Abstract PD13-06: PD13-06 Long-Term and Very-Long-Term Disease Control in Patients From BYLieve Study Cohort A With PIK3CA-Mutant, Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative, Advanced Breast Cancer
Authors: Rugo Hope , Chia Stephen K. , Cortés Javier , Curigliano Giuseppe , Neven Patrick , Dent Rebecca , Tolaney Sara , Ciruelos Eva , Park Yeon H. , Roux Estelle , Chattar Yogesh , Patino Heather , Akdere Murat , Juric Dejan 
Published: March 2023

Abstract
Introduction: PIK3CA mutations, seen in ~40% of patients (pts) with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) advanced breast cancer (ABC), are associated with treatment (Tx) resistance and shorter survival. Alpelisib (ALP) is an α-selective PI3K inhibitor and degrader indicated for treating this population in combination with fulvestrant (FUL) after endocrine therapy (ET). Previous results from the SOLAR-1 study showed that progression-free survival (PFS) ≥18 mo is achievable for pts treated with ALP on/after prior Tx with aromatase inhibitor (AI). Here, we analyze pts from BYLieve study Cohort A who achieved long-term (LT) and very-long-term (VLT) disease control with ALP + FUL after prior Tx with cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) and AI.
Methods: BYLieve was a Phase II, nonrandomized, open-label, 3-cohort study of ALP + ET in pts with PIK3CA-mutated, HR+, HER2– ABC whose disease progressed on/after prior CDK4/6i. In Cohort A, median (m) PFS was 7.26 mo. LT disease control was defined as ≥12 mo PFS and VLT disease control as ≥18 mo PFS. Pts with &lt; 12 mo PFS were defined as non-LT. Baseline characteristics are summarized by duration of disease control. Incidence rate (IR) per 100 patient-treatment years (PTY) was calculated to assess exposure-adjusted adverse events (AE). To assess tumor complexity in LT/VLT pts, median circulating tumor DNA (ctDNA) fraction, chromosome (chr) 8/11 amplification, and ESR1 mutations were determined by next-generation sequencing.
Results: In BYLieve Cohort A, 31 of 121 pts (25.6%) achieved LT disease control with an mPFS of 24.8 mo (95% CI 18.2 mo to not estimable [NE]) and 20 of 121 pts (16.5%) achieved VLT disease control (mPFS NE; 95% CI 22.1 mo to NE). Pts with LT/VLT disease control had lower BMI and ECOG score, longer time from initial diagnosis to first recurrence/relapse, more frequent bone-only lesions, and fewer liver metastases than non-LT pts (Table). Median ALP relative dose intensity was 86.7%, 91.7%, 85.0%, and 85.1% for all Cohort A pts (n=127), non-LT (n=96), LT (n=31), and VLT disease control (n=20), respectively, whereas median ALP exposure was 5.13 mo, 3.61 mo, 21.29 mo, and 25.25 mo respectively. The IRs per 100 PTY of diarrhea, hyperglycemia, and rash were lower in LT (IR 128.4, n=24; IR 78.0, n=20; IR 21.6, n=10 respectively) and VLT (IR 93.5, n=15; IR 51.2, n=11; IR 24.9, n=8 respectively) pts than non-LT pts (IR 250.5, n=57; IR 251.5, n=56; IR 85.4, n=30 respectively). In LT and VLT pts ctDNA fraction was 2% and 5% respectively, whereas ctDNA fraction in non-LT pts was 14%. Incidence of chr 8/11 amplification was 10% in both LT and VLT pts and 20% in non-LT pts; incidence of ESR1 mutations was 26%, 25%, and 27% in LT, VLT, and non-LT pts respectively.
Conclusions: In pts with PIK3CA-mutated, HR+, HER2– ABC treated with ALP + FUL after CDK4/6i, LT and VLT disease control was observed in 25.6% and 16.5% of patients, respectively. Visceral disease, development of AEs, and ESR1 mutations did not preclude LT/VLT disease control. These data confirm that targeting the PIK3CA driver mutation with ALP + FUL post-CDK4/6i Tx may lead to LT disease control.
Table Baseline characteristics in BYLieve Cohort A overall and by duration of disease control
Citation Format: Hope Rugo, Stephen K. Chia, Javier Cortés, Giuseppe Curigliano, Patrick Neven, Rebecca Dent, Sara Tolaney, Eva Ciruelos, Yeon H. Park, Estelle Roux, Yogesh Chattar, Heather Patino, Murat Akdere, Dejan Juric. PD13-06 Long-Term and Very-Long-Term Disease Control in Patients From BYLieve Study Cohort A With PIK3CA-Mutant, Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative, Advanced Breast Cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD13-06.