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Current status of KRAS G12C inhibitors in NSCLC and the potential for combination with anti-PD-(L)1 therapy: a

Fan Zhang1, Banglu Wang1, Menghuan Wu1

  • 1Department of Oncology, The Third Affiliated Hospital of Soochow University, Changzhou, China.

Frontiers in Immunology
|April 30, 2025
PubMed

Insights

Targeted therapies for non-small cell lung cancer (NSCLC) show promise, but KRAS G12C inhibitors face resistance. Combining KRAS G12C inhibitors with anti-PD-(L)1 therapies may improve outcomes, though safety requires further study.

Area of Science:

  • Oncology
  • Precision Medicine
  • Immunotherapy

Background:

  • Non-small cell lung cancer (NSCLC) treatment has advanced with targeted therapies and anti-PD-(L)1 therapies.
  • KRAS mutations, particularly KRAS G12C, present therapeutic challenges due to their unique activation mechanisms.
  • Specific KRAS G12C inhibitors like AMG 510 and MRTX849 have shown potential but face limitations such as resistance and survival benefits.

Purpose of the Study:

  • To review the development of KRAS G12C inhibitors in monotherapy and combination treatments for NSCLC.
  • To discuss major clinical trials involving KRAS G12C inhibitors.
  • To explore future research directions for optimizing KRAS G12C inhibitor therapies.

Main Methods:

  • Review of clinical trial data for KRAS G12C inhibitors in NSCLC.
  • Analysis of preclinical and clinical studies on combination strategies, including KRAS G12C inhibitors and anti-PD-(L)1 therapies.
  • Examination of resistance mechanisms and their impact on treatment efficacy.

Main Results:

  • While KRAS G12C inhibitors show promise, monotherapy efficacy is limited by acquired resistance.
  • The CodeBreaK 200 trial showed AMG 510 did not significantly improve overall survival versus docetaxel.
  • Combination therapy with anti-PD-(L)1 agents may overcome resistance and enhance anti-tumor immunity, but safety profiles need careful evaluation.

Conclusions:

  • KRAS G12C inhibitors represent a significant advancement in NSCLC precision medicine.
  • Combination strategies, particularly with immunotherapy, hold potential but require further research to optimize patient selection and manage toxicities.
  • Ongoing research is essential to refine treatment regimens and improve survival and quality of life for NSCLC patients with KRAS G12C mutations.
Keywords:
KRAS G12C inhibitorsanti-PD-(L)1 therapiescombination therapynon-small cell lung cancer (NSCLC)targeted therapies

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