A phase 2 trial of zanidatamab in HER2-overexpressed advanced endometrial carcinoma and carcinosarcoma (ZW25-IST-2) Journal Article
| Authors: | Lumish, M.; Chui, M. H.; Zhou, Q.; Iasonos, A.; Sarasohn, D.; Cohen, S.; Friedman, C.; Grisham, R.; Konner, J.; Kyi, C.; Rubinstein, M.; Troso-Sandoval, T.; Aghajanian, C.; Makker, V. |
| Article Title: | A phase 2 trial of zanidatamab in HER2-overexpressed advanced endometrial carcinoma and carcinosarcoma (ZW25-IST-2) |
| Abstract: | Objective: 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. Methods: 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. Results: 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. Conclusions: 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.gov identifier: NCT04513665 © 2024 Elsevier Inc. |
| Keywords: | immunohistochemistry; adult; cancer chemotherapy; clinical article; controlled study; aged; overall survival; clinical trial; fatigue; paresthesia; advanced cancer; cancer growth; diarrhea; drug efficacy; drug safety; side effect; systemic therapy; nuclear magnetic resonance imaging; follow up; endometrial cancer; antineoplastic agent; endometrium carcinoma; anorexia; gene overexpression; metastasis; computer assisted tomography; phase 2 clinical trial; gene amplification; anemia; mucosa inflammation; nausea; vomiting; myalgia; epidermal growth factor receptor 2; abdominal pain; coughing; pruritus; rash; heart palpitation; malaise; fluorescence in situ hybridization; open study; trastuzumab; gastroesophageal reflux; dyspepsia; alopecia; radiosensitizing agent; good clinical practice; antibody; oral mucositis; genetic heterogeneity; her2; dysgeusia; nose obstruction; muscle cramp; sinus tachycardia; second-line treatment; overall response rate; uterine carcinosarcoma; body weight loss; response evaluation criteria in solid tumors; Common Terminology Criteria for Adverse Events; high throughput sequencing; infusion related reaction; human; female; article; pembrolizumab; trastuzumab deruxtecan; zanidatamab |
| Journal Title: | Gynecologic Oncology |
| Volume: | 182 |
| ISSN: | 0090-8258 |
| Publisher: | Elsevier Inc. |
| Date Published: | 2024-03-01 |
| Start Page: | 75 |
| End Page: | 81 |
| Language: | English |
| DOI: | 10.1016/j.ygyno.2023.12.028 |
| PUBMED: | 38262242 |
| PROVIDER: | scopus |
| PMCID: | PMC11264355 |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PDF. Corresponding MSK author is Vicky Makker -- Source: Scopus |
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