RLY-2608 Mutant-Selective PI3Kα Inhibitor Achieves 31% ORR and 9-Month mPFS with Minimal Grade 3 Hyperglycemia in Post-CDK4/6 HR+/HER2⁻ mBC

RLY-2608 is an oral, allosteric PI3Kα inhibitor that binds only oncogenic PIK3CA variants, sparing wild-type signaling to reduce metabolic toxicity. In the phase 1 ReDiscover trial, 52 heavily pre-treated HR+/HER2⁻ metastatic breast-cancer patients lacking PTEN/AKT co-alterations received the RP2D 600 mg BID plus standard-dose fulvestrant; all had prior endocrine therapy and CDK4/6 inhibition, 22% had prior chemo/ADC. Confirmed objective response rate was 30.8% (8/26 evaluable), 69% showed any tumor shrinkage, and median PFS reached 9.2 months (95% CI 5.5–12.4). Safety was dominated by low-grade hyperglycemia (42% any grade, 2% grade 3), nausea (40%, 1% grade 3) and rash-diarrhea ≤ 1% grade 3—contrasting with alpelisib’s 36% grade 3 hyperglycemia and 14% grade 3 rash in SOLAR-1.

https://aacrjournals.org/clincancerres/article/31/12_Supplement/PS7-01/753567/Abstract-PS7-01-Efficacy-of-RLY-2608-a-mutant