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HexaBody\u2010DR5\/DR5 is designed to activate the TRAIL pathway through DR5 clustering. This phase 1\/2a, open\u2010label, multi\u2010center study aimed to determine the safety, pharmacokinetics (PK), pharmacodynamics, and preliminary antitumor activity of HexaBody\u2010DR5\/DR5 in patients with advanced solid tumors. In the study, 46 patients received biweekly intravenous injections of HexaBody\u2010DR5\/DR5 at doses ranging from 0.1 to 3.0\u2009mg\/kg, including patients with colorectal, gastric, non\u2010small\u2010cell lung, pancreatic, and triple\u2010negative breast cancer. Safety evaluations revealed that 76.1% of patients experienced at least one grade (G)\u2009\u2265\u20093 treatment\u2010emergent adverse event (TEAE), and 45.7% had drug\u2010related G\u2009\u2265\u20093 events. The most frequent G\u2009\u2265\u20093 drug\u2010related 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\u2010targeted biological activity. Nonclinical studies in\u00a0vitro using human liver models demonstrated that HexaBody\u2010DR5\/DR5 directly inhibits viability of hepatocytes, but not Kupffer cells. The non\u2010clinical liver toxicity was driven by dual epitope binding and hexamerization features, independent of Fc\u03b3R\u2010mediated crosslinking. Overall, these findings suggest that the TRAIL pathway has potential as a target for cancer therapy, provided tumor\u2010specificity is sufficiently high to achieve an acceptable therapeutic index.<\/jats:p>","DOI":"10.1111\/cts.70546","type":"journal-article","created":{"date-parts":[[2026,5,23]],"date-time":"2026-05-23T06:51:29Z","timestamp":1779519089000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Safety and Efficacy of\n                    <scp>HexaBody<\/scp>\n                    \u2010\n                    <scp>DR5<\/scp>\n                    \/\n                    <scp>DR5<\/scp>\n                    in Malignant Solid Tumors: Phase 1\/2a Results and Translational Insights Into Observed Hepatotoxicity"],"prefix":"10.1111","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-5295-2339","authenticated-orcid":false,"given":"Marije B.","family":"Overdijk","sequence":"first","affiliation":[{"name":"Genmab B.V.  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