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

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.

Inclusion criteria

• Willing and able to provide written informed consent (ICF).
• 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.
• HER2-positive by IHC (3+; or 2+ with FISH testing). No time window restriction on FISH.
• Age 18-75 years, male or female.
• ECOG performance status 0-1; no contraindication to surgery.
• Adequate organ function for successful abdominal surgery.
• Life expectancy >= 3 months.
• Laboratory parameters within 7 days before enrollment:

• 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.
• Total bilirubin <= 1.5 x ULN; AST and ALT <= 2.5 x ULN.
• Creatinine <= 1.5 x ULN, or CrCl > 60 mL/min (Cockcroft-Gault).
• No anticoagulation: INR and aPTT <= 1.5 x ULN. On stable anticoagulation: maintain stable dose.
• Good compliance; able to complete protocol-specified examinations and specimen collection.
• 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

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