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

Autor: Lumish M; 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., Chui MH; Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, United States of America., Zhou Q; Department of Epidemiology & Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, United States of America., Iasonos A; Department of Epidemiology & Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, United States of America., Sarasohn D; Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, United States of America., Cohen S; 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., Friedman C; 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., Grisham R; 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., Konner J; 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., Kyi C; 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., Rubinstein M; 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., Troso-Sandoval T; 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., Aghajanian C; 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., Makker V; 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. Electronic address: makkerv@mskcc.org.
Jazyk: angličtina
Zdroj: Gynecologic oncology [Gynecol Oncol] 2024 Mar; Vol. 182, pp. 75-81. Date of Electronic Publication: 2024 Jan 22.
DOI: 10.1016/j.ygyno.2023.12.028
Abstrakt: 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: govidentifier: NCT04513665.
Competing Interests: Declaration of Competing Interest V Makker reports meeting/travel support by Eisai and Merck; participation on Data Safety Monitoring or Advisory Board of Duality, Merck, Karyopharm, Exelexis, Eisai, Karyopharm, BMS, Clovis, Faeth Immunocore, Morphosys, AstraZeneca, Novartis, GSK, Bayer (all unpaid); and study support to the institution by Merck, Eisai, AstraZeneca, Faeth, Karyopharm, Zymeworks, Duality, Clovis, Bayer and Takeda. CF Friedman reports institutional research support from Seagen, Merck, BMS, AstraZeneca, Mersana, and Hotspot Therapeutics; consulting fees from BMS, Seagen, and Aadi Biosciences; honoraria for lectures from Onclive; meeting/travel support by PUMA; and participation on Data Safety Monitoring or Advisory Board of Merck, Genentech, and Marengo (all uncompensated). A Iasonos reports consulting fees from Mylan. MM Rubinstein reports research funding from Merk, Zentalis, and AstraZeneca. C Kyi reports grant funding from Conquer Cancer Foundation; grant funding paid to the institution from Merus, Gritstone, and BMS; and consulting fees from Scenic Immunology B.V. and OncLive. RN Grisham reports honoraria from GSK, AstraZeneca, Natera, Springworks, Corcept, MJH, and PER. C Aghajanian reports clinical trial funding paid to the institution from AstraZeneca; consulting fees (advisory board) from Eisai/Merck, Roche/Genentech, Abbvie, AstraZeneca/Merck, and Repare Therapeutics; advisory board participation (no fee) for Blueprint Medicine; and leadership/fiduciary roles for the GOG Foundation Board of Directors (travel cost reimbursement) and NRG Oncology Board of Directors (unpaid). The other authors do not have potential conflicts of interest to declare.
(Copyright © 2024 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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