A phase 1 dose-finding and pharmacokinetic study of acasunlimab alone or in combination with pembrolizumab in Japanese patients with advanced or metastatic solid tumors

BACKGROUND: Acasunlimab is a PD-L1 × 4-1BB bispecific antibody that induces T-cell activation through conditional 4-1BB stimulation, which is dependent on simultaneous PD-L1 binding, while the acasunlimab PD-L1-specific arm inhibits PD-1/PD-L1 activity without 4-1BB binding. Acasunlimab may produce prolonged, synergistic antitumor responses in patients with advanced solid malignancies. METHODS: This phase 1, open-label, dose-escalation trial evaluated acasunlimab monotherapy and combination therapy with pembrolizumab in Japanese adult patients with advanced or metastatic solid tumors. Using a 3 + 3 design, patients received single intravenous acasunlimab infusions (15-800 mg every 3 weeks [Q3W]), or acasunlimab 100 mg plus pembrolizumab 200 mg Q3W. Primary endpoints included adverse events, dose-limiting toxicity (DLT), and pharmacokinetics. Pharmacodynamics and antitumor activity were also evaluated. RESULTS: Eighteen patients were enrolled with diverse tumor types. Grade 3 treatment-related adverse events (TRAEs) occurred in 5 of 15 patients receiving acasunlimab monotherapy and 1 of 3 patients who received acasunlimab plus pembrolizumab. No grade 4 or 5 TRAEs occurred, and no DLTs or TRAEs leading to death at any monotherapy or combination dose were reported. Pharmacokinetics for acasunlimab in Japanese patients were comparable to those in non-Japanese patients from other clinical studies. Six patients receiving acasunlimab monotherapy experienced a best overall response of stable disease, as did one patient receiving acasunlimab plus pembrolizumab. CONCLUSIONS: Acasunlimab demonstrated a manageable safety profile, with comparable pharmacokinetics in Japanese and non-Japanese patients. Antitumor activity was demonstrated in a small number of patients with diverse tumor types.