Zanidatamab Combined With Chemotherapy as Neoadjuvant/Conversion Therapy for HER2-Positive (IHC 3+ or IHC 2+) Advanced Gastric or Gastroesophageal Junction Adenocarcinoma: a Phase II Open-Label Study

A Phase II Open-Label Study Evaluating the Efficacy and Safety of Zanidatamab Combined With Chemotherapy as Neoadjuvant/Conversion Therapy in Patients With HER2-Positive (IHC 3+ or IHC 2+) Locally Advanced or Metastatic Gastric/Gastroesophageal Junction Adenocarcinoma

This is a phase II open-label study to evaluate the efficacy and safety of zanidatamab combined with chemotherapy as neoadjuvant/conversion therapy in patients with HER2-positive (IHC 3+ or IHC 2+) locally advanced or metastatic gastric/gastroesophageal junction adenocarcinoma. The study consists of two cohorts: a neoadjuvant cohort (Simon's two-stage design, n=46) for treatment-naive stage III locally advanced disease, and an exploratory conversion cohort for oligometastatic disease. Patients receive zanidatamab (30 mg/kg Q3W) plus oxaliplatin-based chemotherapy, with or without PD-1 inhibitor (tislelizumab or sintilimab). The primary endpoint is pathological complete response (pCR).

Study Overview

• Status: Not yet recruiting
• Conditions: Gastric Cancer; HER2-positive Gastric Cancer; Gastroesophageal Junction Adenocarcinoma
• Intervention / Treatment: Drug: Zanidatamab; Drug: Oxaliplatin; Drug: Capecitabine; Drug: S-1; Drug: Tislelizumab

Detailed Description

Background:

HER2 overexpression (IHC 3+ or IHC 2+) occurs in approximately 12-20% of gastric and gastroesophageal junction adenocarcinomas. While perioperative trastuzumab-based regimens have shown promising pathological responses (pCR rates of 9.6% in NEOHX, 21.4% in HER-FLOT, 35% in PETRARCA), there remains an unmet need for more effective HER2-directed therapies in the neoadjuvant/conversion setting, particularly for IHC 2+ patients whose in situ hybridization testing rates are low in real-world practice.

Zanidatamab is a humanized bispecific IgG1-like antibody targeting two distinct HER2 epitopes (ECD4 and ECD2), demonstrating unique mechanisms including enhanced receptor clustering, complement-dependent cytotoxicity, antibody-dependent cellular cytotoxicity, and superior in vivo antitumor activity compared to trastuzumab plus pertuzumab. In a phase II study (NCT03929666), zanidatamab combined with chemotherapy as first-line treatment for HER2-positive advanced gastroesophageal adenocarcinoma achieved a confirmed objective response rate of 76.2%, median progression-free survival of 12.5 months, and median overall survival of 36.5 months, with manageable safety.

Study Design:

This is an investigator-initiated, phase II, open-label, two-cohort study. Neoadjuvant Cohort: Treatment-naive patients with stage III locally advanced gastric/gastroesophageal junction adenocarcinoma (cT3-4aN+M0, or cT4bNany M0 not amenable to R0 resection as assessed by MDT, or technically resectable but with high-risk factors such as bulky nodal fusion or invasion of critical structures) receive 3 cycles of zanidatamab (30 mg/kg Q3W) plus oxaliplatin-based chemotherapy (SOX or CAPOX per 2025 CSCO guidelines), followed by D2 radical gastrectomy 4-6 weeks after treatment completion. This cohort uses a Simon's two-stage design with a planned enrollment of 46 patients (H0: pCR <= 9.6%, H1: pCR >= 25%, one-sided alpha=0.05, power=80%). If <=2 pCRs among the first 17 patients, study terminates for futility; if >=7 pCRs among all 46, superiority over historical control is declared.

Conversion Cohort (Exploratory): Patients with oligometastatic disease (M1, <=2 organs, <=5 total metastatic lesions), including liver metastases (C-GCLM type I and II), confirmed retroperitoneal lymph node metastases, or other single-organ metastases, deemed potentially resectable by MDT, receive zanidatamab (30 mg/kg Q3W) plus oxaliplatin-based chemotherapy, with tislelizumab (200 mg Q3W, or sintilimab 200 mg Q3W) for patients without immunotherapy contraindications. Treatment continues up to 8 cycles with tumor assessment every 3 cycles; surgery timing at investigator's discretion.

