Background: Current standard of care for SCLC relapsed within six months after first-line treatment was mainly chemotherapy alone, such as irinotecan or docetaxel, of which the clinical benefit is unsatisfactory. Anlotinib, a novel oral multi-target tyrosine kinase inhibitor primarily targeting VEGFR2/3, FGFR1-4, PDGFRα/β and c-Kit, significantly improved progression-free survival (PFS) and overall survival (OS) for SCLC in third-line setting and beyond treatment (ALTER1202 trial). Here, we conducted a single-arm phase II trial to evaluate the efficacy and safety of anlotinib combined with irinotecan or docetaxel in SCLC relapsed within six months after first-line treatment. Methods: Eligible patients with cytologically or histologically confirmed SCLC, aged 18-75 years, ECOG PS 0-1, relapsed within six months after first-line platinum-based treatment, received anlotinib (12mg, QD, from day 1 to 14 of a 21-day cycle) combined with irinotecan (65mg/m², day1,8, q3w, up to 4 cycles) or docetaxel (60mg/m², q3w, up to 4 cycles) until disease progression or intolerable toxicity. The primary endpoint was the objective response rate (ORR). Secondary endpoints included PFS, the disease control rate (DCR), OS and safety. Results: Between March 2020 and February 2021, 21 patients with a median age of 61.7 years, male (76.2%), ECOG PS 1 (81.0%), brain metastasis (42.9%), liver metastasis (38.1%), were enrolled in this trial. At data cut-off (February 8, 2021), 15 patients were evaluable, among which 5 patients reached partial response (PR) and 8 had stable disease (SD). The ORR was 33.3% (5/15) and the DCR was 86.7% (13/15), respectively. The median PFS was 4.0 months (95%Cl: 3.18-4.83). The most common grade 1-2 treatment-related adverse events (TRAEs) were weakness (64.7%), anorexia (41.2%), anemia (29.4%), hypertension (23.5%), leukopenia (17.6%), oral mucositis (17.6%). Grade 3 TRAEs mainly included leukopenia (11.8%), thrombocytopenia (11.8%) and anemia (5.9%). There were no grade 4 or higher toxicities. Conclusions: Anlotinib combined with irinotecan or docetaxel showed promising ORR, DCR and PFS in SCLC relapsed within six months after first-line platinum-based treatment and was well-tolerated. No unexpected toxicities were observed. Further exploration and longer follow-up are ongoing. Clinical trial information: NCT04757779