Relay Therapeutics announces interim data for RLY-2608

Relay Therapeutics announced interim data for RLY-2608, the first known investigational allosteric, pan-mutant and isoform-selective inhibitor of PI3Kalpha. The data showed that despite heavy pre-treatment, patients with PI3Kalpha-mutated, HR+, HER2- locally advanced or metastatic breast cancer who received RLY-2608 600mg BID + fulvestrant demonstrated clinically meaningful progression free survival. ReDiscover – RLY-2608 First-in-Human Study: RLY-2608 is currently being evaluated in ReDiscover, an ongoing first-in-human study, which was designed to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics and preliminary antitumor activity of RLY-2608 alone, in combination with fulvestrant, and in combination with fulvestrant and ribociclib or atirmociclib. As of the August 12, 2024 interim data cut-off, the RLY-2608 + fulvestrant arm of the study had enrolled 118 patients with PI3Kalpha-mutated, HR+, HER2- locally advanced or metastatic breast cancer across all doses in both the dose escalation and dose expansion portions of the study, including 64 patients at the company’s recommended Phase 2 dose of 600mg BID. Among these 64 patients, 31 had a kinase mutation and 33 had a non-kinase mutation. Twelve patients also had a PTEN or AKT co-mutation and were therefore excluded from the efficacy analysis, consistent with the currently proposed pivotal population. An abstract has been submitted for presentation at the San Antonio Breast Cancer Symposium, taking place December 10-13, 2024. Patients were Heavily Pre-Treated: All patients across doses had received a significant level of prior therapy in the advanced setting, including at least one prior endocrine therapy and at least one prior CDK4/6 inhibitor. Among the 64 patients who received the RP2D: 45% of patients had received two or more prior lines of therapy; 52% of patients had received a prior selective estrogen-receptor degrader, such as fulvestrant or a novel SERD; 25% of patients had received chemotherapy or an ADC; 59% percent of patients had visceral metastases; 34% of patients had a BMI of at least 30 and/or HbA1c of at least 5.7%. Promising Efficacy Data in Proposed Pivotal Population: Among the 52 patients who received the RP2D and did not have a PTEN or AKT co-mutation: Median PFS was 9.2 months across all mutations and 10.3 months among patients with kinase mutations; Clinical benefit rate was 57% across all patients; Among the 30 patients with measurable disease, one third achieved a partial response; Nearly three quarters of patients experienced tumor reductions; Among the 15 patients with measurable disease who had a kinase mutation, more than half achieved a PR; Median follow-up was 7.5 months. Maintained Meaningfully Differentiated Tolerability Profile: RLY-2608 + fulvestrant was generally well tolerated in the 118 patients treated across all doses as of the data cut-off date. The overall tolerability profile consisted of mostly low-grade treatment-related adverse events that were manageable and reversible. Safety outcomes were generally as expected across dose levels based on exposure and consistent with mutant-selective PI3Kalpha inhibition. Among the 64 patients who received the RP2D: The low rate of TRAE-related dose modifications allowed for 95% median dose intensity; Only two patients discontinued treatment due to TRAEs; The majority of hyperglycemia was Grade 1; only one patient experienced Grade 3 hyperglycemia; no Grade 4-5 hyperglycemia; Only 25% of patients experienced a Grade 3 TRAE; no Grade 4-5 TRAEs; Continued Progression of Front-Line Breast Cancer Regimens” Two front-line triplet regimens are being progressed – one with the existing CDK4/6 standard-of-care ribociclib and one with Pfizer’s investigative selective-CDK4 inhibitor atirmociclib. RLY-2608 + ribociclib + fulvestrant dose escalation portion of the ReDiscover study is currently testing biologically active doses of RLY-2608; On track to identify a dose of RLY-2608 that is combinable with full-dose ribociclib; Initial safety data expected in the fourth quarter of 2024′ Expect to initiate dose expansion cohort in first half of 2025; RLY-2608 + atirmociclib + fulvestrant triplet on track for initiation by the end of 2024.