Dual-State KRAS G12C Inhibitors as Emerging Therapeutics for Brain and Lung Metastases.

New-generation KRAS G12C inhibitors demonstrate enhanced activity in both peripheral and central nervous system malignancies. Frontier Medicines' pyridopyrimidines and Novartis's spiro-indazole inhibitor (opnurasib) overcome resistance mechanisms by targeting both GDP- and GTP-bound KRAS states. Their blood-brain barrier permeability and synergy with immune checkpoint inhibitors represent a transformative advance for KRAS-driven cancers, especially metastatic nonsmall cell lung cancer (NSCLC).