These new drugs bind almost exclusively to the mutated KRAS protein and not to other similar proteins in the body, reducing the risk of unintended side effects.
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 KRAS G12C dual inhibitors with this warhead class have a lower incidence of off-target toxicity in humans compared to other covalent KRAS inhibitors.
A systematic review and meta-analysis of all published clinical trial safety data for KRAS G12C inhibitors with trisubstituted acrylamide warheads versus acrylamide-based inhibitors, comparing rates of hepatotoxicity, rash, and other cysteine-reactive drug-related adverse events.
Whether KRAS G12C dual inhibitors with high cysteinome selectivity cause fewer adverse events than less selective covalent inhibitors in patients.
A phase II randomized trial of 100+ patients with KRAS G12C-mutant NSCLC comparing a highly selective dual inhibitor (e.g., compound 8) to a less selective covalent inhibitor (e.g., sotorasib), with primary endpoint of grade ≥3 adverse events related to off-target reactivity over 12 months.
Whether patients treated with KRAS G12C dual inhibitors develop immune-mediated toxicities linked to off-target protein modification.
A prospective cohort study of 80+ patients treated with KRAS G12C dual inhibitors, monitoring for immune-related adverse events and measuring anti-drug antibodies and autoantibodies against modified proteins over 24 months.
Whether patients who develop hepatotoxicity on KRAS G12C dual inhibitors have higher off-target cysteine modification profiles than those who do not.
A case-control study comparing cysteinome profiles from plasma samples of 20 patients who developed drug-induced liver injury on a dual-state inhibitor (cases) versus 20 matched controls without toxicity, using mass spectrometry to quantify off-target adducts.
The baseline off-target cysteine reactivity profile of KRAS G12C dual inhibitors in human proteomes.
A cross-sectional analysis of global cysteinome reactivity of compound 8 in human liver, kidney, and plasma proteomes using mass spectrometry-based profiling, identifying all modified cysteines beyond KRAS G12C.