Toripalimab plus chemotherapy in treatment-naïve, advanced esophageal squamous cell carcinoma (JUPITER-06): A multi-center phase 3 trial

Wang, Zi‐Xian; Cui, Chengxu; Yao, Jun; Zhang, Yanqiao; Li, Mengxia; Feng, Jifeng; Yang, Shujun; Fan, Yun; Shi, Jianhua; Zhang, Xizhi; Shen, Lin; Shu, Yongqian; Wang, Cailian; Dai, Tianyang; Mao, Teng; Chen, Long; Guo, Zengqing; Liu, Bo; Pan, Hongming; Cang, Shundong; Jiang, Yi; Wang, Junye; Yang, Min; Chen, Zhendong; Jiang, Da; Lin, Qin; Ren, Wei; Wu, Lin; Xu, Yong; Miao, Zhanhui; Sun, Meili; Xie, Conghua; Liu, Ying; Wang, Qifeng; Zhao, Lina; Li, Qi; Huang, Canhong; Jiang, Ke; Yang, Kunyu; Li, Daojun; Zhu, Zhou; Chen, Rixin; Jia, Liqun; Li, Wei; Liao, Wangjun; Liu, Hongxu; Ma, Deliang; Ma, Jinghong; Qin, Yanru; Shi, Zhihong; Wei, Qichun; Ke, Xiaoyan; Zhang, Yan; Zhang, Ying; Chen, Xin; Dai, Guanghai; He, Jianxing; Jun-he, LI; Li, Guanghui; Liu, Yong; Liu, Zhihua; Yuan, Xianglin; Zhang, Junping; Fu, Zhichao; He, Yong; Fang, Ju; Tang, Peng; Wang, Zhihui; Wang, Weibo; Zhang, Jing; Xian-ming, Luo; Tang, Xiongwen; May, R.; Feng, Hui; Yao, Sheng; Keegan, Patricia; Xu, Rui‐hua; Wang, Feng

doi:10.1016/j.ccell.2022.02.007

Cited by 253 publications

(231 citation statements)

References 30 publications

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“…The recent ESCORT-1st study (ClinicalTrials.gov identifier: NCT03691090 ) found that adding camrelizumab (another monoclonal antibody against PD-1) to the first-line chemotherapy (paclitaxel and cisplatin) significantly improved overall survival and progress-free survival compared to chemotherapy alone in patients with advanced and/or metastatic ESCC [ 54 ]. In addition, a multicenter phase 3 trial (JUPITER-06) demonstrated the efficacy and safety of toripalimab plus paclitaxel/cisplatin as the first-line treatment for patients with advanced ESCC; compared with paclitaxel/cisplatin alone, toripalimab plus paclitaxel/cisplatin extended progression-free survival and overall survival, irrespective of PD-L1 expression [ 55 ]. Given our finding that high expression of both LSD1 and G9a was correlated with the lowest survival in patients with ESCC, future clinical studies are clearly needed in order to determine whether targeting both LSD1 and G9a can improve PD-1-based therapies.…”

Section: Discussionmentioning

confidence: 99%

Targeting the LSD1-G9a-ER Stress Pathway as a Novel Therapeutic Strategy for Esophageal Squamous Cell Carcinoma

et al. 2022

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Despite recent advances in the management and treatment of esophageal squamous cell carcinoma (ESCC), the prognosis remains extremely poor, and current nonsurgical treatment options are limited. To identify new therapeutic targets, we screened a curated library of epigenetic compounds using a panel of cancer cell lines and found that coinhibiting the histone demethylase LSD1 and the histone methyltransferase G9a potently suppresses cell growth; similar results were obtained by knocking down both LSD1 and G9a expression. Importantly, we also found that inhibiting LSD1 and G9a significantly decreased tumor growth in a xenograft mouse model with ESCC cell lines. To examine the clinical relevance of these findings, we performed immunohistochemical analyses of microarray profiling data obtained from human esophageal squamous cancer tissues and found that both LSD1 and G9a are upregulated in cancer tissues compared to healthy tissues, and this increased expression was significantly correlated with poor prognosis. Mechanistically, we discovered that inhibiting LSD1 and G9a induces cell death via S-phase arrest and apoptosis, and cotargeting ER stress pathways increased this effect both in vitro and in vivo. Taken together, these findings provide compelling evidence that targeting LSD1, G9a, and ER stress-related pathways may serve as a viable therapeutic strategy for ESCC.

