Abstract Background: Porustobart (HBM4003) is a fully human heavy chain only monoclonal antibody targeting CTLA-4. In addition to blocking the CTLA-4 pathway, porustobart was engineered to deplete Treg cells by enhanced antibody-dependent cellular cytotoxicity (ADCC) that was clinically validated. The prognosis of advanced high-grade NENs is poor without standard second line treatments. 4003.6, a multi-center phase Ib study is evaluating porustobart plus toripalimab (an anti-PD-1 antibody) in advanced high-grade NENs (NCT05167071). Methods: Patients (pts) with pretreated advanced high-grade NENs received porustobart at one of the two dose levels (0.3 mg/kg and 0.45 mg/kg) plus toripalimab 240 mg every three weeks (Q3W). The primary endpoint is objective response rate (ORR) per RECIST 1.1 by investigator. Results: As of 31 Aug 2022, 21 pts had been dosed, including 15 pts with neuroendocrine carcinoma (NEC), 3 pts with grade 3 neuroendocrine tumor (G3-NET) and 3 pts with mixed neuroendocrine-non-neuroendocrine neoplasm (MiNEN). 66.7% (14/21) pts received at least 2 prior lines of chemotherapy. Nine tested pts were all microsatellite stable (MSS). Median follow up time was 163 days for 0.3mg/kg dose group and 56 days for 0.45mg/kg dose group.Sixteen pts had post-baseline tumor assessments. The ORR and DCR were 37.5% and 62.5%, respectively. Median duration of response was not reached. For the 11 evaluable pts with NEC, the ORR and DCR were 36.4% and 72.7%, respectively. No significant difference in efficacy was observed between the two dose groups. Treatment-related adverse events (TRAEs) were reported in 100.0% (21/21) pts, and ≥Grade 3 TRAEs were reported in 33.3% (7/21) pts. In 0.3mg/kg dose group, 75% (6/8) pts received 5-16 cycles of study treatment, and 50% (4/8) pts experienced ≥Grade 3 TRAEs. In 0.45mg/kg dose group, 92.3% (12/13) pts received ≤4 cycles, and 23.1% (3/13) pts experienced ≥Grade 3 TRAEs. Most common (≥20%) TRAEs by pooled term were hepatic function abnormal, hyperthyroidism, rash, leukopenia, anaemia, pyrexia, hypothyroidism, neutrophil count decreased and thrombocytopenia. PK data indicated no potential interaction between porustobart and toripalimab. Increase of T cell proliferation were observed in the peripheral blood of all pts. Conclusions: Porustobart 0.3 mg/kg or 0.45 mg/kg plus toripalimab 240mg Q3W showed promising anti-tumor activity and an acceptable safety profile in pts with advanced high-grade NENs. Citation Format: Ming Lu, Panpan Zhang, Lin Shen, Kai Chen, Jianwei Yang, Lijie Song, Humphrey Gardner, Kedan Lin, Luyin Ding, Shuai Zhao, Yuan Geng, Jie Ding, Zailian Lu, Yedong Wang. A phase Ib dose-expansion study of porustobart, an anti-CTLA-4 heavy chain only monoclonal antibody, in combination with toripalimab in patients with advanced high-grade neuroendocrine neoplasms (NENs) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT263.