PEPN1924, A Phase II Study of Trastuzumab Deruxtecan in Patients With Recurrent Human Epidermal Growth Factor Receptor 2+ Osteosarcoma: A Children’s Oncology Group Pediatric Early-Phase Clinical Trial Network Study

Reed DR, Janeway KA, Minard CG, Hall D, Crompton BD, Lazar AJ, Wang WL, Zylber R, Contreras A, Carrero G, Voss SD, Reid JM, Safgren SL, Militano O, Gorlick R, Pickett CA, Fox E, Weigel BJ. PEPN1924, A Phase II Study of Trastuzumab Deruxtecan in Patients With Recurrent Human Epidermal Growth Factor Receptor 2+ Osteosarcoma: A Children’s Oncology Group Pediatric Early-Phase Clinical Trial Network Study. JCO Oncol Adv. 2025;2:e2500094. doi: 10.1200/oa-25-00094. Epub 2025 Oct 14. PMID: 42131734; PMCID: PMC13166107.

Human epidermal growth factor receptor 2 (HER2), a transmembrane receptor with kinase activity involved in cell signaling through the RAS pathway, is expressed in osteosarcoma (OST). Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate with a HER2-targeting monoclonal antibody, trastuzumab, linked to a topoisomerase I inhibitor. We report results of a phase II study of T-DXd in adolescents and young adults with HER2-positive relapsed, unresectable OST (ClinicalTrials.gov identifier: NCT04616560). Patients age 12-39 years with relapsed, unresectable OST were eligible for centrally evaluated HER2 expression screening by immunohistochemistry. Patients with >10% of OST cells with cytoplasmic or membranous HER2 expression of any intensity were eligible to receive T-DXd at 5.4 mg/kg intravenously once every 3 weeks for up to 2 years. The study used a 9 + 15 Simon’s optimal two-stage design with a primary end point of event-free survival at 24 weeks. Fifty patients were screened for HER2, and 41 met the inclusion criteria of 10% of OST cells having membranous or cytoplasmic HER2 expression. Nine eligible patients, two younger than 18 years, were enrolled and received T-DXd. With a single patient having more than 24 weeks of stable disease (SD) of the nine planned in the first stage, this study did not meet criteria to progress to stage II. The estimated SD rate at 24 weeks is 11.1%. The median (range) number of cycles of therapy was 2 (2-12). Grade 3 and 4 possibly related adverse events occurred in three of nine patients and included nausea, vomiting, tumor hemorrhage, cytopenias (n = 3), wound infection, and hypertension. T-DXd did not demonstrate sufficient activity to expand enrollment to the planned second stage in patients with OST. No new safety signals were observed.