Abstract 1088: An evaluation of patritumab deruxtecan (HER3-DXd, U3-1402) against pediatric PDX models for hepatoblastoma and rhabdomyosarcoma - A report from the NCI PIVOT Program
Authors: Kurmasheva Raushan , Houghton Peter , Del Pozo Vanessa , Ghilu Samson , Nakamura Ryuichi , Fan Pang-Dian , Jocoy Emily , Stearns Tim , Neuhauser Steve , Chuang Jeff , Bult Carol J. , Teicher Beverly A. , Smith Malcolm A. 
Published: March 2024

Introduction: HER3-DXd is an ADC consisting of a fully human monoclonal antibody to HER3 attached to a topoisomerase I inhibitor payload (DXd, an exatecan derivative) that has demonstrated clinically meaningful efficacy with durable responses in adults with non-small cell lung cancer. Two childhood cancers with HER3 expression are rhabdomyosarcoma (RMS) and hepatoblastoma (HB), and the goal of this work was to evaluate the activity of HER3-DXd against PDX models for these cancer types.

Methods: IHC testing was conducted on FFPE tissue (slides or TMA) using HER3/ErbB3 (D22C5) XP rabbit mAB and membrane expression was determined. HB models were evaluated using HER3-DXd and control IgG ADC (C-ADC) with a DXd payload, both at 10 mg/kg weekly x 3. RMS models were evaluated using HER3-DXd and C-ADC at 3 mg/kg and 10 mg/kg administered weekly x 3. Activity was assessed by the PIVOT objective response measure (ORM) targeting partial, complete, or maintained complete responses (PR, CR, and MCR) as compared to stable disease (SD) or progressive disease, with or without growth delay (PD2 and PD1, respectively).

Results: For 11 HB models, HER3 expression was 0 (n=2), 1+ (n=5), 2+ (n=1), and 3+ (n=3). For 8 RMS models, median IHC scores were 0 (n=1), 1+ (n=5), and 2+ (n=2). HER3-DXd activity by ORM is shown in the table. Three of 4 HB models treated with HER3-DXd showed MCR, while one had PD. The 3 HB models with MCR responses to HER3-DXd showed lesser responses to C-ADC. HER3-DXd was highly active against RMS models at 3 and 10 mg/kg with most models having MCR. C-ADC was also highly active against RMS models at both dose levels. At 10 mg/kg HER3-DXd, 2 of 4 HB models and 3 of 6 evaluable RMS models had time to event &gt; 100 days.

Conclusions: Many HB and RMS models show HER3 expression by IHC. HER3-DXd is highly active against both HB and RMS models. The high activity of C-ADC for RMS models suggests exquisite sensitivity of RMS models to the DXd payload

Treatment response categories to treatment of pediatric PDX models with HER3-Dxd PD1 PD2 SD PR CR MCR HB (HER3-Dxd, 10 mg/kg) 1 - - - - 3 HB (C-ADC, 10 mg/kg) 2 1 - 1 - - RMS (HER3-Dxd, 3 mg/kg) - 1 - - - 5 RMS (C-ADC, 3 mg/kg) - - - 1 2 2 RMS (HER-Dxd, 10 mg/kg) - - - - - 6 RMS (C-ADC, 10 mg/kg) - - - - 2 4

Citation Format: Raushan Kurmasheva, Peter Houghton, Vanessa Del Pozo, Samson Ghilu, Ryuichi Nakamura, Pang-Dian Fan, Emily Jocoy, Tim Stearns, Steve Neuhauser, Jeff Chuang, Carol J. Bult, Beverly A. Teicher, Malcolm A. Smith. An evaluation of patritumab deruxtecan (HER3-DXd, U3-1402) against pediatric PDX models for hepatoblastoma and rhabdomyosarcoma - A report from the NCI PIVOT Program [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1088.