Monte Rosa Therapeutics announced interim data from the Phase 1 dose escalation part of its ongoing Phase 1/2 open-label, multicenter study of MRT-2359 in patients with MYC-driven solid tumors, including lung cancers and high-grade neuroendocrine cancer. MRT-2359 is an investigational, orally bioavailable, GSPT1-directed MGD discovered by Monte Rosa Therapeutics. Summary of available study results: As of the analysis cutoff date of September 7, 2023, 21 patients had been dosed, with 15 of the 21 patients evaluable for efficacy. Optimal PD modulation of GSPT1 by MRT-2359 was observed at all dose levels, consistent with its designed activity based on preclinical studies. This represents a sizable patient group, encompassing many cancer types, that currently experience significant unmet need. As of the analysis cutoff date of September 7, 2023, 21 patients had been dosed, with 15 of the 21 patients evaluable for efficacy.
Optimal PD modulation of GSPT1 by MRT-2359 was observed at all dose levels, consistent with its designed activity based on preclinical studies. Following MRT-2359 dosing, approximately 60% reduction in GSPT1 protein expression was observed in peripheral blood mononuclear cells and tumor tissue biopsies. Similar levels of degradation were observed across all dose levels, suggesting saturated PD responses from 0.5 mg to 2 mg and supporting that pharmacodynamically, 0.5 mg is a fully active dose. The level of GSPT1 degradation observed was in line with the levels seen in preclinical studies that were associated with anti-tumor activity. Of the 15 evaluable patients that have been administered MRT-2359 across three dose cohorts (0.5 mg, 1 mg, and 2 mg in a 5 days on-drug, 9 days off-drug dosing schedule), six were identified as biomarker-positive in indicated tumor types, specifically N-MYC high non-small cell lung cancer (NSCLC) adenocarcinoma, L-/N-MYC high small cell lung cancer (SCLC), L-/N-MYC high-grade neuroendocrine tumors (prostate, bladder, and others) and neuroendocrine tumors of the lung.
Clinical activity was seen across all dose levels. Of the six biomarker-positive patients, two achieved a partial response (PR), one confirmed and one unconfirmed, and one patient experienced durable stable disease (SD). Additionally, one patient who had an unevaluable biomarker status also experienced durable SD. The MRT-2359 safety profile supports further clinical development, with no signs of hypotension, cytokine release syndrome (CRS) or clinically significant hypocalcemia observed at any dose level, all of which have been reported as safety limitations of other GSPT1 degraders. The 0.5 mg and 1 mg dose levels resulted in Grade 1 or 2 treatment-related adverse events (AEs) only. At the 2 mg dose level, Grade 4 thrombocytopenia (dose-limiting toxicity (DLT), n=2) and Grade 4 neutropenia (non-DLT, n=1) were observed, findings consistent with preclinical toxicology studies. No patients discontinued treatment due to AEs at any dose level, and the Grade 4 AEs observed at the 2 mg dose were transient and resolved with dose reductions.