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Section: Discussionmentioning

confidence: 99%

Targeting the LSD1-G9a-ER Stress Pathway as a Novel Therapeutic Strategy for Esophageal Squamous Cell Carcinoma

et al. 2022

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“… 14 Beyond these preclinical observations, several phase III clinical trials have evaluated the added benefit of combining immunotherapy and chemotherapy in the first-line setting for ESCC patients. According to recently released results, 22 , 23 , 24 , 25 , 26 chemoimmunotherapy combinations using TP regimen appear to confer better survival than using 5-FU and cisplatin regimen, indicating that TP regimen could generate a more favorable tumor microenvironment to maximize the immunotherapy or targeted therapy efficacy and might be more suitable for combination. Notably, evidence from clinical studies of head and neck squamous cell carcinoma also supported the combination of cetuximab and the TP regimen, reporting a slightly longer time to treatment failure (TTF) and improved safety profile with a taxane versus 5-FU in combination with anti-EGFR antibody and platinum.…”

Section: Discussionmentioning

confidence: 99%

Paclitaxel and cisplatin with or without cetuximab in metastatic esophageal squamous cell carcinoma: a randomized, multicenter phase II trial

Lü¹,

Zhang²,

Fan³

et al. 2022

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“…The emergence of immune checkpoint inhibitors (ICIs) has revolutionized the treatment of advanced or metastatic gastroesophageal cancers (4)(5)(6)(7). Recently, the largest randomized, placebo-controlled, phase 3 study (KEYNOTE-590) to date had confirmed better survival benefits of pembrolizumab plus chemotherapy over placebo plus chemotherapy in 749 patients with unresectable locally advanced or metastatic EC.…”

Section: Introductionmentioning

confidence: 99%

Conversion Surgery Following Immunochemotherapy in Initially Unresectable Locally Advanced Esophageal Squamous Cell Carcinoma—A Real-World Multicenter Study (RICE-Retro)

Huang

Cheng

et al. 2022

Front. Immunol.

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PurposeThe present study sets out to evaluate the feasibility, safety, and effectiveness of conversion surgery following induction immunochemotherapy for patients with initially unresectable locally advanced esophageal squamous cell carcinoma (ESCC) in a real-world scenario.Materials and MethodsIn this multi-center, real-world study (NCT04822103), patients who had unresectable ESCC disease were enrolled across eight medical centers in China. All patients received programmed death receptor-1 (PD-1) inhibitor plus chemotherapy every 3 weeks for at least two cycles. Patients with significant relief of cancer-related clinical symptoms and radiological responsive disease were deemed surgical candidates. Feasibility and safety profile of immunochemotherapy plus conversion surgery, radiological and pathological tumor responses, as well as short-term survival outcomes were evaluated. Moreover, data of an independent ESCC cohort receiving induction chemotherapy (iC) were compared.ResultsOne hundred and fifty-five patients were enrolled in the final analysis. Esophagectomy was offered to 116 patients, yielding a conversion rate of 74.8%. R0 resection rate was 94%. Among the 155 patients, 107 (69.0%) patients experienced at least one treatment-related adverse event (TRAE) and 45 (29.0%) patients reported grade 3 and above TRAEs. Significant differences in responsive disease rate were observed between iC cohort and induction immunochemotherapy (iIC) cohort [objective response rate: iIC: 63.2% vs. iC: 47.7%, p = 0.004; pathological complete response: iIC: 22.4% vs. iC: 6.7%, p = 0.001). Higher anastomosis fistula rate was observed in the iC group (19.2%) compared with the iIC group (4%). Furthermore, Significantly higher event-free survival was observed in those who underwent conversion surgery.ConclusionOur results supported that conversion surgery following immunochemotherapy is feasible and safe for patients with initially unresectable locally advanced ESCC. Both radiological and pathological response rates were significantly higher in the iIC cohort compared with those in the traditional iC cohort.

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Toripalimab plus chemotherapy in treatment-naïve, advanced esophageal squamous cell carcinoma (JUPITER-06): A multi-center phase 3 trial

Cited by 253 publications

References 30 publications

Targeting the LSD1-G9a-ER Stress Pathway as a Novel Therapeutic Strategy for Esophageal Squamous Cell Carcinoma

Targeting the LSD1-G9a-ER Stress Pathway as a Novel Therapeutic Strategy for Esophageal Squamous Cell Carcinoma

Paclitaxel and cisplatin with or without cetuximab in metastatic esophageal squamous cell carcinoma: a randomized, multicenter phase II trial

Conversion Surgery Following Immunochemotherapy in Initially Unresectable Locally Advanced Esophageal Squamous Cell Carcinoma—A Real-World Multicenter Study (RICE-Retro)

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