American Association for Cancer Research
cd-22-1420_supplementary_figure_s1_suppsf1.pdf (115.34 kB)

Supplementary Figure S1 from Comutations and KRASG12C Inhibitor Efficacy in Advanced NSCLC

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journal contribution
posted on 2023-07-07, 08:21 authored by 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, Ferdinandos Skoulidis

Clinical outcomes in Cohorts A (left) and B (right). A) progression-free survival; B) overall survival.


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Molecular modifiers of KRASG12C inhibitor (KRASG12Ci) efficacy in advanced KRASG12C-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 KEAP1, SMARCA4, and CDKN2A as major independent determinants of inferior clinical outcomes with KRASG12Ci 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 KRASG12Ci. Pathway-level integration of less prevalent coalterations in functionally related genes nominated PI3K/AKT/MTOR pathway and additional baseline RAS gene alterations, including amplifications, as candidate drivers of inferior outcomes with KRASG12Ci, and revealed a possible association between defective DNA damage response/repair and improved KRASG12Ci efficacy. Our findings propose a framework for patient stratification and clinical outcome prediction in KRASG12C-mutant NSCLC that can inform rational selection and appropriate tailoring of emerging combination therapies. In this work, we identify co-occurring genomic alterations in KEAP1, SMARCA4, and CDKN2A as independent determinants of poor clinical outcomes with KRASG12Ci monotherapy in advanced NSCLC, and we propose a framework for patient stratification and treatment personalization based on the comutational status of individual tumors.See related commentary by Heng et al., p. 1513.This article is highlighted in the In This Issue feature, p. 1501

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