Introduction:PIK3CA (encoding phosphatidylinositol 3-kinase alpha [PI3Kα]) is a driver oncogene mutated (mut) in ~40% of HR+, HER2- ABCs, leading to endocrine therapy (ET) resistance and poor prognosis. Alpelisib (ALP) is the first oral α-selective PI3K inhibitor and degrader approved in this patient (pt) population. Primary analyses of Cohorts A and B from BYLieve, an ongoing Phase II noncomparative study, demonstrated efficacy and a consistent safety profile of ALP + ET (fulvestrant [FUL] or letrozole [LET]) in pts with PIK3CA-mut, HR+, HER2- ABC in the post CDK4/6i setting. Post hoc analyses of ALP benefit in pts with centrally confirmed PIK3CA mut, based on median duration of prior CDK4/6i, supported the efficacy of ALP + ET in CDK4/6i-resistant, HR+, HER2- ABC. Here we assessed whether those who achieved a short duration of disease control (6-month [mo] cutoff), with prior CDK4/6i + ET received clinical benefit with ALP + ET. Methods: In Cohorts A and B, pts with PIK3CA-mut, HR+, HER2- ABC had received CDK4/6i + aromatase inhibitor (AI) or FUL, respectively, as immediate prior therapy (majority in first line). Pts in Cohort A received ALP 300 mg PO QD + FUL 500 mg IM Q28D + C1D15; pts in Cohort B received ALP 300 mg PO QD + LET 2.5 mg PO QD. Within each cohort, pts were divided based on duration of prior CDK4/6i therapy (≤6 mo or >6 mo), and the association of progression-free survival (PFS) with this covariate was analyzed using a stratified log-rank test and Cox Proportional Hazards model. A 6-mo cutoff was selected based on the ESO-ESMO ABC5 cutoff for primary ET resistance, as current guidelines do not specify cutoffs for CDK4/6i resistance. This analysis is based on the PFS endpoint and included pts for whom duration of prior CDK4/6i therapy was known. Results: Of the 121 pts in Cohort A with centrally confirmed PIK3CA-mut disease (modified full analysis set, mFAS), 120 had duration of prior CDK4/6i available; 26 had CDK4/6i for ≤6 mo and 94 for >6 mo, with similar demographics/disease characteristics between subgroups. The hazard ratio (HR) of median PFS (mPFS) between the ≤6-mo group and >6-mo group was 0.50 (95% confidence interval [CI], 0.27-0.94), indicating a lower risk of progression in the ≤6-mo group, with mPFS 10.0 mo (95% CI, 5.55-not estimable) and 6.0 mo (95% CI, 5.16-8.31), respectively. Grade ≥3 adverse events (AEs) were experienced by 67.5% (n=85) of all pts (safety set) in Cohort A and by 76.9% (n=20)/65.0% (n=65) in the ≤6-mo/>6-mo subgroups, respectively. Of the 115 pts in Cohort B with centrally confirmed PIK3CA-mut disease (mFAS), 113 had duration of prior CDK4/6i available; 31 had CDK4/6i for ≤6 mo and 82 for >6 mo, with similar demographics/disease characteristics between subgroups. The HR of mPFS between the ≤6-mo and >6-mo groups was 0.76 (95% CI, 0.47-1.23), with the wide CI indicating no difference in risk of progression between subgroups, and mPFS was 5.9 mo (95% CI, 3.55-10.97) and 5.6 mo (95% CI, 3.68-7.10), respectively. Grade ≥3 AEs were experienced by 69.9% (n=86) of all pts (safety set) in Cohort B and by 63.6% (n=21)/72.2% (n=65) in the ≤6-mo/>6-mo subgroups, respectively. Conclusions: This demonstrates that pts with PIK3CA-mut, HR+, HER2- ABC who achieved ≤6-mo duration of disease control with prior CDK4/6i had a numerically longer PFS in Cohort A, and almost the same clinical efficacy in Cohort B, to ALP + ET vs pts with >6-mo duration of disease control, with a comparable safety profile. This confirms targeting PI3Kα with ALP provides clinical benefit in pts with CDK4/6i-resistant ABC, including early progressors, and supports consideration of ALP + ET as an immediate next-line option in this setting, possibly delaying chemotherapy.

Citation Format: Stephen Chia, Eva M Ciruelos, Hope S Rugo, Florence Lerebours, Manuel Ruiz-Borrego, Pamela Drullinsky, Aleix Prat, Thomas Bachelot, Nicholas Turner, Ennan Gu, Christina Arce, Murat Akdere, Dejan Juric. Effect of duration of prior cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) therapy (≤6 mo or >6 mo) on alpelisib benefit in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), PIK3CA-mutated advanced breast cancer (ABC) from BYLieve [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-18-08.