Adjuvant therapy: For the neoadjuvant cohort, adjuvant therapy (4-5 cycles starting 4-6 weeks post-surgery) may be administered at the investigator's discretion. Total perioperative treatment duration should not exceed 8 cycles. Conversion cohort adjuvant therapy is at the investigator's discretion.

Endpoints: Primary endpoint is pathological complete response (pCR, ypT0N0). Secondary endpoints include MPR, R0 resection rate, down-staging rate, NCCN TRG 0/1, RFS, OS, treatment completion rate, and safety (CTCAE v5.0). Conversion cohort additionally evaluates ORR (RECIST v1.1, with iRECIST for pseudoprogression), PFS, and surgical conversion rate.

• Study Type: Interventional
• Enrollment (Estimated): 46
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Jianjun Yang, Prof.; Phone Number: +86-029-84775507; Email: yangjj@fmmu.edu.cn

Study Locations

• China
  • Shaanxi
    • Xi'an, Shaanxi, China
      • Xijing Hospital, Air Force Medical University
      • Contact: Jianjun Yang; Phone Number: +86-13572533693

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Willing and able to provide written informed consent (ICF).

2. Histologically and radiologically (CT/MRI) confirmed gastric or gastroesophageal junction adenocarcinoma.

   • Neoadjuvant cohort: Clinical stage III (cT3-4aN+M0) or locally advanced unresectable (cT4bNany M0) assessed by MDT as not amenable to R0 resection, or technically resectable but with high-risk factors (e.g., bulky nodal fusion, invasion of critical structures).
   • Conversion cohort: Not amenable to direct surgery (e.g., invasion of adjacent organs or vessels) or with distant metastases, including liver metastases (C-GCLM type I and II), confirmed retroperitoneal lymph node metastases, or other single-organ metastases.
3. HER2-positive by IHC (3+; or 2+ with FISH testing). No time window restriction on FISH.
4. Age 18-75 years, male or female.
5. ECOG performance status 0-1; no contraindication to surgery.
6. Adequate organ function for successful abdominal surgery.
7. Life expectancy >= 3 months.

8. Laboratory parameters within 7 days before enrollment:

   1. WBC > 4.0 x 10^9/L and < 15 x 10^9/L; ANC > 1.5 x 10^9/L; Hb >= 90 g/L; PLT >= 100 x 10^9/L.
   2. Total bilirubin <= 1.5 x ULN; AST and ALT <= 2.5 x ULN.
   3. Creatinine <= 1.5 x ULN, or CrCl > 60 mL/min (Cockcroft-Gault).
   4. No anticoagulation: INR and aPTT <= 1.5 x ULN. On stable anticoagulation: maintain stable dose.
9. Good compliance; able to complete protocol-specified examinations and specimen collection.
10. Female patients of childbearing potential must agree to contraception from ICF signing through at least 5 months after last dose and refrain from breastfeeding. Male patients must agree to contraception from first dose through at least 7 months after last dose.

Exclusion Criteria:

1. Synchronous or metachronous malignancies of other organs, or recurrent disease.
2. Prior systemic therapy for gastric cancer (neoadjuvant cohort).
3. History of malignancy within 5 years before screening, except those with > 90% 5-year overall survival.
4. Significant cardiopulmonary dysfunction.
5. Major surgery within 4 weeks before study treatment initiation, or anticipated major surgery during study period (excluding diagnostic procedures).
6. Severe infection within 4 weeks before study treatment initiation.
7. Prior chemotherapy or molecular targeted therapy (neoadjuvant cohort).
8. Known hypersensitivity to study drugs or excipients, or history of severe allergic reactions to monoclonal antibodies.
9. Factors affecting oral medication intake (e.g., dysphagia >= grade 2, chronic diarrhea).
10. Significant uncontrolled comorbidities that may affect protocol compliance or interpretation of outcomes.
11. Pregnancy or breastfeeding, or planning pregnancy during the study.
12. Diagnosis of immunodeficiency or receiving systemic corticosteroid (> 10 mg/day prednisone equivalent) or other immunosuppressive therapy within 2 weeks before first dose.
13. Active hepatitis B (HBV DNA >= 1 x 10^3 copies/mL or >= 200 IU/mL), positive anti-HCV, or positive HIV.
14. Participation in another anti-tumor clinical trial within 28 days before first dose.
15. Any condition that in the investigator's judgment may lead to premature study termination (e.g., serious illness including psychiatric disorders requiring concomitant treatment, severe laboratory abnormalities, family/social factors affecting subject safety or data collection).
16. Patient or family refusal to sign informed consent.

