Neoadjuvant ChemoRadiotherapy Followed by Immunotherapy and Surgery for Resectable Esophageal Squamous Cell Carcinoma（CRIS-2 Trial）

Summary

Based on our previous single-arm Phase Ib study (CRIS trial, NCT06303583), we observed that neoadjuvant chemoradiotherapy followed by immunotherapy (nCRIT) significantly increased the pathological complete response (pCR) rate, achieving approximately 60% in locally advanced esophageal squamous cell carcinoma(ESCC). We plan to initiate a multicenter, prospective, randomized phase II trial designed to compare the efficacy and safety of neoadjuvant chemoimmunotherapy (nCIT) versus neoadjuvant chemoradiotherapy followed by immunotherapy (nCRIT) in treating esophageal squamous cell carcinoma. The primary study population includes patients with operable or potentially operable thoracic ESCC classified as cT3-4aN0 or T2-4aN+ based on endoscopy, enhanced chest and abdominal CT, and whole-body PET scans. Eligible participants are aged 18-75 years with an ECOG performance status of 0-1. Qualified patients will be randomly assigned in a 1:1 ratio to either the nCRIT group or the nCIT group. Patients in the nCRIT group will receive neoadjuvant concurrent chemoradiotherapy: radiation therapy will be administered using IMRT or VMAT with involved-field irradiation at a dose of PTV 41.4 Gy/23 fractions/31 days. Chemotherapy will consist of weekly administration of paclitaxel (albumin-bound) 50 mg/m² and carboplatin (AUC=2) for five weeks, given on the days of radiotherapy. Patients who do not progress on CT and meet immunotherapy criteria will receive fixed-dose tislelizumab (200 mg IV) on days 8 and 29 after chemoradiotherapy, followed by minimally invasive esophagectomy four weeks after completing immunotherapy. Patients in the nCIT group will receive two cycles of TC chemotherapy combined with immunotherapy, specifically paclitaxel (albumin-bound) 100 mg/m² on days 1, 8, 15 or 260mg/m² d1, carboplatin (AUC=5) on days 1, and tislelizumab (200 mg) on days 1. Minimally invasive esophagectomy will be performed 4-6 weeks after completing chemotherapy, and adjuvant immunotherapy is recommended for one year after surgery. The primary endpoint of the study is the pathological complete response (pCR). Secondary endpoints include treatment safety, CT imaging response rate, R0 resection rate, major pathological response (MPR), 2-year event-free survival (EFS), 2-year overall survival (OS) in the intention-to-treat (ITT) population, and analysis of treatment failure reasons.

Timeline

Start

2024-08-01

Primary completion

2026-08-01

Completion

2027-08-01

Publications

• Background van Hagen P, Hulshof MC, van Lanschot JJ, Steyerberg EW, van Berge Henegouwen MI, Wijnhoven BP, Richel DJ, Nieuwenhuijzen GA, Hospers GA, Bonenkamp JJ, Cuesta MA, Blaisse RJ, Busch OR, ten Kate FJ, Creemers GJ, Punt CJ, Plukker JT, Verheul HM, Spillenaar Bilgen EJ, van Dekken H, van der Sangen MJ, Rozema T, Biermann K, Beukema JC, Piet AH, van Rij CM, Reinders JG, Tilanus HW, van der Gaast A; CROSS Group. Preoperative chemoradiotherapy for esophageal or junctional cancer. N Engl J Med. 2012 May 31;366(22):2074-84. doi: 10.1056/NEJMoa1112088.
• Background Luo H, Lu J, Bai Y, Mao T, Wang J, Fan Q, Zhang Y, Zhao K, Chen Z, Gao S, Li J, Fu Z, Gu K, Liu Z, Wu L, Zhang X, Feng J, Niu Z, Ba Y, Zhang H, Liu Y, Zhang L, Min X, Huang J, Cheng Y, Wang D, Shen Y, Yang Q, Zou J, Xu RH; ESCORT-1st Investigators. Effect of Camrelizumab vs Placebo Added to Chemotherapy on Survival and Progression-Free Survival in Patients With Advanced or Metastatic Esophageal Squamous Cell Carcinoma: The ESCORT-1st Randomized Clinical Trial. JAMA. 2021 Sep 14;326(10):916-925. doi: 10.1001/jama.2021.12836.
• Background Qin J, Xue L, Hao A, Guo X, Jiang T, Ni Y, Liu S, Chen Y, Jiang H, Zhang C, Kang M, Lin J, Li H, Li C, Tian H, Li L, Fu J, Zhang Y, Ma J, Wang X, Fu M, Yang H, Yang Z, Han Y, Chen L, Tan L, Dai T, Liao Y, Zhang W, Li B, Chen Q, Guo S, Qi Y, Wei L, Li Z, Tian Z, Kang X, Zhang R, Li Y, Wang Z, Chen X, Hou Z, Zheng R, Zhu W, He J, Li Y. Neoadjuvant chemotherapy with or without camrelizumab in resectable esophageal squamous cell carcinoma: the randomized phase 3 ESCORT-NEO/NCCES01 trial. Nat Med. 2024 Sep;30(9):2549-2557. doi: 10.1038/s41591-024-03064-w. Epub 2024 Jul 2.

Drugs

Indications