This study reports the discovery and preclinical activity of APS03118, a novel selective RET inhibitor featuring a novel tricyclic pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridine hinge-binding scaffold designed to overcome acquired resistance to first-generation selective RET inhibitors (SRIs). By enhancing hydrogen bonding with conserved hinge residues (Glu805, Ala807), APS03118 potently inhibits wild-type RET and diverse resistance mutations, including solvent-front (G810R/S/C), gatekeeper (V804M/L/E), roof (L730I/M), and hinge (Y806C/N/H) variants. In preclinical models, APS03118 induced complete tumor regression in KIF5B-RET and CCDC6-RET V804 M patient-derived xenografts (PDXs) and significantly prolonged survival in an intracranial CCDC6-RET metastasis model. It demonstrated >20-fold selectivity over off-target kinases (except FLT3: 8.6-fold and YES: 13.6-fold) and superior activity against RET G810 mutations versus approved RET inhibitors. Optimized pharmacokinetic properties (38.9% oral bioavailability in monkey) and central nervous system penetration support clinical translation. APS03118 is currently in phase Ib trials (NCT05653869) for patients progress on first-generation SRIs, offering a promising strategy to address acquired resistance.