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

Official title

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

Overview

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).

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.

Interventions

• 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.
• Drug Oxaliplatin
  Oxaliplatin 130 mg/m2 IV infusion over \> 2 hours, D1 of each 21-day cycle. Administered after zanidatamab. Manufacturer not restricted.
• Drug Capecitabine
  Capecitabine 1000 mg/m2 PO BID, D1-14 of each 21-day cycle. Alternative to S-1 as part of CAPOX backbone.
• 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.
• 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.

Primary outcome measures

• Pathological Complete Response (pCR) [Time frame: 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 (11)

• Major Pathological Response (MPR) [Time frame: At the time of surgery, approximately 4-6 weeks after completion of neoadjuvant treatment]
• R0 Resection Rate [Time frame: At the time of surgery, approximately 4-6 weeks after completion of neoadjuvant treatment]
• Down-Staging Rate [Time frame: At the time of surgery, approximately 4-6 weeks after completion of neoadjuvant treatment]
• Tumor Regression Grade 0/1 Rate (NCCN TRG) [Time frame: At the time of surgery, approximately 4-6 weeks after completion of neoadjuvant treatment]
• Recurrence-Free Survival (RFS) [Time frame: From date of complete response after treatment until date of recurrence or death, assessed up to 60 months]
• Overall Survival (OS) [Time frame: From date of enrollment until date of death from any cause, assessed up to 36 months]
• Objective Response Rate (ORR) - Conversion Cohort [Time frame: 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 [Time frame: From date of enrollment until date of disease progression or death, assessed up to 36 months]
• Neoadjuvant Treatment Completion Rate [Time frame: At the end of neoadjuvant treatment period, approximately 9 weeks (3 cycles of 21 days each)]
• Surgical Conversion Rate - Conversion Cohort [Time frame: During conversion treatment period, up to 8 cycles (each cycle is 21 days)]
• Incidence of Treatment-Emergent Adverse Events [Time frame: From first dose through 30 days after last dose of study treatment]

Eligibility criteria

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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

China · 1 center

• Xijing Hospital, Air Force Medical University — Xi'an

Identifiers

NCT: NCT07685704 · KY20252609-F-1

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