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Updated: Nov 3, 2025
Author Spotlight: Advancements in Molecular Biomarker Testing for Non-Squamous Non-Small Cell Lung Cancer
Published on: September 8, 2023
Targeting KRAS in non-small-cell lung cancer: recent progress and new approaches
M Reck1, D P Carbone2, M Garassino3
1Department of Thoracic Oncology, Lung Clinic Grosshansdorf, Airway Research Center North, German Center for Lung Research, Grosshansdorf, Germany.
Abstract:
Rat sarcoma (RAS) is the most frequently mutated oncogene in human cancer, with Kirsten rat sarcoma (KRAS) being the most commonly mutated RAS isoform. Overall, KRAS accounts for 85% of RAS mutations observed in human cancers and is present in 35% of lung adenocarcinomas (LUADs). While the use of targeted therapies and immune checkpoint inhibitors (CPIs) has drastically changed the treatment landscape of advanced non-small-cell lung cancer (NSCLC) in recent years, historic attempts to target KRAS (both direct and indirect approaches) have had little success, and no KRAS-specific targeted therapies have been approved to date for patients in this molecular subset of NSCLC. With the discovery by Ostrem, Shokat, and colleagues of the switch II pocket on the surface of the active and inactive forms of KRAS, we now have an improved understanding of the complex interactions involved in the RAS family of signaling proteins which has led to the development of a number of promising direct KRASG12C inhibitors, such as sotorasib and adagrasib. In previously treated patients with KRASG12C-mutant NSCLC, clinical activity has been shown for both sotorasib and adagrasib monotherapy; these data suggest promising new treatment options are on the horizon. With the stage now set for a new era in the treatment of KRASG12C-mutated NSCLC, many questions remain to be answered in order to further elucidate the mechanisms of resistance, how best to use combination strategies, and if KRASG12C inhibitors will have suitable activity in earlier lines of therapy for patients with advanced/metastatic NSCLC.
Insights
New KRAS G12C inhibitors offer hope for lung cancer patients. Sotorasib and adagrasib show promise in previously treated non-small-cell lung cancer, marking a new era in targeted therapy.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Kirsten rat sarcoma (KRAS) is a frequently mutated oncogene in human cancers, particularly lung adenocarcinoma (LUAD).
- Targeting KRAS mutations in non-small-cell lung cancer (NSCLC) has historically been challenging, with limited success for direct and indirect approaches.
- Recent discoveries have identified the switch II pocket of KRAS, enabling the development of direct KRAS G12C inhibitors.
Purpose of the Study:
- To review the development and clinical activity of novel KRAS G12C inhibitors.
- To discuss the potential of these inhibitors as new treatment options for KRAS G12C-mutated NSCLC.
- To highlight remaining questions regarding resistance mechanisms, combination strategies, and earlier line of therapy use.
Main Methods:
- Review of preclinical and clinical data for KRAS G12C inhibitors.
- Analysis of the structural basis for KRAS G12C inhibition.
- Discussion of clinical trial outcomes in previously treated patients.
Main Results:
- Sotorasib and adagrasib are promising direct KRAS G12C inhibitors.
- Both agents have demonstrated clinical activity as monotherapy in previously treated KRAS G12C-mutant NSCLC patients.
- These findings suggest a new therapeutic avenue for this patient subset.
Conclusions:
- Direct KRAS G12C inhibitors represent a significant advancement in NSCLC treatment.
- Further research is needed to address resistance, optimize combination therapies, and evaluate efficacy in earlier treatment lines.
- The development of KRAS G12C inhibitors heralds a new era for precision medicine in NSCLC.
