Mirati Therapeutics: Cancer Discovery publishes results from MRTX1719 trial

Mirati Therapeutics announced Cancer Discovery published preclinical and initial clinical data from a first-in-human Phase 1/2 clinical trial of MRTX1719, a PRMT5 / methylthioadenosine-cooperative inhibitor evaluated in methylthioadenosine phosphorylase deleted cancers. These results provide preclinical and early clinical proof-of-concept for this differentiated approach and demonstrate that MRTX1719 may represent a promising targeted therapy for the ~10% of cancer patients with this biomarker. The publication can be found here. In preclinical studies, MRTX1719 was demonstrated to be a potent, selective inhibitor of the PRMT5/MTA complex. This compound exploits the elevated MTA levels present in MTAP-deleted cancers and turns this altered metabolic state into a therapeutic vulnerability to selectively kill MTAP deleted cancer cells while sparing normal cells. Preclinical results showed marked anti-tumor activity of MRTX1719, including regression, across lung, pancreatic, mesothelioma, and other solid tumor models. As of June 13, 2023, there were 18 patients with solid tumors harboring MTAP deletions in the Phase 1/2 trial of MRTX1719 that were evaluable for clinical response at dose levels of 100mg QD or greater. Initial dose level started at 50mg administered once-daily orally over 21-day cycles followed by 100% dose escalations for subsequent dose levels. Six individual case narratives were selected for inclusion in the Cancer Discovery publication: There were six confirmed objective responses observed in the Phase 1 study including one patient who achieved a response which subsequently confirmed post-data cutoff; MRTX1719 achieved apparent complete PRMT5 inhibition in MTAP deleted tumor cells at a dose of 200 mg QD as evidenced by pretreatment and on-treatment tumor biopsies of the PRMT5 biochemical biomarker symmetric dimethyl arginine; It was notable that four patients were on therapy for multiple cycles before experiencing an initial objective response, with their tumors continuing to decrease in size over the course of treatment. These findings suggest that tumor response may continue to deepen over time indicating the importance of evaluating tumor response kinetics and response rates across a broader patient population with longer follow up. MRTX1719 was well-tolerated with no dose limiting toxicities observed at dose levels up to 400mg QD. None of the patients treated with MRTX1719 experienced dose-limiting adverse events associated with first generation PRMT5 inhibitors such as thrombocytopenia, anemia or neutropenia.