A Phase 1b Study of Botensilimab and Balstilimab in Treatment-Refractory Hepatocellular Carcinoma.

Introduction: Botensilimab (BOT) is a fragment crystallizable (Fc)-enhanced multifunctional anti-cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) antibody with differentiated mechanisms of action, designed to extend therapy to cold/poorly immunogenic solid tumors. Patients with hepatocellular carcinoma (HCC) who progress on or after first-line immunotherapy have limited treatment options. Here, we report findings from a phase 1b study of BOT plus balstilimab (BAL; anti-programmed cell death protein 1 [PD-1] antibody) in previously treated patients with HCC. Methods: This is an open-label, nonrandomized, phase 1b, multicenter study of BOT±BAL in patients with advanced solid tumors. The study began with dose escalation (3 + 3 design) then dose expansion with multiple disease-specific cohorts. An expanded cohort of 19 patients with HCC who progressed on or after prior immunotherapy (primarily atezolizumab/bevacizumab) are included in this analysis. Patients with HCC received BOT intravenously at 1 or 2 mg/kg once every 6 weeks for up to 2 years plus BAL intravenously 3 mg/kg once every 2 weeks, for up to 2 years. Endpoints included safety, objective response rate (ORR), disease control rate, duration of response, and progression-free survival (PFS). Overall survival (OS) was an exploratory endpoint. Results: Among 18 efficacy evaluable patients (with ≥1 post-baseline 6-week imaging scan), ORR was 17% (3/18; 95% CI: 4-41), and 18-week clinical benefit rate (a complete or partial response or stable disease) 50% (9/18; 95% CI: 26-74). Median PFS was 4.4 months (95% CI: 1.4-6.9), and median OS was 12.3 months (95% CI: 8.4-21.4). Thirteen patients (68%) experienced any-grade immune-mediated treatment-related adverse events (TRAEs), with 37% (7/19) grade 3. The most common immune-mediated TRAEs included diarrhea/colitis (37% [7/19]; 16% grade 3 [3/19]), hepatitis (21% [4/19]; 16% grade 3 [3/19]), and dermatologic events (21% [4/19]; 5% grade 3 [1/19]). There were no treatment-related deaths or new safety signals outside of the class. Conclusions: The BOT+BAL combination demonstrated durable responses and manageable safety in treatment-refractory patients with HCC previously treated with immunotherapy, supporting further investigation in randomized studies. Despite the small sample size and high percentage of patients with albumin-bilirubin grade 2 liver disease, these results provide early evidence of antitumor activity in a difficult-to-treat disease setting.