Porustobart (HBM4003) plus toripalimab as second-line therapy in patients with advanced hepatocellular carcinoma: a multicenter, open-label, phase I study

Abstract Purpose: To evaluate porustobart (HBM4003), a novel anti-CTLA-4 monoclonal antibody, combined with toripalimab as second-line therapy in advanced 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; 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: Totally, 16 patients were enrolled in cohort 1 and 12 in cohort 2. In the 26 patients with evaluable efficacy data, ORR was 23.1% (95% CI 9.0-43.6). Cohort 1 exhibited an ORR of 40.0%, while 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 for cohort 2. Biomarker exploration revealed higher abundance of intratumoral Tregs 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 (96.4%) patients, treatment-related adverse events (TRAEs) were reported in 25 patients (89.3%), among whom 13 (46.5%) had grade ≥3 TRAEs. Serious adverse events (SAEs) were observed in 12 patients (42.9%), and treatment-related SAEs were observed in 9 (32.1%) patients. 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. Trial Registration: ClinicalTrials.gov identifier: NCT05149027.