BACKGROUND: Patients with extensive-stage small-cell lung cancer (ES-SCLC) have a particularly poor prognosis. And the treatment options for patients with relapsed or refractory ES-SCLC are limited. Thus, we conducted an open-label, multicenter, single-arm phase II clinical trial to assess the efficacy and safety of apatinib plus etoposide capsules as the third- or further-line treatment in ES-SCLC patients. METHODS: Patients with ES-SCLC who experienced disease progression following 2 to 3 previous therapies from 11 medical centers in China were enrolled to receive apatinib (250 mg/d, continuously) and etoposide capsules (50 mg/d, on day 1-21, per 28 days). The treatment continued until disease progression, treatment intolerance, or death. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were objective response rate (ORR), overall survival (OS), and safety. RESULTS: Fifty-six patients with relapsed or refractory ES-SCLC were enrolled from January 2018 to February 2020 and 53 of them were eventually included in the evaluation population. The median follow-up was 9.8 months. At the data cut-off time (March 5, 2020), 39 patients (74%) had died and 44 (83%) had progressed. The median PFS was 3.0 months (95% CI, 2.1-3.9) and the median OS was 5.0 months (95% CI, 3.6-6.4). No complete responses were seen. Eleven patients (21%) showed a best response of partial response and 37 (70%) patients achieved stable disease. The ORR was 20.8% (11/53), and the disease control rate (DCR) was 90.6% (48/53). The 6-month OS rate was 40.1% (95% CI, 26.2-54). After 12 months, the OS rate was 18.4% (95% CI, 4.7-32.1). Possible treatment-related grade III/IV adverse events included leukopenia [8 (15.1%)], neutropenia [7 (13.2%)], anemia [4 (7.4%)], and hand-foot syndrome [2 (3.8%)]. During the study, no mortality occurred as a consequence of treatment. CONCLUSIONS: Apatinib combined with etoposide capsules exhibits efficacy and has an acceptable safety profile. It could be used as a later-line treatment for ES-SCLC patients who have been heavily pretreated with standard therapies. Further exploration of apatinib combined with etoposide capsules in phase III trials is warranted.