Porustobart (HBM4003) plus Toripalimab as Second-Line Therapy in Patients with Advanced Hepatocellular Carcinoma: A Multicenter, Open-Label, Phase I Study

Abstract Purpose: The study was conducted to evaluate porustobart (HBM4003), a novel anti–cytotoxic T lymphocyte–associated protein 4 monoclonal antibody, combined with toripalimab as second-line therapy in advanced hepatocellular carcinoma (HCC). Patients and Methods: This phase I study included two cohorts of patients with advanced HCC: cohort 1 included patients who were anti–PD-1/PD-L1 naïve and had received first-line anti-VEGFR tyrosine kinase inhibitor, and cohort 2 included patients who had failed prior first-line anti–PD-1/PD-L1 and anti-VEGF/VEGFR therapies. Porustobart (0.45 mg/kg) and toripalimab (240 mg) were administered every 21 days. The primary endpoint was the objective response rate (ORR). Results: In total, 16 patients were enrolled in cohort 1 and 12 in cohort 2. In the 26 patients with evaluable efficacy data, the ORR was 23.1% (95% confidence interval, 9.0–43.6). Cohort 1 exhibited an ORR of 40.0%, whereas cohort 2 presented no objective response. The median progression-free survival was 4.2 months, with 5.7 months for cohort 1 and 3.8 months for cohort 2. Biomarker exploration revealed higher abundance of intratumoral regulatory T cells in responders before treatment and a substantial elevation of CD4+Ki67+ and CD8+Ki67+ T cells after treatment. For safety, treatment-emergent adverse events were reported in 27 patients (96.4%), and treatment-related adverse events were reported in 25 patients (89.3%), among whom 13 (46.5%) had grade ≥3 treatment-related adverse events. Serious adverse events were observed in 12 patients (42.9%), and treatment-related serious adverse events were observed in nine patients (32.1%). Conclusions: The combination of porustobart and toripalimab shows promising efficacy as a second-line therapy in anti–PD-1/PD-L1–naïve patients with advanced HCC and a manageable safety profile.