Toripalimab Plus Paclitaxel and Carboplatin as Neoadjuvant Therapy in Locally Advanced Resectable Esophageal Squamous Cell Carcinoma

Wenwu He, Xuefeng Leng, Tianqin Mao, Xi Luo, Lingxiao Zhou, Jiaxin Yan, Lin Peng, Qiang Fang, Guangyuan Liu, Xing Wei, Kangning Wang, Chenghao Wang, Sha Zhang, Xudong Zhang, Xudong Shen, Depei Huang, Huan Yi, Ting Bei, Xueke She, Wenguang Xiao, Yongtao Han, Wenwu He, Xuefeng Leng, Tianqin Mao, Xi Luo, Lingxiao Zhou, Jiaxin Yan, Lin Peng, Qiang Fang, Guangyuan Liu, Xing Wei, Kangning Wang, Chenghao Wang, Sha Zhang, Xudong Zhang, Xudong Shen, Depei Huang, Huan Yi, Ting Bei, Xueke She, Wenguang Xiao, Yongtao Han

Abstract

Introduction: Immune checkpoint inhibitors (ICIs) are effective in the treatment of advanced esophageal squamous cell carcinoma (ESCC); however, their efficacy in locally advanced resectable ESCC and the potential predictive biomarkers have limited data.

Methods: In this study, locally advanced resectable ESCC patients were enrolled and received neoadjuvant toripalimab (240 mg, day 1) plus paclitaxel (135 mg/m2, day 1) and carboplatin (area under the curve 5 mg/mL per min, day 1) in each 3-week cycle for 2 cycles, followed by esophagectomy planned 4-6 weeks after preoperative therapy. The primary endpoints were safety, feasibility, and the major pathological response (MPR) rate; the secondary endpoints were the pathological complete response (pCR) rate, disease-free survival (DFS), and overall survival (OS). Association between molecular signatures/tumor immune microenvironment and treatment response was also explored.

Results: Twenty resectable ESCC patients were enrolled. Treatment-related adverse events (AEs) occurred in all patients (100%), and 4 patients (22.2%) experienced grade 3 or higher treatment-related AEs. Sixteen patients underwent surgery without treatment-related surgical delay, and the R0 resection rate was 87.5% (14/16). Among the 16 patients, the MPR rate was 43.8% (7/16) and the pCR rate was 18.8% (3/16). The abundance of CD8+ T cells in surgical specimens increased (P = .0093), accompanied by a decreased proportion of M2-type tumor-associated macrophages (P = .036) in responders upon neoadjuvant therapy. Responders were associated with higher baseline gene expression levels of CXCL5 (P = .03) and lower baseline levels of CCL19 (P = .017) and UMODL1 (P = .03).

Conclusions: The combination of toripalimab plus paclitaxel and carboplatin is safe, feasible, and effective in locally advanced resectable ESCC, indicating its potential as a neoadjuvant treatment for ESCC.

Clinical trial registration: NCT04177797.

Keywords: chemotherapy; esophageal squamous cell carcinoma; neoadjuvant therapy; toripalimab.

© The Author(s) 2022. Published by Oxford University Press.

Figures

Figure 1.
Figure 1.
(a) Patient enrollment overview. ESCC, esophageal squamous cell carcinoma. (b) Percentage pathological regression after neoadjuvant immunotherapy and chemotherapy shown per tumor. The horizontal dotted line depicts the demarcation for major pathological responses with 90% tumor regression. (c) Cases of radiological and pathological response after neoadjuvant immunotherapy and chemotherapy. The vertical black line separates patients with good efficacy (left) and stable disease (right). (i) Top left: CT imaging of the chest of a 68-year-old man with stage III/T3N1M0, middle third before treatment. Top right: Posttreatment CT scan showed no notable disease. Middle row: pre- and posttreatment endoscopic pictures of the tumor. Bottom: pre- and posttreatment pathological assessment with microscopy by HE staining. (ii) Top left: CT imaging of the chest of a 62-year-old woman with stage III/T3N2M0, middle third before treatment. Top right: Posttreatment CT scan showing notable disease. Bottom: pre- and posttreatment pathological assessment with microscopy by HE staining.
Figure 2.
Figure 2.
(a) The landscape of genomic alterations in baseline tissue samples of 18 patients with ESCC undergoing treatment. (b-e) Immune gene signatures and differences between the responders and nonresponders in 31 immune-related genes expression. (b) Immune gene signatures according to response. (c) Differences between the responders and nonresponders in CXCL5 expression. (d) Differences between the responders and nonresponders in CCL19 expression. (e) Differences between the responders and nonresponders in UMODL1 expression. (f-p) Comparisons between responders and nonresponders before treatment for subsets of biomarkers. (f) Absolute neutrophil counts. (g) Absolute natural killer cell counts. (h) Lactate dehydrogenase. (i) Neutrophil-to-lymphocyte ratio. (j) TMB. (k) CD8+ T cells density. (l) CD68+HLA-DR+ density. (m) CD68+HLA-DR- density. (n) CD56+dim density. (o) PD-L1 expression TPS. (p) PD-L1 expression CPS. ESCC, esophageal squamous cell carcinoma; TMB, tumor mutation burden; TPS, tumor proportion score.
Figure 3.
Figure 3.
Differences in TIME between pre- and posttreatment, and pre- to posttreatment changes in responders and nonresponders. (a) Differences between pre- and posttreatment in PD-L1 expression TPS. (b) Differences between pre- and posttreatment in PD-L1 expression CPS. (c) Differences between pre- and posttreatment in CD8+ T cells density in 17 pared samples. (d) Differences between pre- and posttreatment in CD8+ T cells density in nonresponders (left) and in responders (right). (e) Differences between pre- and posttreatment in CD68+HLA-DR- density in nonresponders (left) and in responders (right). CPS, combined positive score; TIME, tumor immune microenvironment; TPS, tumor proportion score.

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