Co-clinical Trial of Novel Bispecific Anti-HER2 Antibody Zanidatamab in Patient-Derived Xenografts

Authors

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 R Pohlmann
V Behrana Jensen
Milind Javle
Jordi Rodon
Funda Meric-Bernstam

Publication Date

5-1-2024

Journal

Cancer Discovery

Abstract

Zanidatamab is a bispecific human epidermal growth factor receptor 2 (HER2)-targeted antibody that has demonstrated antitumor activity in a broad range of HER2-amplified/expressing solid tumors. We determined the antitumor activity of zanidatamab in patient-derived xenograft (PDX) models developed from pretreatment or postprogression biopsies on the first-in-human zanidatamab phase I study (NCT02892123). Of 36 tumors implanted, 19 PDX models were established (52.7% take rate) from 17 patients. Established PDXs represented a broad range of HER2-expressing cancers, and in vivo testing 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 and demonstrated that MET inhibitors have single-agent activity and can enhance zanidatamab activity in vitro and in vivo. These findings provide evidence that PDXs can be developed from pretreatment biopsies in clinical trials and may provide insight into mechanisms of resistance.

Keywords

Animals, Humans, Mice, Antibodies, Bispecific, Antibodies, Monoclonal, Humanized, Receptor, ErbB-2, Xenograft Model Antitumor Assays

DOI

10.1158/2159-8290.CD-23-0838

PMID

38358339

PMCID

PMC11064988

PubMedCentral® Posted Date

February 2024

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes