WCLC 2025 - Posters & ePosters-P3.12.42 Concurrent KRAS Mutations Render Single-Agent EGFR Inhibitors Futile in Advanced NSCLC

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This study investigates the impact of concurrent KRAS alterations on the efficacy of single-agent EGFR tyrosine kinase inhibitors (TKIs) in advanced non-small cell lung cancer (NSCLC) patients harboring EGFR mutations. Utilizing the Flatiron Health–Foundation Medicine Clinico-Genomic Database, the research included 859 advanced NSCLC patients treated with EGFR TKIs and assessed for EGFR and KRAS mutation status via next-generation sequencing before treatment.<br /><br />Results show that patients with both EGFR mutations and KRAS co-alterations exhibit significantly shorter progression-free survival (PFS) and a trend toward reduced overall survival (OS) compared to EGFR-mutant patients without KRAS alterations. Specifically, those with KRAS co-alterations had a median PFS of 4.6 months versus 10.6 months with chemotherapy alone, indicating potential resistance driven by dual pathway signaling. This negative effect persisted in patients treated with EGFR TKIs, including Osimertinib, with co-altered patients demonstrating shorter PFS (4.2 vs. 12.4 months) and numerically decreased OS, though some differences did not reach statistical significance due to small sample sizes.<br /><br />Baseline characteristics reveal that KRAS co-alterations, though rare (11 of 878 patients), are associated with factors such as a higher prevalence of smoking history and brain metastases. These findings position KRAS co-alteration as a robust negative biomarker for EGFR TKI responsiveness.<br /><br />In conclusion, co-occurring KRAS mutations significantly diminish the clinical benefit of EGFR-targeted therapies in advanced EGFR-mutant NSCLC. This subgroup represents a critical need for further validation, detailed KRAS subtype analysis, exploration of resistance mechanisms, and development of novel therapeutic strategies to overcome dual oncogenic signaling and improve patient outcomes.

Asset Subtitle

Misako Nagasaka

Meta Tag

Speaker Misako Nagasaka

Topic Metastatic Non-small Cell Lung Cancer – Targeted Therapy

Keywords

KRAS co-alteration

EGFR mutations

non-small cell lung cancer

EGFR tyrosine kinase inhibitors

progression-free survival

overall survival

Osimertinib resistance

clinico-genomic database

smoking history

brain metastases