Sintilimab Combined With Chemoradiotherapy as Neoadjuvant Therapy for Locally Advanced Gastroesophageal Junction Cancer

This study is designed as a multicenter, prospective, single-arm, exploratory clinical study to evaluate the preliminary efficacy, safety, and clinical feasibility of sintilimab combined with induction chemotherapy, concurrent chemoradiotherapy, and optional consolidation chemotherapy as neoadjuvant treatment in patients with locally advanced gastroesophageal junction cancer. In addition, imaging data obtained before treatment will be collected to develop a radiomics-based predictive model and to explore its predictive value for pathological complete response (pCR) after neoadjuvant treatment.

The study consists of a screening period, neoadjuvant treatment period, surgical treatment period, and follow-up period. The screening period begins after the participant signs the informed consent form and ends no more than 28 days before the first administration of study treatment. The neoadjuvant treatment period includes an induction treatment phase with sintilimab plus XELOX, a concurrent chemoradiotherapy phase with sintilimab plus capecitabine, and an optional consolidation treatment phase with sintilimab plus XELOX. Whether consolidation treatment is administered will be determined based on the participant's treatment response, recovery from toxicity, nutritional status, surgical feasibility, and multidisciplinary team (MDT) assessment. The neoadjuvant treatment period will continue until completion of the protocol-specified treatment, determination by the MDT that the participant is eligible for surgery, disease progression, occurrence of intolerable toxicity, withdrawal of informed consent, death, or study completion, whichever occurs first. Participants will subsequently enter the surgical treatment period and follow-up period, including safety follow-up and survival follow-up.

After signing the informed consent form and being confirmed to meet all eligibility criteria, participants will first receive one cycle of induction therapy with sintilimab plus XELOX. The induction regimen consists of sintilimab 200 mg administered by intravenous infusion on Day 1; oxaliplatin 130 mg/m² administered by intravenous infusion on Day 1; and capecitabine 1,000 mg/m² administered orally twice daily on Days 1-14. Each treatment cycle is 21 days.

After completion of induction therapy, participants will enter the concurrent chemoradiotherapy phase and receive sintilimab plus capecitabine concurrent with radiotherapy. Intensity-modulated radiation therapy (IMRT) or volumetric modulated arc therapy (VMAT) will be used. The radiation field will include the primary tumor and regional lymphatic drainage areas, with a total dose of 45 Gy delivered in 25 fractions, five fractions per week over 5 weeks. Concurrent chemotherapy will consist of capecitabine 825 mg/m² administered orally twice daily on radiotherapy days only as a radiosensitizing agent. Sintilimab 200 mg will be administered by intravenous infusion once every 3 weeks.

After completion of concurrent chemoradiotherapy, the investigator will determine whether to administer one cycle of consolidation therapy with sintilimab plus XELOX based on the participant's treatment response, recovery from toxicity, nutritional status, surgical feasibility, and MDT assessment. The consolidation regimen consists of sintilimab 200 mg administered by intravenous infusion on Day 1; oxaliplatin 130 mg/m² administered by intravenous infusion on Day 1; and capecitabine 1,000 mg/m² administered orally twice daily on Days 1-14. Each treatment cycle is 21 days. Participants with a favorable treatment response who have already achieved surgical eligibility, as well as those with insufficient recovery from toxicity, poor nutritional status, or a high risk of surgical delay, may not receive consolidation therapy and may proceed directly to preoperative evaluation and surgical preparation.

After completion of neoadjuvant treatment, participants will undergo preoperative imaging examinations, gastroscopy and/or endoscopic ultrasonography, as appropriate, within the protocol-specified time frame. The treatment response and feasibility of radical surgery will then be assessed by the MDT. Participants who are considered eligible for surgery will, in principle, undergo radical resection of the gastroesophageal junction tumor and regional lymph node dissection within 4-8 weeks after completion of neoadjuvant treatment.

During the study, radiological tumor response will be assessed according to the Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1). Pathological outcomes will be evaluated based on postoperative pathological examination, including pathological complete response (pCR), major pathological response (MPR), tumor regression grade (TRG), pathological downstaging rate, and R0 resection rate. The primary endpoint of the study is the pathological complete response rate (pCR rate).

At the same time, pretreatment imaging data will be collected for radiomics analysis. Radiomics features will be extracted from pretreatment imaging data to develop and validate a radiomics-based predictive model for pCR after neoadjuvant treatment. The predictive value of the model for treatment response stratification and its potential role in supporting individualized treatment decisions will be further explored.

For participants who develop disease progression, intolerable toxicity, or who are considered unsuitable for continued treatment with the original regimen based on MDT assessment, study treatment will be discontinued. The investigator will determine subsequent optimal treatment according to the participant's individual clinical condition. If a participant voluntarily withdraws informed consent, is lost to follow-up, dies, or if the investigator determines that continued participation is not in the participant's best interest, study treatment will be discontinued or the participant will be withdrawn from the study, as appropriate.

Safety monitoring will be performed throughout the treatment period and after completion of study treatment. The investigator will assess adverse events (AEs) according to their severity, onset, and relationship to study treatment and will take appropriate management measures to ensure participant safety. After the last administration of study treatment, each participant will undergo safety follow-up for at least 30 days for AEs and at least 90 days for serious adverse events (SAEs). After completion of surgery and the safety follow-up period, participants will undergo regular survival follow-up according to the protocol. Information regarding disease recurrence, disease progression, death, and subsequent antitumor treatment will be collected to preliminarily evaluate long-term outcomes, including disease-free survival (DFS), progression-free survival (PFS), and overall survival (OS).