Anti-HER2 Bispecific Antibody Zanidatamab (ZW25) Activity in Combination With Chemotherapy With/Without Tislelizumab

Phase 1b/2 Study Investigating Safety, Tolerability, Pharmacokinetics and Preliminary Antitumor Activity of Anti-HER2 Bispecific Antibody ZW25 in Combination With Chemotherapy With/Without Tislelizumab in Patients With Advanced HER2-positive Breast Cancer or Gastric/Gastroesophageal Junction Adenocarcinoma

The purpose of the study is to assess the safety, tolerability and preliminary antitumor activity of zanidatamab in combination with docetaxel in participants with human epidermal growth factor receptor 2 (HER2)-positive breast cancer, and zanidatamab in combination with tislelizumab and chemotherapy in participants with HER2-positive gastric/gastroesophageal Junction (GEJ) adenocarcinoma

Study Overview

• Status: Completed
• Conditions: Breast Cancer; Gastric Cancer; Gastroesophageal Junction Cancer
• Intervention / Treatment: Drug: Docetaxel; Drug: Capecitabine; Drug: Oxaliplatin; Biological: Zanidatamab; Biological: Tislelizumab

• Study Type: Interventional
• Enrollment (Actual): 71
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• China
  • Beijing Municipality
    • Beijing, Beijing Municipality, China, 100142
      • Beijing Cancer Hospital
    • Beijing, Beijing Municipality, China, 100071
      • The Affiliated Hospital of Military Medical Sciences
  • Chongqing Municipality
    • Chongqing, Chongqing Municipality, China, 400030
      • Chongqing Cancer Hospital
  • Guangdong
    • Guangzhou, Guangdong, China, 510120
      • Guangdong Provincial Peoples Hospital Huifu Branch
  • Jiangxi
    • Nanchang, Jiangxi, China, 330009
      • The Third Hospital of Nanchang
  • Jilin
    • Changchun, Jilin, China, 130021
      • Jilin Cancer Hospital
  • Liaoning
    • Shenyang, Liaoning, China, 110042
      • Liaoning Cancer Hospital and Institute
  • Zhejiang
    • Hangzhou, Zhejiang, China, 310022
      • Zhejiang Cancer Hospital
• South Korea
  • Gyeonggi-do
    • Goyang-si, Gyeonggi-do, South Korea, 10408
      • National Cancer Center
    • Seongnam-si, Gyeonggi-do, South Korea, 13620
      • Seoul National University Bundang Hospital
  • Seoul Teugbyeolsi
    • Seoul, Seoul Teugbyeolsi, South Korea, 03080
      • Seoul National University Hospital
    • Seoul, Seoul Teugbyeolsi, South Korea, 05505
      • Asan Medical Center
    • Seoul, Seoul Teugbyeolsi, South Korea, 06273
      • Gangnam Severance Hospital, Yonsei University Health System
    • Seoul, Seoul Teugbyeolsi, South Korea, 06351
      • Samsung Medical Center
    • Seoul, Seoul Teugbyeolsi, South Korea, 03722
      • Severance Hospital Yonsei University Health System
    • Seoul, Seoul Teugbyeolsi, South Korea, 08308
      • Korea University Guro Hospital
• Taiwan
  • Kaohsiung City, Taiwan, 83301
    • Kaohsiung Chang Gung Memorial Hospital
  • Taichung, Taiwan, 40447
    • China Medical University Hospital
  • Tainan, Taiwan, 704
    • National Cheng Kung University Hospital
  • Taipei, Taiwan, 11217
    • Taipei Veterans General Hospital
  • Taipei, Taiwan, 100225
    • National Taiwan University Hospital East Campus

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Key Inclusion Criteria:

1. Disease diagnosis and prior treatment:

   1. Cohort 1 (the first-line breast cancer treatment cohort):

      • Female participants with histologically or cytologically confirmed unresectable, locally advanced, recurrent or metastatic adenocarcinoma of the breast and candidate for chemotherapy. Locally recurrent disease must not be amenable to resection with curative intent.
      • Human epidermal growth factor receptor 2 (HER2) IHC 3+ or in situ hybridization positive on the archival tumor tissue or fresh biopsy sample.
      • Have not received previous systemic anticancer therapy for locally advanced unresectable or metastatic disease.

