Abstract Background Patients with small-cell lung cancer (SCLC) have few treatment options and dismal overall survival (OS) after failed platinum-based chemotherapy. Methods The eligibility criteria of this phase II clinical trial included patients with measurable disease, age of 18 to 75 years, a confirmed diagnosis of disease progression or recurrence after prior platinum-based chemotherapy with a pathologically proven diagnosis of SCLC. Patients were treated with anlotinib at a dosage of 12 mg once daily (QD) and S-1 at 60 mg twice daily (BID) for 2 weeks, followed by a 1-week treatment-free interval. After six cycles of the above treatment, patients continued the maintenance therapy using S-1 monotherapy at 60 mg/ BID for 2 weeks, followed by a 1-week treatment-free interval until disease progression. Results From March 2019 to June 2020, a total of 71 patients were initially assessed for eligibility in this study. Out of these, 52 patients who met the inclusion criteria were enrolled, and 48 patients received at least two doses of the study drug. The median follow-up time was 25.1 months. The ORR was seen in 21 patients (43.8%). The median PFS was 4.5 months (95% CI, 3.5–5.5 months), and the median OS was 5.9 months (95% CI, 4.6–7.3 months). The most common grade 3–4 treatment-related adverse events were thrombocytopenia (16.7%), anemia (14.6%), neutropenia (14.6%), and hypertension (10.4%). No treatment-related death occurred. Conclusions The combination of anlotinib with oral fluoropyrimidine S-1 demonstrated notable activity in relapsed or refractory SCLC, showing a favorable ORR and an acceptable, manageable safety profile. Trial registration This trial was registered with ClinicalTrial.gov (NCT03823118) on 3 January 2019.
