Abstract LB402: In vivo efficacy of anti-B7-H3 antibody-drug conjugate (ADC) ifinatamab deruxtecan (I-DXd; DS-7300): An update from the Pediatric Preclinical In Vivo Testing (PIVOT) Program
Authors: Gorlick Richard , Gill Jonathan , Zhang Wendong , Mosse Yael , Maris John , Groff David , Smith Malcolm , Teicher Beverly , Neuhauser Steve , Stearns Tim , Philip Vivek , Jocoy Emily , Chuang Jeff , Bult Carol J. , Hasegawa Jun , Qian Xiaozhong , Houghton Peter , Kurmasheva Raushan 
Published: April 2024

Abstract
Introduction: I-DXd (DS-7300) is a B7-H3-directed ADC with a topoisomerase 1 inhibitor payload (an exatecan derivative, DXd). I-DXd has demonstrated clinical efficacy in adults with heavily pretreated solid tumors (Patel et al., ESMO 2023). We previously reported that I-DXd induced objective responses in PDX models for multiple B7-H3 (CD276) expressing pediatric histologies, including rhabdomyosarcoma, osteosarcoma, neuroblastoma, and Wilms tumor. We extend these results with dose-response testing and include an isotype control ADC (IC-ADC) to evaluate whether B7-H3 expression is required for optimal response.
Methods: PDX models were dosed with vehicle, I-DXd, or IC-ADC, the latter two at 1, 3, and 10 mg/kg intravenously on days 1 and 15. Testing was performed using 5 animals per treatment group. Activity was assessed by the PIVOT objective response measure (ORM) (Ped Blood Cancer 2007;49:928-940) that defines objective response as partial, complete, or maintained complete response (PR, CR, and MCR) compared to stable disease (SD) or progressive disease, with or without growth delay (PD2 and PD1, respectively).
Results: I-DXd showed dose-dependent activity with MCR for all 5 models at 10 mg/kg. PR or MCR responses were observed in 4 of 5 models to I-DXd at 3 mg/kg, with no objective responses to I-DXd at 1 mg/kg. Only the RMS model showed objective response to IC-ADC. For all models I-DXd was significantly more active than IC-ADC.
Conclusions: We confirm significant anti-tumor activity for I-DXd for multiple pediatric solid tumors with B7-H3 expression and provide evidence of a dose response effect for I-DXd and for enhanced efficacy for I-DXd versus IC-ADC. Testing in additional preclinical models (neuroblastoma and glioblastoma) is underway. Due to the uniform high expression of B7-H3 in multiple pediatric histologies, I-DXd warrants evaluation for clinical activity in pediatric solid tumor patients.

TABLE 1. NAND Activity for DS-7300a and Isotype Control using the PIVOT Objective Response Measure (ORM) Line IHC B7-H3 H-Score Diagnosis DS-7300a Isotype Control 1 mg/kg 3 mg/kg 10 mg/kg 1 mg/kg 3 mg/kg 10 mg/kg OS-9 230 Osteosarcoma PD2 PR MCR PD1 PD1 PD1 OS-33 240 Osteosarcoma PD2 MCR MCR PD1 PD2 SD Rh30 140 Rhabdomyosarcoma PD2 MCR MCR PD1 PR MCR WT11 150 Wilms tumor PD1 PD2 MCR PD1 PD1 PD1 Felix 210 Neuroblastoma PD2 MCR MCR PD1 PD1 PD2
Citation Format: Richard Gorlick, Jonathan Gill, Wendong Zhang, Yael Mosse, John Maris, David Groff, Malcolm Smith, Beverly Teicher, Steve Neuhauser, Tim Stearns, Vivek Philip, Emily Jocoy, Jeff Chuang, Carol J. Bult, Jun Hasegawa, Xiaozhong Qian, Peter Houghton, Raushan Kurmasheva. In vivo efficacy of anti-B7-H3 antibody-drug conjugate (ADC) ifinatamab deruxtecan (I-DXd; DS-7300): An update from the Pediatric Preclinical In Vivo Testing (PIVOT) Program [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB402.