TY - JOUR
T1 - KRAS G12C in advanced NSCLC
T2 - Prevalence, co-mutations, and testing
AU - Lim, Tony Kiat Hon
AU - Skoulidis, Ferdinandos
AU - Kerr, Keith M.
AU - Ahn, Myung Ju
AU - Kapp, Joshua R.
AU - Soares, Fernando A.
AU - Yatabe, Yasushi
N1 - Publisher Copyright:
© 2023 The Authors
PY - 2023/10
Y1 - 2023/10
N2 - 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 KRAS G12C 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.
AB - 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 KRAS G12C 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.
KW - Adagrasib
KW - Clinical practice
KW - Driver oncogene
KW - Real-world evidence
KW - Sotorasib
KW - Targeted therapy
UR - http://www.scopus.com/inward/record.url?scp=85171143685&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85171143685&partnerID=8YFLogxK
U2 - 10.1016/j.lungcan.2023.107293
DO - 10.1016/j.lungcan.2023.107293
M3 - Review article
C2 - 37683526
AN - SCOPUS:85171143685
SN - 0169-5002
VL - 184
JO - Lung Cancer
JF - Lung Cancer
M1 - 107293
ER -