Background: Immune checkpoint inhibitors plus anti-VEGFR agents have emerged as a powerful strategy for aHCC. This has been confirmed by several phase 3 trials: 1) atezolizumab + bevacizumab showed an ORR of 27.3%, mPFS of 6.8 months, and mOS of 19.2 months in IMbrave150; 2) sintilimab + IBI305 (bevacizumab biosimilar) showed an ORR of 21%, mPFS of 5.6 months and mOS of 22.1 months in Orient-32; 3) camrelizumab + Apatinib showed an ORR of 25.4%, mPFS of 5.6 months and mOS 22.1 months in SHR-1210-III-310. To our knowledge, data from a trial about PD-1 inhibitor plus different antiangiogenic drugs have not been reported. Here, we present the result of the Pucotenlimab (HX008) plus bevacizumab (B) or lenvatinib (L) as the first-line treatment for aHCC. Methods: This study is a single-arm, multiple-center trial. Eligible pts aged 18 to 75 years had 1) histologically or cytologically confirmed aHCC naïve to systemic treatment; 2) BCLC stage C or B not amenable to surgery and/or locoregional therapy or showed radiographic progression after treatment; 3) Child-Pugh class A/B7; 4) ECOG PS 0 or 1. Pts of C1 received HX008 200 mg IV Q3W plus B 15 mg/kg, IV, Q3W; Pts of C2 received HX008 (200mg IV Q3W) plus L (12mg/d for BM ≥60 kg or 8 mg/d for <60 kg). The primary endpoint was ORR. Secondary endpoints included PFS, OS, and safety. Results: Between Dec. 30, 2020, and Oct. 12, 2022, 75 pts were sequentially assigned to C1 (n = 28) or C2 (n=47). The pts characteristics are presented in table below. With a median follow-up duration of 15.2 and 12.5 months, investigator-assessed ORR per RECIST v1.1 showed a similar magnitude of benefit (p=0.6150) between C1 (28.6%) and C2 (36.2%). Also, there were no statistically significant differences (p=0.4606) in median PFS, 7.5 and 9.6 months (HR:1.26 [0.674-2.373]). OS result is not mature, the 12-mo rate was 88.6% and 81.8%. The most common TEAEs were platelet count decreased (42.9%), and proteinuria (35.7%) in C1; and platelet count decreased (44.7%), proteinuria (42.6%), and hypothyroidism (40.4%) in C2. Grade ≥3 TEAEs were reported in 9 pts (32.1%) and 24 pts (51.1%) in C1 and C2, respectively, with hypertension (10.7% and 12.9%) being the most commonly reported. The most commonly SAE reported were abdominal infection (3.6%) in C1, and diarrhea (4.3%) in C2. Conclusions: Pucotenlimab plus bevacizumab or lenvatinib has demonstrated clinical efficacy in aHCC patients naïve to systemic therapy, and no unexpected safety signals emerged. The two cohorts are comparable in terms of effectiveness, but safety profiles presented some differences. The findings need to be confirmed by additional studies. Clinical trial information: NCT04741165.