Elisrasib (D3S-001) GDP-bound KRAS G12C inhibitor posts 56% ORR in 2L+ NSCLC and 32% post–G12Ci

Elisrasib is an oral, next-generation KRAS G12C inhibitor designed to bind the GDP-bound state and sustain target engagement despite growth factor–driven nucleotide exchange (a hypothesized resistance lever for 1st-gen covalent G12C inhibitors). In the ongoing Phase 1/2 NCT05410145 study in previously treated locally advanced/metastatic KRAS G12C-mutant NSCLC (n=165 treated; as of Jan 6, 2026), grade ≥3 TRAEs were 11.5% with any-grade TRAEs in 87.9%. In 2L+ G12Ci-naïve patients, ORR was 57.1% (48/84) with mPFS 8.8 months and mDOR 12.5 months; at the 600mg QD expansion dose ORR was 55.9% (38/68) with mPFS 11.8 months and mDOR 14.9 months—numerically above historical benchmarks for approved 1st-gen KRAS G12C inhibitors in this setting (sotorasib ORR ~37% and mPFS ~6.8 months; adagrasib mPFS ~6.9 months in KRYSTAL-1). In 2L+ G12Ci-refractory disease (600mg QD; 31 evaluable), ORR was 32.3% with mPFS 8.1 months and mDOR 8.2 months (notable given typical post-G12Ci outcomes are generally poor and non-targeted options often revert to docetaxel±ramucirumab–type efficacy ranges rather than >30% ORR); ctDNA molecular response (≥90% KRAS G12C MAF reduction) occurred in 93% (G12Ci-naïve) and 76% (G12Ci-refractory) among those with baseline detectable G12C ctDNA, and tumor shrinkage was reported in 4/5 with KRAS G12C amplification.