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

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Neoadjuvant Cohort: Zanidatamab + Chemotherapy; Patients with previously untreated stage III locally advanced gastric/gastroesophageal junction adenocarcinoma (cT3-4aN+M0, or cT4bNany M0 not amenable to R0 resection per MDT assessment) receive 3 cycles of zanidatamab (30 mg/kg Q3W) plus oxaliplatin-based chemotherapy (SOX: oxaliplatin 130 mg/m2 IV D1 + S-1 40 mg/m2 PO BID D1-14, Q3W; or CAPOX: oxaliplatin 130 mg/m2 IV D1 + capecitabine 1000 mg/m2 PO BID D1-14, Q3W), followed by D2 radical gastrectomy 4-6 weeks after treatment. Simon's two-stage design: n=46, H0 pCR <= 9.6%, H1 pCR >= 25%, one-sided alpha=0.05, power=80%.	Drug: Zanidatamab; Zanidatamab injection, 300 mg/vial (manufacturer: Wuxi WuXi Biologics). Administered 30 mg/kg IV Q3W. Premedication (corticosteroids, antihistamines, antipyretics) 30-60 min before infusion. First two infusions over 120-150 min; subsequent may be shortened to 60-90 min if tolerated.; Other Names: ZIIHERA; Drug: Oxaliplatin; Oxaliplatin 130 mg/m2 IV infusion over > 2 hours, D1 of each 21-day cycle. Administered after zanidatamab. Manufacturer not restricted.; Other Names: Eloxatin; Drug: Capecitabine; Capecitabine 1000 mg/m2 PO BID, D1-14 of each 21-day cycle. Alternative to S-1 as part of CAPOX backbone.; Other Names: Xeloda; Drug: S-1; S-1 (Tegafur, Gimeracil, Oteracil) 40 mg/m2 PO BID, D1-14 of each 21-day cycle. Alternative to capecitabine as part of SOX backbone.; Other Names: Teysuno
Experimental: Conversion Cohort: Zanidatamab + Chemotherapy +/- PD-1 Inhibitor; Patients with oligometastatic disease (M1, <=2 organs, <=5 total lesions, including liver metastases C-GCLM type I/II, retroperitoneal lymph node metastases, or other single-organ metastases) deemed potentially resectable by MDT receive zanidatamab (30 mg/kg Q3W) plus oxaliplatin-based chemotherapy, plus tislelizumab (200 mg Q3W) or sintilimab (200 mg Q3W) if no immunotherapy contraindication. Up to 8 cycles, tumor assessment every 3 cycles. Exploratory cohort; no sample size calculation.	Drug: Zanidatamab; Zanidatamab injection, 300 mg/vial (manufacturer: Wuxi WuXi Biologics). Administered 30 mg/kg IV Q3W. Premedication (corticosteroids, antihistamines, antipyretics) 30-60 min before infusion. First two infusions over 120-150 min; subsequent may be shortened to 60-90 min if tolerated.; Other Names: ZIIHERA; Drug: Oxaliplatin; Oxaliplatin 130 mg/m2 IV infusion over > 2 hours, D1 of each 21-day cycle. Administered after zanidatamab. Manufacturer not restricted.; Other Names: Eloxatin; Drug: Capecitabine; Capecitabine 1000 mg/m2 PO BID, D1-14 of each 21-day cycle. Alternative to S-1 as part of CAPOX backbone.; Other Names: Xeloda; Drug: S-1; S-1 (Tegafur, Gimeracil, Oteracil) 40 mg/m2 PO BID, D1-14 of each 21-day cycle. Alternative to capecitabine as part of SOX backbone.; Other Names: Teysuno; Drug: Tislelizumab; Tislelizumab 200 mg Q3W IV. Alternatively, sintilimab 200 mg Q3W may be used at investigator's discretion. Conversion cohort only, for patients without immunotherapy contraindication.; Other Names: BGB-A317

