Impact of EGFR exon 19 deletion subtypes on clinical outcomes in EGFR-TKI-Treated advanced non-small-cell lung cancer

Objective: Exon 19 deletion (19del) is a sensitive mutation of epidermal growth factor receptor (EGFR) observed in non-small cell lung cancer (NSCLC), and consists of a large number of variants. It remains unclear whether 19del subtype impacts clinical outcomes following EGFR tyrosine kinase inhibitor (TKI) therapy. Methods: We systematically searched web databases and identified eligible studies comparing the clinical outcomes of various EGFR 19del subtypes with EGFR-TKIs. The hazard ratio (HR) for progression-free survival (PFS) and overall survival (OS), as well as the risk ratio (RR) for objective response rate and the frequency of acquired T790M mutation were used as study endpoints. Results: A total of eleven retrospective studies and one prospective study involving 1,630 NSCLC patients with EGFR 19del were included in this meta-analysis. Most of studies were from Asia, and the 19del subtypes in these studies were grouped differently. Patients harboring deletions starting from E746 had significantly longer OS than those with deletions starting from L747 (HR, 0.79; 95% CI: 0.65 to 0.96, P = 0.019), and relatively but not significantly longer PFS (HR, 0.86; 95% CI: 0.69 to 1.06, P = 0.160). Patients with E746_A750del, the most common 19del subtype, had a significantly higher frequency of acquired T790M mutation when treated with first-or second-generation EGFR-TKIs compared to those with other 19del subtypes (RR, 0.76; 95% CI: 0.64-0.89, P = 0.001). There were no differences in PFS between the E746_A750del group and the uncommon group, or between the 15-nucleotide deletion group and other patients. Conclusion: This is the first meta-analysis to present survival outcomes and acquired T790M mutation frequency in the context of EGFR 19del subtype with EGFR-TKI therapy. Patients with a deletion starting from E746 show better OS than those with other subtypes, and patients with E746_A750del subtype have a higher frequency of acquired T790M mutation.