Dr Hong on Preliminary Activity With RMC-6291 in Advanced KRAS G12C–Mutant Solid Tumors

David S. Hong, MD, deputy chair, Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, discusses preliminary efficacy data from a phase 1 trial (NCT05462717) of the KRAS G12C inhibitor RMC-6291 in advanced KRAS G12C–mutant solid tumors.

In this multicenter, open-label, dose-escalation and -expansion study, RMC-6291 is being assessed as a monotherapy for patients with advanced solid tumors harboring KRAS G12C mutations.

Preliminary safety and efficacy data presented at the 2023 Molecular Targets and Therapeutics Annual Meeting included 63 patients with KRAS G12C–mutated non–small cell lung cancer (NSCLC; n = 23), colorectal cancer (CRC; n = 33), and other tumor types (n = 7). Evaluable patients began treatment with a 50 mg of oral RMC-6291 once per day, and doses were escalated to up to 400 mg twice per day.

At the data cutoff of October 5, 2023, 37 patients were evaluable for efficacy, including 17 with NSCLC and 20 with CRC. Among the 10 patients with NSCLC who had previously been treated with a KRAS G12C inhibitor, 50% achieved a partial response (PR) as the best response, Hong reports, and the disease control rate (DCR) in this population was 100%. In the 7 patients with NSCLC who were naïve to KRAS G12C inhibitors, the PR rate was 43%, the stable disease (SD) rate was 57%, and the DCR was 100%. Efficacy-evaluable patients with CRC who were naïve to a KRAS G12C inhibitor achieved an overall response rate of 40%, with all 8 patients experiencing a PR. The SD rate was 40%, and the DCR was 80%.

One of the limitations commonly associated with KRAS G12C inhibition is the development of multiple resistance mechanisms, Hong continues. However, the novel “on” mechanism of RMC-6291 demonstrated an ability to overcome some of these resistance mechanisms in several patients, he states. While the precise data and outcomes will need to be further evaluated in larger patient cohorts, the results are encouraging, Hong emphasizes.

Like most phase 1 trials, these results occurred in a limited patient population, Hong cautions. However, findings support the ongoing development of RMC-6291 in advanced solid tumors harboring KRAS G12C mutations, he concludes.