Relay Therapeutics says RLY-2608 selectively targets multiple PI3Ka mutations

Relay Therapeutics announced initial clinical data for RLY-2608, the first known investigational allosteric, pan-mutant and isoform-selective inhibitor of PI3Kalpha. The data support initial clinical proof of mechanism, demonstrating that RLY-2608 achieved selective target engagement at multiple predicted efficacious doses with a favorable initial safety and tolerability profile. These data are being presented today at the American Association for Cancer Research Annual Meeting 2023. RLY-2608 is currently being evaluated in an ongoing dose-escalation portion of ReDiscover, a first-in-human trial, which was designed to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics and preliminary antitumor activity across two separate arms. The monotherapy arm started in December 2021 and enrolled 19 patients with unresectable or metastatic solid tumors with a PI3Kalpha mutation. This arm included a broad diversity of solid tumors, predominantly tumor types not predicted to be sensitive to single agent PI3Kalpha inhibition. The RLY-2608 + fulvestrant combination arm started April 2022 and enrolled 23 patients with PI3Kalpha-mutant, HR+, HER2- locally advanced or metastatic breast cancer. Across both arms of the study, enrolled patients had received a significant level of prior therapy, including all breast cancer patients who had received at least one prior endocrine therapy and CDK4/6 inhibitor. The cut-off date for data reported at AACR was March 9, 2023. Among the 27 patients with breast cancer, 12 had kinase mutations, 10 had helical mutations and nine had other mutations. In the monotherapy arm, patients received seven different doses, ranging from 50mg twice daily to 400mg BID. In the combination arm, patients received five different BID doses, ranging from 100mg to 800mg BID. RLY-2608 reached selective target exposure at multiple doses, with target exposure being defined as continuous inhibition of mutant PI3Kalpha of approximately 80 percent or greater. This was reached at 400mg BID monotherapy and at 600mg BID and 800mg BID combination doses. RLY-2608 demonstrated mutant selective PI3Kalpha target engagement at multiple doses. There was limited observed impact on glucose homeostasis overall and no Grade 3 hyperglycemia was observed. Glucose homeostasis is believed to be an important indicator of both RLY-2608’s clinical selectivity profile and its potential ability to avoid this key off-target toxicity associated with wild-type inhibition. Declines of PI3Kalpha mutations in ctDNA from patient samples support initial clinical validation of RLY-2608’s ability to selectively inhibit a wide range PI3Kalpha mutations in a dose-dependent manner. RLY-2608 has been generally well tolerated in the 42 patients treated as of the cut-off date: The overall safety profile consisted of mostly low-grade adverse events that were manageable and reversible; Across all doses, there were no dose-limiting toxicities, no AEs leading to treatment discontinuation and no Grade 4-5 AEs; Among patients receiving doses at target exposures, AEs were mostly low-grade events that were manageable and reversible: No Grade 3 hyperglycemia, diarrhea, or rash, which are the AEs most commonly associated with treatment discontinuation for existing investigational and approved therapies; No dose reductions or discontinuations due to AE; The low rate of AE-related dose modifications allowed for median dose intensity of at least 98 percent across all dose levels. A patient with metastatic HR+/HER2- breast cancer, with two PI3Kalpha mutations, who progressed following 12 lines of prior therapy, including chemotherapy, endocrine and HER2-directed therapies, received RLY-2608 400mg BID monotherapy. An unconfirmed partial response by Response Evaluation Criteria in Solid Tumors was recorded at 8 weeks. Subsequent to the data cut-off, this partial response was confirmed, and the patient remains on treatment with no AEs reported as of April 4, 2023. Early anti-tumor activity was seen across a range of doses and across helical, kinase and other mutations, demonstrating selective target engagement of mutant PI3Kalpha. Among the 16 breast cancer patients with measurable disease: Nine experienced radiographic tumor reductions; 12 exhibited a best overall response of stable disease and 1 partial response; 11 remain on treatment as of the cut-off date; Median duration of treatment for all breast cancer patients was approximately 4 months: 70 percent remain on treatment as of the cut-off date; 600mg BID dose: approximately 4-month median follow-up; Six of seven 600mg BID patients remain on treatment.