Relay Therapeutics (RLAY) Study Update summary

Clinical context and unmet need

• PI3K alpha mutations are present in over 500,000 patients in the U.S., with 140,000 in hormone receptor-positive, HER2-negative breast cancer.

• Existing PI3K inhibitors are limited by toxicity, restricting efficacy and combinability.

• Second-line post-CDK4/6 setting remains the largest area of unmet need, with current agents offering less than six months PFS and significant toxicity.

• PIK3CA mutations drive resistance to endocrine therapy in about 40% of patients.

• There is a strong demand for a mutant-specific, better-tolerated, and more efficacious PIK3CA inhibitor.

Study design and patient population

• RLY-2608 is a pan-mutant, isoform-selective PI3K alpha inhibitor developed using the Dynamo platform.

• The Rediscover trial enrolled heavily pretreated, hormone receptor-positive, HER2-negative metastatic breast cancer patients; 118 patients enrolled in the RLY-2608 + fulvestrant arm, with 64 at RP2D.

• Dose escalation identified 600 mg b.i.d. as the recommended phase 2 dose (RP2D).

• Inclusion criteria allow prediabetic patients, with baseline fasting glucose up to 140 and HbA1c up to 7.

• Phase 3 will focus on patients with any PIK3CA mutation, excluding those with PTEN or AKT co-mutations.

Efficacy results

• At RP2D, median PFS was 9.2 months in all patients, and 11.4 months in true second-line and kinase mutation patients; confirmed ORR was 39% overall and 67% in kinase mutations.

• Clinical benefit rate (CBR) was 67% across all patients; 74% experienced tumor reductions.

• 97% of patients had a decline in PIK3CA ctDNA, and 53% achieved complete ctDNA clearance by cycle 2 day 1.

• Efficacy metrics surpass those of current standards like capivasertib (median PFS ~5.5 months).

• Efficacy consistent across kinase and non-kinase PIK3CA mutations.