Divarasib

Overview

Divarasib (RG6330; GDC-6036) is an investigational, orally administered small-molecule inhibitor of KRAS G12C. Clinical development includes monotherapy and combinations with EGFR or PD-1 inhibitors in KRAS G12C-positive solid tumors. Evidence remains based primarily on non-randomized early-phase studies and conference abstracts; phase 3 trials are ongoing. (nejm.org)

Mechanism of action

Divarasib selectively and covalently binds cysteine-12 in the switch-II pocket of GDP-bound KRAS G12C, stabilizing its inactive state and suppressing downstream oncogenic signaling. Structural and preclinical studies support strong target engagement and selectivity for mutant over wild-type KRAS. (pmc.ncbi.nlm.nih.gov)

In colorectal cancer, EGFR-mediated reactivation of RAS–MAPK signaling can limit KRAS G12C inhibitor activity, providing the rationale for combining divarasib with cetuximab. (nature.com)

Efficacy

• Single-agent, previously treated NSCLC: In long-term follow-up of a phase 1 study, the confirmed objective response rate (ORR) was 55.6% among 63 response-evaluable patients. Median duration of response was 18.0 months, and median progression-free survival (PFS) was 13.8 months overall and 15.3 months at the 400-mg dose. (ascopubs.org)
• Single-agent colorectal cancer: In the initial phase 1 study, confirmed ORR was 29.1% and median PFS was 5.6 months across dose levels. At 400 mg, ORR was 35.9% and median PFS was 6.9 months. (nejm.org)
• Other solid tumors: Partial responses were observed in 8 of 22 patients, including patients with pancreatic, biliary, gastric and other cancers; these tumor-specific samples were very small. (nejm.org)
• Divarasib plus cetuximab in previously treated colorectal cancer: A phase 1b trial reported a confirmed ORR of 62.5% among 24 KRAS G12C inhibitor-naive patients, with median response duration of 6.9 months and median PFS of 8.1 months. (nature.com)
• First-line divarasib plus pembrolizumab in advanced NSCLC: A 2026 phase 1b/2 conference abstract reported a confirmed ORR of 73% and median PFS of 19.3 months in a cohort with 12.2 months’ median follow-up. These preliminary, single-arm findings have not yet been confirmed in a randomized trial. (ascopubs.org)

Safety

With single-agent divarasib in NSCLC, 94% of patients experienced treatment-related adverse events, but most were grade 1–2; 17% had grade 3–4 events and none had grade 5 events. The most frequent events were nausea, vomiting and diarrhea. Treatment-related events led to dose reduction in 23% and discontinuation in 4.6%. No new severe toxicities emerged among patients treated beyond one year. (ascopubs.org)

With divarasib plus cetuximab, all 29 patients experienced a treatment-related event. Common events included rash, diarrhea, nausea and vomiting; grade 3 and grade 4 events occurred in 37.9% and 6.9%, respectively, with no grade 5 events. (nature.com)

In the preliminary pembrolizumab combination study, grade 3–4 treatment-related events occurred in 65% of patients. Diarrhea and elevations in ALT or AST were prominent, and 25% discontinued treatment because of treatment-related events. (ascopubs.org)

Further reading

• Phase 1 single-agent study — New England Journal of Medicine
• Long-term NSCLC follow-up — Journal of Clinical Oncology
• Divarasib plus cetuximab in colorectal cancer — Nature Medicine
• KRAS G12C–divarasib structural study
• First-line divarasib plus pembrolizumab ASCO 2026 abstract

Last updated: Sep 2026