Molecular determinants of sotorasib clinical efficacy in KRASG12C-mutated non-small-cell lung cancer
Ferdinandos Skoulidis, Bob T. Li, Adrianus J. de Langen, David S. Hong, H. Léna, Juergen Wolf, Grace K. Dy, Alessandra Curioni‐Fontecedro, Pascale Tomasini, Vamsidhar Velcheti, Anthonie J. van der Wekken, Christophe Dooms, Luis Paz‐Ares, Giannis Mountzios, Adrian G. Sacher, Ernest Nadal, S. Couraud, Sang‐We Kim, Kenneth J. O’Byrne, Danilo Rocco, Ryo Toyozawa, Izabela Chmielewska, Colin R. Lindsay, Antreas Hindoyan, Lata Mukundan, Tomasz Wilmanski, Abraham Anderson, Christine Ardito-Abraham, Amrita Pati, Anita Reddy, Bhakti Mehta, Martin Schüler
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. This large integrated analysis of the KRASG12C inhibitor sotorasib clinical efficacy biomarkers from the phase 2 CodeBreaK 100 and phase 3 CodeBreaK 200 trials shows that low expression of TTF-1 and high expression of NRF2 determine anti-tumor efficacy of sotorasib in non–small-cell lung cancer.