Comutations and KRASG12C Inhibitor Efficacy in Advanced NSCLC-Reference-Cited by-同舟云学术

Comutations and KRASG12C Inhibitor Efficacy in Advanced NSCLC

Published:2023-04-17 Issue:7 Volume:13 Page:1556-1571
ISSN:2159-8274
Container-title:Cancer Discovery
language:en
Short-container-title:

Author:

Negrao Marcelo V.¹^ORCID,Araujo Haniel A.¹^ORCID,Lamberti Giuseppe²^ORCID,Cooper Alissa J.³^ORCID,Akhave Neal S.¹^ORCID,Zhou Teng¹^ORCID,Delasos Lukas⁴^ORCID,Hicks J. Kevin⁵^ORCID,Aldea Mihaela⁶⁷^ORCID,Minuti Gabriele⁸^ORCID,Hines Jacobi⁹^ORCID,Aredo Jacqueline V.¹⁰^ORCID,Dennis Michael J.¹¹^ORCID,Chakrabarti Turja¹²^ORCID,Scott Susan C.¹³^ORCID,Bironzo Paolo¹⁴^ORCID,Scheffler Matthias¹⁵^ORCID,Christopoulos Petros¹⁶^ORCID,Stenzinger Albrecht¹⁷^ORCID,Riess Jonathan W.¹⁸^ORCID,Kim So Yeon¹⁹^ORCID,Goldberg Sarah B.¹⁹^ORCID,Li Mingjia²⁰^ORCID,Wang Qi²¹^ORCID,Qing Yun²²^ORCID,Ni Ying²³^ORCID,Do Minh Truong¹^ORCID,Lee Richard¹^ORCID,Ricciuti Biagio²^ORCID,Alessi Joao Victor²^ORCID,Wang Jing²¹^ORCID,Resuli Blerina⁸^ORCID,Landi Lorenza⁸^ORCID,Tseng Shu-Chi²⁴^ORCID,Nishino Mizuki²⁴^ORCID,Digumarthy Subba R.²⁵^ORCID,Rinsurongkawong Waree¹^ORCID,Rinsurongkawong Vadeerat¹^ORCID,Vaporciyan Ara A.²⁶^ORCID,Blumenschein George R.¹,Zhang Jianjun¹^ORCID,Owen Dwight H.²⁰^ORCID,Blakely Collin M.¹²^ORCID,Mountzios Giannis²⁷^ORCID,Shu Catherine A.²⁸^ORCID,Bestvina Christine M.⁹^ORCID,Garassino Marina Chiara⁹^ORCID,Marrone Kristen A.¹³^ORCID,Gray Jhanelle E.⁵^ORCID,Patel Sandip Pravin¹¹^ORCID,Cummings Amy L.²⁹^ORCID,Wakelee Heather A.¹⁰^ORCID,Wolf Juergen¹⁵^ORCID,Scagliotti Giorgio Vittorio³⁰^ORCID,Cappuzzo Federico⁸^ORCID,Barlesi Fabrice⁶⁷^ORCID,Patil Pradnya D.⁴^ORCID,Drusbosky Leylah³¹^ORCID,Gibbons Don L.¹^ORCID,Meric-Bernstam Funda³²^ORCID,Lee J. Jack²¹^ORCID,Heymach John V.¹^ORCID,Hong David S.³²^ORCID,Heist Rebecca S.³^ORCID,Awad Mark M.²^ORCID,Skoulidis Ferdinandos¹^ORCID

Affiliation:

1. 1Department of Thoracic and Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

2. 2Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.

3. 3Massachussetts General Hospital, Boston, Massachusetts.

4. 4Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio.

5. 5Department of Thoracic Oncology, H. Lee Moffitt Cancer Center, Tampa, Florida.

6. 6Institut Gustave Roussy, Villejuif, France.

7. 7Paris-Saclay University, Paris, France.

8. 8Istituto Nazionale Tumori IRCCS “Regina Elena,” Rome, Italy.

9. 9University of Chicago Medical Center, Chicago, Illinois.

10. 10Stanford University, Stanford, California.

11. 11Moores Cancer Center, University of California San Diego, San Diego, California.

12. 12Department of Medicine, Division of Hematology and Oncology, University of California San Francisco, San Francisco, California.

13. 13Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.

14. 14Department of Oncology, University of Turin, Turin, Italy.

15. 15Department for Internal Medicine, Center for Integrated Oncology Köln-Bonn, University Hospital Cologne, Cologne, Germany.

16. 16Department of Thoracic Oncology, Thoraxklinik and National Center for Tumor Diseases at Heidelberg University Hospital, Heidelberg, Germany.

17. 17Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.

18. 18University of California Davis Comprehensive Cancer Center, Sacramento, California.

19. 19Yale School of Medicine, New Haven, Connecticut.

20. 20Division of Medical Oncology, The Ohio State University–James Comprehensive Cancer Center, Columbus, Ohio.

21. 21Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

22. 22Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas.

23. 23Center for Immunotherapy and Precision Immuno-Oncology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.

24. 24Department of Radiology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Boston, Massachusetts.

25. 25Department of Radiology, Massachusetts General Hospital, Boston, Massachusetts.

26. 26Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.

27. 27Fourth Department of Medical Oncology and Clinical Trials Unit, Henry Dunant Hospital Center, Athens, Greece.

28. 28Department of Medicine, Columbia University, New York, New York.

29. 29University of California Los Angeles, Los Angeles, California.

30. 30Department of Oncology, University of Turin, S. Luigi Hospital, Turin, Italy.

31. 31Guardant Health, Redwood City, California.

32. 32Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Abstract

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 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. 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. See related commentary by Heng et al., p. 1513. This article is highlighted in the In This Issue feature, p. 1501

Funder

National Cancer Institute

NIH Clinical Center

Publisher

American Association for Cancer Research (AACR)

Subject

Oncology

Link

https://aacrjournals.org/cancerdiscovery/article-pdf/doi/10.1158/2159-8290.CD-22-1420/3300148/cd-22-1420.pdf

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