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Single-Agent Divarasib (GDC-6036) in Solid Tumors with a KRAS G12C Mutation.

Adrian Sacher1, Patricia LoRusso1, Manish R Patel1

  • 1From the Princess Margaret Cancer Centre, University Health Network, and the Departments of Medicine and Immunology, University of Toronto, Toronto (A. Sacher), and the Lady Davis Institute and the Segal Cancer Center, Jewish General Hospital, McGill University, Montreal (W.H.M.); Yale Cancer Center, Yale University, New Haven, CT (P.L.); Florida Cancer Specialists/Sarah Cannon Research Institute, Sarasota (M.R.P.); Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron University Hospital, Barcelona (E.G.), Hospital Universitario Virgen del Rocio, Seville (A.F.), and Hospital Universitario 12 de Octubre, H120-CNIO Lung Cancer Unit, Universidad Complutense and Ciberonc (L.P.-A.), and START MADRID-CIOCC, Hospital Universitario HM Sanchinarro (M.M.), Madrid - all in Spain; the UCL Cancer Institute, University College London Hospitals NHS Trust, London (M.D.F.), and the Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester and Christie NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester (M.G.K.) - both in the United Kingdom; IRCCS Humanitas Research Center, Humanitas Cancer Center, and the Department of Biomedical Sciences, Humanitas University, Milan (A. Santoro); Asan Medical Center (T.W.K.), Seoul National University Hospital and Seoul National University Cancer Research Institute (S.-W.H.), and Seoul National University Bundang Hospital (J.-S.L.) - all in Seoul, South Korea; Linear Clinical Research, Perth, WA (S.B.), and the Peter MacCallum Cancer Centre and the Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC (J.D.) - all in Australia; Dana-Farber Cancer Institute and Harvard Medical School - both in Boston (M.L.C.); Memorial Sloan Kettering Cancer Center, New York (K.A.); and City of Hope, Duarte (E.M.), and Genentech, South San Francisco (Y.C., Z.S., S.M., M.T.L., S.R.-J., J.C., N.V.D., J.L.S.) - both in California.

The New England Journal of Medicine
|August 23, 2023
PubMed
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Divarasib shows durable clinical responses in patients with KRAS G12C-mutated cancers, including non-small-cell lung cancer and colorectal cancer. This covalent KRAS G12C inhibitor was well-tolerated with manageable adverse events in a Phase 1 study.

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Area of Science:

  • Oncology
  • Molecular Biology
  • Clinical Pharmacology

Background:

  • Divarasib (GDC-6036) is a potent and selective covalent inhibitor targeting the KRAS G12C mutation.
  • The KRAS G12C mutation is prevalent in various solid tumors, driving oncogenesis.

Purpose of the Study:

  • To evaluate the safety, pharmacokinetics, and antitumor activity of divarasib in patients with advanced solid tumors harboring the KRAS G12C mutation.
  • To identify biomarkers of response and resistance to divarasib treatment.

Main Methods:

  • A Phase 1, open-label, dose-escalation study of orally administered divarasib (50-400 mg once daily).
  • 137 patients with advanced or metastatic solid tumors (NSCLC, colorectal cancer, other) were enrolled.
  • Safety, pharmacokinetics, antitumor response (RECIST criteria), and circulating tumor DNA (ctDNA) were assessed.

Main Results:

  • Divarasib was generally well-tolerated; no dose-limiting toxicities or treatment-related deaths occurred.
  • Confirmed response rates were 53.4% in NSCLC and 29.1% in colorectal cancer patients.
  • Median progression-free survival was 13.1 months for NSCLC and 5.6 months for colorectal cancer; ctDNA analysis revealed target engagement and resistance mechanisms.

Conclusions:

  • Divarasib demonstrated durable clinical responses in patients with KRAS G12C-positive solid tumors.
  • The drug exhibited a manageable safety profile with mostly low-grade adverse events.
  • Biomarker analysis provided insights into treatment response and resistance pathways.