53.4% Confirmed Response Rate: Roche’s KRAS G12C Inhibitor Divarasib Shows Promising Clinical Results

▎WuXi

Edited by Kant Content Team

Recently, the New England Journal of Medicine published the phase 1 trial results of divarasib (GDC-6036), a KRAS G12C inhibitor developed by Genentech, a subsidiary of Roche, in patients with KRAS G12C-mutant solid tumors. The authors noted that divarasib can produce durable clinical responses in KRAS G12C-positive tumors.The drug achieved confirmed response rates of 53.4% in non-small cell lung cancer (NSCLC) patients and 29.1% in colorectal cancer patients. The majority of observed adverse events were low-grade.

The purpose of this Phase 1 trial was to evaluate the effects of once-daily oral divarasib (dose range 50-400mg) in patients with advanced or metastatic solid tumors carrying the KRAS G12C mutation. The primary objective was to assess the safety of the drug, while also examining its pharmacokinetic profile, investigator-assessed anti-tumor activity, and biomarkers indicating patient response and resistance. A total of 137 patients were enrolled in the trial, including 60 patients with NSCLC, 55 with colorectal cancer, and 22 with other solid tumors.

Analysis shows,In NSCLC patients, a confirmed response was observed in 53.4% of patients (95% CI: 39.9-66.7), with a median progression-free survival of 13.1 months (95% CI: 8.8–not estimable). In colorectal cancer patients, a confirmed response was observed in 29.1% of patients (95% CI: 17.6-42.9), with a median progression-free survival of 5.6 months (95% CI: 4.1-8.2).Responses were also observed in patients with other solid tumors. Evaluation of circulating tumor DNA revealed a decrease in KRAS G12C variant allele frequency, indicating potential responses in patients. The study also identified genomic alterations associated with divarasib resistance.

In terms of safety, treatment-related adverse events occurred in 127 patients (93%); grade 3 events occurred in 15 patients (11%), and grade 4 events occurred in 1 patient (1%). Treatment-related adverse events led to dose reductions in 19 patients (14%) and treatment discontinuation in 4 patients (3%).

Industry media BioSpace pointed out that although the Phase 1 trial data of divarasib appears to be more effective compared to other KRAS G12C inhibitors, the trial scale was relatively small, with limited ethnic diversity among the patients. Additionally, patient response was evaluated by the researchers rather than through a blinded independent review, so it remains unclear whether the drug demonstrates superior efficacy.

References:

[1] Sacher, Adrian et al. “Single-Agent Divarasib (GDC-6036)in Solid Tumors with a KRAS G12C Mutation.” The New England journal of medicinevol. 389,8 (2023): 710-721. doi:10.1056/NEJMoa2303810

[2] Roche’s Divarasib Scores Phase I Win in KRAS-Mutated Solid Tumors.Retrieved August 24, 2023 from https://www.biospace.com/article/roche-s-divarasib-scores-phase-i-win-in-kras-mutated-solid-tumors-/