Neoadjuvant Pembrolizumab and Chemotherapy in Resectable Esophageal Cancer: An Open-Label, Multicenter, Single-Arm Study
Authors: Duan Hongtao , Shao Changjian , Shang Xiaobin , Liu Honggang , Dong Xiaoping , Zhang Yong , Tong Liping , Feng Yingtong , Zhou Yongan , Wang Yuanyuan , Wang Lu , Pan Minghong , Newman Neil B. , Sarkaria Inderpal S. , Reynolds John V , De Cobelli Francesco , Jiang Hongjing , Jiang Tao , Yan Xiaolong 
Published: August 2021

Abstract
Background: Multimodal therapies, such as perioperative chemotherapy and neoadjuvant chemoradiotherapy together with surgical advances, have improved the outcomes of patients with resectableesophageal cancer (EC).However, the 5-year survival of these patients remains below 50%. The advent of immunotherapy has resulted in novel approaches to advanced or metastatic disease, but the role of immunotherapy in the neoadjuvant settings has not yet to be established. In this single-arm study, the efficacy and safetyofneoadjuvant pembrolizumab plus chemotherapy were evaluatedin patients with resectableesophageal squamous cell carcinoma (ESCC).Methods: This study was conducted at 2 hospitals(in Xi'an and Tianjin)and included patients with ESCC of clinical stage II–IVAwho underwent surgery within 4 to 6 weeks after completing treatment withpembrolizumab(200mg) combined with a conventional chemotherapy regimen (3 cycles). The efficacy and safety of this combination treatment were evaluated as primary endpointsof the study. This study was retrospectively registered (Registration number: ChiCTR2100048917).Results:A total of 22 patients (including 18 men) were enrolled, of whom 17 patients progressed to surgery,4 patients refused surgery due to tumor regression and symptomatic relief, and 1 patient had progressive disease. As determinedby the Response Evaluation Criteria in Solid Tumors(RECIST,version 1.1), 7 patients (31.8%) had a partial response and 4 (18.2%) patients hada complete response, which translated to an objective response rate of 50%. The symptom remission rate was 90.9% according to the Stooler classification. Five patients (22.7%) experienced serious treatment-related adverse events of grade 3–4 (including anorexia, vomiting, fatigue, alopecia and hypoadrenalism). Postoperative pathology revealed a major pathological response in 14 cases (82.3%) and a complete pathological response in 8 cases (47.1%). Programmed death-ligand 1expression in pretreatment specimens was not significantly associated with the percentage of residual viable tumor (RVT)(r=-0.55, p=0.08). Changes in counts of CD68+ macrophage between pre- and post-treatment specimens wereweakly correlated with RVT(r=0.71; p=0.07), while a positive correlation was observed between postoperative Foxp3+T cells/CD4+Tcellsratios and RVT(r=0.84, p=0.03).Conclusion: The combination of neoadjuvantimmunotherapy and chemotherapy for ESCC is associated with a high pathological response and immunologic effects in the tumor microenvironment. It has acceptable toxicity and great efficacy, suggesting a strong rationale for its further evaluation in randomized clinical trials.Trial registration: ChiCTR, ChiCTR2100048917. Registered 19 July 2021 - Retrospectively registered, https://www.chictr.org.cn/edit.aspx?pid=130073&htm=4