Data from Comutations and KRAS<sup>G12C</sup> Inhibitor Efficacy in Advanced NSCLC
Authors: Negrao Marcelo V. , Araujo Haniel A. , Lamberti Giuseppe , Cooper Alissa J. , Akhave Neal S. , Zhou Teng , Delasos Lukas , Hicks J. Kevin , Aldea Mihaela , Minuti Gabriele , Hines Jacobi , Aredo Jacqueline V. , Dennis Michael J. , Chakrabarti Turja , Scott Susan C. , Bironzo Paolo , Scheffler Matthias , Christopoulos Petros , Stenzinger Albrecht , Riess Jonathan W. , Kim So Yeon , Goldberg Sarah B. , Li Mingjia , Wang Qi , Qing Yun , Ni Ying , Do Minh Truong , Lee Richard , Ricciuti Biagio , Alessi Joao Victor , Wang Jing , Resuli Blerina , Landi Lorenza , Tseng Shu-Chi , Nishino Mizuki , Digumarthy Subba R. , Rinsurongkawong Waree , Rinsurongkawong Vadeerat , Vaporciyan Ara A. , Blumenschein George R. , Zhang Jianjun , Owen Dwight H. , Blakely Collin M. , Mountzios Giannis , Shu Catherine A. , Bestvina Christine M. , Garassino Marina Chiara , Marrone Kristen A. , Gray Jhanelle E. , Patel Sandip Pravin , Cummings Amy L. , Wakelee Heather A. , Wolf Juergen , Scagliotti Giorgio Vittorio , Cappuzzo Federico , Barlesi Fabrice , Patil Pradnya D. , Drusbosky Leylah , Gibbons Don L. , Meric-Bernstam Funda , Lee J. Jack , Heymach John V. , Hong David S. , Heist Rebecca S. , Awad Mark M. , Skoulidis Ferdinandos 
Published: July 2023

<div>Abstract<p>Molecular modifiers of KRAS<sup>G12C</sup> inhibitor (KRAS<sup>G12Ci</sup>) efficacy in advanced <i>KRAS</i><sup>G12C</sup>-mutant NSCLC are poorly defined. In a large unbiased clinicogenomic analysis of 424 patients with non–small cell lung cancer (NSCLC), we identified and validated coalterations in <i>KEAP1, SMARCA4</i>, and <i>CDKN2A</i> as major independent determinants of inferior clinical outcomes with KRAS<sup>G12Ci</sup> monotherapy. Collectively, comutations in these three tumor suppressor genes segregated patients into distinct prognostic subgroups and captured ∼50% of those with early disease progression (progression-free survival ≤3 months) with KRAS<sup>G12Ci</sup>. Pathway-level integration of less prevalent coalterations in functionally related genes nominated PI3K/AKT/MTOR pathway and additional baseline <i>RAS</i> gene alterations, including amplifications, as candidate drivers of inferior outcomes with KRAS<sup>G12Ci</sup>, and revealed a possible association between defective DNA damage response/repair and improved KRAS<sup>G12Ci</sup> efficacy. Our findings propose a framework for patient stratification and clinical outcome prediction in <i>KRAS</i><sup>G12C</sup>-mutant NSCLC that can inform rational selection and appropriate tailoring of emerging combination therapies.</p>Significance:<p>In this work, we identify co-occurring genomic alterations in <i>KEAP1</i>, <i>SMARCA4</i>, and <i>CDKN2A</i> as independent determinants of poor clinical outcomes with KRAS<sup>G12Ci</sup> monotherapy in advanced NSCLC, and we propose a framework for patient stratification and treatment personalization based on the comutational status of individual tumors.</p><p><i><a href="https://aacrjournals.org/cancerdiscovery/article/doi/10.1158/2159-8290.CD-23-0489" target="_blank">See related commentary by Heng et al., p. 1513.</a></i></p><p><i><a href="https://aacrjournals.org/cancerdiscovery/article/doi/10.1158/2159-8290.CD-13-7-ITI" target="_blank">This article is highlighted in the In This Issue feature, p. 1501</a></i></p></div>