A first-in-human phase I/II study evaluating CTS3497, an MTA-cooperative PRMT5 inhibitor, in advanced or metastatic <i>MTAP</i> -deficient solid tumors.

Abstract

3115 Background: Protein arginine methyltransferase 5 (PRMT5) methylates multiple protein substrates with a variety of biological functions known to be dysregulated in cancer. CTS3497 is an orally available, brain-penetrable, MTA (methylthioadenosine) -cooperative PRMT5 inhibitor that preferentially targets the MTA-bound PRMT5 in MTAP (MTA phosphorylase) -deficient tumors and potently inhibits tumor growth in various preclinical models. Here we present clinical data from an ongoing Phase I/II study of CTS3497 in solid tumors (NCT06971523). Methods: Eligible pts with homozygous MTAP deletion (by next generation sequencing), or MTAP protein loss (by immunohistochemistry [IHC]) and advanced solid tumors in the dose-escalation stage received 50, 200, 300, 400 mg BID of CTS3497 orally, while pts in the dose-expansion stage were treated with 200, 300 or 400 mg BID until disease progression or intolerable toxicity. Efficacy, safety, PK, PD and biomarker profiles were evaluated. Results: As of 22 Jan 2026, 41 patients received ≥1 dose of CTS3497 treatment. No DLT was observed, and MTD was not reached; CTS3497 was well-tolerated. Most common (≥20%) treatment-related adverse events (TRAEs) were anemia (34%), white blood cell count decreased (32%), platelet count decreased (27%) and neutrophil count decreased (22%). The most common Grade ≥3 TRAE (occurring in ≥5% of patients) was platelet count decreased. No central nervous system (CNS) effects were reported. Among 21 centrally-confirmed MTAP-deficient, efficacy-evaluable patients, including 9 gastrointestinal (GI) cancers (ampullary cancer, biliary tract carcinoma, esophageal squamous cell carcinoma, gastric cancer and pancreatic ductal adenocarcinoma), 5 non-small cell lung cancer (NSCLC), 1 urothelial carcinoma and 6 rare cancers, the objective response rate (ORR) was 43%, and the disease control rate (DCR) was 91%. In GI cancers, the ORR and DCR were 56% and 89%. In NSCLC, the ORR and DCR were 60% and 80%. The exposures (Cmax, AUC0-24h) of CTS3497 increased in a linear, dose-proportional manner. The pharmacodynamic (PD) marker, plasma symmetric dimethylarginine (SDMA) level, showed a significant decrease. Conclusions: CTS3497 demonstrated a favorable safety profile and promising efficacy in heavily pretreated pts with MTAP-deficient advanced solid tumors, including GI cancers, NSCLC. Clinical trial information: NCT06971523 .