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Immunotherapy in advanced, KRAS G12C-mutant non-small-cell lung cancer: current strategies and future directions

Nadia Ghazali1, Marina C Garassino2, Natasha B Leighl1

  • 1Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada.

Therapeutic Advances in Medical Oncology
|March 17, 2025
PubMed

Insights

KRAS G12C mutations drive non-small cell lung cancer (NSCLC). New KRAS G12C inhibitors offer targeted therapy, with emerging strategies like dual checkpoint blockade showing promise for advanced NSCLC.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Kirsten rat sarcoma (KRAS) mutations are found in up to 25% of non-small-cell lung cancer (NSCLC).
  • KRAS G12C is the most frequent KRAS mutation, accounting for about half of all KRAS-mutant NSCLC cases.
  • KRAS mutations activate the RAF-MEK-ERK pathway, promoting tumor cell proliferation and survival.

Purpose of the Study:

  • To review emerging therapeutic strategies for KRAS G12C-mutant NSCLC.
  • To focus on treatment approaches for advanced disease settings.
  • To discuss novel combination therapies including checkpoint inhibitors.

Main Methods:

  • Literature review of recent advances in KRAS G12C targeted therapies.
  • Analysis of clinical trial data for KRAS G12C inhibitors.
  • Exploration of preclinical and clinical studies on combination strategies.

Main Results:

  • KRAS G12C inhibitors, such as sotorasib and adagrasib, have been approved for NSCLC treatment.
  • Emerging strategies involve dual checkpoint blockade and combinations with existing checkpoint inhibitors.
  • These novel approaches aim to overcome resistance and improve outcomes in advanced NSCLC.

Conclusions:

  • Targeted therapies and combination strategies represent a significant advancement in treating KRAS G12C-mutant NSCLC.
  • Further research is needed to optimize these treatments for advanced disease.
  • Combination therapies hold potential for enhanced efficacy in KRAS G12C-mutant NSCLC patients.
Keywords:
KRAS G12CKRAS G12C inhibitorschemoimmunotherapyimmunotherapynon-small cell lung cancer

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