopausal pts with HR+, HER2- ABC who relapsed on/after endocrine therapy and a mammalian target of rapamycin inhibitor to receive PO BUP or PBO plus IM FUL. PIK3CA mutation status was determined by PCR in tumor tissue or BEAMing in ctDNA at baseline in a subset of pts with available samples. Results: BELLE-2 randomized 1147 pts, including 587 with PIK3CA status per BEAMing and 1002 per PCR. A clinically meaningful improvement in PFS was seen in 200 pts with PIK3CA-mutant status per BEAMing treated with BUP+FUL vs PBO+FUL (median=7.0 vs 3.2 months; hazard ratio [HR] 0.56 [95% confidence interval {CI} 0.39-0.80]; 1-sided nominal P=0.0005), but not in 387 with wild-type status (median=6.8 vs 6.8 months; HR 1.05 [95% CI 0.82-1.34]; 1-sided nominal P=0.642), suggesting a predictive utility of PIK3CA status per BEAMing in ctDNA at baseline. Analysis based on PIK3CA status per PCR showed that PFS was prolonged with BUP+FUL vs PBO+FUL in both 412 pts with PIK3CA-mutant status (median=7.1 vs 5.1 months; HR 0.73 [95% CI 0.57-0.92]; 1-sided nominal P=0.004) and 590 with wild-type status (median=6.8 vs 4.6 months; HR 0.84 [95% CI 0.70-1.02]; 1-sided nominal P=0.042). BELLE-3 randomized 432 pts, including 348 with PIK3CA status per BEAMing and 313 per PCR. PFS benefit was more pronounced in 135 pts with PIK3CA-mutant status per BEAMing treated with BUP+FUL vs PBO+FUL (4.2 vs 1.6 months; HR 0.46 [95% CI 0.29-0.73]; 1-sided nominal P&lt;0.001) than in 213 with wild-type status (3.9 vs 2.7 months; HR 0.73 [95% CI 0.53-1.00]; 1-sided nominal P=0.026). PFS benefit was also more pronounced in 109 pts with PIK3CA-mutant status per PCR treated with BUP+FUL vs PBO+FUL (4.7 vs 1.4 months; HR 0.39 [95% CI 0.23-0.65]; 1-sided nominal P&lt;0.001) than in 204 with wild-type status (2.8 vs 1.7 months; HR 0.81 [95% CI 0.59-1.12]; 1-sided nominal P=0.099). Conclusions: Results from the large randomized BELLE-2 and BELLE-3 studies suggest that PIK3CA mutation status determined by PCR in tumor tissue or BEAMing in ctDNA is a positive predictive biomarker of PI3K inhibitor treatment efficacy in pts with HR+, HER2- ABC. ctDNA has the potential to drive study designs, given the flexibility of plasma sample collection and accurate determination of current PIK3CA status prior to treatment start.
Citation Format: José Baselga, Dalila Sellami, Mona El-Hashimy, Bharani Dharan, Amanda Wang, Nicolas Scheuer, Banu Sankaran, Angelo Di Leo. PIK3CA mutation status in tumor tissue and ctDNA as a biomarker for PFS in patients with HR+, HER2- ABC treated with buparlisib or placebo plus fulvestrant: results from the BELLE-2 and BELLE-3 randomized studies [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A050.