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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.
Background:
Divarasib (GDC-6036) is a covalent KRAS G12C inhibitor that was designed to have high potency and selectivity.
Methods:
In a phase 1 study, we evaluated divarasib administered orally once daily (at doses ranging from 50 to 400 mg) in patients who had advanced or metastatic solid tumors that harbor a KRAS G12C mutation. The primary objective was an assessment of safety; pharmacokinetics, investigator-evaluated antitumor activity, and biomarkers of response and resistance were also assessed.
Results:
A total of 137 patients (60 with non-small-cell lung cancer [NSCLC], 55 with colorectal cancer, and 22 with other solid tumors) received divarasib. No dose-limiting toxic effects or treatment-related deaths were reported. Treatment-related adverse events occurred in 127 patients (93%); grade 3 events occurred in 15 patients (11%) and a grade 4 event in 1 patient (1%). Treatment-related adverse events resulted in a dose reduction in 19 patients (14%) and discontinuation of treatment in 4 patients (3%). Among patients with NSCLC, a confirmed response was observed in 53.4% of patients (95% confidence interval [CI], 39.9 to 66.7), and the median progression-free survival was 13.1 months (95% CI, 8.8 to could not be estimated). Among patients with colorectal cancer, a confirmed response was observed in 29.1% of patients (95% CI, 17.6 to 42.9), and the median progression-free survival was 5.6 months (95% CI, 4.1 to 8.2). Responses were also observed in patients with other solid tumors. Serial assessment of circulating tumor DNA showed declines in KRAS G12C variant allele frequency associated with response and identified genomic alterations that may confer resistance to divarasib.
Conclusions:
Treatment with divarasib resulted in durable clinical responses across KRAS G12C-positive tumors, with mostly low-grade adverse events. (Funded by Genentech; ClinicalTrials.gov number, NCT04449874.).
Insights
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.
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.
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