This study will test a new personalized treatment approach for patients with stomach or esophageal cancer. It will take place in two stages and aims to find the best combination of chemotherapy, immunotherapy, and targeted drugs based on each patient's tumor biomarkers.
Upon enrollment onto the study, patients will consent to tumor biomarker testing and may receive one cycle of standard chemotherapy while awaiting results. Those with a matching biomarker will join the corresponding treatment group that combines chemotherapy, an immune checkpoint inhibitor, and/or a targeted therapy. In Stage I of the study, treatment lasts about four months before surgery, followed by an additional eight months of therapy for a total of one year.
The most effective treatments from Stage I will be studied further in Stage II of the study to see whether some patients can safely avoid surgery. Those patients enrolled during Stage II will receive four months of the same combination treatment (chemotherapy, an immune checkpoint inhibitor, and/or a targeted therapy) but may be eligible to skip surgery if their cancer completely disappears after pre-surgery therapy. All patients will then receive an additional eight months of therapy and those who skipped surgery will be closely monitored with scans and endoscopies.
Histologically confirmed, resectable adenocarcinoma of the stomach, esophagus, or gastroesophageal junction (Stage II or higher, T2N0 with high-risk features).
Complete surgical resection deemed achievable by multidisciplinary evaluation.
Willingness to undergo tumor biopsies for biomarker analysis (HER2, FGFR2b, PD-L1, MSI) at screening, progression, or pre/post- surgery.
Life expectancy ≥ 24 weeks. Eastern Cooperative Oncology Group (ECOG) performance status ≤1.
Histologically confirmed diagnosis of resectable (i.e., radical surgery eligible), HER2-positive (defined as 3+ HER2 expression by IHC or 2+ HER2 expression by immunohistochemistry (IHC) with in situ hybridization (ISH)-positivity per central assessment) adenocarcinoma of the stomach or esophagus, including the gastroesophageal junction.
Formalin-fixed, paraffin-embedded (FFPE) tumor sample tested at a central laboratory confirming HER2-positive status.
Left ventricular ejection fraction (LVEF) ≥50% as determined by either echocardiogram or multiple gated acquisition scan (MUGA).
Unresectable disease, peritoneal dissemination, and/or positive cytology on laparoscopy.
Single group
Tislelizumab
Drug150 mg every 2 weeks for 4 months pre-operatively and up to 8 months post-operatively
Leucovorin
Drug400 mg/m² every 2 weeks for 4 months pre-operatively
Oxaliplatin
Drug85 mg/m² every 2 weeks for 4 months pre-operatively
Fluorouracil
Drug2,400 mg/m² every 2 weeks for 4 months pre-operatively
Zanidatamab
Drug1,200 mg for patients weighing less than 70 kg and 1,600 mg for patients weighing 70 kg or more every 2 weeks for 4 months pre-operatively and up to 8 months post-operatively
Zolbetuximab
DrugA loading dose of 800mg/m2 zolbetuximab will be administered at cycle 1, followed by subsequent doses of 400 mg/m2 every 2 weeks for 4 months pre-operatively and up to 8 months post-operatively. In the postoperative maintenance therapy phase, dosing of 600 mg/m2 every 3 weeks may also be used
Pathological Complete Response (pathCR) Rate (Stage I).
Proportion of patients achieving a pathCR in the surgical specimen after perioperative biomarker-directed systemic therapy.
Organ Preservation Rate (Stage II)
Proportion of patients able to avoid surgery and preserve the affected organ due to biomarker-driven treatment response.
Event-Free Survival (Stage I).
: Time from initiation of treatment to the first documented disease progression, recurrence, or death from any cause.
Overall Survival (Stage I).
Time from initiation of treatment to death from any cause.
Tumor Regression Grade.
Assessment of tumor response in surgical specimens using National Comprehensive Cancer Network (NCCN) guidelines.
Correlation between event-free survival and changes in circulating tumor DNA concentration.
Correlation between event-free survival (defined as time from initiation of treatment to the first documented disease progression, recurrence, or death from any cause) and plasma ctDNA concentration (mean tumor molecules per milliliter) measured using a personalized, tumor-informed assay.
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American Association for Cancer Research
Lead sponsor
Jazz Pharmaceuticals
Collaborator
BeOne Medicines
Collaborator
Astellas Pharma Inc
Collaborator
Natera, Inc.
Collaborator
Roche Diagnostics GmbH
Collaborator
