Background: Advanced driver-gene negative non-squamous NSCLC has few second-line treatment choices. Surufatinib is a new antiangiogenic drug that potently inhibits VEGFR1，2，3, FGFR1 and CSF-1R. The purpose of this trial was to determine the recommended phase 2 dose of surufatinib in combination with docetaxel through a phase 1b study and to further analyze the preliminary efficacy and safety of the combination therapy in patients with advanced driver-gene negative non-squamous NSCLC. Methods: Advanced driver-gene negative non-squamous NSCLC patients progressed after first-line platinum-based chemotherapy (the combination with immune checkpoint inhibitors and/or bevacizumab was allowed) were enrolled to treat with surufatinib in combination with docetaxel. Using a 3 + 3 study design in the phase 1b dose-escalation portion, patients received surufatinib at doses ranging from 200 mg/day to 300 mg/day for 21 days per cycle. Surufatinib was started at a dose of 250 mg/day and exploratory dose of 300 mg/day if no patients develop dose-limiting toxicity (DLT) in the first 3 patients in the first treatment cycle. If 2 or more of the 3 patients develop DLT, exploratory dose of 200 mg/day. Concomitant treatment with docetaxel at a dose of 60 mg/m². The primary objective of the study was the recommended phase 2 dose of surufatinib in combination with docetaxel. The secondary objective was the preliminary efficacy and safety. Results: At data cut-off (December 31, 2022), we recruited 9 patients in phase 1b portion. Three patients were enrolled in the surufatinib 250 mg/day dose cohort. Among them, 2 developed DLT (1 patient with grade 3 oral mucositis and 1 patient with grade 3 elevated blood bilirubin) which did not recur with a reduction of dosage to 200 mg/day. A total of 6 patients were enrolled in the 200 mg/day dose cohort and 1 patient developed DLT (grade 3 diarrhoea). The recommended phase 2 dose was established as surufatinib 200 mg/day combined with docetaxel 60 mg/m².At present, there were 3 patients enrolled in phase 2. Among the 12 patients enrolled in this study, 1 patient was lost and 11 patients were assessable for treatment efficacy and safty. The objective response rate (ORR) was 27.2% (3/11) and the disease control rate (DCR) was 100%. The median progression free survival (PFS) was 5.8 months (95% CI = 2.1-9.4). The most common treatment-related adverse events (AEs) were diarrhoea (33.3%), neutropenia (41.7%), hypertension (25%), and anaemia (33.3%). Common grade 3 AEs included diarrhoea (16.7%), neutropenia (33.3%) and anaemia (16.7%), with no unexpected treatment-related AEs (TRAEs). Conclusions: Surufatinib in combination with docetaxel was an effective second-line treatment for patients with advanced driver-gene negative non-squamous NSCLC. The clinical benefit was encouraging, and the safety profile was acceptable. Clinical trial information: ChiCTR2100047313.