Three-year outcomes and multi-omics biomarker discovery of locally advanced esophageal squamous cell carcinoma after neoadjuvant chemoradiotherapy and anti-PD-1 antibody from the phase II trial NEOCRTEC1901.
Abstract
371 Background: This trial aimed to evaluate the long-term survival benefit of neoadjuvant chemoradiotherapy combined with PD-1 inhibitors Toripalimab (NICRT) in treating local advanced esophageal squamous cell carcinoma (ESCC) and explore the biomarkers of treatment efficacy. Methods: From December 2019 to July 2021, 44 ESCC patients were enrolled in this phase II trial. All patients received chemotherapy (paclitaxel and cisplatin), Toripalimab and concurrent radiotherapy (44 Gy /20 times), and were subjected to minimally invasive esophagectomy within 6 to 8 weeks after completing neoadjuvant treatment. Pre-treatment tumor biopsies of 41 patients were subjected to PD-L1 immunohistochemistry staining, 28 of which were also used for RNA sequencing. Results: The median follow-up time was 38.6 months (95%CI: 36.3-40.3 months). A total of 13 tumor recurrence events and 12 deaths were observed, the incidence of non-cancer-related deaths was 2.2% (1/44). The 3-year disease-free survival (DFS) rate was 65.6% (95%CI: 50.5%-85.1%), and 3-year overall survival (OS) rate was 70.5% (95%CI: 58.2%-85.3%). Among patients receiving surgery, 50% of patients (21/42) achieved pathological complete response (pCR) , those with pCR demonstrating a higher 3-yr DFS rate (85.0% in pCR v.s. 44.9% in non-pCR, P=0.047) and OS rate (85.7% v.s. 61.9%, P=0.063) than non-pCR patients. PD-L1 positivity (CPS> 5) indicated better DFS (HR: 0.42, 95%CI: 0.14-1.35, P=0.14) and OS (HR: 0.27, 95%CI：0.09-0.87, P=0.029). Cancer transcriptome analysis revealed a three-gene non-exhausted CD8+ T cell-associated expression signature (CD8A/IL32/VIM) in pre-treatment samples for accurate prediction of pCR in ESCC patients receiving NICRT with an area under the receiver operative characteristics curve (AUC) of 0.9. Moreover, patients with high expression signature (≥median value) experienced significantly better DFS than those with low expression signature (P<0.05). The power of the signature in efficacy stratification was also observed in patients receiving definitive chemoradiotherapy and PD-1 inhibitors (AUC=0.88, P<0.05 in EC-CRT-001 trial). Notably, the expression signature outperformed published esophageal cancer-specific immunotherapy biomarkers in both cohorts. Conclusions: Owing to the improved long-term prognosis and low non-cancer related modalities, NICRT represents a power strategy in treating locally advanced ESCC. PD-L1 positivity (CPS>5) and the three-gene signature in pre-treatment ESCC specimens are promising biomarkers in predicting long-term prognosis of NICRT. Clinical trial information: NCT04006041 .
Article Details
Journal Info
Journal of Clinical Oncology
Lippincott Williams & Wilkins
Authors (15)
Zihang Mai
Sun Yat-sen University; Zhongming Display Technology Co., Ltd., Guangzhou, China
Qian-Wen Liu
Sun Yat-sen University Cancer Center, Guangzhou, China
Qiaoqiao Li
State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica
Yujia Zhu
Lei Zhao
School of Life Sciences, Key Laboratory of Pesticide and Chemical Biology of Ministry of Education, and Hubei Key Laboratory of Genetic Regulation and Integrative Biology, Central China Normal University
Shiliang Liu
Baoqing Chen
Baoqing Chen, MD, State Key Laboratory of Oncology in South China, Collaborative Innovation Centre for Cancer Medicine, Guangdong Esophageal Cancer Institute, Guangzhou, China, Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China, United Laboratory of Frontier Radiotherapy Technology of Sun Yat-sen University & Chinese Academy of Sciences Ion Medical Technology Co, Ltd, Guangzhou, China, Zimeng Li, MM and Xingyuan Cheng, MD, State Key Laboratory of Oncology in South China, Collaborative Innovation Centre for Cancer Medicine, Guangdong Esophageal Cancer Institute, Guangzhou, China, Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China, Mian Xi, MD, State Key Laboratory of Oncology in South China, Collaborative Innovation Centre for Cancer Medicine, Guangdong Esophageal Cancer Institute, Guangzhou, China, Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China, United Laboratory of Frontier Radiotherap...
Mengzhong Liu
State Key Laboratory of Oncology in South China, Collaborative Innovation Centre for Cancer Medicine, Guangdong Esophageal Cancer Institute, Guangzhou, China
Yonghong Hu
State Key Laboratory of Oncology in South China, Collaborative Innovation Centre for Cancer Medicine, Guangdong Esophageal Cancer Institute, Guangzhou, China
Ting Lin
Beijing National Center for Electron Microscopy and Laboratory of Advanced Materials, School of Materials Science and Engineering
Jiyang Chen
Sun Yat-sen University Cancer Center, Guangzhou, China
Yingxin Lv
State Key Laboratory of Oncology in South China, Collaborative Innovation Centre for Cancer Medicine, Guangdong Esophageal Cancer Institute, Guangzhou, China
Jianhua Fu
Mian Xi
Baoqing Chen, MD, State Key Laboratory of Oncology in South China, Collaborative Innovation Centre for Cancer Medicine, Guangdong Esophageal Cancer Institute, Guangzhou, China, Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China, United Laboratory of Frontier Radiotherapy Technology of Sun Yat-sen University & Chinese Academy of Sciences Ion Medical Technology Co, Ltd, Guangzhou, China, Zimeng Li, MM and Xingyuan Cheng, MD, State Key Laboratory of Oncology in South China, Collaborative Innovation Centre for Cancer Medicine, Guangdong Esophageal Cancer Institute, Guangzhou, China, Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China, Mian Xi, MD, State Key Laboratory of Oncology in South China, Collaborative Innovation Centre for Cancer Medicine, Guangdong Esophageal Cancer Institute, Guangzhou, China, Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China, United Laboratory of Frontier Radiotherap...
Hong Yang
The First Affiliated Hospital of Air Force Military Medical University Xi’an China