A subset analysis of clinical activity and pharmacodynamic biomarkers in patients with sarcomas in the phase 1 dose-escalation study of STC-15, a METTL3 inhibitor.

Abstract

11548 Background: The RNA methyltransferase METTL3 is responsible for the generation of N6-methyladenosine (m6A), the most abundant modification on mRNA and long non-coding RNA. Accumulating evidence suggests numerous roles of METTL3 in cancer initiation and progression highlighting the rationale for targeting this enzyme in oncology. STC-15, a first in class small molecule inhibitor of METTL3 developed by Storm Therapeutics, demonstrated efficacy in pre-clinical models of cancer characterized by their dependence on m6A-mediated mRNA metabolism, including sarcomas that derive from a common mesenchymal progenitor. We report the clinical activity and pharmacodynamic (PD) biomarkers observed in a subset analysis of sarcomas from a first-in-human trial in patients with advanced malignancies. Full results of the study have been previously presented. Methods: This multi-center, open-label, dose escalation study of STC-15 administered oral capsules daily (QD) or three times a week (TIW) in 21-d treatment cycles. Dose escalation followed a 3+3 modified Fibonacci regimen. Primary objectives (safety and pharmacokinetics (PK)) and secondary objectives (efficacy) were previously presented. A subset analysis of sarcoma and selected patients evaluates anticancer activity and PD biomarkers, including target engagement, gene expression analysis, and targeted m6A RNA sequencing using the EpiPlex platform. Results: Of 42 patients enrolled, 35 were evaluable and 13 were sarcoma patients with a mean of 3 prior lines of therapy. Of 13 sarcoma patients with at least 1 on-treatment scan, DCR was 54% at 12 weeks with 1 confirmed PR (8% ORR) in angiosarcoma (DOR 22 months), and mPFS of 5.5 months as of 27 January 2026. Seven sarcoma patients presenting with four subtypes experienced a best response of SD, including tumor regressions. Treatment duration ranged from 15-828 days, with two sarcoma patients remaining on treatment for 590 and 828 days, respectively. An average of >50% reduction in m6A on mRNA in peripheral blood within the first 24h post dosing was observed in dose-escalating cohorts from 60 mg QD to 200 mg TIW, confirming target engagement. Moreover, we present an expanded analysis using the m6A-directed NGS EpiScout platform, where we evaluate both the effects of STC-15 on global m6A mRNA abundance and transcriptional changes that may contribute to an anti-tumor response specific to soft tissue and bone sarcomas. Conclusions: Treatment with STC-15 offers a new paradigm for the treatment of a broad range of sarcomas by halting the cell differentiation process from mesenchymal progenitors. Early biomarker data provide proof of mechanism in target engagement and changes in gene expression, consistent with pharmacological activity and clinical response. Further investigation of efficacy and biomarkers of STC-15 in a Phase 2 sarcoma study is ongoing. Clinical trial information: NCT05584111 .