biostudies-literatureSkoulidis FNCI NIH HHSAmgen Inc.2755-2767https://www.ebi.ac.uk/biostudies/studies/S-EPMC12353874biostudies-literatureUnknown31(8)Molecular determinants of KRAS(G12C)inhibitor efficacy in KRAS^G12C-mutated non-small-cell lung cancer (NSCLC) remain poorly characterized. Here we report one of the largest integrated analyses to date of sotorasib clinical efficacy biomarkers from the phase 2 CodeBreaK 100 and phase 3 CodeBreaK 200 studies. We reveal differential sotorasib activity and relative benefit compared to docetaxel across KRAS^G12C-mutated NSCLC co-mutational subsets and transcriptional subtypes. We also identify low expression of TTF1 and KEAP1 co-mutations/NRF2 activation as major determinants of sotorasib anti-tumor efficacy and adverse prognostic features. Exploratory analyses highlight potential tumor cell-extrinsic contributors to sotorasib anti-tumor activity and suggest that early on-tNature medicineMolecular determinants of sotorasib clinical efficacy in KRAS<sup>G12C</sup>-mutated non-small-cell lung cancer.PMC12353874P30 CA008748Couraud SKim SWLena HDooms CLindsay CRPaz-Ares Rodriguez LToyozawa RMountzios GSkoulidis FWolf JChmielewska IMukundan LDy GKNadal EVelcheti VHindoyan AAnderson AHong DSLi BTTomasini PWilmanski Tvan der Wekken AJReddy ACurioni Fontecedro Ade Langen AJMehta BSacher APati ARocco DArdito-Abraham CSchuler MO'Byrne KfalseMolecular determinants of sotorasib clinical efficacy in KRAS<sup>G12C</sup>-mutated non-small-cell lung cancer.Molecular determinants of KRAS(G12C)inhibitor efficacy in KRAS^G12C-mutated non-small-cell lung cancer (NSCLC) remain poorly characterized. Here we report one of the largest integrated analyses to date of sotorasib clinical efficacy biomarkers from the phase 2 CodeBreaK 100 and phase 3 CodeBreaK 200 studies. We reveal differential sotorasib activity and relative benefit compared to docetaxel across KRAS^G12C-mutated NSCLC co-mutational subsets and transcriptional subtypes. We also identify low expression of TTF1 and KEAP1 co-mutations/NRF2 activation as major determinants of sotorasib anti-tumor efficacy and adverse prognostic features. Exploratory analyses highlight potential tumor cell-extrinsic contributors to sotorasib anti-tumor activity and suggest that early on-t2025-01-01T00:00:00Z2025 Aug2026-05-29T15:07:28.504Z2026-04-08T05:10:49.098ZS-EPMC123538744043727210.1038/s41591-025-03732-5