Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, United States of America; Department of Medicine, Weill Cornell Medical College, New York, NY, United States of America.
Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, United States of America.
Gynecol Oncol. 2024 Mar;182:75-81. doi: 10.1016/j.ygyno.2023.12.028. Epub 2024 Jan 22.
HER2 overexpression is associated with decreased overall survival in metastatic endometrial cancer. Trastuzumab with chemotherapy has demonstrated efficacy for first-line management of advanced HER2+ endometrial carcinoma, but HER2-directed therapy in the recurrent setting is limited. Zanidatamab (ZW25), a humanized, bispecific antibody that simultaneously binds the 2 distinct HER2 epitopes bound by trastuzumab and pertuzumab, has demonstrated safety and activity in HER2+ tumors. Here, we report the results of a phase 2, open-label study evaluating the efficacy and safety of zanidatamab in patients with HER2+ metastatic endometrial carcinoma/carcinosarcoma who received prior treatment.
We enrolled 16 patients with HER2+ endometrial carcinoma/carcinosarcoma after progression on ≤2 lines of therapy on a single-arm phase 2 study of zanidatamab. The primary endpoint was overall response rate (ORR; complete or partial response) by Response Evaluation Criteria in Solid Tumors version 1.1. HER2 immunohistochemistry and fluorescence in situ hybridization (FISH) were performed on pretreatment samples. Intratumor HER2 genetic heterogeneity was assessed.
This study did not meet its primary efficacy endpoint. Although a clinical benefit rate of 37.5% was observed by 24 weeks, only 1 patient achieved a partial response (ORR, 6.2%). Eight patients had HER2 intratumor heterogeneity or lacked HER2 amplification by FISH. Decreased HER2 expression on repeat pretreatment samples was observed in 3 (75%) of 4 patients evaluated.
We observed a low response rate to zanidatamab in recurrent HER2+ endometrial carcinoma/carcinosarcoma, which may be driven by downregulation of HER2 expression. Repeat HER2 testing should be considered prior to second-line HER2-directed therapy.
govidentifier: NCT04513665.
HER2 过表达与转移性子宫内膜癌的总生存期降低有关。曲妥珠单抗联合化疗已被证明对晚期 HER2+子宫内膜癌的一线治疗有效，但在复发环境中，HER2 靶向治疗有限。Zanidatamab（ZW25）是一种人源化双特异性抗体，可同时结合曲妥珠单抗和帕妥珠单抗结合的 2 个不同的 HER2 表位，在 HER2+肿瘤中显示出安全性和活性。在这里，我们报告了一项 2 期、开放标签研究的结果，该研究评估了 zanidatamab 在先前接受过治疗的 HER2+转移性子宫内膜癌/癌肉瘤患者中的疗效和安全性。
我们在 zanidatamab 的单臂 2 期研究中招募了 16 名 HER2+子宫内膜癌/癌肉瘤患者，这些患者在接受≤2 线治疗后进展。主要终点是根据实体瘤反应评价标准 1.1 版评估的总缓解率（ORR；完全或部分缓解）。在预处理样本上进行了 HER2 免疫组织化学和荧光原位杂交（FISH）检测。评估了肿瘤内 HER2 遗传异质性。
这项研究没有达到其主要疗效终点。尽管在 24 周时观察到 37.5%的临床获益率，但只有 1 名患者达到部分缓解（ORR，6.2%）。8 名患者存在肿瘤内 HER2 异质性或 FISH 缺乏 HER2 扩增。在评估的 4 名患者中，有 3 名（75%）患者的重复预处理样本中观察到 HER2 表达降低。
我们观察到复发性 HER2+子宫内膜癌/癌肉瘤对 zanidatamab 的反应率较低，这可能是由于 HER2 表达下调所致。在进行二线 HER2 靶向治疗之前，应考虑重复进行 HER2 检测。
govidentifier：NCT04513665。
