Co-Clinical Trial of Novel Bispecific Anti-HER2 Antibody Zanidatamab in Patient-Derived Xenografts
Menée à l'aide de 19 xénogreffes dérivées de tumeurs HER2+ issues de 17 patients atteints d'un cancer de stade avancé ou métastatique et inclus dans un essai de phase I, cette étude examine l'activité antitumorale du zanidatamab, un anticorps bispécifique ciblant HER2, identifie un mécanisme de résistance à cet anticorps et démontre l'intérêt des inhibiteurs de MET pour accroître son activité antitumorale
Zanidatamab is a bispecific HER2-targeted antibody which 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 pre-treatment or post-progression 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 pre-treatment biopsies in clinical trials and may provide insight into mechanisms of resistance.
Cancer Discovery , article en libre accès, 2023