Skoulidis Ferdinandos, Li Bob T, de Langen Adrianus Johannes, Hong David S, Lena Herve, Wolf Juergen, Dy Grace K, Curioni Fontecedro Alessandra, Tomasini Pascale, Velcheti Vamsidhar, van der Wekken Anthonie J, Dooms Christophe, Paz-Ares Rodriguez Luis, Mountzios Giannis, Sacher Adrian, Nadal Ernest, Couraud Sebastien, Kim Sang-We, O'Byrne Kenneth, Rocco Danilo, Toyozawa Ryo, Chmielewska Izabela, Lindsay Colin R, Hindoyan Antreas, Mukundan Lata, Wilmanski Tomasz, Anderson Abraham, Ardito-Abraham Christine, Pati Amrita, Reddy Anita, Mehta Bhakti, Schuler Martin
University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Memorial Sloan Kettering Cancer Center, Weill Cornell Medicine, New York, NY, USA.
Nat Med. 2025 May 28. doi: 10.1038/s41591-025-03732-5.
Molecular determinants of KRAS(G12C)inhibitor efficacy in KRAS-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-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 KRAS- circulating tumor DNA may refine clinical response prediction algorithms. Our findings advance precision medicine for patients with KRAS-mutated NSCLC and establish a framework for patient stratification and selection for treatment intensification with rationally applied therapeutic combinations.
KRAS（G12C）抑制剂在KRAS突变的非小细胞肺癌（NSCLC）中的疗效分子决定因素仍未得到充分表征。在此，我们报告了迄今为止对索托拉西布临床疗效生物标志物进行的最大规模综合分析之一，该分析来自2期CodeBreaK 100和3期CodeBreaK 200研究。我们揭示了与多西他赛相比，索托拉西布在KRAS突变的NSCLC共突变亚组和转录亚型中的不同活性和相对益处。我们还确定TTF1低表达和KEAP1共突变/NRF2激活是索托拉西布抗肿瘤疗效和不良预后特征的主要决定因素。探索性分析突出了索托拉西布抗肿瘤活性的潜在肿瘤细胞外因素，并表明KRAS循环肿瘤DNA的早期治疗清除可能会完善临床反应预测算法。我们的研究结果推动了KRAS突变NSCLC患者的精准医学发展，并建立了一个患者分层和选择框架，以便通过合理应用治疗组合进行强化治疗。
