Comutations and KRASG12C Inhibitor Efficacy in Advanced NSCLC

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

doi:10.1158/2159-8290.CD-22-1420

Comutations and KRAS^G12C Inhibitor Efficacy in Advanced NSCLC

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. RiessSo 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^*

^*Corresponding author for this work

Medicine, Hematology Oncology Division

Research output: Contribution to journal › Article › peer-review

91 Scopus citations

Abstract

Molecular modifiers of KRAS^G12C inhibitor (KRAS^G12Ci) efficacy in advanced KRAS^G12C-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 KRAS^G12Ci 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^G12Ci. Pathway-level integration of less preva-lent 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 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. SIGNIFICANCE: 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.

Original language	English (US)
Pages (from-to)	1556-1571
Number of pages	16
Journal	Cancer discovery
Volume	13
Issue number	7
DOIs	https://doi.org/10.1158/2159-8290.CD-22-1420
State	Published - 2023

Funding

M.V. Negrao acknowledges research funding from Rexanna’s Foundation for Fighting Lung Cancer. J. Hines acknowledges research funding from an NIH Clinical Therapeutics Training Grant (T32-GM07019). M.M. Awad was supported in part by the Elva J. and Clayton L. McLaughlin Fund for Lung Cancer Research, Team Stuie, and LUNGSTRONG. Work in F. Skoulidis’s laboratory was supported in part by NIH/NCI 1R01 CA262469-01 and the Tammi Hissom Grant from Rexanna’s Foundation for Fighting Lung Can-cer. This work was supported by the generous philanthropic contributions to The University of Texas MD Anderson Lung Moon Shot Program and the MD Anderson Cancer Center Support Grant P30 CA016672. We acknowledge the MD Anderson GEMINI Team for their contributions to this article. The publication costs of this article were defrayed in part by the payment of publication fees. Therefore, and solely to indicate this fact, this article is hereby marked “advertisement” in accordance with 18 USC section 1734. M.V. Negrao acknowledges research funding from Rexanna’s Foundation for Fighting Lung Cancer. J. Hines acknowledges research funding from an NIH Clinical Therapeutics Training Grant (T32-GM07019). M.M. Awad was supported in part by the Elva J. and Clayton L. McLaughlin Fund for Lung Cancer Research, Team Stuie, and LUNGSTRONG. Work in F. Skoulidis’s laboratory was supported in part by NIH/NCI 1R01 CA262469-01 and the Tammi Hissom Grant from Rexanna’s Foundation for Fighting Lung Cancer. This work was supported by the generous philanthropic contributions to The University of Texas MD Anderson Lung Moon Shot Program and the MD Anderson Cancer Center Support Grant P30 CA016672. We acknowledge the MD Anderson GEMINI Team for their contributions to this article.

ASJC Scopus subject areas

Oncology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1158/2159-8290.CD-22-1420

Cite this

Negrao, M. V., Araujo, H. A., Lamberti, G., Cooper, A. J., Akhave, N. S., Zhou, T., Delasos, L., Hicks, J. K., Aldea, M., Minuti, G., Hines, J., Aredo, J. V., Dennis, M. J., Chakrabarti, T., Scott, S. C., Bironzo, P., Scheffler, M., Christopoulos, P., Stenzinger, A., ... Skoulidis, F. (2023). Comutations and KRAS^G12C Inhibitor Efficacy in Advanced NSCLC. Cancer discovery, 13(7), 1556-1571. https://doi.org/10.1158/2159-8290.CD-22-1420

@article{58e39c3bfea64e8f82759a57477cc755,

title = "Comutations and KRASG12C Inhibitor Efficacy in Advanced NSCLC",

abstract = "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 preva-lent 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. SIGNIFICANCE: 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.",

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

note = "Publisher Copyright: {\textcopyright} 2023 American Association for Cancer Research.",

