Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2023 Oct:184:107293.
doi: 10.1016/j.lungcan.2023.107293. Epub 2023 Jul 13.

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

Tony Kiat Hon Lim  1 , Ferdinandos Skoulidis  2 , Keith M Kerr  3 , Myung-Ju Ahn  4 , Joshua R Kapp  5 , Fernando A Soares  6 , Yasushi Yatabe  7
Affiliations
Free article
Review

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

Tony Kiat Hon Lim et al. Lung Cancer. 2023 Oct.
Free article

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

PubMed Disclaimer

Conflict of interest statement

Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Tony Kiat Hon Lim received payment or honoraria from AstraZeneca, Amgen, Bayer, and Johnson & Johnson. Ferdinandos Skoulidis received consulting fees from Amgen, AstraZeneca, Novartis, BeiGene, Tango Therapeutics, Calithera Biosciences, Navire Pharma, Medscape LLC, Intellisphere LLC, Guardant Health, and BerGenBio; received payment or honoraria from Bristol Myers Squibb, RV Mais Promoção e Eventos Ltda, the Visiting Speakers Program in Oncology at McGill University and the Université de Montréal, AIM Group International, and ESMO; received fees for travel, food, and beverage from Tango Therapeutics, AstraZeneca, Amgen, Guardant Health, and Dava Oncology; holds stock or stock options in BioNTech SE and Moderna; received grants or contracts (to institution) from Amgen, Mirati Therapeutics, Boehringer Ingelheim, Merck & Co, and Novartis; and received Study Chair funds (to institution) from Pfizer. Keith M. Kerr received consulting fees from Amgen, AstraZeneca, Bayer, Debiopharm Diaceutics, Merck Serono, Merck Sharp & Dohme, Novartis, Pfizer, Regeneron, and Roche; received payment or honoraria from AstraZeneca, Amgen, Boehringer Ingelheim, Merck Serono, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Roche Diagnostics/Ventana, Medscape LLC, Prime Oncology, and PeerVoice; and received conference registration fees for ESMO 2022 from Amgen. Myung-Ju Ahn received consulting fees from Alpha Pharmaceuticals, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Merck Sharp & Dohme, and Takeda; and received payment or honoraria from AstraZeneca, Eli Lilly, Merck Sharp & Dohme, and Takeda. Joshua R. Kapp is an employee of Amgen (Europe) GmbH and holds stock in Amgen. Fernando A. Soares received payment or honoraria from Bayer, Novartis, Roche Diagnostics, AstraZeneca, Bristol Myers Squibb, Ipsen, and Astellas. Yasushi Yatabe received grants or contracts from ArcherDX, Chugai Pharma, Thermo Fisher Scientific, NEC, and Konica Minolta; received consulting fees from AstraZeneca; received payment or honoraria from Amgen, Bayer, Ono Pharma, Daiichi-Sankyo, Eli Lilly, Merck Biopharma, Pfizer, MSD, Novartis, AstraZeneca, Agilent/Dako, ArcherDX, Sysmex, Chugai Pharma, Boehringer Ingelheim, Janssen Pharma, Roche-Ventana, Thermo Fisher Scientific, Takeda, Johnson & Johnson, and Guardant Health Japan; and participated in advisory boards for MSD, Chugai Pharma, AstraZeneca, Novartis, Amgen, and Daiichi-Sankyo.

Publication types

MeSH terms