Trastuzumab Deruxtecan, Antibody–Drug Conjugate Targeting HER2, Is Effective in Pediatric Malignancies: A Report by the Pediatric Preclinical Testing Consortium

Pooja Hingorani, Wendong Zhang, Zhongting Zhang, Zhaohui Xu, Wei Lien Wang, Michael E. Roth, Yifei Wang, Jonathan B. Gill, Douglas J. Harrison, Beverly A. Teicher, Stephen W. Erickson, Gregory Gatto, Edward A. Kolb, Malcolm A. Smith, Raushan T. Kurmasheva, Peter J. Houghton, Richard Gorlick

Research output: Contribution to journalArticlepeer-review

Abstract

HER2 is expressed in many pediatric solid tumors and is a target control was administered intravenously to mice harboring estabfor innovative immune therapies including CAR-T cells and antilished flank tumors at a dose of 5 mg/kg on day 1. Event-free survival body–drug conjugates (ADC). We evaluated the preclinical efficacy (EFS) and objective response were compared between treatment of trastuzumab deruxtecan (T-DXd, DS-8201a), a humanized and control groups. HER2 mRNA expression was observed across monoclonal HER2-targeting antibody conjugated to a topoisomhistologies, with the highest expression in WT (median ¼ 22 erase 1 inhibitor, DXd, in patient- and cell line–derived xenograft FPKM), followed by MRT, OS, and EWS. The relationship between (PDX/CDX) models. HER2 mRNA expression was determined HER2 protein and mRNA expression was inconsistent. T-DXd using RNA-seq and protein expression via IHC across multiple significantly prolonged EFS in 6/7 OS, 2/2 MRT, and 3/3 WT PDX pediatric tumor PDX models. Osteosarcoma (OS), malignant rhabmodels. Complete response (CR) or maintained CR (MCR) were doid tumor (MRT), and Wilms tumor (WT) models with varying observed for 4/5 WT and MRT models, whereas stable disease was HER2 expression were tested using 10 mice per group. Additional the best response among OS models. SMT experiments also demhistologies such as Ewing sarcoma (EWS), rhabdomyosarcoma onstrated activity across multiple solid tumors. Clinical trials (RMS), neuroblastoma (NB), and brain tumors were evaluated assessing the efficacy of a HER2-directed ADC in pediatric patients using single mouse testing (SMT) experiments. T-DXd or vehicle with HER2-expressing tumors should be considered.

Original languageEnglish (US)
Pages (from-to)1318-1325
Number of pages8
JournalMolecular cancer therapeutics
Volume21
Issue number8
DOIs
StatePublished - Aug 2022

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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