Perioperative toripalimab plus neoadjuvant chemotherapy might improve outcomes in resectable esophageal cancer: an interim analysis of a phase III randomized clinical trial

Abstract

Background: In the era of immunotherapy, neoadjuvant immunochemotherapy (NAIC) for the treatment of locally advanced esophageal squamous cell carcinoma (ESCC) is used clinically but lacks of high-level clinical evidence. This study aimed to compare the safety and long-term efficacy of NAIC followed by minimally invasive esophagectomy (MIE) with those of neoadjuvant chemotherapy (NAC) followed by MIE.

Methods: A prospective, single-center, open-label, randomized phase III clinical trial was conducted at Henan Cancer Hospital, Zhengzhou, China. Patients were randomly assigned to receive either neoadjuvant toripalimab (240 mg) plus paclitaxel (175 mg/m²) + cisplatin (75 mg/m²) (toripalimab group) or paclitaxel + cisplatin alone (chemotherapy group) every 3 weeks for 2 cycles. After surgery, the toripalimab group received toripalimab (240 mg every 3 weeks for up to 6 months). The primary endpoint was event-free survival (EFS). The pathological complete response (pCR) and overall survival (OS) were key secondary endpoints. Adverse events (AEs) and quality of life were also assessed.

Results: Between May 15, 2020 and August 13, 2021, 252 ESCC patients ranging from T1N1-3M0 to T2-3N0-3M0 were enrolled for interim analysis, with 127 in the toripalimab group and 125 in the chemotherapy group. The 1-year EFS rate was 77.9% in the toripalimab group compared to 64.3% in the chemotherapy group (hazard ratio [HR] = 0.62; 95% confidence interval [CI] = 0.39 to 1.00; P = 0.05). The 1-year OS rates were 94.1% and 83.0% in the toripalimab and chemotherapy groups, respectively (HR = 0.48; 95% CI = 0.24 to 0.97; P = 0.037). The patients in the toripalimab group had a higher pCR rate (18.6% vs. 4.6%; P = 0.001). The rates of postoperative Clavien-Dindo grade IIIb or higher morbidity were 9.8% in the toripalimab group and 6.8% in the chemotherapy group, with no significant difference observed (P = 0.460). The rates of grade 3 or 4 treatment-related AEs did not differ between the two groups (12.5% versus 12.4%).

Conclusions: The interim results of this ongoing trial showed that in resectable ESCC, the addition of perioperative toripalimab to NAC is safe, may improve OS and might change the standard treatment in the future.

Keywords: esophageal squamous cell carcinoma; minimally invasive esophagectomy; neoadjuvant chemotherapy; neoadjuvant immunochemotherapy; survival.

FIGURE 1

Study design. Abbreviations: ECOG, Eastern Cooperative Oncology Group; ESCC, esophageal squamous cell carcinoma; EFS, event‐free survival; MPR, major pathological response; N, node; OS, overall survival; pCR, pathological complete response; Q, quaque; R, random; T, tumor; W, week.

FIGURE 2

CONSORT flow chart of patient enrollment. ^*Six patients in the toripalimab group refused toripalimab, and they were excluded from the safety analysis. The patients were added to the chemotherapy group for safety analysis. Abbreviations: AE, adverse event; CT, computed tomography.

FIGURE 3

The EFS in this study. The 95% CI of the HR for EFS was 0.39 to 1.00. At this first prespecified interim analysis, the P value for OS did not cross the boundary for statistical significance. Abbreviations: CI, confidence interval; EFS, event free survival; HR, hazard ratio; NAIC, immunochemotherapy; N/A, not available; NAC, neoadjuvant chemotherapy; OS, overall survival.

FIGURE 4

The OS in this study. The 95% CI of the HR for OS was 0.24 to 0.97. At this first prespecified interim analysis, the P value for OS was statistical significance. Abbreviations: CI, confidence interval; HR, hazard ratio; N/A, not available; NAIC, immunochemotherapy; NAC, neoadjuvant chemotherapy; OS, overall survival.