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HERIZON-GEA-01: A phase 3 study of zanidatamab in combination with chemotherapy with or without tislelizumab in first-line human epidermal growth factor receptor 2 positive (HER2+) advanced/metastatic gastroesophageal adenocarcinoma (GEA)
Background
Gastroesophageal adenocarcinomas (GEAs), including gastric, esophageal, and gastroesophageal junction (GEJ) adenocarcinomas, are common cancers with high morbidity and mortality. In approximately 25% of GEA cases, HER2 is overexpressed/amplified. Patients with advanced/metastatic HER2+ GEA are typically treated with trastuzumab, a HER2-targeted therapy, plus chemotherapy in the first-line setting. Preliminary data suggests that the addition of an immune checkpoint inhibitor to the treatment regimen may further improve patient outcomes. Zanidatamab is a novel, bispecific HER2-targeting monoclonal antibody (mAb) that binds to two non-overlapping extracellular domains (ECD4 and ECD2) on HER2. This bispecific binding forms HER2 clusters and induces greater internalization and downregulation of cell surface HER2 compared to trastuzumab (as observed in preclinical studies). Zanidatamab also causes growth signal reduction and triggers immune-mediated antitumor activity through antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and complement-dependent cytotoxicity (CDC). Early studies have shown that zanidatamab has a manageable safety profile with encouraging antitumor activity in HER2+ GEA, when used both as a monotherapy and in combination with chemotherapy in later-line treatment. In the first-line setting in a phase 2 study, zanidatamab plus chemotherapy demonstrated a confirmed objective response rate (ORR) of 75%, median duration of response (DOR) of 16.4 months, and median progression-free survival (PFS) of 12.0 months. Separately, the anti-programmed cell death-1 (PD1) mAb tislelizumab has demonstrated a manageable safety profile and clinical activity in multiple cancers, including gastric and GEJ adenocarcinoma. The combination of zanidatamab with chemotherapy plus tislelizumab is being studied in an ongoing phase 1b/2 study and has recently completed accrual. HERIZON-GEA-01 (NCT05152147; EudraCT#: 2021-000296-36), is a global, randomized, open-label, active-comparator, phase 3 study that will further investigate the efficacy and safety of zanidatamab in combination with chemotherapy with or without tislelizumab as first-line treatment for patients with advanced/metastatic HER2+ GEA.
Trial design
Key eligibility criteria include: age ≥ 18 years, untreated, unresectable locally advanced/metastatic GEA that is HER2+ (IHC3+ or IHC2+/ISH+) per central testing, ECOG PS of 0 or 1, and adequate organ function, including LVEF > 50%. Enrolled patients will be assigned randomly (1:1:1) to either: trastuzumab (6 mg/kg IV Q3W) plus chemotherapy; zanidatamab (1800 mg IV [patient 2 IV Q3W and capecitabine 1000 mg/m2 oral BID on days 1–15) or FP (cisplatin 80 mg/m2 IV Q3W and 5-fluorouracil 800 mg/m2 continuous IV on days 1–5). The primary endpoints of the study are PFS per RECIST v1.1 assessed by blinded independent central review (BICR), and overall survival. Secondary endpoints include: BICR-assessed confirmed ORR and DOR; investigator-assessed PFS, ORR, and DOR; incidence and severity of AEs; and changes in health-related quality of life (HRQoL). 714 patients are planned to be enrolled from ∼300 sites in 30+ countries across North America (not including the US), South America, Europe, Africa, Asia, and Oceania. The study is currently recruiting patients.
Clinical trial identification
NCT05152147; EudraCT#: 2021-000296-36.
Legal entity responsible for the study
Sponsor.
Funding
This study is sponsored by Zymeworks Inc. and BeiGene, Ltd.
Disclosures
J. Tabernero: Honoraria (self): educational collaboration with Imedex, Medscape Education, MJH Life Sciences, PeerView Institute for Medical Education and Physicians Education Resource (PER).; Advisory / Consultancy: scientific consultancy role for Array Biopharma, AstraZeneca, Avvinity, Bayer, Boehringer Ingelheim, Chugai, Daiichi Sankyo, F. Hoffmann-La Roche Ltd, Genentech Inc, HalioDX SAS, Hutchison MediPharma International, Ikena Oncology, Inspirna Inc, IQVIA, Lilly, Menarini, Merck Serono, Merus, MSD, Mirati, Neophore, Novartis, Ona Therapeutics, Orion Biotechnology, Peptomyc, Pfizer, Pierre Fabre, Samsung Bioepis, Sanofi, Seattle Genetics, Scandion Oncology, Servier, Sotio Biotech, Taiho, Tessa Therapeutics and TheraMyc. E. Elimova: Honoraria (Institution): BMS, Zymeworks, Beigene; Advisory / Consultancy: Adaptimmune, BMS; Research grant / Funding (institution): BMS, Zymeworks, Astra zeneca; Spouse / Financial dependant: Merck. G. Ku: Advisory / Consultancy: BMS, Eli Lilly, Merck, Pieris; Research grant / Funding (institution): Arog, AstraZeneca, BMS, Daiichi Sankyo, Merck, Oncolys, Pieris, Zymeworks. K. Shitara: Honoraria (self): Takeda, Bristol-Myers Squibb; Advisory / Consultancy: Eli Lilly and Company; Bristol Myers Squibb; Takeda; Pfizer, Ono Pharmaceutical; Merck Pharmaceutical; Taiho Pharmaceutical; Novartis, AbbVie; GlaxoSmithKline; Daiichi Sankyo; Amgen; Boehringer Ingelheim; Janssen; Research grant / Funding (institution): Astellas; Ono Pharmaceutical; Daiichi Sankyo; , Taiho Pharmaceutical; Chugai; Merck Pharmaceutical, Medi Science; Eisai; Amgen. L. Shen: Advisory / Consultancy: BMS/AstraZeneca/BI/MSD/Daiichi Sankyo/Roche; Research grant / Funding (institution): Yaojie Ankang (Nanjing) Technology Co., Ltd./QiLu Pharmaceutical, Baiji Shenzhou (Beijing) Biotechnology Co., Ltd/Zaiding Pharmaceutical, Beijing Xiantong Biomedical Technology Co., Ltd. X. Lin: Full / Part-time employment: BeiGene. L. Boyken: Full / Part-time employment: Zymeworks. H. Li: Honoraria (self): BeiGene (Shanghai) Co., Ltd.; Travel / Accommodation / Expenses: BeiGene (Shanghai) Co., Ltd.; Shareholder / Stockholder / Stock options: BeiGene (Shanghai) Co., Ltd.. J. Grim: Shareholder / Stockholder / Stock options: Zymeworks, Inc; Full / Part-time employment: Zymeworks, Inc. J. Ajani: Honoraria (self): BeiGene, BMS, Merck, Amgen, novartis, ; Research grant / Funding (institution): BMS, Merck, Amgen, Roche, Zymeworks, Taiho, Prolinx, Beigene, Leap. The author has declared no conflicts of interest.
