Nilvanstomig (ZG005), an anti-PD-1/TIGIT bispecific antibody, plus bevacizumab vs. sintilimab plus bevacizumab biosimilar as first-line therapy for advanced hepatocellular carcinoma: A randomized, multi-center, phase II trial.

Abstract

4014 Background: Checkpoint inhibitors combined with anti-angiogenic therapy represents one of the standard first-line therapies for advanced hepatocellular carcinoma (aHCC). Nilvanstomig (ZG005) is a recombinant humanized anti-PD-1/TIGIT bispecific antibody. By blocking both pathways, it can synergistically activate T cells and enhance the anti-tumor activity of NK cells. This study evaluated ZG005 plus bevacizumab vs. sintilimab plus IBI305 (a bevacizumab biosimilar) as first-line therapy for aHCC. Methods: In this randomized, open-label, multicenter, phase 2 trial conducted in China, patients with aHCC who had not previously received systemic treatment were randomly assigned (1:1:1) to receive ZG005 10 mg/kg plus bevacizumab 15 mg/kg (Arm A); ZG005 20 mg/kg plus bevacizumab 15 mg/kg (Arm B); or sintilimab 200 mg plus IBI305 15 mg/kg (Arm C). All treatments were administered intravenously every 3 weeks until disease progression or unacceptable toxicity. Randomization was stratified by baseline AFP level ( < 400 vs. ≥400 ng/mL), macrovascular invasion or extrahepatic metastasis (presence vs. absence). The primary endpoint was IRC-assessed PFS per RECIST v1.1, with key secondary endpoints including PFS per mRECIST, ORR and DCR by both criteria, and OS. Results: As of the data cutoff (Nov 25, 2025), 95 patients were enrolled and received at least one dose of treatment (Arm A, n = 31; Arm B, n = 32; Arm C, n = 32). Baseline characteristics were well-balanced across the treatment arms. For all patients enrolled, the median age was 61 years (range, 37-75), with 85.3% of patients being male. Disease characteristics included BCLC stage B (28.4%) or C (71.6%), Child-Pugh score A5 (83.2%) or A6 (16.8%), baseline AFP ≥400 ng/mL in 45.3% of patients, and HBV positivity in 73.7%. Macrovascular invasion and/or extrahepatic metastasis were present in 71.6% (68/95) of patients. With a median follow-up of about 5 months, the IRC-assessed ORR was 32.3% in Arm A, 37.5% in Arm B, and 25.0% in Arm C per RECIST v1.1; the corresponding ORRs per mRECIST were 54.8%, 50.0%, and 34.4%. The IRC-assessed median PFS per RECIST v1.1 was not reached in Arm A or B, compared with 5.8 months in Arm C (Arm A vs. C: HR 0.40, 95% CI 0.15-1.05; Arm B vs. C: HR 0.28, 95% CI 0.10-0.79). The safety profiles were comparable across the three arms. No grade ≥3 hemorrhagic adverse events were reported in either Arm A or B. Conclusions: The combination of ZG005 and bevacizumab as first-line treatment in patients with aHCC demonstrated an early encouraging efficacy with an acceptable safety profile. Higher response rates and prolonged PFS were observed with the ZG005-based regimens. Longer follow up of the current study and future phase 3 trials are warranted to validate the efficacy and safety of ZG005 in combination with bevacizumab in aHCC. Clinical trial information: NCT06558227 .