   2. Cohort 2 (the first-line gastric/gastroesophageal junction adenocarcinoma treatment cohort):

      • Histologically or cytologically confirmed unresectable, locally advanced, recurrent or metastatic adenocarcinoma of the stomach or gastroesophageal junction
      • HER2 IHC 3+ or HER2 IHC 2+ together with in situ hybridization positive on the archival tumor tissue or fresh biopsy sample.
      • Have not received previous systemic anticancer therapy for locally advanced unresectable or metastatic disease, including any approved or investigational estimated glomerular filtration rate (EGFR) or anti-HER2 agents or vaccines, cytotoxic chemotherapy or checkpoint inhibitors
2. At least 1 measurable lesion as defined per RECIST Version 1.1
3. Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 1
4. Adequate organ function
5. Left ventricular ejection fraction (LVEF) ≥ 50% at baseline as determined by either echocardiogram or multigated acquisition scan (MUGA) (echocardiogram is the preferred method) within 28 days before the first dose of study drug

Key Exclusion Criteria:

1. Prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2 or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways

2. History of approved or investigative tyrosine kinase/HER inhibitors in any treatment setting

   a. except trastuzumab with or without pertuzumab used in neoadjuvant or adjuvant setting for Cohort 1

3. Active leptomeningeal disease, untreated or uncontrolled brain metastasis
4. Any active malignancy ≤ 2 years before the first dose of study drug, except for the specific cancer under investigation in this trial and any localized cancer that has been treated curatively (eg, resected basal or squamous cell skin cancer, superficial bladder cancer, carcinoma in situ of the cervix)
5. Any condition that required systemic treatment with either corticosteroids (> 10 mg daily of prednisone or equivalent) or other immunosuppressive medication ≤ 14 days before the first dose of study drug

Note: Participants who are currently or have previously been on any of the following steroid regimens are not excluded:

1. Adrenal replacement steroid (dose ≤ 10 mg daily of prednisone or equivalent)
2. Topical, ocular, intra-articular, intranasal, or inhaled corticosteroid with minimal systemic absorption
3. Short course (≤ 7 days) of corticosteroid prescribed prophylactically (eg, for contrast dye allergy) or for the treatment of a non-autoimmune condition (eg, delayed-type hypersensitivity reaction caused by contact allergen)

NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort 1A: Breast Cancer: Zanidatamab 30 mg/kg + Docetaxel; Participants with HER2+ breast cancer received zanidatamab 30 mg/kg intravenously (IV) and docetaxel 75 mg/m^2 IV once every 3 weeks (Q3W) for an initial period of up to six cycles. After cycle 6, continuation of docetaxel treatment was at the discretion of the investigator. Zanidatamab was administered until disease progression, intolerable toxicity, or another criterion for treatment discontinuation was met.	Drug: Docetaxel; Administered intravenously; Biological: Zanidatamab; Administered intravenously; Other Names: ZW25
Experimental: Cohort 1B: Breast Cancer: Zanidatamab 1800 mg + Docetaxel; Participants with HER2+ breast cancer received zanidatamab 1800 mg/kg IV and docetaxel 75 mg/m^2 IV Q3W for an initial period of up to six cycles. After cycle 6, continuation of docetaxel treatment was at the discretion of the investigator. Zanidatamab was administered until disease progression, intolerable toxicity, or another criterion for treatment discontinuation was met.	Drug: Docetaxel; Administered intravenously; Biological: Zanidatamab; Administered intravenously; Other Names: ZW25
Experimental: Cohort 2A: Gastric/GEJC: Zanidatamab 30 mg/kg + Tislelizumab + CAPOX; Participants with HER2+ gastric / gastroesophageal junction cancer (GEJC) received zanidatamab 30 mg/kg IV and tislelizumab 200 mg IV once every 3 weeks until disease progression, intolerable toxicity, or another criterion for treatment discontinuation was met. Participants also received CAPOX chemotherapy (1000 mg/m^2 oral capecitabine twice daily for 14 days in each cycle and 130 mg/m^2 oxaliplatin IV once every 3 weeks) for up to 6 six cycles. After cycle 6, oxaliplatin was discontinued and continuation of capecitabine as maintenance treatment was at the investigator's discretion.	Drug: Capecitabine; Administered orally; Drug: Oxaliplatin; Administered intravenously; Biological: Zanidatamab; Administered intravenously; Other Names: ZW25; Biological: Tislelizumab; Administered intravenously; Other Names: BGB-A317
Experimental: Cohort 2B: Gastric/GEJC : Zanidatamab 1800/2400 mg + Tislelizumab + CAPOX; Participants with HER2+ gastric / GEJC received zanidatamab 1800 mg (participants with body weight < 70 kg) or 2400 mg (participants with body weight ≥ 70 kg) IV and tislelizumab 200 mg IV Q3W until disease progression, intolerable toxicity, or another criterion for treatment discontinuation was met. Participants also received CAPOX chemotherapy (1000 mg/m^2 oral capecitabine twice daily for 14 days in each cycle and 130 mg/m^2 oxaliplatin IV once every 3 weeks) for up to 6 six cycles. After cycle 6, oxaliplatin was discontinued and continuation of capecitabine as maintenance treatment was at the investigator's discretion.	Drug: Capecitabine; Administered orally; Drug: Oxaliplatin; Administered intravenously; Biological: Zanidatamab; Administered intravenously; Other Names: ZW25; Biological: Tislelizumab; Administered intravenously; Other Names: BGB-A317

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants Experiencing Adverse Events (AEs) and Serious Adverse Events (SAEs)	An AE is defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of study treatments, whether considered related to study treatments or not. A serious AE (SAE) was any untoward medical occurrence that, at any dose - resulted in death, - was life threatening, - required hospitalization or prolongation of existing hospitalization, - resulted in disability/incapacity, - was a congenital anomaly/birth defect.	From the first dose of study drug(s) to 30 days after the last dose; up to approximately 42 months
Objective Response Rate (ORR)	ORR is defined as the percentage of participants who had a best overall response of complete response or partial response per the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1. Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.	Response was assessed every 6 weeks from cycle 1 day 1 for the first 36 weeks and then every 12 weeks thereafter; maximum time on study follow-up was 42months.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Duration of Response (DOR)	DOR is defined as the time from the first determination of an objective response until the first documentation of disease progression or death, whichever occurred first.	From the start date of study treatment to the first documentation of progression or death, whichever occurs first, up to approximately 42 months
Time to Response (TTR)	Time to response is defined as the time from the start date of study treatment to the first determination of an objective response assessed by investigator per RECIST v 1.1.	From the start date of study treatment to the first documentation of response, whichever occurs first, up to approximately 42 months
Progression-free Survival (PFS)	PFS is defined as the time from the start date of study drug to the date of the first objectively documented tumor progression assessed by investigator per RECIST Version 1.1 or death, whichever occurred first.	From the start date of study treatment to the first documentation of progression or death, whichever occurs first, up to approximately 42 months
Disease Control Rate (DCR)	DCR is defined as the percentage of participants with best overall response (BOR) of CR, PR, and stable disease by investigator per RECIST Version 1.1. BOR is the best response recorded from the start of the study drug treatment until the end of treatment taking into account any requirement for confirmation.	Response was assessed every 6 weeks from cycle 1 day 1 for the first 36 weeks and then every 12 weeks thereafter; maximum time on study follow-up was 42 months.
Overall Survival (OS)	Time from the start date of study drug to the date of death due to any cause.	From the start date of study treatment to the documented death date or the last known alive date, up to approximately 41 months
Serum Concentration of Zanidatamab as a Function of Time		Day 1 end of infusion of Cycle 1, 2, 5, 9, 17, 26 and 35. Each cycle is 21 days
Area Under the Plasma Concentration-time Curve From Time Zero to the Last Measurable Timepoint (AUC(0-t)) of Zanidatamab		Cycle 1: predose and 0, 2, 4, 24, 96, 168, and 336 hours postdose. Cycle 2: predose and 0, 168, and 336 hours postdose. Each cycle is 21 days.
Observed Maximum Plasma Concentration of Zanidatamab During a Sample Interval (Cmax)		Cycle 1: predose and 0, 2, 4, 24, 96, 168, and 336 hours postdose. Cycle 2: predose and 0, 168, and 336 hours postdose. Each cycle is 21 days.
Observed Time to Maximum Plasma Concentration of Zanidatamab During a Sampling Interval (Tmax)		Cycle 1: predose and 0, 2, 4, 24, 96, 168, and 336 hours postdose. Cycle 2: predose and 0, 168, and 336 hours postdose. Each cycle is 21 days.
Terminal Elimination Half-life (t1/2) of Zanidatamab		Cycle 1: predose and 0, 2, 4, 24, 96, 168, and 336 hours postdose. Cycle 2: predose and 0, 168, and 336 hours postdose. Each cycle is 21 days.
Apparent Clearance After Oral Administration (CL/F) of Zanidatamab		Cycle 1: predose and 0, 2, 4, 24, 96, 168, and 336 hours postdose
Number of Participants With Anti-zanidatamab Antibodies		From the first dose of study drug(s) to 30 days after the last dose; up to approximately 42 months
Number of Participants With AEs and SAEs in Participants Who Entered the Long-term Extension Period		From the first dose of study drug(s) to 30 days after the last dose; up to approximately 51 months

