Multicenter phase 1-2 trial of daraxonrasib for previously treated advanced RAS-mutant non-small cell lung cancer

RAS mutations, as a group, are the most common oncogenic drivers of non-small cell lung cancer (NSCLC), and they occur in approximately 30% of patients. The multicenter phase 1-2 RMC-6236-001 trial evaluated daraxonrasib, an oral RAS(ON) multiselective inhibitor of GTP-bound mutant and wild-type RAS protein isoforms, in patients with previously treated advanced RAS-mutant NSCLC. The patients received oral daraxonrasib in doses of 10 to 400 mg once daily. The primary endpoint was safety. Secondary endpoints included investigator-assessed objective response (ORR) and the duration of response. As of the data-cutoff date, a total of 136 patients treated with daraxonrasib at doses of 300 mg or less had been evaluated for safety and efficacy. Adverse events of any grade, regardless of attribution, were reported in 99% of the patients, with rash, diarrhea, nausea, vomiting, and mucositis or stomatitis occurring in at least 30% of patients. Adverse events of grade 3 or higher were reported in 54% of the patients; four grade 5 adverse events occurred. The ORR was 31% with daraxonrasib at a dose of 120 mg or less, 34% at doses of 160 to 220 mg, and 37% at a dose of 300 mg. The authors conclude that among patients with previously treated advanced RAS-mutant NSCLC receiving daraxonrasib at a dose of 300 mg or less daily, 54% had adverse events of grade 3 or higher, and antitumor activity was reported in more than 30%.