Abstract LB-217: Preclinical evaluation of trastuzumab deruxtecan (T-DXd; DS-8201a), a HER2 antibody-drug conjugate, in pediatric solid tumors by the Pediatric Preclinical Testing Consortium (PPTC)

Abstract

Introduction: HER2 is expressed in a subset of pediatric solid tumors and is a target of interest for innovative immune therapies including CAR-T cells and antibody-drug conjugates (ADCs). We evaluated preclinical efficacy of T-DXd, a humanized monoclonal HER2 antibody conjugated to a topoisomerase 1 inhibitor payload, DXd, in solid tumor patient derived xenograft (PDX) models. Methods: 7 osteosarcoma (OS), 2 rhabdoid tumor (RT) and 3 Wilms tumor (WT) PDX models with varying HER2 expression were tested using 10 mice per group. ERBB2 mRNA expression was determined using RNA seq. T-DXd or vehicle control was administered IV to mice harboring flank tumors at a dose of 5mg/kg on Day 1. Standard PPTC statistical methods were employed for EFS for treatment (T) and control (C) groups, minimum relative tumor volume (minRTV) and objective response measure. Results: Among PPTC solid tumor models ERBB2 mRNA expression was observed across multiple histologies, with highest expression observed for WT (median = 22 FPKM), followed by RT, OS, and Ewing sarcoma. The relationship between HER2 expression by IHC and by RNAseq was inconsistent. Mice tolerated T-DXd with minimal toxicity. T-DXd significantly prolonged EFS in 5/7 OS, 2/2 RT and 3/3 WT PDX models (see table). Complete response (CR) or maintained CR were observed for 4 of 5 WT and RT models, while stable disease was the best response among OS models. Conclusions: T-DXd exhibits single agent anti-tumor activity in models of pediatric solid tumors. Single mouse testing experiments will be used to extend knowledge of the range of activity of T-DXd for pediatric solid tumors. Correlations between ERBB2 gene expression, HER2 expression by IHC, and genetic changes associated with camptothecin sensitivity are ongoing and will be presented. Clinical trials assessing efficacy of a HER2-directed ADC in pediatric patients with HER2-expressing tumors should be considered. EFS T - C(days)EFS T/C Ratiop-value Gehan-WilcoxonminRTVmean±SDminRTVp-valueObjective Response MeasureOS-120.31.85p < 0.0011.152±0.090p = 0.023PD1OS-230.12.76p < 0.0010.815±0.183p < 0.001PD2OS-94.11.14p = 0.1031.334±0.203p = 1.000PD1OS-1734.01.97p = 0.0091.172±0.179p = 0.017PD1OS-3111.91.84p < 0.0011.676±0.395p = 0.015PD1OS-3361.34.87p < 0.0010.486±0.220p < 0.001SDOS-603.81.11p = 0.0161.084±0.103p = 0.007PD1BT29 (RT)> 58.4> 3.28p < 0.0010.019±0.041p < 0.001MCRRBD2 (RT)> 97.3> 13.57p < 0.0010.021±0.066p < 0.001CRKT-10 (WT)> 85.1> 7.57p < 0.0010.000±0.000p < 0.001MCRKT-11 (WT)18.32.62p < 0.0010.954±0.486p < 0.001PD2KT-13 (WT)> 71.5> 3.69p < 0.0010.019±0.060p < 0.001MCR Citation Format: Pooja Hingorani, Wendong Zhang, Raushan Kurmasheva, Zhongting Zhang, Yifei Wang, Zhaohui Xu, Michael Roth, Jonathan Gill, Douglas Harrison, Stephen Erickson, Edward A. Kolb, Malcolm Smith, Peter Houghton, Richard Gorlick. Preclinical evaluation of trastuzumab deruxtecan (T-DXd; DS-8201a), a HER2 antibody-drug conjugate, in pediatric solid tumors by the Pediatric Preclinical Testing Consortium (PPTC) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-217.