Novel METTL3 Inhibitor Elicits Clinical Activity Across Tumor Types
STC-15, an investigational RNA methyltransferase inhibitor, has shown promising clinical activity and an encouraging safety profile across various tumor types.
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The investigational METTL3 RNA methyltransferase inhibitor STC-15 was well tolerated with clinical activity seen across multiple tumor types, according to results from a phase 1 study (NCT05584111) presented at the Society of Immunotherapy for Cancer (SITC) 39th Annual Meeting.1
Across tumor types, tumor regressions were observed in all dose levels, which ranged from 60 mg to 200 mg, 3 times a week. Sustained partial responses (PRs) were achieved in multiple tumor types at doses of 60 mg, 100 mg, and 200 mg. Notably, 3 patients had sustained PRs.
Gene expression pathways related to interferon signaling, response to virus, and double-stranded RNA binding were enriched in patients who had longer durations of STC-15 treatment. These findings suggest that STC-15’s mechanism of action involves modulation of immune pathways, which may contribute to its antitumor effects.1
“The ability to activate the innate immune system while maintaining tolerability and efficacy is what is truly unique about STC-15. STC-15 targets METTL3, initiating a novel immunologic mechanism that demonstrates remarkable safety for an immuno-oncology drug. The early efficacy and safety data in the advanced cancer setting supports further clinical development in phase 2, in multiple tumor types,” said Kyriakos P. Papadopoulos, co-director of clinical research at START San Antonio, principal investigator for the STC-15 phase 1 study and lead author of the SITC presentation, in a press release.
Looking at safety and tolerability, the agent was well tolerated with treatment-emergent adverse events (AEs), including those that were target-related, being mild, transient, and manageable with supportive care. There were no dose-limiting toxicities observed.
Evidence of M1 macrophages within the TME was seen and consistent with preclinical data. Further, METTL3 target engagement was robust, with rapid and sustained inhibition of m6A RNA methylation.1
About the Phase 1 Study of STC-15
STC-15 targets METTL3, an RNA methyltransferase involved in the regulation of innate immune responses and tumor immune evasion. STC-15 marks the first RME inhibitor to enter human clinical evaluation.
Preclinically, STC-15 has been shown to inhibit tumor growth through mechanisms involving anticancer immune responses. This included changes in interferon signaling and constructive interaction with T-cell checkpoint blockade.1
Data from the study that were presented at SITC follow the presentation at the 36th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics in October 2024. The multicenter, open-label, first-in-human trial is evaluating the safety and pharmacology of STC-15 in patients with solid tumors.2
The study is utilizing a 3+3 cohort design with dose levels determined by a modified Fibonacci algorithm.2 A total of 42 patients were enrolled in the phase 1 study across 5 dose-escalation cohorts ranging from 60 mg to 200 mg. Treatment was explored daily and 3 times a week via oral dosing regimens.
Eligible patients for the trial are those aged 18 years or older with a histologic or cytologic confirmation of advanced malignancy that has failed standard of care (SOC) therapy and who has no further SOC therapy available. Patients who have declined additional SOC therapy are also eligible for enrollment. Further, patients must have adequate organ and marrow function and an ECOG performance status of 0 or 1.
AEs and pharmacokinetics were the primary end points of the study. Secondary end points included duration of response, progression-free survival, disease control rate, objective response rate, and to determine the recommended phase 2 dose.
No maximum-tolerated dose was reached at the highest dose of 200 mg 3 times a week, suggesting that higher doses may be feasible, and further exploration of optimal dosing in phase 2 studies is warranted.1
REFERENCES:
STORM Therapeutics presents new clinical data on its first-in-class METTL3 inhibitor STC-15 at SITC 2024. News release. STORM Therapeutics Ltd. November 11, 2024. Accessed November 20, 2024. https://tinyurl.com/mr3xmwzd
ClinicalTrials.gov. Updated August 13, 2024. Accessed November 20, 2024. https://www.clinicaltrials.gov/study/NCT05584111?term=NCT05584111&rank=1
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