492TiP A phase I study of synthetic lethal, IDE397 (MAT2A inhibitor) as a monotherapy and in combination with chemotherapy in advanced solid tumors harboring MTAP deletion

Abstract

Methylthioadenosine phosphorylase (MTAP) deletion occurs in ∼15% of solid tumors in the setting of 9p21 loss and is associated with poor survival (Nature Communications; 2021; 12:5606; Han G). Loss of MTAP results in methylthioadenosine (MTA) accumulation and partial inhibition of protein arginine methyltransferase-5 (PRMT5). Inhibition of methionine adenosyltransferase-2a (MAT2A) results in reduction of s-adenosyl methionine (SAM), starving PRMT5 of its methylation substrate with resulting selective sensitivity of MTAP null cancer cells. IDE397 is a novel MAT2A inhibitor being evaluated in cancer patients harboring a tumor having MTAP deletion. IDE397 has superior cellular potency, selectivity, and drug properties, including lack of liver toxicity signals and high solubility, compared to the other MAT2A inhibitors under clinical investigation. In preclinical models, including patient derived xenografts, IDE397 has been shown to exploit the synthetic lethal relationship between MTAP deletion and MAT2A with broad activity and regressions of tumors with MTAP loss as a single agent and in combination with taxanes and other chemotherapy agents across multiple solid tumor indications. Preclinically, IDE397 shows robust pharmacodynamic modulation of SAM and symmetric dimethylarginine (SDMA). (IDEAYA Data). Study IDE397-001 (NCT04794699), is a phase I, muticenter, open-label study of IDE397 as a single agent in adult participants with advanced solid tumors harboring MTAP deletion. Additional escalation, expansion and combination arms with taxanes and other agents are planned across multiple indications (NSCLC, esophagogastric and other solid tumors). All participants will receive oral daily dosing of IDE397, as monotherapy or in combination with chemotherapy, until disease progression, unacceptable toxicity, or other withdrawal criteria are met. Primary endpoints include safety and tolerability, RP2D determination, investigator-assessed tumor response by RECIST v1.1. Enrollment in the monotherapy dose escalation is ongoing with clearance of the first 5 dose levels without DLT. NCT04794699. IDEAYA Biosciences, Inc.