Collaborators and Investigators

• Sponsor: BeiGene
• Investigators: Study Director: Study Director, BeiGene

Publications and helpful links

General Publications

• Wang X, Lee KS, Zeng X, Sun T, Im YH, Li H, Wang K, Zhou P, Li V, Chen S, Jiang Z. Zanidatamab in combination with docetaxel in first-line HER2-positive breast cancer: results from an open-label, multicenter, phase Ib/II study. ESMO Open. 2025 Nov;10(11):105852. doi: 10.1016/j.esmoop.2025.105852. Epub 2025 Nov 6.
• Lee KW, Bai LY, Jung M, Ying J, Im YH, Oh DY, Cho JY, Oh SC, Chao Y, Kim JW, Chen Y, Li V, Chen S, Kang YK. Phase Ib/II Study of Zanidatamab in Combination with Tislelizumab and Chemotherapy in First-Line HER2-Positive Gastric/Gastroesophageal Junction Adenocarcinoma. Clin Cancer Res. 2026 Jan 16;32(2):312-323. doi: 10.1158/1078-0432.CCR-24-4295.

Study record dates

Study Major Dates

• Study Start (Actual): March 23, 2020
• Primary Completion (Actual): December 7, 2023
• Study Completion (Actual): October 31, 2024

Study Registration Dates

• First Submitted: February 4, 2020
• First Submitted That Met QC Criteria: February 18, 2020
• First Posted (Actual): February 19, 2020

Study Record Updates

• Last Update Posted (Actual): September 2, 2026
• Last Update Submitted That Met QC Criteria: August 12, 2026
• Last Verified: August 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Stomach Diseases; Skin Diseases; Breast Diseases; Skin and Connective Tissue Diseases; Stomach Neoplasms; Breast Neoplasms; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleic Acids, Nucleotides, and Nucleosides; Hydrocarbons; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Terpenes; Coordination Complexes; Taxoids; Cyclodecanes; Diterpenes; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Nucleosides; Uracil; Pyrimidinones; Deoxyribonucleosides; Fluorouracil; Docetaxel; Capecitabine; Oxaliplatin; zanidatamab; tislelizumab
• Other Study ID Numbers: BGB-A317-ZW25-101; CTR20210237 (Other Identifier: ChinaDrugTrials)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes