Preoperative pembrolizumab (anti-PD-1 antibody) combined with chemoradiotherapy for esophageal squamous cell carcinoma: a phase 1/2 trial (PALACE-2)

The role of preoperative anti-PD-1 antibody (pembrolizumab) plus chemoradiotherapy (PPCT) in locally advanced, resectable esophageal squamous cell carcinoma (ESCC) is still unclear. We aimed to investigate the therapeutic effect and safety of PPCT followed by surgery in this study (NCT03792347, NCT04435197). Patients with histologically confirmed, locally advanced, and surgically resectable ESCC were enrolled. They received PPCT with paclitaxel/carboplatin or nab-paclitaxel/carboplatin, followed by esophagectomy 4-6 weeks after treatment. The primary endpoint was the pathologic complete response (pCR) rate. Tumor specimens, blood samples and subcutaneous tumor mouse models were utilized to explore and validate the dynamic characteristics of the tumor microenvironment (TME) of ESCC after PPCT. Among the 143 patients enrolled, 140 received neoadjuvant treatment, and 125 underwent surgery. The pCR rate reached 43.2% (54/125). During neoadjuvant period, 75.7% (106/140) of patients experienced grade three or higher-grade adverse events. After a median follow-up of 17.4 months, patients showed a one-year disease-free survival rate of 91.1%, and an overall survival rate of 96.5%. Using scRNA-seq and cytokine profiling, we identified high IL-6 levels as a predictor of response to PPCT. In vivo experiment revealed that IL-6 neutralization enhanced the efficacy of immunotherapy by increasing CD4<sup>+</sup> T-cell cytotoxicity. This is the first large-scale, multicenter, phase 1/2 trial reporting the short-term results of PPCT for locally advanced resectable ESCC. Although the short-term efficacy was not superior to that of neoadjuvant chemoradiotherapy, PPCT demonstrated acceptable safety and comparable one-year survival. We also revealed an association between the therapeutic response and the ability of anti-IL-6 blockade to enhance the efficacy of immunotherapy.

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Publication Details

Journal
Signal Transduction and Targeted Therapy
Published
2025-11-27
DOI
https://doi.org/10.1038/s41392-025-02477-4
Citations
2
Primary Topic
Esophageal Cancer Research and Treatment
Type
article
Field-Weighted Citation Impact
4.01

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article

Preoperative pembrolizumab (anti-PD-1 antibody) combined with chemoradiotherapy for esophageal squamous cell carcinoma: a phase 1/2 trial (PALACE-2)

Chengqiang Li, Bentong Yu, Zenghui Cheng, Xueyu Chen et al.
2 citations
Signal Transduction and Targeted Therapy
Esophageal Cancer Research and Treatment
4.01
article

Preoperative pembrolizumab (anti-PD-1 antibody) combined with chemoradiotherapy for esophageal squamous cell carcinoma: a phase 1/2 trial (PALACE-2)

Chengqiang Li, Bentong Yu, Zenghui Cheng, Xueyu Chen, Liqiang Shi, Jiaming Che, Xiaozheng Kang, Guowen Zou, Yuqin Cao, Huan Li, Xiaoyan Chen, Yan Yan, Jian Li, Bin Li, Hecheng Li, Yin Li, Xipeng Wang, Yichao Han, Yuyan Zheng, Hui Jing, Wei Guo, Lianggang Zhu, Yajie Zhang, Junbiao Hang, Tong Lu, Jie Xiang, Liqin Zhao, Dingpei Han, Runsen Jin, Shengguang Zhao
article en
2 citations

Abstract

The role of preoperative anti-PD-1 antibody (pembrolizumab) plus chemoradiotherapy (PPCT) in locally advanced, resectable esophageal squamous cell carcinoma (ESCC) is still unclear. We aimed to investigate the therapeutic effect and safety of PPCT followed by surgery in this study (NCT03792347, NCT04435197). Patients with histologically confirmed, locally advanced, and surgically resectable ESCC were enrolled. They received PPCT with paclitaxel/carboplatin or nab-paclitaxel/carboplatin, followed by esophagectomy 4-6 weeks after treatment. The primary endpoint was the pathologic complete response (pCR) rate. Tumor specimens, blood samples and subcutaneous tumor mouse models were utilized to explore and validate the dynamic characteristics of the tumor microenvironment (TME) of ESCC after PPCT. Among the 143 patients enrolled, 140 received neoadjuvant treatment, and 125 underwent surgery. The pCR rate reached 43.2% (54/125). During neoadjuvant period, 75.7% (106/140) of patients experienced grade three or higher-grade adverse events. After a median follow-up of 17.4 months, patients showed a one-year disease-free survival rate of 91.1%, and an overall survival rate of 96.5%. Using scRNA-seq and cytokine profiling, we identified high IL-6 levels as a predictor of response to PPCT. In vivo experiment revealed that IL-6 neutralization enhanced the efficacy of immunotherapy by increasing CD4<sup>+</sup> T-cell cytotoxicity. This is the first large-scale, multicenter, phase 1/2 trial reporting the short-term results of PPCT for locally advanced resectable ESCC. Although the short-term efficacy was not superior to that of neoadjuvant chemoradiotherapy, PPCT demonstrated acceptable safety and comparable one-year survival. We also revealed an association between the therapeutic response and the ability of anti-IL-6 blockade to enhance the efficacy of immunotherapy.

Signal Transduction and Targeted TherapyVol. 10(1)
Nanchang University (CN), Shanghai Jiao Tong University (CN), Chinese Academy of Medical Sciences & Peking Union Medical College (CN), Ruijin Hospital (CN), National Cancer Center (US), First Affiliated Hospital of Nanchang University (CN)
Natural Science Foundation of Shanghai, Shanghai Municipal Health Commission, Beijing Xisike Clinical Oncology Research Foundation, National Natural Science Foundation of China, Shanghai Jiao Tong University
Openalex Percentile: Top 5%
Esophageal Cancer Research and Treatment
4.01
DOIOpen Access PDFOpenAlex
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