Molecular determinants of sotorasib clinical efficacy in KRAS(G12C)-mutated non-small-cell lung cancer Journal Article
| Authors: | Skoulidis, F.; Li, B. T.; de Langen, A. J.; Hong, D. S.; Lena, H.; Wolf, J.; Dy, G. K.; Curioni Fontecedro, A.; Tomasini, P.; Velcheti, V.; van der Wekken, A. J.; Dooms, C.; Paz-Ares Rodriguez, L.; Mountzios, G.; Sacher, A.; Nadal, E.; Couraud, S.; Kim, S. W.; O’Byrne, K.; Rocco, D.; Toyozawa, R.; Chmielewska, I.; Lindsay, C. R.; Hindoyan, A.; Mukundan, L.; Wilmanski, T.; Anderson, A.; Ardito-Abraham, C.; Pati, A.; Reddy, A.; Mehta, B.; Schuler, M. |
| Article Title: | Molecular determinants of sotorasib clinical efficacy in KRAS(G12C)-mutated non-small-cell lung cancer |
| Abstract: | Molecular determinants of KRAS(G12C)inhibitor efficacy in KRASG12C-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 KRASG12C-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-treatment clearance of KRASG12C- circulating tumor DNA may refine clinical response prediction algorithms. Our findings advance precision medicine for patients with KRASG12C-mutated NSCLC and establish a framework for patient stratification and selection for treatment intensification with rationally applied therapeutic combinations. © The Author(s) 2025. |
| Journal Title: | Nature Medicine |
| ISSN: | 1078-8956 |
| Publisher: | Nature Publishing Group |
| Publication status: | Online ahead of print |
| Date Published: | 2025-05-28 |
| Online Publication Date: | 2025-05-28 |
| Language: | English |
| DOI: | 10.1038/s41591-025-03732-5 |
| PROVIDER: | scopus |
| PUBMED: | 40437272 |
| DOI/URL: | |
| Notes: | Source: Scopus |
