What does this research mean for the field?

The MTA-cooperative PRMT5 inhibitor CTS3497 is well-tolerated and demonstrates promising clinical efficacy, including a 43% objective response rate, in patients with heavily pretreated MTAP-deficient advanced solid tumors. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

What question did this study set out to answer?

This study aims to evaluate the safety and efficacy of CTS3497 in patients with advanced MTAP-deficient solid tumors.

May 29, 2026

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

Key Points

This study aims to evaluate the safety and efficacy of CTS3497 in patients with advanced MTAP-deficient solid tumors.
Eligible patients with homozygous MTAP deletion or MTAP protein loss received escalating doses of CTS3497.
Patients were treated until disease progression or intolerable toxicity.
Efficacy, safety, pharmacokinetics, pharmacodynamics, and biomarker profiles were assessed.
Objective response rate was 43% with a disease control rate of 91% among efficacy-evaluable patients.
In gastrointestinal cancers, the objective response rate was 56% and the disease control rate was 89%.
No dose-limiting toxicities were observed, with common treatment-related adverse events including anemia and decreased blood cell counts.

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 .

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

Key Points

Abstract

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