In a phase I study reported in The New England Journal of Medicine, Sacher et al found that the covalent KRAS G12C inhibitor divarasib (also referred to as GDC-6036) produced durable responses in patients with advanced or metastatic solid tumors with a KRAS G12C mutation.

In the study, 137 patients from sites in 12 countries received oral divarasib at doses of 50, 100, 200, or 400 mg once daily between July 2020 and October 2022. Treatment continued until disease progression or unacceptable toxicity. Eligible patients were those with disease progression after at least one available standard therapy, disease for which standard therapy proved to be ineffective or associated with unacceptable side effects, or disease for which a clinical trial of an investigational agent was a recognized standard of care. Patients enrolled in the trial included 60 with non–small cell lung cancer (NSCLC), 55 with colorectal cancer, and 22 with other solid tumors.

Safety

No dose-limiting toxicity was reported. Among all patients, treatment-related adverse events of any grade occurred in 93%, most commonly nausea (74%), diarrhea (61%), and vomiting (58%). Grade 3 or 4 treatment-related adverse events occurred in 12% of patients (one grade 4 event), most commonly diarrhea (4%) and increased aspartate aminotransferase (3%). Serious treatment-related adverse events occurred in two patients; treatment-related adverse events led to treatment discontinuation in 3%. No treatment-related deaths were reported. 

Responses

At all dose levels among 58 patients with NSCLC with measurable disease at baseline, confirmed objective response (complete response in 1 patient, 2%) was observed in 53.4% of patients (95% confidence interval [CI] = 39.9%–66.7%). Median response duration was 14.0 months (95% CI = 8.3 months to not estimable). Median progression-free survival was 13.1 months (95% CI = 8.8 months to not estimable).

At all dose levels among 55 patients with colorectal cancer and measurable disease at baseline, confirmed objective response (complete response in 1 patient, 2%) was observed in 29.1% of patients (95% CI = 17.6%–42.9%). Median response duration was 7.1 months (95% CI = 5.5–7.8 months). Median progression-free survival was 5.6 months (95% CI = 4.1–8.2 months).

Among 22 patients with other solid tumors, partial response was observed in 8 (36%), including in 3 patients with pancreatic adenocarcinoma and 1 patient each with anal adenocarcinoma, cholangiocarcinoma, endometrial squamous cell carcinoma, large-cell neuroendocrine carcinoma of the lung, and stomach adenocarcinoma.  

Serial evaluation of circulating tumor DNA showed that declines in KRAS G12C variant allele frequency were associated with response, and identified genomic alterations that may confer resistance to divarasib.

The investigators concluded, “Treatment with divarasib resulted in durable clinical responses across KRAS G12C–positive tumors, with mostly low-grade adverse events.”

Adrian Sacher, MD, of Princess Margaret Cancer Centre, Toronto, and Jayesh Desai, MB, BS, of Peter MacCallum Cancer Centre, Melbourne, are the corresponding authors for The New England Journal of Medicine article.

Disclosure: The study was funded by Genentech. For full disclosures of the study authors, visit nejm.org.