Abstract B126: Co-clinical trial of novel bispecific anti-HER2 antibody Zanidatamab in Patient-Derived Xenografts

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Abstract Background: Zanidatamab is a bispecific HER2-targeted antibody in clinical development which has demonstrated antitumor activity in a broad range of HER2 amplified/expressing solid tumors. We report the antitumor activity of zanidatamab in vivo by utilizing patient-derived xenograft (PDX) models developed from pre-treatment or post-progression biopsies from the first-in-human zanidatamab phase I study (NCT02892123). Methods: PDXs were established by implanting 1-2 core biopsies from HER2 expressing tumors into immunodeficient mice. The PDXs that developed were expanded and treated with zanidatamab monotherapy or novel combinations targeting co-alterations and the relevant treatment controls. PDXs models were also characterized by DNA and RNA sequencing, HER2 IHC, and reverse phase protein arrays (RPPA). Antitumor activity in patients was assessed by RECIST1.1. Antitumor activity in PDXs was assessed by change in tumor volume from baseline, objective response, and event-free survival defined as time to tumor volume doubling (EFS-2). Results: From the thirty-six patient tumors implanted, 19 PDX models were established (52.7% take rate) from 17 individual patients. Established PDXs represented a broad range of HER2-expressing cancers; however, a higher take-rate was observed in gastrointestinal (GI) tumors (64.0%) compared to non-GI tumors (27.3%). Patients whose biopsies grew as PDXs had shorter median progression-free survival (PFS) and overall survival (OS) than patients whose biopsies did not grow as PDXs (PFS: 58 days vs 112 days; OS: 92 days vs. 574 days). PDXs were developed from patients with a range of objective responses to zanidatamab. In vivo testing in PDXs demonstrated an association between antitumor activity in PDXs and matched patients in 7 of 8 co-clinical models tested. We also identified amplification of MET as a potential mechanism of acquired resistance to zanidatamab in 2 of 4 post-progression PDXs and demonstrated that MET inhibitors have single agent activity and enhance zanidatamab activity in vitro and in vivo in a post- zanidatamab progression model. Conclusions: Our findings provide evidence that PDXs can be developed from pre-treatment biopsies in clinical trials and may provide insight into mechanisms of resistance. Citation Format: Timothy P DiPeri, Kurt W Evans, Bailiang Wang, Ming Zhao, Argun Akcakanat, Maria Gabriela Raso, Yasmeen Q Rizvi, Xiaofeng Zheng, Anil Korkut, Kaushik Varadarajan, Burak Uzunparmak, Ecaterina E Dumbrava, Shubham Pant, Jaffer A Ajani, Paula Pohlmann, V Behrana Jensen, Milind Javle, Jordi Rodon, Funda Meric-Bernstam. Co-clinical trial of novel bispecific anti-HER2 antibody Zanidatamab in Patient-Derived Xenografts [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B126.