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Comutations and KRASG12C Inhibitor Efficacy in Advanced NSCLC

Marcelo V Negrao1, Haniel A Araujo1, Giuseppe Lamberti2

  • 1Department of Thoracic and Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Cancer Discovery
|April 17, 2023
PubMed

Insights

Genomic alterations in KEAP1, SMARCA4, and CDKN2A predict poor outcomes for KRASG12C-mutant non-small cell lung cancer (NSCLC) patients treated with KRASG12C inhibitors. This finding aids in stratifying patients and personalizing treatment strategies.

Area of Science:

  • Oncology
  • Genomics
  • Molecular Biology

Background:

  • KRASG12C inhibitors show promise for non-small cell lung cancer (NSCLC).
  • Molecular factors influencing KRASG12C inhibitor efficacy in advanced NSCLC are not well understood.
  • Identifying these factors is crucial for optimizing treatment strategies.

Purpose of the Study:

  • To identify molecular modifiers of KRASG12C inhibitor (KRASG12Ci) efficacy in advanced KRASG12C-mutant NSCLC.
  • To develop a framework for patient stratification and treatment personalization based on genomic alterations.

Main Methods:

  • Clinicogenomic analysis of 424 patients with advanced KRASG12C-mutant NSCLC.
  • Identification and validation of co-occurring genomic alterations.
  • Pathway-level integration of less prevalent co-alterations.

Main Results:

  • Co-alterations in KEAP1, SMARCA4, and CDKN2A were identified as independent determinants of inferior clinical outcomes with KRASG12Ci monotherapy.
  • These comutations segregated patients into distinct prognostic subgroups, capturing approximately 50% of those with early disease progression.
  • PI3K/AKT/MTOR pathway alterations and additional RAS gene alterations were nominated as candidate drivers of inferior outcomes.
  • Defective DNA damage response/repair showed a possible association with improved KRASG12Ci efficacy.

Conclusions:

  • Co-occurring genomic alterations in KEAP1, SMARCA4, and CDKN2A significantly impact KRASG12Ci efficacy in NSCLC.
  • A framework for patient stratification and clinical outcome prediction can be established based on tumor comutational status.
  • These findings can inform the rational selection and tailoring of combination therapies for KRASG12C-mutant NSCLC.

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