Molecular characteristics and responses to EGFR tyrosine kinase inhibitors in non-small cell lung cancer patients with EGFR exon 19 insertions

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BACKGROUND: Epidermal growth factor receptor (EGFR) exon 19 insertions (19ins) represent a unique subclass of exon 19 alterations that has a relatively low frequency. Here, we aimed to elucidate the molecular characteristics and response to EGFR tyrosine kinase inhibitors (EGFR-TKIs) in lung cancer patients with EGFR 19ins. METHODS: Next-generation sequencing was performed to profile the molecular characteristics of 83 non-small cell lung cancer (NSCLC) patients with EGFR 19ins. Detailed molecular profiling and efficacy analyses were performed on these patients, with comparisons to 68 EGFR 19 deletion (19del) patients. Potential resistance mechanisms were also explored. RESULTS: The prevalence of EGFR 19ins mutations was 0.17% of all the primary NSCLC patients. EGFR 19ins variants identified were I740_K745dup (86.7%) and K745_E746insVPVAIK (13.3%). Concurrent mutations frequently observed were in TP53 (50.6%), CDKN2A (12.0%), PIK3CA (10.8%), LRP1B (8.4%), and SMAD4 (8.4%). Notably, CTNNB1 was significantly associated with 19ins (p = 0.043). Efficacy analysis showed median progression-free survival (mPFS) for EGFR 19ins patients receiving first-line EGFR-TKI treatment was significantly shorter than for EGFR 19del patients (hazard ratio (HR) 1.98, p = 0.005). Gefitinib was significantly less effective compared to other first-generation TKIs (HR 19.86, p < 0.001). Furthermore, osimertinib did not generate favorable outcomes as 19dels in the first-line setting either (p = 0.025). Post-treatment samples revealed higher occurrences of TP53 mutations (84.6%) and presence of EGFR T790M (23.1%) at progression, with case studies highlighting osimertinib's limited efficacy post-first-line treatment. CONCLUSIONS: Comprehensive analysis of EGFR 19ins in lung cancer patients revealed genomic characteristics and clinical response, helping better inform clinical action and might facilitate the development of more precise therapeutic options for patients with these uncommon driver mutations.

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