Abstract 2996: TNG462, an MTA-cooperative PRMT5 inhibitor, demonstrates strong efficacy in combination with clinically relevant targeted therapies in MTAP-null preclinical models

Abstract TNG462 is a clinical-stage, MTA-cooperative PRMT5 inhibitor currently being evaluated in an ongoing phase I/II clinical trial for solid tumors with MTAP loss. Approximately 10-15% of all human cancers exhibit MTAP deletions, including 10-15% of lung cancer and more than 20% of pancreatic adenocarcinomas. MTAP deletion frequently co-occurs with other genetic alterations: ∼30% of MTAP-deleted lung adenocarcinomas and ∼92% of MTAP-deleted pancreatic ductal adenocarcinomas (PDAC) also harbor KRAS mutations, while ∼20% of MTAP-deleted lung adenocarcinomas are also EGFR mutant. Although TNG462 monotherapy drives deep and durable tumor regressions in MTAP-null preclinical models, we investigated its potential in combination with therapies targeting actionable genetic alterations. In relevant models, the combination of TNG462 with either KRAS or EGFR inhibitors led to significant tumor regressions, surpassing the effects of either agent alone. This supports our clinical development plans for TNG462, which include targeted combinations with two RAS(ON) inhibitors, RMC-6236 and RMC-9805 from Revolution Medicines, as well as the EGFR inhibitor osimertinib from AstraZeneca. Additionally, nearly all MTAP-deleted cancers are also CDKN2A-deleted due to the proximity of the two genes on chromosome 9p, resulting in de-repression of the cyclin D-dependent CDK4/6 complexes, which creates a susceptibility to CDK4/6 inhibition. Significant efficacy was observed in preclinical models with the combination of TNG462 and CDK4/6 inhibitors, supporting a potential development path in GBM for our next generation CNS penetrant PRMT5 inhibitor, TNG456, with abemaciclib. Lastly, MTAP loss also sensitizes cells to MAT2A inhibition, providing strong rationale for combining PRMT5 inhibitors with MAT2A inhibitors. Preclinical data demonstrated significant efficacy when subtherapeutic doses of both agents are combined. However, TNG462 monotherapy at a clinically relevant dose achieved comparable benefits to the combination. Collectively, these findings strongly support evaluating TNG462 in combination with other targeted therapies in clinical trials for patients with cancers that exhibit MTAP loss. Citation Format: Minjie Zhang, Alice Tsai, Kevin M. Cottrell, Brian B. Haines, Alan Huang, Jannik N. Andersen, Adam S. Crystal, Kimberly J. Briggs. TNG462, an MTA-cooperative PRMT5 inhibitor, demonstrates strong efficacy in combination with clinically relevant targeted therapies in MTAP-null preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2996.