Updated efficacy of mutant-selective PI3Kα inhibitor RLY-2608 in combination with fulvestrant in patients with PIK3CA -mutant HR+HER2- advanced breast cancer: ReDiscover trial.

作者：Sarah Sammons, C. Saura Manich, Antoine Italiano, Alison M. Schram, Pablo Tolosa, Anne F. Schott, Ángel Guerrero, Santiago Ponce Aix, Rita Nanda, Kari B. Wisinski, Jennifer Segar, Mei Wei, Jia Liu, Alexander I. Spira, Julia E. McGuinness, Jordi Rodon Ahnert, X. Cynthia, Milana A. Bergamino, Giuseppe Curigliano, Andreas Varkaris · 发表于：Journal of Clinical Oncology · 年份：2025 · DOI：10.1200/jco.2025.43.16_suppl.1086 · 被引用次数：6 · 研究领域：Advanced Breast Cancer Therapies、PI3K/AKT/mTOR signaling in cancer、Chronic Lymphocytic Leukemia Research

1086 Background: Oncogenic PIK3CA mutations constitutively activate PI3Kα and drive approximately 40% of HR+HER2- breast cancer (BC); however, the toxicity (hyperglycemia, rash, diarrhea, stomatitis) of non-selective inhibitors (i) limits their tolerability and efficacy. RLY-2608 is the first oral, pan-mutant-selective, allosteric PI3Kαi designed to overcome these limitations. We report efficacy and safety of RLY-2608 + standard-dose fulvestrant (F) in pts with PIK3CA- mutant, HR+HER2- BC treated in the FIH study, ReDiscover (NCT05216432). Methods: Previously treated adult pts with advanced HR+HER2- BC and PIK3CA mutation per local assessment were eligible. Pts were eligible to enroll with measurable or non-measurable disease. Key objectives were investigator-assessed efficacy per RECIST 1.1 and adverse events (AEs) per CTCAE v5.0. Results: As of 4NOV24, safety was assessed in 118 pts treated across RLY-2608 doses 100-1000 mg BID, and efficacy in the 52 pts without detectable PTEN/AKT co-alterations treated at the RP2D (600 mg BID). All pts received prior endocrine therapy and CDK4/6i with 48% having ≥ 2 prior systemic therapies for advanced disease including 56% with prior F/SERD and 25% with prior chemotherapy or antibody-drug conjugate. Median follow-up was approximately 9.5 months. The RP2D provided exposure in the target therapeutic range and rapid clearance of mutant PIK3CA ctDNA. 31/52 pts had measurable disease with 26/31 (83.9%) achieving disease control, 23/31 (74.2...