year = "2023",

doi = "10.1158/2159-8290.CD-22-1420",

language = "English (US)",

volume = "13",

pages = "1556--1571",

journal = "Cancer discovery",

issn = "2159-8274",

publisher = "American Association for Cancer Research Inc.",

number = "7",

}

Negrao, MV, Araujo, HA, Lamberti, G, Cooper, AJ, Akhave, NS, Zhou, T, Delasos, L, Hicks, JK, Aldea, M, Minuti, G, Hines, J, Aredo, JV, Dennis, MJ, Chakrabarti, T, Scott, SC, Bironzo, P, Scheffler, M, Christopoulos, P, Stenzinger, A, Riess, JW, Kim, SY, Goldberg, SB, Li, M, Wang, Q, Qing, Y, Ni, Y, Do, MT, Lee, R, Ricciuti, B, Alessi, JV, Wang, J, Resuli, B, Landi, L, Tseng, SC, Nishino, M, Digumarthy, SR, Rinsurongkawong, W, Rinsurongkawong, V, Vaporciyan, AA, Blumenschein, GR, Zhang, J, Owen, DH, Blakely, CM, Mountzios, G, Shu, CA, Bestvina, CM, Garassino, MC, Marrone, KA, Gray, JE, Patel, SP, Cummings, AL, Wakelee, HA, Wolf, J, Scagliotti, GV, Cappuzzo, F, Barlesi, F, Patil, PD, Drusbosky, L, Gibbons, DL, Meric-Bernstam, F, Lee, JJ, Heymach, JV, Hong, DS, Heist, RS, Awad, MM & Skoulidis, F 2023, 'Comutations and KRAS^G12C Inhibitor Efficacy in Advanced NSCLC', Cancer discovery, vol. 13, no. 7, pp. 1556-1571. https://doi.org/10.1158/2159-8290.CD-22-1420

TY - JOUR

T1 - Comutations and KRASG12C Inhibitor Efficacy in Advanced NSCLC

AU - Negrao, Marcelo V.

AU - Araujo, Haniel A.

AU - Lamberti, Giuseppe

AU - Cooper, Alissa J.

AU - Akhave, Neal S.

AU - Zhou, Teng

AU - Delasos, Lukas

AU - Hicks, J. Kevin

AU - Aldea, Mihaela

AU - Minuti, Gabriele

AU - Hines, Jacobi

AU - Aredo, Jacqueline V.

AU - Dennis, Michael J.

AU - Chakrabarti, Turja

AU - Scott, Susan C.

AU - Bironzo, Paolo

AU - Scheffler, Matthias

AU - Christopoulos, Petros

AU - Stenzinger, Albrecht

AU - Riess, Jonathan W.

AU - Kim, So Yeon

AU - Goldberg, Sarah B.

AU - Li, Mingjia

AU - Wang, Qi

AU - Qing, Yun

AU - Ni, Ying

AU - Do, Minh Truong

AU - Lee, Richard

AU - Ricciuti, Biagio

AU - Alessi, Joao Victor

AU - Wang, Jing

AU - Resuli, Blerina

AU - Landi, Lorenza

AU - Tseng, Shu Chi

AU - Nishino, Mizuki

AU - Digumarthy, Subba R.

AU - Rinsurongkawong, Waree

AU - Rinsurongkawong, Vadeerat

AU - Vaporciyan, Ara A.

AU - Blumenschein, George R.

AU - Zhang, Jianjun

AU - Owen, Dwight H.

AU - Blakely, Collin M.

AU - Mountzios, Giannis

AU - Shu, Catherine A.

AU - Bestvina, Christine M.

AU - Garassino, Marina Chiara

AU - Marrone, Kristen A.

AU - Gray, Jhanelle E.

AU - Patel, Sandip Pravin

AU - Cummings, Amy L.

AU - Wakelee, Heather A.

AU - Wolf, Juergen

AU - Scagliotti, Giorgio Vittorio

AU - Cappuzzo, Federico

AU - Barlesi, Fabrice

AU - Patil, Pradnya D.

AU - Drusbosky, Leylah

AU - Gibbons, Don L.

AU - Meric-Bernstam, Funda

AU - Lee, J. Jack

AU - Heymach, John V.

AU - Hong, David S.

AU - Heist, Rebecca S.

AU - Awad, Mark M.

AU - Skoulidis, Ferdinandos

PY - 2023

Y1 - 2023

N2 - 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 preva-lent 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. SIGNIFICANCE: 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.

AB - 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 preva-lent 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. SIGNIFICANCE: 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.

UR - http://www.scopus.com/inward/record.url?scp=85161277371&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85161277371&partnerID=8YFLogxK

U2 - 10.1158/2159-8290.CD-22-1420

DO - 10.1158/2159-8290.CD-22-1420

M3 - Article

C2 - 37068173

AN - SCOPUS:85161277371

SN - 2159-8274

VL - 13

SP - 1556

EP - 1571

JO - Cancer discovery

JF - Cancer discovery

IS - 7

ER -