AbstractAlthough first-line immunochemotherapy has improved prognosis for patients with advanced esophageal squamous cell carcinoma (ESCC), more effective strategies still require further investigation. This multi-center, phase II study (ClinicalTrials.gov NCT05013697) assessed the feasibility of benmelstobart (a novel PD-L1 inhibitor) plus anlotinib (multitargeted TKI) and chemotherapy in advanced or metastatic/recurrent ESCC.

摘要尽管一线免疫化疗改善了晚期食管鳞状细胞癌（ESCC）患者的预后，但更有效的策略仍需要进一步研究。这项多中心II期研究（ClinicalTrials.gov NCT05013697）评估了benmelstobart（一种新型PD-L1抑制剂）加阿洛替尼（多靶点TKI）和化疗在晚期或转移性/复发性ESCC中的可行性。

Eligible patients received 4–6 cycles (21-day) of benmelstobart (1200 mg), anlotinib (10 mg) plus paclitaxel (135 mg/m2)/cisplatin (60–75 mg/m2), then maintained with benmelstobart and anlotinib. Primary endpoint was progression-free survival (PFS) assessed according to RECIST v1.1. Secondary endpoints were tumor response, overall survival (OS), and safety assessed by adverse events (AEs).

符合条件的患者接受4-6个周期（21天）的benmelstobart（1200 mg），安洛替尼（10 mg）加紫杉醇（135 mg/m2）/顺铂（60-75 mg/m2），然后维持使用benmelstobart和安洛替尼。主要终点是根据RECIST v1.1评估的无进展生存期（PFS）。次要终点是肿瘤反应，总生存期（OS）和不良事件（AE）评估的安全性。

From September 2021 to November 2023, 50 patients were enrolled and received study treatment. With median follow-up of 23.7 months as of April 1, 2024, median PFS was 14.9 months (95% CI, 11.4-not estimable [NE]) and the 1-year PFS was 58.5% (95% CI, 41.9%–71.9%). Among 50 patients, confirmed objective response rate was 72.0% and disease control rate was 84.0%.

从2021年9月至2023年11月，招募了50名患者并接受了研究治疗。截至2024年4月1日，中位随访时间为23.7个月，中位PFS为14.9个月（95%CI，11.4-不可估计[NE]），1年PFS为58.5%（95%CI，41.9%–71.9%）。50例患者中，确诊客观缓解率为72.0%，疾病控制率为84.0%。

Median duration of response of 36 responders was 16.2 months (95% CI, 10.2-NE). At the cutoff date, 31 patients remained alive; median OS was not reached (95% CI, 13.2 months-NE) with 1-year OS of 74.8% (95% CI, 59.8%–84.8%). Forty-six (92.0%) patients reported treatment-related AEs, with 37 (74.0%) were grade ≥3.

36名应答者的中位应答持续时间为16.2个月（95%CI，10.2-NE）。在截止日期，31名患者仍然活着；中位OS未达到（95%CI，13.2个月NE），1年OS为74.8%（95%CI，59.8%–84.8%）。46例（92.0%）患者报告了与治疗相关的AE，其中37例（74.0%）为≥3级。

Overall, benmelstobart plus anlotinib and chemotherapy showed promising efficacy and acceptable toxicity in advanced or metastatic/recurrent ESCC..

总体而言，benmelstobart加安洛替尼和化疗在晚期或转移性/复发性ESCC中显示出有希望的疗效和可接受的毒性。。

IntroductionEsophageal squamous cell carcinoma (ESCC) accounts for approximately 90% of esophageal cancer and is particularly prevalent in Central to East Asia.1 Unfortunately, due to its highly aggressive behavior and the lack of early symptoms, most ESCC cases are advanced stage at diagnosis.2,3 Combination chemotherapy currently remains the standard first-line strategy for advanced ESCC, but with dismal survival.4With the revolution of immuno-oncology therapies, several pivotal trials, such as CheckMate 648, KEYNOTE-590, and JUPITER-06,5,6,7 have established immunochemotherapy as the new standard for first-line treatment of this disease.

引言食管鳞状细胞癌（ESCC）约占食管癌的90%，在中亚至东亚地区尤为普遍[1]。不幸的是，由于其高度侵袭性行为和缺乏早期症状，大多数ESCC病例在诊断时处于晚期[2,3]。联合化疗目前仍然是晚期ESCC的标准一线策略，但生存率很低[4]。随着免疫肿瘤学治疗的革命，一些关键试验，如CheckMate 648，KEYNOTE-590和JUPITER-06,5,6,7已经将免疫化疗确立为该病一线治疗的新标准。

Nevertheless, such combinations only provided limited clinical benefits, demonstrating overall survival (OS) ranging from 12 to 17 months.5,6,7 Notably, immunochemotherapy mainly benefits a subset of PD-L1-positive ESCC patients,5,8 potentially because of the immune evasion caused by vascular abnormalities.9Given the highly angiogenic nature of ESCC and the synergistic effects of immunotherapy and antiangiogenic agents,10,11 numerous efforts are going to address the above issues with combination strategies.

然而，这种组合只能提供有限的临床益处，显示总生存期（OS）为12至17个月[5,6,7]。值得注意的是，免疫化疗主要有益于PD-L1阳性ESCC患者的一部分，5,8可能是由于血管异常引起的免疫逃避[9]。鉴于ESCC的高度血管生成性质以及免疫治疗和抗血管生成药物的协同作用，10,11许多努力将通过组合策略来解决上述问题。

Current efforts mainly put the focus on PD-1 inhibitors-based triple regimens, such as the LEAP-014 trial, which evaluates pembrolizumab combined with lenvatinib and chemotherapy,12 and another phase II study assessing PD-1 blockades combined with anlotinib.13 However, the definitive benefits of these combinations have yet to be fully established, pending results from ongoing trials.

