Divarasib

Overview

Divarasib (GDC-6036; also known as RG6330, RO7435846) is an oral, covalent KRAS G12C inhibitor in clinical development by Genentech/Roche for KRAS G12C–mutant solid tumors. As of October 7, 2025, divarasib remains investigational and is being studied in Phase I/II programs across tumor types. (drugs.ncats.io)

Mechanism of action

Divarasib binds irreversibly to the switch II pocket of KRAS G12C in its inactive GDP-bound state, locking KRAS in an inactive conformation and suppressing downstream MAPK signaling. Preclinical and translational reports describe high potency and selectivity versus wild-type KRAS. (nejm.org)

Efficacy

• Single-agent (Phase I, dose-escalation/expansion; NCT04449874)
• Across KRAS G12C–mutant solid tumors (n=137), investigator-assessed confirmed response rate (cRR) was:
  • NSCLC: 53.4% (95% CI, 39.9–66.7); median PFS 13.1 months (95% CI, 8.8–NE). At the 400 mg dose, cRR 56.4% and median PFS 13.7 months. (nejm.org)
  • Colorectal cancer (CRC): cRR 29.1% (95% CI, 17.6–42.9); median PFS 5.6 months (95% CI, 4.1–8.2). (nejm.org)
• Long-term follow-up updates reported in KRAS G12C–mutant NSCLC:
  • cRR 55.6% (95% CI, 42.5–68.1); median duration of response 18.0 months (95% CI, 11.1–24.9); median PFS 13.8 months overall and 15.3 months at 400 mg. (pubmed.ncbi.nlm.nih.gov)

• Congress update (ESMO 2024) at 400 mg dose showed:

  • NSCLC: ORR 59.1%, median PFS 15.3 months; CRC: ORR 33.3%, median PFS 6.9 months; other solid tumors: ORR 33.3%, median PFS 7.1 months. (oncologypro.esmo.org)

• Combination therapy: Divarasib + cetuximab in KRAS G12C–mutant CRC (Phase 1b arm of NCT04449874)

• In KRAS G12C inhibitor–naive patients (n=24), ORR 62.5% (95% CI, 40.6–81.2); median PFS 8.1 months (95% CI, 5.5–12.3); median DOR 6.9 months. Results published in Nature Medicine (2024). (pubmed.ncbi.nlm.nih.gov)

• Earlier AACR 2023 abstract reported encouraging activity for the combination in CRC; details align with the subsequent Nature Medicine publication. (aacrjournals.org)

• Additional combinations under evaluation within NCT04449874 include SHP2 inhibition (migoprotafib/GDC-1971), anti-EGFR (cetuximab), anti-VEGF (bevacizumab), EGFR TKI (erlotinib), PD-L1 blockade (atezolizumab), and PI3Kα inhibition (inavolisib); early clinical activity of divarasib + SHP2 inhibitor has been presented in NSCLC. (mycancergenome.org)

Safety

• Single-agent (Phase I, NCT04449874; NEJM 2023):
• No dose-limiting toxicities or treatment-related deaths were reported.
• Treatment-related AEs occurred in 93%; grade 3 in 11% and grade 4 in 1%.
• Dose reductions in 14% and discontinuations in 3%, most commonly for gastrointestinal events (nausea, vomiting, diarrhea) and liver enzyme elevations. (nejm.org)
• Long-term follow-up in NSCLC showed safety consistent with earlier reports over ≥1 year of therapy. (pubmed.ncbi.nlm.nih.gov)
• Divarasib + cetuximab (CRC Phase 1b) had a safety profile consistent with the single agents; divarasib dose reductions in 13.8% and no treatment withdrawals due to adverse events in the reported cohort. (pubmed.ncbi.nlm.nih.gov)

Further reading

• Single-agent divarasib Phase I (solid tumors; NEJM 2023). (nejm.org)
• Long-term follow-up in KRAS G12C–mutant NSCLC (PubMed, 2025). (pubmed.ncbi.nlm.nih.gov)
• Divarasib + cetuximab in KRAS G12C–mutant CRC (Nature Medicine 2024). (snucm.elsevierpure.com)
• AACR abstract: discovery of GDC-6036 and potency/selectivity profile. (aacrjournals.org)
• Trial record and combinations under study: NCT04449874 (GO42144). (mycancergenome.org)
• Review perspective on divarasib among KRAS G12C inhibitors in NSCLC (Targeted Oncology, 2024). (link.springer.com)

Notes - Reported efficacy metrics above are from early-phase, mostly single-arm cohorts with investigator assessment; cross-trial comparisons should be made cautiously. (nejm.org)

Last updated: Oct 2025