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

Abstract

<div>Abstract<p>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 <i>in vivo</i> 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 <i>MET</i> as a potential mechanism of acquired resistance to zanidatamab and demonstrated that MET inhibitors have single-agent activity and can enhance zanidatamab activity <i>in vitro</i> and <i>in vivo</i>. These findings provide evidence that PDXs can be developed from pretreatment biopsies in clinical trials and may provide insight into mechanisms of resistance.</p>Significance:<p>We demonstrate that PDXs can be developed from pretreatment and postprogression biopsies in clinical trials and may represent a powerful preclinical tool. We identified amplification of <i>MET</i> as a potential mechanism of acquired resistance to the HER2 inhibitor zanidatamab and MET inhibitors alone and in combination as a therapeutic strategy.</p><p><i><a href="https://aacrjournals.org/cancerdiscovery/article/doi/10.1158/2159-8290.CD-14-5-ITI" target="_blank">This article is featured in Selected Articles from This Issue, p. 695</a></i></p></div>