The Sequence of Chemotherapy and Toripalimab Might Influence the Efficacy of Neoadjuvant Chemoimmunotherapy in Locally Advanced Esophageal Squamous Cell Cancer-A Phase II Study

Abstract

Background: There is no standard neoadjuvant therapy for locally advanced esophageal cancer in China. The role of neoadjuvant chemotherapy plus immunotherapy for locally advanced esophageal cancer is still being explored.

Methods: This open-label, randomized phase II study was conducted at a single center between July 2019 and September 2020; 30 patients with locally advanced esophageal squamous cell carcinoma (ESCC) (T3, T4, or lymph-node positive) were enrolled. Patients were randomized according to the enrollment order at a 1:1 ratio to receive chemotherapy on day 1 and toripalimab on day 3 (experimental group) or chemotherapy and toripalimab on day 1 (control group). The chemotherapeutic regimen was paclitaxel and cisplatin. Surgery was performed 4 to 6 weeks after the second cycle of chemoimmunotherapy. The primary endpoint was pathological complete response (pCR) rate, and the secondary endpoint was safety and disease-free survival.

Results: Thirty patients completed at least one cycle of chemoimmunotherapy; 11 in the experimental group and 13 in the control group received surgery. R0 resection was performed in all these 24 patients. Four patients (36%) in the experimental group and one (7%) in the control group achieved pCR. The experimental group showed a statistically non-significant higher pCR rate (p = 0.079). PD-L1 combined positive score (CPS) examination was performed in 14 patients; one in the control group had a PD-L1 CPS of 10, and pCR was achieved; the remaining 13 all had ≤1, and 11 of the 13 patients received surgery in which two (in the experimental group) achieved pCR. Two patients endured ≥grade 3 adverse events, and one suffered from grade 3 immune-related enteritis after one cycle of chemoimmunotherapy and dropped off the study. Another patient died from severe pulmonary infection and troponin elevation after surgery.

Conclusions: Although the primary endpoint was not met, the initial results of this study showed that delaying toripalimab to day 3 in chemoimmunotherapy might achieve a higher pCR rate than that on the same day, and further large-sample clinical trials are needed to verify this.

Clinical trial registration: ClinicalTrials.gov, identifier NCT03985670.

Keywords: chemoimmunotherapy; esophageal squamous cell carcinoma; pathological complete response; sequence; toripalimab.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2021 Xing, Zhao, Zheng, Liu, Liu, Li, Zhang, Ma, Yang, Shang, Fu, Liang, Yuan, Qu, Chai, Zhang, Wang, Lin, Liu, Ren, Zhang and Gao.

Figures

Figure 1

Consolidated Standards of Reporting Trials (CONSORT) diagram.

Figure 2

The changes of esophageal lesions in magnetic resonance imaging. (A, B) show the esophageal lesion in patient 4 before and after neoadjuvant chemoimmunotherapy, the lesion reduced significantly. (C, D) show esophageal lesion in patient 7 before and after neoadjuvant chemoimmunotherapy. (E, F) show esophageal lesion in patient 1 before and after neoadjuvant chemoimmunotherapy. (G, H) show esophageal lesion in patient 8 before and after neoadjuvant chem.

Figure 3

The pathological changes before and after neoadjuvant chemoimmunotherapy and the PD-L1 expression. (A, B) The pathological changes in patient 1; after neoadjuvant chemoimmunotherapy, the tumor cells disappeared, and many lymphocytes infiltrated. (C) The expression of PD-L1 combined positive score (CPS) in the sample before therapy in patient 1; and the expression of PD-L1 CPS was lower than 1. (D, E) The pathological changes in patient 4; after neoadjuvant chemoimmunotherapy, the tumor cells disappeared, and some lymphocytes infiltrated. (F) The expression of PD-L1 CPS in the sample before therapy in patient 4, and the expression of PD-L1 CPS was 10.

Figure 4

The pathological changes before and after neoadjuvant chemoimmunotherapy and the PD-L1 expression. (A, B) The pathological changes in patient 7; after neoadjuvant chemoimmunotherapy, there are a large number of tumor cells left in the section, and a few lymphocytes infiltrated. (C) The expression of PD-L1 combined positive score (CPS) in the sample before therapy in patient 7, and the expression of PD-L1 CPS was lower than 1. (D, E) The pathological changes in patient 8; after neoadjuvant chemoimmunotherapy, there are a large number of tumor cells left in the section and few lymphocytes infiltrated. (F) The expression of PD-L1 CPS in the sample before therapy in patient 8, and the expression of PD-L1 CPS was lower than 1.