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KRAS G12C-mutant non-small cell lung cancer: A practical guide for clinicians
Jordi Remon1, Giulia La-Cava2, Maxime Borgeaud3
1Department of Medical Oncology, Thoracic Group, Gustave Roussy, Villejuif, France; Paris-Saclay University, Paris, France.
Abstract:
KRAS G12C-mutant non-small cell lung cancer (NSCLC) occurs in approximately 15% of NSCLC with historically limited targeted treatment options. Both KRAS "OFF"" G12C inhibitors, sotorasib and adagrasib, are considered standard second-line therapy, albeit with a modest progression-free survival benefit over standard chemotherapy. Emerging next-generation KRAS "OFF" G12C inhibitors, as well as KRAS "ON", dual "ON/OFF", and pan-(K)RAS "ON" inhibitors, show promising early efficacy and safety profiles in second-line, though confirmatory phase III trials are pending. In the first-line setting, KRAS inhibitor-immunotherapy combinations appear particularly promising in tumors with high programmed death-ligand 1 (PD-L1) expression. However, incorporating KRAS inhibitors into chemoimmunotherapy regimens may yield more consistent and clinically meaningful benefit across patient populations, irrespective of PD-L1 expression. Critical clinical questions remain open regarding the optimal patient population for combinations, the influence of co-occurring genomic alterations, intracranial activity of KRAS inhibitors and dose optimization. This review synthesizes current evidence on the biology, clinical efficacy, safety, and practical considerations for treating KRAS G12C-mutant NSCLC, providing clinicians with an up-to-date, evidence-based framework for therapeutic decision-making and highlighting areas requiring further investigation.
Insights
KRAS G12C inhibitors offer new hope for non-small cell lung cancer (NSCLC) patients. Research reviews current and emerging KRAS G12C inhibitors, combinations, and future directions for this NSCLC subtype.
Area of Science:
- Oncology
- Molecular Biology
- Genomics
Background:
- KRAS G12C mutations are present in ~15% of non-small cell lung cancer (NSCLC) cases.
- Targeted therapies for KRAS G12C-mutant NSCLC have historically been limited.
- Current standard second-line therapies (sotorasib, adagrasib) offer modest progression-free survival benefits.
Purpose of the Study:
- To review the current evidence on KRAS G12C-mutant NSCLC treatment.
- To synthesize information on the biology, efficacy, safety, and practical considerations of KRAS inhibitors.
- To provide an evidence-based framework for clinical decision-making.
Main Methods:
- Literature review of preclinical and clinical studies.
- Synthesis of data on KRAS G12C inhibitors, including next-generation and combination therapies.
- Analysis of safety profiles and clinical efficacy data.
Main Results:
- First-generation KRAS G12C inhibitors (sotorasib, adagrasib) are standard in second-line therapy.
- Emerging KRAS inhibitors show promising early efficacy in second-line settings.
- KRAS inhibitor-immunotherapy combinations are promising in first-line, especially with high PD-L1 expression; chemoimmunotherapy combinations may offer broader benefit.
Conclusions:
- KRAS G12C inhibitors represent a significant advancement in NSCLC treatment.
- Optimal use in combinations, patient selection, and managing co-occurring alterations require further investigation.
- Ongoing research is crucial for refining therapeutic strategies and addressing remaining clinical questions.
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