Background: Combination therapy of ipilimumab plus PD-1 inhibitors has shown promising efficacy in various tumor types, demonstrating higher rates of response than either agent alone. HBM4003 is a fully human heavy chain only monoclonal antibody to CTLA-4, which is engineered to deplete Treg cells by enhanced antibody-dependent cellular cytotoxicity and has shown preliminary anti-tumor activity in phase I (Ph) trial in patients (pts) with advanced solid tumors. Toripalimab is a humanized immunoglobulin G4 monoclonal antibody against PD-1 and has been approved by China NMPA for second-line treatment of metastatic melanoma as single agent. Methods: This is a Ph I study to evaluate the safety, anti-tumor activity, PK/PD and recommended phase II dose (RP2D) of HBM4003 in combination with toripalimab. In part 1 (dose-escalation, presented here), pts were enrolled to receive HBM4003 at 3 dose levels (DLs) (0.03 mg/kg Q3W, 0.1 mg/kg Q3W, and 0.3 mg/kg Q3W) combined with toripalimab 240 mg. Part 2 is a dose-expansion phase. ClinicalTrials.gov number: NCT04727164. Results: The study is ongoing. As of 30 Nov 2021, in total 11 pts have been treated at 1 site in China, including 9 pts with melanoma, 1 pt with renal cell carcinoma, and 1 pt with urothelial carcinoma. 4 pts received ≥ 2 lines of previous systemic therapies and 8 received previous PD-1/PD-L1 treatment. The median follow-up time is 2.5 months. The most common HBM4003-related treatment-related adverse event (TRAE) (≥ 10%) of all grades was leukopenia (4 [36.4%] pts), followed by lymphopenia (3 [27.3%] pts). Grade (Gr) 3 TRAE occurred in 2 (18.2%) pts: lymphopenia and diarrhea. All other TRAEs were Gr 1 or 2. There was 1 DLT (0.3 mg/kg Q3W): Gr 2 colitis and Gr 3 diarrhea, which were also considered as treatment-related serious adverse events (TRSAEs) and led to discontinuation of HBM4003 and toripalimab. No DLT was observed in other two DLs. No other TRSAE and TRAE leading to treatment discontinuation was reported. At the 0.3 mg/kg Q3W DL, 6 pts were evaluable for efficacy: 2 had SD as best response, whereas 1 pt had PR as best response (mucosal melanoma, 2 lines of previous treatment including toripalimab), with tumor shrinkage of 32.6% (Week 12). HBM4003 showed dose-proportional PK. In peripheral blood, the temporal depletion of Treg cells, sustaining increase of CD4+Ki67+ T cells together with CD8+Ki67+ T cells were observed at all 3 DLs and were dose-dependent. PK and PD data appeared no potential interaction between HBM4003 and toripalimab. Conclusions: HBM4003 0.3 mg/kg Q3W+ toripalimab showed promising antitumor activity and a tolerable safety profile in advanced melanoma. Hence, 0.3 mg/kg Q3W was selected as the recommended dose for dose-expansion in advanced melanoma. Clinical trial information: NCT04727164.