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Purpose: As for local advanced non-small cell lung cancer (NSCLC), synchronous radiotherapy and chemotherapy is the standard treatment mode. But for patients with progress in half a year, which means the second-line chemotherapy effect is not ideal for them. We observed the efficacy and safety of anlotinib hydrochloride combined with PD-1 blockade as the second-line treatment for those patients in this trial. Patients and Methods: From January 2018 to December 2019, 57 patients with the progress of local advanced NSCLC treated with anlotinib plus PD-1 blockade until disease progression or intolerance as a result of adverse events. Patients have been assessed using computed tomography prior to treatment and during follow-up every 2 months until disease progression or death. The primary endpoint was objective response rate (ORR). The secondary endpoints included overall survival (OS), progression-free survival (PFS) and safety. Survival curves were created using the Kaplan–Meier method. Results: 57 patients were enrolled. The median age was 64 years, and 61.4% of the patients were men. The ORR was 50.9% with a median OS time of 14 months and the 1-year OS rates and PFS rates were 81.8% and 33.3%, respectively. The patients with squamous cell carcinoma, no brain or liver metastases had longer PFS than patients with liver metastasis. When the PFS was calculated from the time of second treatment, the median PFS was 9 months. Most adverse events (AEs) were grade 1– 3, one drug-related death was noted. Conclusion: The expected outcome of this study is that anlotinib combined with PD-1 blockade has tolerable toxicity and better ORR, OS than second-line chemotherapy. The results may indicate additional treatment options for patients with progress of local advance NSCLC in half a year after standard treatment. [ABSTRACT FROM AUTHOR]