Background: Anlotinib is a multi-target receptor tyrosine kinase inhibitor that has been developed in China. It works by inhibiting various kinases involved in angiogenesis and tumor cell proliferation, including VEGFR, FGFR, PDGFR, and c-Kit. The results of the Phase II ALTER1202 trial showed that patients who received anlotinib as a third-line or later treatment after failing at least two chemotherapy regimens had a better progression-free survival (PFS) and overall survival (OS) compared to those who received placebo. In light of these results, the combination of anlotinib and penpulimab (a novel PD-1 inhibitor) is being studied as a second-line treatment for small cell lung cancer patients who failed first-line chemotherapy with platinum-containing drugs. Methods: This open-label, single-arm, multi-center, Phase II exploratory study (NCT050019710) enrolled patients with small cell lung cancer who had previously received platinum-based chemotherapy. Participants were given 200mg of penpulimab every three weeks and 10mg of anlotinib daily, with a two-week on and one-week off schedule, until disease progression, unacceptable toxicity, or study discontinuation. The primary objective of the study was to evaluate the antitumor activity of the combination therapy using the objective response rate (ORR) as measured by RECIST v1.1. Secondary objectives included evaluating the disease control rate (DCR), PFS, OS, and the safety and tolerability of the combination therapy. Results: As of January 31, 2023, 21 patients (median age 58 years, with 66% having ECOG performance status of 0 or 1, 95% being male) had been enrolled and received treatment. Of these, 18 patients were evaluable for RECIST and had an ORR of 33.33% (6/18) and a DCR of 77.78% (14/18). The median PFS was 5.934 months with a 6-month PFS rate of 33.33%. The median duration of response was 8 months. Nineteen of the 21 patients (90%) experienced treatment-related adverse events, with 4 patients (21%) experiencing grade 3 or higher adverse events. The most common adverse events related to anlotinib were hepatic injury, hematotoxicity, and hypertension. Conclusions: The combination of penpulimab and anlotinib showed promising clinical benefits and a favorable safety profile in small cell lung cancer patients who failed first-line platinum-based chemotherapy. Clinical trial information: NCT05001971.