Single-agent therapy with the covalent KRAS G12C inhibitor divarasib (GDC-6036) “resulted in durable clinical responses across KRAS G12C–positive tumors, with mostly low-grade adverse events,” the GO42144 study group reports. The authors conclude that divarasib is promising as a single agent and note that is also “being investigated in combination with other anticancer therapies, including atezolizumab, cetuximab, bevacizumab, erlotinib, GDC-1971 (an inhibitor of Src homology region 2–containing protein tyrosine phosphatase-2), and inavolisib (a PI3Kα inhibitor), in this current, ongoing study.”
The open-label, dose-escalation, and dose-expansion phase 1 trial assessed once-daily oral divarasib in doses ranging from 50 to 400 mg in patients who had advanced or metastatic solid tumors that harbor a KRAS G12C mutation. Based on a primary objective of safety assessment, the trial showed the following: “A total of 137 patients (60 with non–small-cell lung cancer [NSCLC], 55 with colorectal cancer, and 22 with other solid tumors) received divarasib. No dose-limiting toxic effects or treatment-related deaths were reported. Treatment-related adverse events occurred in 127 patients (93%); grade 3 events occurred in 15 patients (11%) and a grade 4 event in 1 patient (1%). Treatment-related adverse events resulted in a dose reduction in 19 patients (14%) and discontinuation of treatment in 4 patients (3%). Among patients with NSCLC, a confirmed response was observed in 53.4% of patients (95% confidence interval [CI], 39.9 to 66.7), and the median progression-free survival was 13.1 months (95% CI, 8.8 to could not be estimated). Among patients with colorectal cancer, a confirmed response was observed in 29.1% of patients (95% CI, 17.6 to 42.9), and the median progression-free survival was 5.6 months (95% CI, 4.1 to 8.2). Responses were also observed in patients with other solid tumors. Serial assessment of circulating tumor DNA showed declines in KRAS G12C variant allele frequency associated with response and identified genomic alterations that may confer resistance to divarasib.”