Divarasib yields durable response across KRAS G12C-positive tumours

The covalent KRAS G12C inhibitor divarasib shows durable antitumour activity in patients harbouring KRAS G12C-positive tumours, with mostly low-grade adverse events, as shown in the phase I GO42144 study.

GO42144 included 137 patients with advanced or metastatic solid tumours harbouring a KRAS G12C mutation. Of these, 60 had nonsmall-cell lung cancer (NSCLC), 55 had colorectal cancer, and 22 had other solid tumours. All patients were treated with divarasib, administered orally once a day at doses ranging from 50 to 400 mg.

The primary objective was to evaluate safety. Pharmacokinetics, investigator-evaluated antitumour activity, and biomarkers of response and resistance were also examined.

There were no reports of dose-limiting toxic effects or treatment-related deaths. A total of 127 patients (93 percent) had treatment-related adverse events (TEAEs), including 15 (11 percent) with grade 3 events and one (1 percent) with a grade 4 event. TEAEs led to a dose reduction in 19 patients (14 percent) and treatment discontinuation in four (3 percent).

Among patients with NSCLC, 53.4 percent (95 percent confidence interval [CI], 39.9–66.7) had a confirmed response, with the median progression-free survival (PFS) being 13.1 months (95 percent CI, 8.8 to could not be estimated).

Among patients with colorectal cancer, 29.1 percent (95 percent CI, 17.6–42.9) had a confirmed response, with the median PFS being 5.6 months (95 percent CI, 4.1–8.2). Patients with other solid tumours also responded to divarasib.

Results of serial assessment of circulating tumour DNA showed reductions in KRAS G12C variant allele frequency associated with response and identified genomic alterations that may confer resistance to divarasib.