IDEAYA Biosciences has opened the monotherapy expansion portion of its Phase 1/2 study of IDE892 in patients with MTAP-deleted pancreatic and lung cancers after dose escalation reached projected efficacious exposures.

The South San Francisco precision oncology company said on July 27 that the study achieved continuous target coverage at the projected EC90 exposure level. Dose escalation is continuing in parallel, and a maximum tolerated dose has not been reached.

IDE892 is an MTA-cooperative inhibitor of PRMT5. Deletion of the MTAP gene causes methylthioadenosine to accumulate inside tumour cells, increasing their dependence on PRMT5 and MAT2A, enzymes involved in methylation and RNA splicing. Drug developers are attempting to exploit that dependency as a synthetic lethal vulnerability while sparing normal cells.

IDEAYA said IDE892 was designed with approximately 1,400-fold selectivity for MTA-PRMT5 cooperative binding over SAM-PRMT5 cooperative binding. The molecule also lacks brain penetration and has a drug interaction profile intended to support combination therapy.

The expansion is focused on non-small cell lung cancer and pancreatic ductal adenocarcinoma. MTAP deletion is estimated to occur in roughly 15% to 20% of non-small cell lung cancers and up to 40% of pancreatic ductal adenocarcinomas. No therapies are currently approved specifically for MTAP-deleted cancers.

The program is part of a broader strategy rather than a single-agent bet. IDEAYA is already evaluating IDE892 with its Phase 2 MAT2A inhibitor IDE397 in MTAP-deleted lung and pancreatic cancers. It also has a collaboration with Roche to study IDE892 with RG6505, Roche’s Phase 1 pan-RAS inhibitor, in MTAP-deleted pancreatic cancer. First patient dosing for that combination is targeted for the second half of 2026.

IDEAYA is also advancing a preclinical CDKN2A program toward a planned investigational application in the first half of 2027. CDKN2A loss frequently occurs alongside MTAP deletion, particularly in pancreatic cancer, giving the company another potential combination strategy.

The start of expansion does not yet provide evidence of clinical efficacy. IDEAYA has disclosed exposure and dose progression, not response rates, duration of response, or comparative safety data. Those results will determine whether the molecule’s selectivity produces a meaningful therapeutic window in patients.

The trial design nevertheless shows how synthetic lethality developers are planning for tumour heterogeneity from the beginning. Pancreatic cancers often contain overlapping alterations and adaptive pathways that can limit the durability of targeted monotherapy. IDEAYA is building parallel combinations around PRMT5, MAT2A, RAS, and CDKN2A biology to address that problem.

The company plans an investor research event in the fourth quarter covering MTAP deletion, CDKN2A, KRAS, and pancreatic cancer. The most closely watched updates will be early antitumour activity from the IDE892 expansion and whether ongoing escalation continues without reaching dose-limiting toxicity.