Comutations and KRASG12C Inhibitor Efficacy in Advanced NSCLC

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.