Introduction: Ivonescimab is a humanized IgG1 bispecific anti-programmed cell death protein 1/vascular endothelial growth factor antibody. This study aimed to evaluate the safety and tolerance of ivonescimab combined with etoposide and carboplatin as first-line treatment in patients with extensive-stage SCLC and to explore the primary efficacy of this regimen. Methods: Eligible patients received intravenous ivonescimab 3 mg/kg, 10 mg/kg, or 20 mg/kg every 3 weeks combined with etoposide and carboplatin for up to four cycles, followed by ivonescimab as maintenance. The primary end points were safety and objective response rate (ORR). Results: Between April 23, 2021, and December 2, 2021, 35 patients were enrolled. At data cutoff (October 25, 2023), the median follow-up was 13.3 (range: 0.3-28.5) months. For all patients, the confirmed ORR and disease control rate were 80% and 91.4%, respectively. The ORR was 66.7%, 90.9%, and 76.2% at the dose of 3 mg/kg, 10 mg/kg, and 20 mg/kg, respectively. Grade more than or equal to 3 treatment-related adverse events (TRAEs) were observed in 21 patients (60%), and the most frequent toxicities were decreased neutrophil count (n = 8, 22.9%), decreased white blood cell count (n = 5, 14.3%), and anemia (n = 5, 14.3%). Grade more than or equal to 3 TRAEs occurred in 66.7%, 54.5%, and 61.9% of patients in 3, 10, and 20 mg/kg groups, respectively. TRAEs leading to death were reported in two patients (5.7%). Immune-related adverse events, most of them grade 1 or 2, occurred in 14 patients (40.0%). Conclusions: Ivonescimab in combination with etoposide and carboplatin was well tolerated and found to have promising antitumor activity in extensive-stage SCLC.