Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) has been approved as first-line standard treatment for stage IV non-small cell lung cancer (NSCLC) patients harboring active EGFR mutation. As reported, EGFR-TKI could radiosensitize tumor cells in vitro and thoracic radiotherapy (TRT) could improve the local control of primary lesion. A prospective CERTAIN study on the combination of EGFR-TKI with TRT as first-line treatment for stage IV NSCLC patients has been registered on ClinicalTrials.gov (NCT 02353741). This is an open-labeled, single-arm, phase II clinical trial aiming to evaluate the efficacy and safety of EGFR-TKI combined with TRT as first-line treatment for stage IV NSCLC patients harboring EGFR active mutation. According to ENSURE study (Wu YL, et al. Ann Oncol. 2015, 26(9):1883), the 1-year progression-free survival (PFS) rate of erlotinib group is 43% and the PFS is 11.0 months. In the current study, the estimated 1-year PFS rate is 60%. According to Freedman rule at one-sided α=0.1, β=0.2, the sample size should be 47. Enrolled patients receive EGFR-TKI (gefitinib 250mg or erlotinib 150 mg qd) plus TRT (54-60Gy/27-30F/5.5-6w) within 2 weeks until disease progression or intolerable toxicities. The primary endpoint is 1-year PFS rate. The secondary endpoints include PFS, time to progression of irradiated lesion (iTTP), objective response rate (ORR), overall survival (OS), and side effects. From January 2015 to February 2018, the median follow-up was 14.3 months. Altogether 175 patients were screened, among whom there were 53 patients declining radiotherapy, 79 cases with uncontrolled intracranial metastasis, pleural effusion and bone metastases, 24 cases who previously received chemotherapy, 8 cases who received TRT more than two weeks later, and 2 cases with uncompleted TRT. Finally, 9 patients (5 male and 4 female) with a median age of 53.7 years (range, 40-75) were eligible. The mean dose limit of both lungs was V20 12%, V30 8%, V5 40%, MLD 5.25Gy. Kaplan-Meier analysis showed that the 1-year PFS rate was 44.4%, PFS was 9.6 months. iTTP was 12.6 months, ORR was 77.8% and OS was immature. The incidence of treatment-related side effects of all grades was 44.4% (4/9). The side effects of grade 3 or higher were radiation pneumonia (33.3%, 3/9) and rash (22.2%, 2/9). One patient died of radiation pneumonia. Compared with ENSURE study, the current study showed no significant improvement in 1-year PFS rate or PFS. The iTTP was 12.6 months, suggesting that TRT could achieve a long-term local control. The risk of severe radiation pneumonia should be considered.