In mice with KRAS G12C tumors, the new dual-binding drugs turn off cancer signals faster than older drugs, but both types shrink tumors equally well when given at high enough doses.
Evidence from Studies
No evidence studies found yet.
What Would Prove This
Per GRADE and EBM methodology, here is what ideal scientific evidence would look like to definitively prove or disprove this claim, ordered from strongest to weakest.
Whether dual-state KRAS G12C inhibitors improve overall survival or tumor response rates compared to inactive-state inhibitors in patients with KRAS G12C-mutant cancers.
A systematic review and meta-analysis of all completed and ongoing phase III trials comparing dual-state and inactive-state KRAS G12C inhibitors, with primary endpoint of overall survival and secondary endpoints of objective response rate and duration of response, stratified by tumor type and prior therapy.
Whether dual-state KRAS G12C inhibitors improve tumor shrinkage or survival compared to inactive-state inhibitors in patients.
A multicenter, double-blind, randomized controlled trial of 400+ adults with advanced KRAS G12C-mutant NSCLC, randomized to receive compound 8 (150 mg daily) or divarasib (120 mg daily) for 24 months, with primary endpoint of objective response rate by RECIST 1.1 and secondary endpoint of progression-free survival.
Whether patients with higher levels of KRAS G12C target engagement after first dose of dual-state inhibitors have better clinical outcomes.
A prospective cohort study of 120+ patients with KRAS G12C-mutant NSCLC treated with a dual-state inhibitor, measuring KRAS G12C covalent adduct levels in tumor biopsies at 1 hour and 24 hours post first dose, and correlating with tumor shrinkage and progression-free survival.
Whether tumors that respond poorly to dual-state inhibitors have lower target engagement than those that respond well.
A case-control study comparing KRAS G12C target engagement levels in tumor biopsies from 30 patients with partial response to dual-state inhibitors (cases) versus 30 with stable disease or progression (controls), measured by mass spectrometry at 1 hour post-dose.
The range of KRAS G12C target engagement and pERK suppression achieved by dual-state inhibitors in mouse xenografts at various doses and time points.
A cross-sectional analysis of KRAS G12C covalent adduct levels and pERK suppression in MIA PaCa-2 and H2122 xenografts at 0.5, 1, 3, 7, and 24 hours after oral doses of 15, 50, 150 mg/kg of compound 8 and divarasib, with n=5 per group per time point.