Faculty, Staff and Student Publications
Publication Date
10-1-2023
Journal
Lung Cancer
DOI
10.1016/j.lungcan.2023.107293
PMID
37683526
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 KRASG12C-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
Humans, Carcinoma, Non-Small-Cell Lung, Kelch-Like ECH-Associated Protein 1, Proto-Oncogene Proteins p21(ras), Prevalence, Lung Neoplasms, NF-E2-Related Factor 2, Mutation, Adagrasib, Clinical practice, Driver oncogene, Real-world evidence, Sotorasib, Targeted therapy
Published Open-Access
yes
Recommended Citation
Lim, Tony Kiat Hon; Skoulidis, Ferdinandos; Kerr, Keith M; et al., "KRAS G12C in Advanced NSCLC: Prevalence, Co-Mutations, and Testing" (2023). Faculty, Staff and Student Publications. 5014.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/5014
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