Background: PM8001 is a bifunctional protein composed of the extracellular domain of the TGF-β RII receptor (a TGF-β“trap”) fused to a humanized anti-PD-L1 IgG1 single-domain antibody. This is the first dose escalation and expansion phase I/IIa study to evaluate the safety and preliminary anti-tumor activity of PM8001 in advanced tumors. Methods: This study is comprised of a standard 3+3 dose escalation (Part A: 1, 3, 10, 20, 30, and 45 mg/kg Q2W) followed by dose expansion (Part B). Primary endpoints include safety for Part A, and ORR per RECIST 1.1 for Part B. Secondary endpoints include pharmacokinetics (PK), immunogenicity, DCR, PFS, and OS. Results: As of 16 December, 2021, a total of 108 subjects had received at least 1 dose of PM8001 with 25 subjects in Part A (0.3 mg/kg [n = 1], 1 mg/kg [n = 3], 3 mg/kg [n = 3], 10 mg/kg [n = 4], 20 mg/kg [n = 7], 30 mg/kg [n = 3], and 45 mg/kg [n = 4]) and 83 subjects in Part B (10 mg/kg Q2W [n = 1], 20 mg/kg Q2W [n = 63], 20 mg/kg Q3W [n = 11]), and 30 mg/kg Q3W [n = 8]). In Part A, only 1 DLT occurred in the 20 mg/kg dose group. MTD was not reached. Finally, 20 mg/kg Q2W was recommended as the RP2D for Part B. Of the 108 subjects, the median duration of PM8001 exposure was 6.9 weeks (range, 1.4-71.9). Any-grade TRAEs occurred in 84 subjects (77.9%), with 18 subjects (16.7%) reported with ≥ Grade 3. The most commonly reported ≥ Grade 3 TRAEs were anemia and rash (3 subjects each). Any-grade irAEs occurred in 66 subjects (61.1%), with 13 subjects (12.0%) reported with ≥ Grade 3. The most commonly reported ≥ Grade 3 irAEs were anemia (3 subjects). PK analysis showed a nearly linear dose-exposure relationship with PM8001 dosing from 1 to 45 mg/kg. Pharmacodynamic analysis demonstrated close to 100% PD-L1 target occupancy on PBMCs from the 20 to 45 mg/kg groups after multiple doses. An adequate inhibition to below the limit of quantitation of TGF-β1 was observed in the 1 mg/kg and higher dose groups. Of the 108 enrolled subjects, 67 subjects completed at least one efficacy evaluation. The ORR per RECIST 1.1 by investigator was 10.4% (7/67; 95% CI, 4.3%-20.4%), with 7 subjects achieving PR; the DCR was 53.7% (36/67; 95% CI, 41.1%-66.0%). Four additional PRs were observed after the data cut-off date. Of the total 11 PRs, 4 PRs occurred in patients who previously progressed after anti-PD-1 treatment. Most responses (10/11) occurred within 6 infusions, which indicates a rapid response towards PM8001 treatment. To date, 8 responders are still on treatment. Conclusions: PM8001 showed an acceptable safety profile and promising anti-tumor activity in advanced solid tumors, especially in patients previously treated with checkpoint inhibitors, which supports further studies to explore the safety and efficacy of PM8001 as a monotherapy and in combination with other anti-tumor agents. Global Phase II monotherapy and combination studies are currently ongoing. Clinical trial information: ChiCTR2000033828.