STC-15, a Novel METTL3 Inhibitor, Shows Clinical Promise Across Multiple Tumor Types in Phase 1 Trial
核心洞察
STC-15, a first-in-class METTL3 (搜索) inhibitor, demonstrated clinical activity across various tumor types in a phase 1 study, with tumor regressions observed at all dose levels.
The study highlighted that STC-15 was well-tolerated, with treatment-emergent adverse events being mild and manageable, and no dose-limiting toxicities were observed.
Gene expression analysis suggests STC-15 modulates immune pathways, potentially contributing to its antitumor effects by activating the innate immune system.
STC-15, an investigational METTL3 (搜索) RNA methyltransferase inhibitor, has shown promising clinical activity across various tumor types, according to the results of a phase 1 study (NCT05584111) presented at the Society for Immunotherapy of Cancer (SITC) 39th Annual Meeting. The first-in-human trial demonstrated that STC-15 was well-tolerated, with encouraging signs of efficacy in heavily pre-treated patients with advanced solid tumors (搜索).
Clinical Activity Across Tumor Types
The phase 1 study explored dose levels ranging from 60 mg to 200 mg, administered three times a week. Notably, tumor regressions were observed across all dose levels. Sustained partial responses (PRs) were achieved in multiple tumor types at doses of 60 mg, 100 mg, and 200 mg, with three patients experiencing sustained PRs. These early efficacy signals suggest that STC-15 may offer a novel approach to treating cancers that have progressed despite standard-of-care therapies.
Mechanism of Action and Immune Modulation
Gene expression pathway analysis revealed that patients with longer durations of STC-15 treatment exhibited enrichment in pathways related to interferon signaling, response to viruses, and double-stranded RNA binding. These findings indicate that STC-15's mechanism of action involves the modulation of immune pathways, potentially contributing to its antitumor effects by activating the innate immune system. Evidence of M1 macrophages within the tumor microenvironment (TME) was also observed, consistent with preclinical data.
Kyriakos P. Papadopoulos, co-director of clinical research at START San Antonio, the principal investigator for the STC-15 phase 1 study, noted, "The ability to activate the innate immune system while maintaining tolerability and efficacy is what is truly unique about STC-15... The early efficacy and safety data in the advanced cancer setting supports further clinical development in phase 2, in multiple tumor types."
Safety and Tolerability
STC-15 was well-tolerated in the phase 1 study. Treatment-emergent adverse events (AEs), including those that were target-related, were mild, transient, and manageable with supportive care. Importantly, no dose-limiting toxicities were observed, and the maximum-tolerated dose was not reached at the highest dose of 200 mg three times a week. This suggests that higher doses may be feasible, warranting further exploration of optimal dosing in phase 2 studies.
Study Design and Patient Population
The multicenter, open-label, first-in-human trial employed a 3+3 cohort design with dose levels determined by a modified Fibonacci algorithm. A total of 42 patients were enrolled across five dose-escalation cohorts, ranging from 60 mg to 200 mg. Treatment was explored daily and three times a week via oral dosing regimens.
Eligible patients were those aged 18 years or older with a histologic or cytologic confirmation of advanced malignancy (搜索) that had failed standard of care (SOC) therapy and who had no further SOC therapy available or had declined additional SOC therapy. Patients were required to have adequate organ and marrow function and an ECOG performance status of 0 or 1.
Endpoints and Future Directions
The primary endpoints of the study were AEs and pharmacokinetics. Secondary endpoints included duration of response, progression-free survival, disease control rate, objective response rate, and determination of the recommended phase 2 dose. The promising safety profile and early signs of efficacy observed in this phase 1 trial support further investigation of STC-15 in phase 2 studies across a range of tumor types.