ROSETTE trial is an open-label, randomized phase II study designed to investigate treatment strategies for patients with limited metastatic gastric or gastroesophageal adenocarcinoma. Eligible patients are randomized to receive either systemic treatment followed by surgeon-led local treatment, or systemic treatment alone. Systemic treatment combines immunotherapy with chemotherapy, with or without targeted therapy, while the surgeon-led local treatment utilizes a surgery-centric, multi-modality approach involving resection of both primary and metastatic tumors where feasible. For unresected or unresectable metastatic lesions, alternative local therapies are provided. The primary endpoint is the 1-year event-free survival (EFS) rate. Secondary endpoints include objective response rate (ORR), disease control rate (DCR), extended EFS, overall survival (OS), pathologic complete response rate (pCR), major pathologic response rate (MPR), and R0 resection rate.
Men or women aged 18-79.
Pathologically confirmed gastric adenocarcinoma or gastroesophageal junction adenocarcinoma (Siewert II or III only) with known PD-L1 expression status.
Gastric cancer with proficient mismatch repair (pMMR) or microsatellite stability (MSS) as determined by immunohistochemistry or NCI-recommended microsatellite markers.
Primary gastric cancer lesions are resectable, with limited distant metastases meeting the either of the following criteria: (1) condition (a) only; (2) any single condition from (b), with or without (a).
Inability to tolerate oral chemotherapy.
Primary gastric lesion confined to the mucosa or submucosa with isolated ovarian metastasis.
Central nervous system metastasis and/or carcinomatous meningitis.
Allergy to any components of the study medication.
Parallel
Local treatment (Surgical)
Procedure/SurgeryRadical gastrectomy with standard D2 lymphadenectomy will be performed, along with radical surgery for resectable metastatic lesions.
PD-1 Monoclonal Antibody
DrugPD-1 monoclonal antibody will be administered at a dosage of 200 mg via intravenous infusion (or according to the prescribing information of specific drug), once every cycle, each cycle spanning three weeks. The specific PD-1 antibody used will be determined by the investigators based on clinical considerations. Potential options include Sintilimab, Tislelizumab, or other approved PD-1 antibody products indicated for the treatment of metastatic gastric or gastroesophageal adenocarcinoma.
XELOX/SOX Chemotherapy Regimen
DrugOxaliplatin: 130 mg/m² administered via a 3-hour intravenous infusion on D1 of each 3-week cycle. Capecitabine: 1000 mg/m² taken orally twice daily. The first dose is administered on the evening of D1, and the last dose on the morning of D15, consisting of 2 weeks of treatment and a 1-week break in each 3-week cycle. S-1: 40 mg/m² taken orally twice daily. The first dose is administered on the evening of D1, and the last dose on the morning of D15, consisting of 2 weeks of treatment and a 1-week break in each 3-week cycle. During the maintainance phase, only capecitabine/S-1 will be administered.
Local Treatment (Non-surgical)
Procedure/SurgeryAdditional local treatment for unresected metastatic lesions during phase 2 systemic therapy is permitted, including: * Bone metastasis, distant lymph nodes, adrenal metastasis: Radiation therapy. * Lung and liver metastasis: Radiofrequency ablation, interventional embolization, or radiation therapy. * Peritoneal metastasis: Hyperthermic intraperitoneal chemotherapy (HIPEC). * Other metastatic lesions: Non-surgical treatment options discussed by the multidisciplinary team.
Trastuzumab
DrugFor HER2-positive patients, the dosing regimen for the addition of trastuzumab is as follows: During the combination phase with XELOX/SOX chemotherapy: 8 mg/kg administered as an intravenous infusion on D1. During the maintenance phase with capecitabine/S-1: 6 mg/kg administered as an intravenous infusion on D1. This is repeated once every 3 weeks.
Zolbetuximab
DrugFor patients with Claudin18.2-positive expression (IHC 2-3+ in ≥75% of tumor cells), Zolbetuximab may be added with the following dosing regimen: First cycle: 800 mg/m² administered as an intravenous infusion on D1. Subsequent cycles: 600 mg/m² administered as an intravenous infusion on D1. This is repeated once every 3 weeks.
Event-Free Survival (EFS) Rate
Defined as the time from randomization to the first occurrence of any event, including disease progression (local progression, local recurrence, progression of existing distant metastatic lesions, or the emergence of new distant metastases) or death from any cause.
Objective Response Rate (ORR)
The proportion of subjects achieving complete response (CR) or partial response (PR) after completing phase I systemic treatment.
Disease Control Rate (DCR)
The proportion of subjects achieving CR, PR, or stable disease (SD) after completing phase I systemic treatment.
Pathological Complete Response (pCR) Rate
The proportion of surgical cohort subjects with no residual tumor cells and no positive lymph nodes (ypT0N0) in the primary tumor specimen. Non-surgical subjects in the surgical cohort are considered non-pCR.
Major Pathologic Response Rate (MPR)
The proportion of surgical cohort subjects with residual tumor cells \<10% in the primary tumor specimen based on the Becker tumor regression grading (TRG) standard (1a-1b). Non-surgical subjects in the surgical cohort are considered non-MPR.
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