1. Co-mutations and KRAS G12C inhibitor efficacy in advanced NSCLC
- Author
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Marcelo V. Negrao, Haniel A. Araujo, Giuseppe Lamberti, Alissa J. Cooper, Neal S. Akhave, Teng Zhou, Lukas Delasos, J Kevin. Hicks, Mihaela Aldea, Gabriele Minuti, Jacobi Hines, Jacqueline V. Aredo, Michael J. Dennis, Turja Chakrabarti, Susan C. Scott, Paolo Bironzo, Matthias Scheffler, Petros Christopoulos, Albrecht Stenzinger, Jonathan W. Riess, So Yeon Kim, Sarah B. Goldberg, Mingjia Li, Qi Wang, Yun Qing, Ying Ni, Minh Truong Do, Richard Lee, Biagio Ricciuti, Joao Victor. Alessi, Jing Wang, Blerina Resuli, Lorenza Landi, Shu-Chi Tseng, Mizuki Nishino, Subba R. Digumarthy, Waree Rinsurongkawong, Vadeerat Rinsurongkawong, Ara A Vaporciyan, George R. Blumenschein, Jianjun Zhang, Dwight H. Owen, Collin M. Blakely, Giannis Mountzios, Catherine A. Shu, Christine M. Bestvina, Marina Chiara. Garassino, Kristen A. Marrone, Jhanelle E. Gray, Sandip Pravin. Patel, Amy L. Cummings, Heather A. Wakelee, Juergen Wolf, Giorgio Vittorio. Scagliotti, Federico Cappuzzo, Fabrice Barlesi, Pradnya D. Patil, Leylah Drusbosky, Don L. Gibbons, Funda Meric-Bernstam, J. Jack Lee, John V. Heymach, David S. Hong, Rebecca S. Heist, Mark M. Awad, and Ferdinandos Skoulidis
- Subjects
Oncology - Abstract
Molecular modifiers of KRAS G12C inhibitor (KRAS G12Ci) efficacy in advanced KRAS G12C-mutant NSCLC are poorly defined. In a large unbiased clinico-genomic analysis of 424 NSCLC patients, we identified and validated co-alterations in KEAP1, SMARCA4 and CDKN2A as major independent determinants of inferior clinical outcomes with KRAS G12Ci monotherapy. Collectively, co-mutations in these three tumor suppressor genes segregated patients into distinct prognostic subgroups and captured ~50% of those with early disease progression (PFS≤3 months) with KRAS G12Ci. Pathway-level integration of less prevalent co-alterations in functionally related genes nominated PI3K/AKT/MTOR pathway and additional baseline RAS gene alterations, including amplifications, as candidate drivers of inferior outcomes with KRAS G12Ci, and revealed a possible association between defective DNA damage response/repair and improved KRAS G12Ci efficacy. Our findings propose a framework for patient stratification and clinical outcome prediction in KRAS G12C-mutant NSCLC that can inform rational selection and appropriate tailoring of emerging combination therapies.
- Published
- 2023
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