Antitumor Activity of Trastuzumab Deruxtecan in Pediatric Solid Tumors with Variable HER2 Expression

Abstract Trastuzumab deruxtecan (T-DXd) is an ERBB2/HER2-targeting antibody–drug conjugate (ADC) with efficacy across adult cancers exhibiting variable HER2 expression. Prior studies demonstrating HER2 expression in osteosarcoma motivated a clinical trial of T-DXd in pediatric and adolescent/young adults with osteosarcoma, but the trial was terminated early because of inactivity. We evaluated the activity of T-DXd using osteosarcoma patient-derived xenograft (PDX) models and found a 22% objective response rate despite no detectable HER2 expression across PDXs tested. To further assess non-HER2–mediated activity, we evaluated the activity of T-DXd across 31 pediatric cancer cell lines and found osteosarcoma to be amongst the most resistant to T-DXd, as well as unconjugated deruxtecan, providing a potential explanation for the negative results observed in the clinical trial of T-DXd in osteosarcoma. T-DXd evaluation in PDX models representing pediatric histologies with greater intrinsic sensitivity to deruxtecan, including pediatric renal tumors and desmoplastic small round cell tumor, revealed both HER2-enhanced activity as well as substantial non-HER2–mediated activity, as evidenced by equipotent activity using an isotype-matched control ADC. Together, these results underscore translational opportunities for ADC therapeutics in tumor histologies with high sensitivity to the payload and in which enhanced tumor delivery may be mediated by antibody-targeted mechanisms as well as macromolecular characteristics of ADCs (e.g., enhanced permeability and retention effect) and tumor microenvironmental factors (e.g., proteolytic payload release). Our findings challenge the role of HER2 as a biomarker predictive of T-DXd response in pediatric cancers and support further biomarker-agnostic clinical development of T-DXd in desmoplastic small round cell tumor and pediatric renal tumors.