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MEDTECH The covalent KRAS G12C inhibitor was developed to have great efficacy and selectivity.
Divarasib (GDC-6036), a covalent KRAS G12C inhibitor, has demonstrated durable clinical responses in a phase 1 study involving patients with advanced or metastatic solid tumors harboring the KRAS G12C mutation. The study primarily assessed safety, pharmacokinetics, and antitumor activity.
Study Design:
- Phase 1 study evaluating divarasib administered orally once daily at doses ranging from 50 to 400 mg.
- 137 patients participated, with types of cancer including non–small-cell lung cancer (NSCLC), colorectal cancer, and other solid tumors.
- Primary objective: assessment of safety; secondary objectives included pharmacokinetics, investigator-evaluated antitumor activity, and biomarkers of response and resistance.
Key Findings:
- No dose-limiting toxic effects or treatment-related deaths reported.
- Treatment-related adverse events in 93% of patients; grade 3 events in 11% and a grade 4 event in 1%.
- Confirmed response in NSCLC patients: 53.4% (95% CI, 39.9 to 66.7); median progression-free survival: 13.1 months.
- Confirmed response in colorectal cancer patients: 29.1% (95% CI, 17.6 to 42.9); median progression-free survival: 5.6 months.
- Declines in KRAS G12C variant allele frequency associated with response; genomic alterations may confer resistance.
Conclusion
- Divarasib resulted in durable clinical responses across KRAS G12C–positive tumors with mostly low-grade adverse events.
KRAS mutations are found in approximately 30% of all human cancers.
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