目前的努力主要集中在基于PD-1抑制剂的三联疗法上，例如LEAP-014试验，该试验评估了pembrolizumab联合lenvatinib和化疗[12]，以及另一项评估PD-1阻断联合安洛替尼的II期研究[13]。然而，这些组合的明确益处尚未完全确定，尚待正在进行的试验结果。

In the realm of PD-L1 inhibitors, only the ALTER-E003 study has reported preliminary response data for first-line treatment with benmelstobart plus anlotinib.14 Notably, anti-PD-L1-based triple regimens, particularly involving multitargeted tyrosine k.

在PD-L1抑制剂领域，只有ALTER-E003研究报道了苯美司他加阿洛替尼一线治疗的初步反应数据.14值得注意的是，基于抗PD-L1的三联方案，特别是涉及多靶点酪氨酸k。

Data availability

数据可用性

Datasets analyzed in this study are available upon reasonable request to the corresponding author.

本研究中分析的数据集可根据通讯作者的合理要求提供。

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Download referencesAcknowledgementsWe thank all patients, their families, investigators, and research staffs. We thank Chia Tai Tianqing Pharmaceutical Group Co., Ltd. for providing study drugs.FundingHenan Province Health Science and Technology Innovation Young and Middle-Aged Leader Project (YXKC2021008).Author informationAuthor notesThese authors contributed equally: Ning Li, Jin Xia, Xiaohui GaoAuthors and AffiliationsDepartment of Gastrointestinal Oncology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, ChinaNing Li & Suxia LuoDepartment of Medical Oncology, Anyang Tumor Hospital & The Affiliated Anyang Tumor Hospital of Henan University of Science and Technology, Anyang, Henan, ChinaJin Xia, Yonggui Hong, Donghai Cui, Tao Wu & Junsheng WangDepartment of Respiratory Oncology, The First Affiliated Hospital of Henan University of Science and Technology, Luoyang, Henan, ChinaXiaohui Gao & Yanzhen GuoDepartment of Oncology, Henan Provincial People’s Hospital, Zhengzhou, Henan, ChinaJianwei ZhouDepartment of Tumor Radiotherapy, The People’s Hospital of Anyang City, Anyang, Henan, ChinaXuesong ZhaoAuthorsNing LiView author publicationsYou can also search for this author in.

下载参考文献致谢我们感谢所有患者，他们的家人，研究人员和研究人员。我们感谢正大天青药业集团有限公司提供研究药物。。作者信息作者注意到，这些作者做出了同样的贡献：李宁，金霞，高晓辉作者和附属机构郑州大学附属肿瘤医院和河南省肿瘤医院胃肠肿瘤科，中国郑州李宁和苏霞罗医学肿瘤科，安阳肿瘤医院和河南科技大学附属安阳肿瘤医院，河南安阳，中国金霞，洪永贵，崔东海，陶武和王俊生河南科技大学附属第一医院呼吸肿瘤科，河南洛阳，中国高晓辉和郭燕珍河南省人民医院肿瘤科，河南郑州中国河南省安阳市安阳市人民医院肿瘤放疗科赵雪松作者Ning LiView作者出版物您也可以在中搜索该作者。

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PubMed Google ScholarContributionsConceptualization: N.L., J.X., X.G., Y.G., J.W., and S.L.; Methodology: N.L., Y.G., J.W., and S.L.; Data curation: N.L., J.X., X.G., J.Z., Y.H., D.C., X.Z., T.W., J.W., and S.L.; Formal analysis: N.L., J.X., X.G., J.Z., Y.G., J.W., and S.L.; Funding acquisition: N.L.; Writing-original draft: N.L.

PubMed谷歌学术贡献概念：N.L.，J.X.，X.G.，Y.G.，J.W。和S.L。；方法学：N.L.，Y.G.，J.W。和S.L。；数据管理：N.L.，J.X.，X.G.，J.Z.，Y.H.，D.C.，X.Z.，T.W.，J.W。和S.L。；形式分析：N.L.，J.X.，X.G.，J.Z.，Y.G.，J.W。和S.L。；资金获取：N.L。；撰写原稿：N.L。

and J.X.; Writing-review: X.G.; Writing-review and editing: N.L. Y.G., J.W., and S.L.; All authors have read and approved the article.Corresponding authorsCorrespondence to.

和J.X。；写作评论：X.G。；写作评论和编辑：N.L.Y.G.，J.W。和S.L。；所有作者都阅读并批准了这篇文章。通讯作者通讯。

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Reprints and permissionsAbout this articleCite this articleLi, N., Xia, J., Gao, X. et al. First-line benmelstobart plus anlotinib and chemotherapy in advanced or metastatic/recurrent esophageal squamous cell carcinoma: a multi-center phase 2 study.

转载和许可本文引用本文Li，N.，Xia，J.，Gao，X。等人。一线benmelstobart加安洛替尼和化疗治疗晚期或转移性/复发性食管鳞状细胞癌：多中心2期研究。

Sig Transduct Target Ther 9, 303 (2024). https://doi.org/10.1038/s41392-024-02008-7Download citationReceived: 03 June 2024Revised: 10 September 2024Accepted: 04 October 2024Published: 08 November 2024DOI: https://doi.org/10.1038/s41392-024-02008-7Share this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

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