Serum carcinoembryonic antigen (CEA) levels are a predictor of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) efficacy and are associated with epidermal growth factor receptor (EGFR) gene mutations. However, the clinical significance of plasma CEA level changes during different cycles of target therapy is unknown for lung adenocarcinoma patients with sensitizing EGFR mutations. In total, 155 patients with lung adenocarcinoma were enrolled in this retrospective study between 2011 and 2015. EGFR mutations were detected by RT-PCR (real-time quantitative PCR). Plasma CEA levels were measured prior to different EGFR-TKI treatment cycles. Computed tomography (CT) scans were conducted every 2 months to assess the therapeutic efficacy. Serum CEA concentrations were significantly associated with EGFR mutations (p < 0.05). Furthermore, in all patients treated with EGFR-TKIs, the serum CEA levels increased with disease progression (p < 0.005). A COX multivariate analysis revealed that CEA levels 16.2 times above normal were associated with early disease progression (HR, 5.77; 95% CI:2.36 ~ 14.11; p < 0.001). Based on this finding, a threshold was set at the median time of 8.3 months. Patients with EGFR mutations exhibited a median progression-free survival time of 12.8 months. Serum CEA levels were markedly increased compared to levels measured 4.5 months prior to the changes detected via CT scans for patients resistant to EGFR-TKIs. Elevated CEA levels during targeted therapy may be a more sensitive predictor of explosive lung adenocarcinoma progression in patients harboring mutant EGFRs compared to traditional imaging methods.