A phase 2 trial of zanidatamab in HER2-overexpressed advanced endometrial carcinoma and carcinosarcoma (ZW25-IST-2)

• Published in: Gynecologic oncology 2024-03, Vol.182, p.75-81
• Main Authors: Lumish, Melissa, Chui, M. Herman, Zhou, Qin, Iasonos, Alexia, Sarasohn, Debra, Cohen, Seth, Friedman, Claire, Grisham, Rachel, Konner, Jason, Kyi, Chrisann, Rubinstein, Maria, Troso-Sandoval, Tiffany, Aghajanian, Carol, Makker, Vicky
• Format: Article
• Language: English
• Subjects: Antibodies, Bispecific; Antibody; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Carcinosarcoma - drug therapy; Carcinosarcoma - genetics; Clinical trial; Endometrial cancer; Endometrial Neoplasms - drug therapy; Endometrial Neoplasms - genetics; Endometrial Neoplasms - pathology; Female; HER2; Humans; In Situ Hybridization, Fluorescence; Neoplasm Recurrence, Local - pathology; Receptor, ErbB-2 - metabolism; Trastuzumab; Zanidatamab
• ISSN: 0090-8258; 1095-6859; 1095-6859
• DOI: 10.1016/j.ygyno.2023.12.028

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. ClinicalTrials.govidentifier: NCT04513665 •HER2 overexpression associated with decreased survival in advanced endometrial cancer (EC).•Zanidatamab in HER2+ metastatic EC/carcinosarcoma did not meet its primary endpoint.•Intratumor heterogeneity/lack of HER2 amplification could have attributed to poor efficacy.