First-in-human phase I study of HSK41959, an MTA-cooperative PRMT5 inhibitor, in patients with <i>MTAP</i> -deleted advanced solid tumors.

Abstract

e15097 Background: PRMT5 is an essential epigenetic regulator that drives cell proliferation. MTAP deletion, occurring in 10–15% of solid tumors, causes methylthioadenosine (MTA) accumulation and creates a synthetic-lethal vulnerability to PRMT5 inhibition. HSK41959 is an oral, MTA-cooperative PRMT5 inhibitor that can selectively inhibit the growth of MTAP-deleted tumor cells while preserving PRMT5 function in normal cells. Here, we report preliminary results from a phase I study of HSK41959 in patients with MTAP-deleted advanced solid tumors. Methods: This multicenter, open-label, two-part study enrolled adult patients with MTAP-deleted advanced solid tumors. In the dose-escalation (Part 1), HSK41959 was administered orally once daily at doses ranging from 50 to 800 mg in 21-day cycles. Part 2 was cohort expansion. The primary objectives were to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of HSK41959. Secondary objectives included safety, tolerability, pharmacokinetics, pharmacodynamics and preliminary antitumor activity. Results: As of December 26, 2025, 19 patients had received HSK41959 at five dose levels (50, 100, 200, 400, 800 mg/day). No dose-limiting toxicities were observed. Treatment-related adverse events (TRAEs) occurred in 72.2% of patients; the most common were anemia (27.8%), nausea (22.2%) and diarrhea (22.2%). The majority of TRAEs were grade 1. No treatment-related serious adverse events, discontinuations, or deaths were observed. Among 11 efficacy evaluable patients, the objective response rate was 27.3%, and the disease control rate was 81.8%. Three patients with non-small cell lung cancer achieved partial responses and two had stable disease with tumor shrinkage. This trial is ongoing. Conclusions: HSK41959 is well tolerated without unexpected safety issues. Preliminary efficacy data demonstrate favorable activity of HSK41959 in patients with MTAP-deleted solid tumors. Clinical trial information: NCT06968572 .