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pathological Complete Response (pCR)	pCR is defined as the absence of residual tumor cells in the primary tumor and all resected lymph nodes (ypT0N0) after neoadjuvant treatment, assessed by histopathological evaluation of surgical specimens.	At the time of surgery, approximately 4-6 weeks after completion of 3 cycles of neoadjuvant treatment (each cycle is 21 days)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Major Pathological Response (MPR)	MPR is defined as residual tumor cells <= 10% in the primary tumor bed and resected lymph nodes after neoadjuvant treatment.	At the time of surgery, approximately 4-6 weeks after completion of neoadjuvant treatment
R0 Resection Rate	R0 resection is defined as microscopically complete tumor removal with all margins negative on histopathological examination.	At the time of surgery, approximately 4-6 weeks after completion of neoadjuvant treatment
Down-Staging Rate	Down-staging is defined as any decrease in pathological T stage or N stage compared to pretreatment clinical stage (cTNM).	At the time of surgery, approximately 4-6 weeks after completion of neoadjuvant treatment
Tumor Regression Grade 0/1 Rate (NCCN TRG)	Proportion of patients achieving complete (TRG 0, no residual tumor) or near-complete (TRG 1, minimal residual tumor cells) pathological response per NCCN TRG criteria.	At the time of surgery, approximately 4-6 weeks after completion of neoadjuvant treatment
Recurrence-Free Survival (RFS)	Time from complete response after neoadjuvant/conversion therapy to tumor recurrence or death from any cause. DFS and EFS are considered equivalent to RFS.	From date of complete response after treatment until date of recurrence or death, assessed up to 60 months
Overall Survival (OS)		From date of enrollment until date of death from any cause, assessed up to 36 months
Objective Response Rate (ORR) - Conversion Cohort	Proportion of patients achieving CR or PR per RECIST v1.1. For suspected pseudoprogression, iRECIST used for confirmation.	Every 3 cycles during conversion treatment (up to 8 cycles, each cycle is 21 days), assessed per RECIST v1.1
Progression-Free Survival (PFS) - Conversion Cohort		From date of enrollment until date of disease progression or death, assessed up to 36 months
Neoadjuvant Treatment Completion Rate	Proportion of patients in the neoadjuvant cohort who complete all 3 planned cycles and proceed to surgery as scheduled.	At the end of neoadjuvant treatment period, approximately 9 weeks (3 cycles of 21 days each)
Surgical Conversion Rate - Conversion Cohort	Proportion of patients initially deemed unresectable who successfully undergo R0 resection after conversion therapy.	During conversion treatment period, up to 8 cycles (each cycle is 21 days)
Incidence of Treatment-Emergent Adverse Events	Adverse events assessed by NCI CTCAE v5.0, including incidence and severity of AEs, SAEs, and postoperative complications within 30 days (Clavien-Dindo classification).	From first dose through 30 days after last dose of study treatment

Collaborators and Investigators

• Sponsor: Zhifeng Zhao, PhD
• Investigators: Principal Investigator: Jianjun Yang, Prof., Department of Digestive Surgery, Xijing Hospital, Air Force Medical University

Study record dates

Study Major Dates

• Study Start (Estimated): July 1, 2026
• Primary Completion (Estimated): June 1, 2028
• Study Completion (Estimated): December 1, 2028

Study Registration Dates

• First Submitted: June 29, 2026
• First Submitted That Met QC Criteria: June 29, 2026
• First Posted (Actual): July 6, 2026

Study Record Updates

• Last Update Posted (Actual): July 6, 2026
• Last Update Submitted That Met QC Criteria: June 29, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Keywords: HER2; gastric cancer; neoadjuvant therapy; conversion therapy; bispecific antibody; gastroesophageal junction adenocarcinoma; zanidatamab
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Stomach Diseases; Stomach Neoplasms; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleic Acids, Nucleotides, and Nucleosides; Coordination Complexes; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Nucleosides; Uracil; Pyrimidinones; Deoxyribonucleosides; Fluorouracil; Capecitabine; Oxaliplatin; zanidatamab; tislelizumab; S 1 (combination); tegafur-gimeracil-oteracil
• Other Study ID Numbers: KY20252609-F-1

Drug and device information, study documents

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