Background: Unlike bevacizumab, anlotinib, which is also an anti-angiogenic drug, is indicated for lung squamous cell carcinoma(LSCC). A phase IB study showed that the first-line therapy with anlotinib and sintilimab for stage IIIB to IV NSCLC with negative driver genes has the objective response rate of 72.7%. Regardless of the PD-1 expression level, this combination method has consistent therapeutic benefit. According to the IMpower150 study, the four-drug combination therapy has a synergistic effect and prolong the survival time. It is necessary to further explore the efficacy and safety of anlotinib combined with sintilimab and chemotherapy for NSCLC without driver mutations. Methods: We retrospectively analyzed the patients of newly diagnosed unresectable stage IIIA-IVB NSCLC who received platinum-containing dual-drug chemotherapy combined with anlotinib and sintilimab in our hospital from January 2019 to December 2020. Patients receive at least one cycle of treatment, and the efficacy can be evaluated. The main observation indicators are the very early tumor regression rate and the safety. Results: This study included 11 patients with stage IIIA-IVB NSCLC with no driver mutations that were not resectable. Ten patients (90.9%) were male, with a median age of 65 years. The pathological types were LSCC (7, 63.6%), lung adenocarcinoma (3, 27.3%), and poor differentiated carcinoma (1, 9.1%). Six patients were with stage ⅢA-ⅢB, 4 patient with ⅢC-IVB. Eleven patients received an average of 1.63 cycles of treatment. In order to evaluate the efficacy of multi-drug combination therapy in a timely manner, and effectively avoid the risk of hemoptysis caused by anlotinib-induced pulmonary cavity, all patients were evaluated for efficacy after receiving one cycle of treatment. Eight patients achieved very early tumor regression (defined as tumor shrinkage ≥30% after receiving one cycle of treatment in the evaluation of efficacy), 2 patients achieved stable disease, and 1 patients achieved disease progression. The very early tumor regression rate was 72.7%. Three patients with locally advanced (ⅢA-ⅢB) NSCLC underwent radical R0 resection and the downstage rate reached 100%; 2 patients underwent radical radiotherapy. At the last follow-up time in February 2021, one patient died, the remaining patients were alive. No treatment-related grade 3-4 adverse reactions were observed. Conclusions: The high rate of very early tumor regressions in inoperable locally advanced NSCLC provided opportunities for radical surgery and radiotherapy in a short period of time. And the safety is satisfactory. Therefore, our research group has registered the prospective study of anlotinib combined with sintilimab and chemotherapy for the neoadjuvant downstage treatment of stage III NSCLC (Registration number: ChiCTR1900026631).