Divarasib (GDC-6036) is a covalent KRAS G12C inhibitor designed to exhibit high potency and selectivity. It is 5 to 20 times as potent and up to 50 times as selective in vitro as sotorasib and adagrasib. In an ongoing phase I study that is evaluating divarasib as a single agent and in combination with other anticancer treatments in patients with advanced or metastatic solid tumours with a KRAS G12C mutation, single-agent divarasib was shown to have a manageable safety profile and highly promising antitumour activity in patients with previously treated non-small cell lung cancer (NSCLC), colorectal cancer (CRC), or other cancers.
Findings from the ongoing phase I, open-label, multicentre, dose-escalation, and dose-expansion study are published by drs. Adrian Sacher of the Princess Margaret Cancer Centre in Toronto, ON, Canada, Jayesh Desai of the Peter MacCallum Cancer Centre in Melbourne, VIC, Australia, and colleagues from the GO42144 Investigator and Study Group on 24 August 2023 in The New England Journal of Medicine. Drs. Adrian Sacher, Patricia LoRusso, and Manish R. Patel contributed equally to this article.
The authors wrote in the background that the increased activity of the KRAS G12C protein drives oncogenic signalling through multiple downstream pathways that directly promote tumour cell survival, proliferation, and metastasis. The KRAS G12C mutation is present in approximately 12-14% of patients with NSCLC, 4% of patients with CRC, and up to 4% of patients with other solid tumour types with the frequency varying according to race and sex.
Standard therapeutic approaches for KRAS G12C–mutated solid tumours vary but generally consist of non-selective chemotherapy, immunotherapy, or both, with therapy resulting in modest benefits in previously treated patients. Although recently developed KRAS G12C inhibitors, including sotorasib and adagrasib, have shown antitumour activity in patients with previously treated KRAS G12C–mutated cancers, but the extent of the clinical benefit remains limited.
In this phase I study, the study team evaluated divarasib administered orally once daily at doses ranging from 50 to 400 mg in patients who had advanced or metastatic solid tumours that harbour a KRAS G12C mutation. The primary objective was an assessment of safety; pharmacokinetics, investigator-evaluated antitumour activity, and biomarkers of response and resistance were also assessed.
A total of 137 patients of whom 60 with NSCLC, 55 with CRC, and 22 with other solid tumours 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%).
The authors commented that divarasib was associated with mainly low-grade gastrointestinal adverse effects that were reversible and manageable with supportive medications. Among patients receiving divarasib, dose reductions and discontinuation of treatment resulting from divarasib-related adverse events were infrequent, findings that were similar or better than those reported in patients with NSCLC who received sotorasib or adagrasib.
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 (PFS) was 13.1 months (95% CI 8.8 to could not be estimated). Among patients with CRC, a confirmed response was observed in 29.1% of patients (95% CI 17.6 to 42.9), and the median PFS was 5.6 months (95% CI 4.1 to 8.2). Responses were also observed in patients with other solid tumours.
Serial assessment of circulating tumour DNA showed declines in KRAS G12C variant allele frequency associated with response and identified genomic alterations that may confer resistance to divarasib. The study team observed a diverse spectrum of genomic alterations in the KRAS gene and RTK, MAPK, and PI3K pathway components at the end of treatment that may confer acquired resistance in patients receiving single-agent divarasib; these results are like those previously reported for sotorasib and adagrasib.
In addition, the study investigators hypothesize that preexisting mutations in RAS genes (other than KRAS G12C) in a subgroup of patients with limited clinical benefit represent driver mutation heterogeneity in which non–KRAS G12C–mutated tumour cells are unlikely to respond to divarasib.
Divarasib appears to show numerically more responses and longer PFS among patients with either NSCLC or CRC than those observed with existing single-agent KRAS G12C inhibitors; however, conclusions drawn from cross-trial comparisons must be interpreted cautiously. In addition, there were limitations of this phase I study: the responses were assessed by the investigators rather than by blinded independent central review, and racial diversity was limited. Further assessment of divarasib in larger randomised studies is needed.
The authors concluded that the safety profile and encouraging single-agent antitumour activity of divarasib make it a promising clinical candidate. Treatment with divarasib resulted in durable clinical responses across KRAS G12C–positive tumours, with mostly low-grade adverse events. The data reported are from divarasib as a single agent. Divarasib is being investigated in combination with other anticancer therapies, including atezolizumab, cetuximab, bevacizumab, erlotinib, GDC-1971, and inavolisib in this current, ongoing study.
The study was funded by Genentech.
Sacher A, LoRusso P, Patel MR, et al. for the GO42144 Investigator and Study Group. Single-Agent Divarasib (GDC-6036) in Solid Tumors with a KRAS G12C Mutation. N Engl J Med 2023;389:710-721.