Zanidatamab Combined With Chemotherapy as Neoadjuvant Therapy for HER2-high Expression G/GEJC

Phase II Clinical Study of Zanidatamab Combined With Chemotherapy as Neoadjuvant Therapy for Locally Advanced HER2-high Expression (IHC3+/2+FISH+) Gastric/Gastroesophageal Junction Adenocarcinoma

HER2 overexpression is observed in approximately 20% of gastric cancers and gastroesophageal junction (GEJ) cancers, making it a validated target for anti-tumor therapy . In advanced-stage systemic therapy, trastuzumab combined with chemotherapy has demonstrated clinical benefits for HER2-positive gastric and GEJ cancers . However, the combination of trastuzumab and pertuzumab plus chemotherapy did not significantly improve overall survival (OS) compared to trastuzumab monotherapy in HER2-expressed gastric/GEJ cancers .

In neoadjuvant therapy for early-stage or locally advanced gastric cancer, there is currently no standardized perioperative regimen for HER2-positive gastric or GEJ cancers, and effective treatment remains challenging .

Zanidatamab, a humanized bispecific IgG1-like antibody targeting HER2's ECD4 and ECD2 epitopes, exhibits unique enhanced functionality . Phase II studies (NCT03929666) showed that zanidatamab combined with chemotherapy as first-line therapy for HER2-positive advanced gastroesophageal adenocarcinoma (GEA) demonstrated superior survival benefits and durable responses compared to standard therapy (trastuzumab plus chemotherapy) . A Phase III study (HERIZON-GEA-01, NCT05152147) is now underway to further validate its efficacy when combined with chemotherapy ± tislelizumab versus trastuzumab-based chemotherapy .

For previously untreated stage II/III locally advanced gastroesophageal junction adenocarcinoma (cT1-2N+M0, cT3-4aNanyM0) with confirmed HER2 high expression (HER2 3+/2+ FISH+), neoadjuvant zanidatamab combined with chemotherapy (FLOT/SOX/CAPOX) is being explored to evaluate safety and efficacy, potentially offering a new treatment option for HER2-positive GEJ cancers in perioperative settings .

Study Overview

• Status: Not yet recruiting
• Conditions: Gastric/Gastroesophageal Junction Adenocarcinoma
• Intervention / Treatment: Drug: Zanidatamab Combined with Chemotherapy

• Study Type: Interventional
• Enrollment (Estimated): 30
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Xiaohua Li; Phone Number: +8619991901686; Email: xįyylixiaohua@163.com
• Study Contact Backup: Name: Pengfei Yu; Phone Number: +8615249254020; Email: yupengfei8989@163.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Signed informed consent.
2. Histologically/radiologically confirmed Stage II/III (cT1-2N+M0 or cT3-4aNanyM0) Siewert II/III GEJ/gastric adenocarcinoma.
3. HER2-high (IHC 3+/2+FISH+); HER2 2+ requires FISH (no time restriction).
4. Age 18-75, any gender.
5. ECOG 0-1, surgically eligible.
6. Adequate organ function for abdominal surgery.
7. Life expectancy ≥3 months.

Exclusion Criteria:

Exclusion Criteria

1. Unresectable/metastatic (Stage IV) disease.
2. Prior systemic GC therapy.
3. Other malignancies within 5 years (except those with >90% 5-year survival).
4. Cardiopulmonary dysfunction.
5. Major surgery within 4 weeks pre-study.
6. Severe infection within 4 weeks.
7. Prior chemo/targeted therapy.
8. Hypersensitivity to study drugs/excipients/mAbs.
9. Factors impairing oral intake (e.g., ≥Grade 2 dysphagia/chronic diarrhea).
10. Uncontrolled comorbidities affecting compliance/outcomes.
11. Pregnancy/lactation/planned pregnancy.
12. Immunosuppression (>10mg/day prednisone equivalent within 2 weeks).
13. Active HBV (DNA ≥1×10³ copies/mL or ≥200IU/mL), HCV+, or HIV+.
14. Other antitumor trials within 28 days.
15. Other high-risk conditions (e.g., psychiatric disorders) per investigator.
16. Refusal to sign consent.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Experimental: Zanidatamab Combined with Chemotherapy	Drug: Zanidatamab Combined with Chemotherapy; Zanidatamab Combined with Chemotherapy as Neoadjuvant Therapy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Major pathological response rate (MPR)	MPR is defined as 10% or fewer viable cancer cells from the resected tumor following neoadjuvant treatment	24 months

Secondary Outcome Measures

Outcome Measure	Time Frame
Pathological complete response rate(pCR)	24 months
R0 Resection	24 months
Recurrence Free Survival (RFS)	5 years
Treatment-Emergent Adverse Events	24 months

Collaborators and Investigators

• Sponsor: Xijing Hospital

Study record dates

Study Major Dates

• Study Start (Estimated): January 1, 2026
• Primary Completion (Estimated): June 30, 2028
• Study Completion (Estimated): July 31, 2029

Study Registration Dates

• First Submitted: November 26, 2025
• First Submitted That Met QC Criteria: December 8, 2025
• First Posted (Actual): December 10, 2025

Study Record Updates

• Last Update Posted (Actual): December 10, 2025
• Last Update Submitted That Met QC Criteria: December 8, 2025
• Last Verified: October 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Therapeutics; Drug Therapy
• Other Study ID Numbers: XJ-G/GEJC-01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No