Outcomes Following First-Line Immune Checkpoint Inhibitors With or Without Chemotherapy Stratified by KRAS Mutational...

Area of Science:

• Oncology
• Genomics
• Translational Research

Background:

• Previous studies suggested chemoimmunotherapy improves outcomes in advanced NSCLC, regardless of PD-L1 or KRAS status.
• Combined chemoimmunotherapy is considered a preferred comparator for first-line trials in KRAS-mutated NSCLC.
• Real-world data is crucial for understanding treatment efficacy in specific patient subgroups.

Purpose of the Study:

• To analyze real-world outcomes of first-line immune checkpoint inhibitor (ICI) therapies in advanced NSCLC.
• To stratify patient outcomes based on KRAS mutation status and PD-L1 expression levels.
• To investigate the impact of co-occurring STK11, KEAP1, and TP53 mutations on treatment efficacy.

Main Methods:

• Retrospective analysis of deidentified, multimodal real-world data from 1980 advanced NSCLC patients.
• Patients received first-line ICI-containing therapy and were stratified by KRAS mutational status.
• Subgroup analyses utilized Cox models, considering KRAS status, PD-L1 levels, and STK11, KEAP1, TP53 alterations.

Main Results:

• KRAS mutations were present in 33.4% of patients; KRAS-mutated tumors had a higher proportion of PD-L1 high expression.
• Among KRAS-mutated NSCLC, median overall survival (mOS) was highest in the PD-L1 high subgroup.
• Patients with KRAS G12C and high PD-L1 achieved the longest mOS (30.28 months); KEAP1 and STK11 co-mutations correlated with worse outcomes.

Conclusions:

• First-line therapy outcomes in KRAS-mutated advanced NSCLC are variable and influenced by PD-L1 expression.
• The presence of STK11 and KEAP1 co-mutations significantly impacts survival in KRAS-mutated NSCLC.
• KRAS-mutated NSCLC is a heterogeneous disease requiring personalized treatment strategies.