Neoadjuvant therapy with immunoagent (nivolumab) or placebo plus chemotherapy followed by surgery and adjuvant treatment in subjects with resectable esophageal squamous cell carcinoma: study protocol of a randomized, multicenter, double blind, phase II trial (NATION-2203 trial)

Jun Yin; Siyun Lin; Yong Fang; Heng Jiao; Zongwei Chen; Han Tang; Jianmin Gu; Shaoyuan Zhang; Linyi Sun; Yin Li; Yongtao Han; Qixun Chen; Haiquan Chen; Zhigang Li; Lijie Tan

doi:10.21037/jtd-22-1789

Neoadjuvant therapy with immunoagent (nivolumab) or placebo plus chemotherapy followed by surgery and adjuvant treatment in subjects with resectable esophageal squamous cell carcinoma: study protocol of a randomized, multicenter, double blind, phase II trial (NATION-2203 trial)

J Thorac Dis. 2023 Feb 28;15(2):718-730. doi: 10.21037/jtd-22-1789. Epub 2023 Feb 8.

Authors

Jun Yin^#^{1

2}, Siyun Lin^#^{1

2}, Yong Fang^{1

2}, Heng Jiao^{1

2}, Zongwei Chen^{1

2}, Han Tang^{1

2}, Jianmin Gu^{1

2}, Shaoyuan Zhang^{1

2}, Linyi Sun^{1

2}, Yin Li³, Yongtao Han⁴, Qixun Chen⁵, Haiquan Chen⁶, Zhigang Li⁷, Lijie Tan^{1

2}

Affiliations

¹ Department of Thoracic Surgery, Zhongshan Hospital of Fudan University, Shanghai, China.
² Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China.
³ Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
⁴ Department of Thoracic Surgery, Sichuan Cancer Hospital & Research Institute, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China.
⁵ Department of Thoracic Oncological Surgery, Cancer Hospital of University of Chinese Academy of Sciences, Zhejiang Cancer Hospital, Hangzhou, China.
⁶ Department of Thoracic Surgery, Fudan University Shanghai Cancer Center & Institute of Thoracic Oncology & State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, China.
⁷ Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

^# Contributed equally.

Abstract

Background: Neoadjuvant chemotherapy (nCT) has been the recommended treatment for locally advanced esophageal squamous cell carcinoma (ESCC). The addition of programmed cell death protein 1 (PD-1) inhibitor to nCT may improve oncologic outcome and survival. However, high-level evidence of neoadjuvant immunotherapy (nIT) combined with nCT in locally advanced resectable ESCC patients are still lacking. Hence, we describe this randomized controlled trial in order to assess the efficacy and safety of neoadjuvant nivolumab in combination with chemotherapy for locally advanced (stage II-III) ESCC patients.

Methods: This prospective, randomized, multicenter phase II trial aims to enroll 90 locally advanced (stage II-III) ESCC patients who will undergo nivolumab or placebo plus chemotherapy followed by surgery. Patients will be 2:1 randomized to nivolumab/chemo and placebo/chemo group by method of stratified randomization. In both arms, patients who have not achieved complete pathological complete response (pCR) will be administered with adjuvant nivolumab for up to 1 year. The primary endpoint is pCR rate and secondary endpoints include event-free survival (EFS), R0 resection rate, and adverse events (AEs). The safety will be evaluated by AEs, grading by Common Terminology Criteria for Adverse Events (CTCAE) 5.0 classifications. The double-blind will be maintained between subjects and investigators until the final unblinding process.

Discussion: This protocol has been reviewed and approved by the Ethics Committee of Zhongshan Hospital (B2022-004R). This is the first prospective, multicenter, randomized controlled trial to compare the combination of immunotherapy and chemotherapy with standard chemotherapy in neoadjuvant treatment for ESCC, also to explore whether adjuvant immunotherapy offers additional benefit in non-pCR patients after nCT with/without immunotherapy and R0 resection. We hypothesize that the pCR rate, R0 resection rate, EFS and OS of the study group (nivolumab/chemo) is significantly better than those of control group.

Registration: ClinicalTrial.gov: NCT05213312.

Keywords: Esophageal squamous cell carcinoma (ESCC); adjuvant; chemotherapy; neoadjuvant; nivolumab.

Associated data

ClinicalTrials.gov/NCT05213312