Safety and Efficacy of <scp>HexaBody</scp> ‐ <scp>DR5</scp> / <scp>DR5</scp> in Malignant Solid Tumors: Phase 1/2a Results and Translational Insights Into Observed Hepatotoxicity

HexaBody-DR5/DR5 (GEN1029) is a death receptor 5 (DR5) agonist composed of two humanized immunoglobulin G1 (IgG1) antibodies, Hx-DR5-01 and Hx-DR5-05, that bind non-overlapping DR5 epitopes with nanomolar affinity. HexaBody-DR5/DR5 is designed to activate the TRAIL pathway through DR5 clustering. This phase 1/2a, open-label, multi-center study aimed to determine the safety, pharmacokinetics (PK), pharmacodynamics, and preliminary antitumor activity of HexaBody-DR5/DR5 in patients with advanced solid tumors. In the study, 46 patients received biweekly intravenous injections of HexaBody-DR5/DR5 at doses ranging from 0.1 to 3.0 mg/kg, including patients with colorectal, gastric, non-small-cell lung, pancreatic, and triple-negative breast cancer. Safety evaluations revealed that 76.1% of patients experienced at least one grade (G) ≥ 3 treatment-emergent adverse event (TEAE), and 45.7% had drug-related G ≥ 3 events. The most frequent G ≥ 3 drug-related TEAEs were elevations of liver transaminases and diarrhea. According to RECIST criteria, 32.6% of patients showed stable disease. No patients achieved a partial or complete response. Exploratory assessments of cleaved cytokeratin 18 (cCK18) plasma levels indicated apoptotic pathway activation upon treatment. Reductions in circulating tumor DNA (ctDNA) levels and tumor metabolic activity according to PERCIST criteria suggested tumor-targeted biological activity. Nonclinical studies in vitro using human liver models demonstrated that HexaBody-DR5/DR5 directly inhibits viability of hepatocytes, but not Kupffer cells. The non-clinical liver toxicity was driven by dual epitope binding and hexamerization features, independent of FcγR-mediated crosslinking. Overall, these findings suggest that the TRAIL pathway has potential as a target for cancer therapy, provided tumor-specificity is sufficiently high to achieve an acceptable therapeutic index.