Abstract PO2-04-10: Effect of Alpelisib Dose Modification for AE Management on Progression-Free Survival and Treatment Duration in SOLAR-1 and BYLieve Clinical Trials

Abstract Background: Alpelisib (ALP) is an α-selective phosphatidylinositol 3-kinase (PI3K) inhibitor and degrader approved with fulvestrant (FUL) for patients (pts) with phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA)-mutated, hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2−) advanced breast cancer (ABC) following progression on/after endocrine therapy-based treatment (tx). Toxicity limited ALP exposure in some pts in the SOLAR-1 and BYLieve studies. On-target effects of PI3K inhibitors, including hyperglycemia, rash, and diarrhea, are among the most common adverse events (AEs) associated with ALP. During SOLAR-1, median onset times were 15 and 13 days for grade ≥3 hyperglycemia and rash and 46 days for grade 2/3 diarrhea. ALP dose modification can help manage AEs. We report efficacy of ALP + FUL as second-line (2L) tx in pts who underwent ALP dose reduction (DR). Methods: Pts with PIK3CA mutations from SOLAR-1 and BYLieve, treated with ALP + FUL in 2L, were included. Landmark (LM) analyses were performed at 1, 2, 3, 4, 5, and 6 mo after tx initiation to evaluate the association between DR status (yes, no) with progression-free survival (PFS) and duration of tx (DoT), respectively. Pts with PFS or exposure time less than each LM time point were excluded from each LM analysis; pts were then grouped by DR (yes, no) before each LM time point. Median PFS and DoT were obtained using a modified Kaplan-Meier method. Alternatively, Cox regression analysis was used to assess the effect of DR on PFS and DoT, where 2 time-dependent variables were included separately in the model as a covariate: 1) DR status, and 2) DR groups (300 to 250 mg [1 DR] vs no DR, 300 to 250 to 200 mg [2 DR] vs no DR). Association between AEs and DR was evaluated descriptively. A matched analysis of AEs will be presented. Results: In all, the analysis included 212 pts in 2L: 77 from SOLAR-1, and 95 and 40 from BYLieve Cohorts A and C, respectively. Of these pts, 92 (43.4%) had no DR and 120 (56.6%) had DRs: 70 (58.3%) had 1 DR, 43 (35.8%) had 2, and 7 (5.8%) had other types of DR. 25 of 92 pts (27.2%) with no DR and 40 of 120 pts (33.3%) with DR had ≥12-mo exposure to ALP. Hazard ratios (HRs) for PFS and DoT in DR status for the LM analysis are shown (Table). HRs (95% CI) for PFS from the time-dependent covariate analyses were 1.28 (0.94-1.74) with DR status as the covariate, and 1.24 (0.88-1.76) and 1.21 (0.79-1.84) with DR group (1 DR vs no DR, 2 DR vs no DR) as the covariate, respectively; for DoT, these were 1.34 (1.00-1.79) for DR status, and 1.30 (0.93-1.80) and 1.30 (0.87-1.93) for DR group, respectively. During the treatment period, the incidence rate for grade ≥3 AEs was the highest for pts with 2 DR and lowest for those with no DR. Similarly, incidence of AEs leading to DR or tx discontinuation was higher in pts with 2 DR than 1 DR. The post-DR incidence rate for grade ≥3 AE was similar for pts with 2 DR or 1 DR. A matched analysis will assess the relationship between DR group and AE. Conclusions: In this pooled analysis, regardless of if/when DR occurred, PFS was similar and DoT may be sustained with ALP + FUL. ALP DR can potentially reduce AEs, which may allow pts to remain on tx. Using DR as an AE management strategy may enable pts with PIK3CA-mutated, HR+, HER2− ABC to optimize tx duration and clinical benefit of ALP in the 2L. Landmark Analyses of PFS and Tx Duration by DR Group (Yes vs No; Pooled FAS) Citation Format: Hope Rugo, Alessandra Gennari, Stephen Chia, Dejan Juric, Neil Vasan, Sherko Küemmel, Patrick Neven, Florence Lerebours, Manuel Ruíz - Borrego, Pedram Razavi, Jyotika Singh, Yogesh Chattar, Murat Akdere, Eva Ciruelos. Effect of Alpelisib Dose Modification for AE Management on Progression-Free Survival and Treatment Duration in SOLAR-1 and BYLieve Clinical Trials [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-04-10.

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