Objective:Data on the clinical activity of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in patients with non-small-cell lung cancer (NSCLC) and uncommon EGFR mutations remain insufficient.This study aimed to investigate the effect of first-line EGFR-TKIs or platinum-based chemotherapy in NSCLC parents with uncommon EGFR mutations.Methods:We retrospectively enrolled 504 patients with EGFR-mutant NSCLC.The clinical characteristics and treatment outcomes were collected and compared between patients with common and uncommon EGFR-mutant NSCLC.Results:Seventy patients (13.9％) harboring uncommon EGFR mutations were included.Thirty of these patients received EGFR-TKIs and 40 received platinum-based chemotherapy as first-line therapy.The objective response rate (ORR) and median progression-free survival (mPFS) of patients treated with TKIs in the uncommon mutationgroup was significantly inferior to that in the common mutation group (ORR:23.3％ vs.51.8％,P=0.003;mPFS:7.1 vs.10.9 months,P＜0.001).In the uncommon group,mPFS was similar between first-line EGFR-TKIs treatment and platinum-based chemotherapy (7.1 vs.6.1 months,P=0.893).In patients with EGFR G719X or L861Q mutations,the mPFS was longer in the first-line EGFR-TKIs treatment group than in the chemotherapy group,but the difference was not statistically significant (G719X:8.2 vs.5.8 months,P=0.061;L861Q:7.6 vs.4.1 months,P=0.872).Multivariate analyses identified adenocarcinoma (P=0.003) as the independent predictive factor for PFS in parents with uncommon EGFR mutations who were treated with first-line EGFR-TKIs.Conclusions:The current study demonstrated that the effect of first-line EGFR-TKIs was similar to that of platinum-based chemotherapy in patients with uncommon EGFR-mutant NSCLC.Adenocarcinoma was the independent predictive factor for PFS in uncommon EGFR-mutant NSCLC parents treated with first-line EGFR-TKIs.