KRAS G12C in advanced NSCLC: Prevalence, co-mutations, and testing

Tony Kiat Hon Lim; Ferdinandos Skoulidis; Keith M Kerr; Myung-Ju Ahn; Joshua R Kapp; Fernando A Soares; Yasushi Yatabe

doi:10.1016/j.lungcan.2023.107293

KRAS G12C in advanced NSCLC: Prevalence, co-mutations, and testing

Lung Cancer. 2023 Oct:184:107293. doi: 10.1016/j.lungcan.2023.107293. Epub 2023 Jul 13.

Authors

Tony Kiat Hon Lim¹, Ferdinandos Skoulidis², Keith M Kerr³, Myung-Ju Ahn⁴, Joshua R Kapp⁵, Fernando A Soares⁶, Yasushi Yatabe⁷

Affiliations

¹ Division of Pathology, Singapore General Hospital, Singapore.
² Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
³ Department of Pathology, Aberdeen University Medical School and Aberdeen Royal Infirmary, Aberdeen, UK.
⁴ Department of Medicine, Samsung Medical Center Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
⁵ Amgen (Europe) GmbH, Rotkreuz, Switzerland.
⁶ D'Or Institute for Research and Education (IDOR), São Paulo, Brazil; Faculty of Dentistry, University of São Paulo, São Paulo, Brazil.
⁷ Department of Diagnostic Pathology, National Cancer Center, Tokyo, Japan. Electronic address: yyatabe@ncc.go.jp.

PMID: 37683526
DOI: 10.1016/j.lungcan.2023.107293

Abstract

KRAS is the most commonly mutated oncogene in advanced, non-squamous, non-small cell lung cancer (NSCLC) in Western countries. Of the various KRAS mutants, KRAS G12C is the most common variant (~40%), representing 10-13% of advanced non-squamous NSCLC. Recent regulatory approvals of the KRAS^G12C-selective inhibitors sotorasib and adagrasib for patients with advanced or metastatic NSCLC harboring KRASG12C have transformed KRAS into a druggable target. In this review, we explore the evolving role of KRAS from a prognostic to a predictive biomarker in advanced NSCLC, discussing KRAS G12C biology, real-world prevalence, clinical relevance of co-mutations, and approaches to molecular testing. Real-world evidence demonstrates significant geographic differences in KRAS G12C prevalence (8.9-19.5% in the US, 9.3-18.4% in Europe, 6.9-9.0% in Latin America, and 1.4-4.3% in Asia) in advanced NSCLC. Additionally, the body of clinical data pertaining to KRAS G12C co-mutations such as STK11, KEAP1, and TP53 is increasing. In real-world evidence, KRAS G12C-mutant NSCLC was associated with STK11, KEAP1, and TP53 co-mutations in 10.3-28.0%, 6.3-23.0%, and 17.8-50.0% of patients, respectively. Whilst sotorasib and adagrasib are currently approved for use in the second-line setting and beyond for patients with advanced/metastatic NSCLC, testing and reporting of the KRAS G12C variant should be included in routine biomarker testing prior to first-line therapy. KRAS G12C test results should be clearly documented in patients' health records for actionability at progression. Where available, next-generation sequencing is recommended to facilitate simultaneous testing of potentially actionable biomarkers in a single run to conserve tissue. Results from molecular testing should inform clinical decisions in treating patients with KRAS G12C-mutated advanced NSCLC.

Keywords: Adagrasib; Clinical practice; Driver oncogene; Real-world evidence; Sotorasib; Targeted therapy.

Publication types

Review
Research Support, Non-U.S. Gov't

MeSH terms

Carcinoma, Non-Small-Cell Lung* / epidemiology
Carcinoma, Non-Small-Cell Lung* / genetics
Humans
Kelch-Like ECH-Associated Protein 1
Lung Neoplasms* / epidemiology
Lung Neoplasms* / genetics
Mutation / genetics
NF-E2-Related Factor 2
Prevalence
Proto-Oncogene Proteins p21(ras) / genetics

Substances

adagrasib
Kelch-Like ECH-Associated Protein 1
Proto-Oncogene Proteins p21(ras)
NF-E2-Related Factor 2
KRAS protein, human