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.

• Zanidatamab (Drug), also known as ZIIHERA: 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.
• Oxaliplatin (Drug), also known as Eloxatin: Oxaliplatin 130 mg/m2 IV infusion over > 2 hours, D1 of each 21-day cycle. Administered after zanidatamab. Manufacturer not restricted.
• Capecitabine (Drug), also known as Xeloda: Capecitabine 1000 mg/m2 PO BID, D1-14 of each 21-day cycle. Alternative to S-1 as part of CAPOX backbone.
• S-1 (Drug), also known as Teysuno: 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.
• Tislelizumab (Drug), also known as BGB-A317: 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 outcomes

• Pathological Complete Response (pCR) [At the time of surgery, approximately 4-6 weeks after completion of 3 cycles of neoadjuvant treatment (each cycle is 21 days)]: 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.

Secondary outcomes

• Major Pathological Response (MPR) [At the time of surgery, approximately 4-6 weeks after completion of neoadjuvant treatment]: MPR is defined as residual tumor cells <= 10% in the primary tumor bed and resected lymph nodes after neoadjuvant treatment.
• R0 Resection Rate [At the time of surgery, approximately 4-6 weeks after completion of neoadjuvant treatment]: R0 resection is defined as microscopically complete tumor removal with all margins negative on histopathological examination.
• Down-Staging Rate [At the time of surgery, approximately 4-6 weeks after completion of neoadjuvant treatment]: Down-staging is defined as any decrease in pathological T stage or N stage compared to pretreatment clinical stage (cTNM).
• Tumor Regression Grade 0/1 Rate (NCCN TRG) [At the time of surgery, approximately 4-6 weeks after completion of neoadjuvant treatment]: 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.
• Recurrence-Free Survival (RFS) [From date of complete response after treatment until date of recurrence or death, assessed up to 60 months]: Time from complete response after neoadjuvant/conversion therapy to tumor recurrence or death from any cause. DFS and EFS are considered equivalent to RFS.
• 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 [Every 3 cycles during conversion treatment (up to 8 cycles, each cycle is 21 days), assessed per RECIST v1.1]: Proportion of patients achieving CR or PR per RECIST v1.1. For suspected pseudoprogression, iRECIST used for confirmation.
• 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 [At the end of neoadjuvant treatment period, approximately 9 weeks (3 cycles of 21 days each)]: Proportion of patients in the neoadjuvant cohort who complete all 3 planned cycles and proceed to surgery as scheduled.
• Surgical Conversion Rate - Conversion Cohort [During conversion treatment period, up to 8 cycles (each cycle is 21 days)]: Proportion of patients initially deemed unresectable who successfully undergo R0 resection after conversion therapy.
• Incidence of Treatment-Emergent Adverse Events [From first dose through 30 days after last dose of study treatment]: Adverse events assessed by NCI CTCAE v5.0, including incidence and severity of AEs, SAEs, and postoperative complications within 30 days (Clavien-Dindo classification).

Sex: All, ages: 18 Years to 75 Years

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.

• Jianjun Yang, Prof., Principal investigator, Department of Digestive Surgery, Xijing Hospital, Air Force Medical University