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.

中文翻译：

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新型双特异性抗 HER2 抗体 Zanidatamab 在患者异种移植物中的联合临床试验

Zanidatamab 是一种双特异性 HER2 靶向抗体，已在多种 HER2 扩增/表达实体瘤中表现出抗肿瘤活性。我们在首次人体扎尼达单抗 I 期研究 (NCT02892123) 中通过治疗前或进展后活检开发的患者来源异种移植 (PDX) 模型中确定了扎尼达单抗的抗肿瘤活性。在36个植入肿瘤中，17名患者建立了19个PDX模型（成功率52.7%）。已建立的 PDX 代表了广泛的 HER2 表达癌症，体内测试证明了 PDX 的抗肿瘤活性与所测试的 8 个联合临床模型中的 7 个中的匹配患者之间存在关联。我们还确定了 MET 扩增是扎尼达单抗获得性耐药的潜在机制，并证明 MET 抑制剂具有单药活性，并且可以增强扎尼达单抗的体外和体内活性。这些发现提供了证据，表明 PDX 可以在临床试验中从治疗前活检中开发出来，并可能提供对耐药机制的深入了解。