Divarasib in solid tumors with a KRAS G12C mutation

The highly potent and selective covalent KRAS G12C inhibitor divarasib has been shown to elicit durable clinical responses across a variety of KRAS G12C metastatic solid tumors in a paper recently published in The New England Journal of Medicine.

In this phase 1 trial, a total of 137 patients with various advanced or metastatic solid tumors (among them 60 with non-small-cell lung cancer and 55 with colorectal cancer) harboring a KRAS G12C mutation received divarasib administered orally once daily at doses ranging from 50 to 400 mg. Results show no dose-limiting toxic effects or treatment-related deaths, with treatment-related adverse events occurring in 93% of patients (grade 3 events in 11%, grade 4 event in 1%). Treatment-related adverse events resulted in a dose reduction in 14% of patients and discontinuation of treatment in 3%. Among patients with non-small-cell lung cancer, a confirmed response was observed in 53.4% of patients and the median progression-free survival was 13.1 months; among patients with colorectal cancer, a confirmed response was observed in 29.1% of patients and the median progression-free survival was 5.6 months; responses were also observed in patients with other solid tumors. Circulating tumor DNA analysis showed declines in KRAS G12C variant allele frequency associated with response and identified genomic alterations that may confer resistance to divarasib. As authors say, «Divarasib appears to show numerically more responses and longer progression-free survival among patients with either non-small-cell lung cancer or colorectal cancer than those observed with existing single-agent KRAS G12C inhibitors. The safety profile and encouraging single-agent antitumor activity of divarasib make it a promising clinical candidate both as a single agent and in combination with other anticancer therapies. There is a need to identify new effective strategies to delay and prevent resistance to KRAS G12C inhibitors; thus, divarasib is being investigated in combination with other anticancer therapies in this current, ongoing study», authors conclude.