Phase I Study of the Bifunctional Fusion Protein Bintrafusp Alfa in Asian Patients with Advanced Solid Tumors, Including a Hepatocellular Carcinoma Safety‐Assessment Cohort

LESSONS LEARNED: Bintrafusp alfa had a manageable safety profile and demonstrated preliminary clinical activity in heavily pretreated patients with solid tumors (including hepatocellular carcinoma) with no or limited treatment options. Findings from this study suggest bintrafusp alfa may be a novel therapeutic approach for patients with advanced solid tumors. Additional trials are needed to further explore safety and efficacy of bintrafusp alfa in specific tumor types. BACKGROUND: Bintrafusp alfa is a first‐in‐class bifunctional fusion protein composed of the extracellular domain of transforming growth factor‐β (TGF‐β) RII receptor (a TGF‐β “trap”) fused to a human immunoglobulin (Ig) G1 antibody blocking programmed death‐ligand 1 (PD‐L1). Bintrafusp alfa is designed to neutralize TGF‐β signaling by “trapping” and sequestering all TGF‐β isoforms, and this trap function is physically linked to PD‐L1 blockade in the tumor microenvironment. METHODS: NCT02699515 was a phase I, open‐label, dose‐escalation study of bintrafusp alfa (3, 10, and 20 mg/kg every 2 weeks) in Asian patients with advanced solid tumors, including a hepatocellular carcinoma (HCC) safety‐assessment cohort. The primary objective was safety and tolerability; the secondary objective is best overall response. RESULTS: As of August 24, 2018, 23 patients (including 9 in the HCC cohort) received bintrafusp alfa. Eight patients experienced treatment‐related adverse events (TRAEs). Three patients had grade 3 TRAEs (13.0%; hypoacusis, hyponatremia, hypopituitarism, increased blood creatine phosphokinase, and intracranial tumor hemorrhage); one had grade 4 hyponatremia (4.3%). No treatment‐related deaths occurred. In the dose‐escalation cohort, two patients had a confirmed partial response, and 3 had stable disease (SD), for an overall response rate of 14.3% and a disease control rate (DCR) of 35.7%. In the HCC cohort, one patient had SD (DCR, 11.1%). A dose‐proportional pharmacokinetics profile was observed at doses of >3 mg/kg. CONCLUSION: Bintrafusp alfa had a manageable safety profile and preliminary efficacy in heavily pretreated patients with advanced solid tumors, including HCC.