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

Abstract

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%) experiencing radiographic tumor reduction and 12/31 achieving an objective response (38.7%, 95% CI 21.8-57.8) with median time-to-response 8 weeks. mPFS was 9.2 months (95% CI 5.8,18.4) across all 52 RP2D pts, and 11.4 months (95% CI 7.2-NR) in 32 pts receiving RLY-2608 at the RP2D as 2L treatment. Treatment-related AEs (TRAEs) were generally low-grade, manageable and reversible, most commonly hyperglycemia (42.4% any grade; 2.5% Gr 3), nausea (41.5%; 0.8% Gr 3), fatigue (40.7%; 8.5% Gr 3), creatinine increased (34.7%; 0.8% Gr 3), and diarrhea (30.5%; 1.7% Gr 3). There were no grade 4/5 TRAE; and severe, off-target stomatitis and rash were absent or rare. Conclusions: RLY-2608 demonstrates favorable safety/tolerability along with highly encouraging PFS observed across PIK3CA genotypes in pts with advanced PIK3CA- mutant HR+HER2- BC previously exposed to CDK4/6i. These data validate RLY-2608 as the first allosteric pan-mutant selective PI3Kαi and support advancing RLY-2608 + F to pivotal testing, which is planned for later this year. Clinical trial information: NCT05216432 .