Relay Therapeutics announced updated interim clinical data for RLY-2608, the first known investigational allosteric, pan-mutant and isoform-selective inhibitor of PI3Kα, at the American Society of Clinical Oncology (ASCO) 2025 Annual Meeting. The data, with a median follow-up of 12.5 months, demonstrate consistent efficacy outcomes that support the planned initiation of a pivotal Phase 3 study in mid-2025.
The updated results show a median progression-free survival (PFS) of 11.0 months in second-line patients with PI3Kα-mutated, HR+/HER2- locally advanced or metastatic breast cancer who received RLY-2608 600mg twice daily plus fulvestrant. Overall median PFS across all patients was 10.3 months.
"The treatment options for CDK4/6-experienced patients with PI3Kα mutations has not meaningfully advanced in the past 10 years and recent data disclosures and trial discontinuations highlight the level of unmet need in this population," said Don Bergstrom, M.D., Ph.D., President of R&D at Relay Therapeutics. "We are encouraged by the consistency of these updated RLY-2608 + fulvestrant data, which continue to show the potential benefit of a mutant-selective PI3Kα inhibitor for improving both the tolerability profile and progression free survival compared to standard of care."
ReDiscover Study Design and Patient Population
The ongoing first-in-human ReDiscover study enrolled 118 patients with PI3Kα-mutated, HR+, HER2- locally advanced or metastatic breast cancer across all doses. Among the 64 patients who received the recommended Phase 3 dose of 600mg twice daily, 31 had kinase mutations and 33 had non-kinase mutations. Twelve patients with PTEN or AKT co-mutations were excluded from efficacy analysis, consistent with the planned pivotal population.
All patients had received significant prior therapy, including at least one prior endocrine therapy and at least one prior CDK4/6 inhibitor. Among patients receiving the recommended Phase 3 dose, 44% had received two or more prior lines of therapy.
Efficacy Results Show Durable Responses
Among the 52 patients who received the recommended Phase 3 dose and did not have PTEN or AKT co-mutations, the clinical benefit rate was 67% across all patients. For second-line patients, median PFS was 18.4 months for patients with kinase mutations and 8.5 months for patients with non-kinase mutations.
Among 31 patients with measurable disease, 12 achieved a partial response, representing a 39% confirmed objective response rate. Notably, 81% of patients experienced tumor reductions. Among the 15 patients with measurable disease who had kinase mutations, two-thirds achieved a partial response (67% confirmed objective response rate). Even among 15 patients who had received prior fulvestrant, 6 achieved a partial response (40% confirmed objective response rate).
Favorable Safety Profile Maintained
RLY-2608 plus fulvestrant demonstrated a differentiated tolerability profile across 118 patients treated at all doses. The safety profile consisted of mostly low-grade treatment-related adverse events that were manageable and reversible. Among patients receiving the recommended Phase 3 dose, the low rate of treatment-related adverse event-related dose modifications allowed for 92% median dose intensity.
Only two patients discontinued treatment due to treatment-related adverse events (Grade 1 pruritus; Grade 1 nausea and loss of appetite). The majority of hyperglycemia was Grade 1, with only two patients (3%) experiencing Grade 3 hyperglycemia and no Grade 4-5 hyperglycemia reported. Only 36% of patients experienced a Grade 3 treatment-related adverse event, with no Grade 4-5 treatment-related adverse events observed.
Novel Mechanism Addresses Historical Limitations
RLY-2608 represents a departure from traditional PI3Kα inhibitor development, which has focused on the active, or orthosteric, site. The therapeutic index of orthosteric inhibitors has been limited by lack of clinically meaningful selectivity for mutant versus wild-type PI3Kα and off-isoform activity. Toxicity related to inhibition of wild-type PI3Kα and other PI3K isoforms has resulted in sub-optimal inhibition of mutant PI3Kα with reductions in dose intensity and frequent discontinuation.
Relay Therapeutics' Dynamo platform enabled the discovery of RLY-2608 as the first known allosteric, pan-mutant, and isoform-selective PI3Kα inhibitor designed to overcome these limitations. The company solved the full-length cryo-EM structure of PI3Kα and performed computational long time-scale molecular dynamic simulations to elucidate conformational differences between wild-type and mutant PI3Kα.
Combination Studies and Future Development
The company is advancing two front-line triplet regimens - one with Pfizer's investigational selective-CDK4 inhibitor atirmociclib and one with the existing CDK4/6 standard-of-care ribociclib. Dose escalation is ongoing for both arms, with both currently at biologically active doses. The RLY-2608 plus atirmociclib plus fulvestrant arm, initiated in Q4 2024, continues to enroll patients in dose escalation.
Market Opportunity and Next Steps
PI3Kα is the most frequently mutated kinase in all cancers, with oncogenic mutations detected in about 14% of patients with solid tumors. RLY-2608 has the potential, if approved, to address more than 300,000 patients per year in the United States, representing one of the largest patient populations for a precision oncology medicine.
Relay Therapeutics plans to initiate the Phase 3 ReDiscover-2 study of RLY-2608 plus fulvestrant in mid-2025, which would represent the first mutant-selective PI3Kα Phase 3 trial. The company will continue dose escalation for additional breast cancer combination arms and continue enrollment in the Phase 1/2 ReInspire study evaluating RLY-2608 in vascular malformations.
