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新辅助卡雷珠单抗（一种抗PD-1抗体）联合化疗或阿帕替尼（一种VEGFR-2抑制剂）治疗最初不可切除的II–III期非小细胞肺癌癌症：一项多中心、两臂、2期探索性研究

Neoadjuvant camrelizumab (an anti-PD-1 antibody) plus chemotherapy or apatinib (a VEGFR-2 inhibitor) for initially unresectable stage II–III non-small-cell lung cancer: a multicentre, two-arm, phase 2 exploratory study

Nature 等信源发布 2024-06-14 07:13

可切换为仅中文

AbstractThis multicentre, two-arm, phase 2 study aimed to explore the efficacy and safety of neoadjuvant camrelizumab plus chemotherapy or apatinib in patients with initially unresectable stage II–III non-small-cell lung cancer (NSCLC). Eligible patients regardless of PD-L1 expression received neoadjuvant camrelizumab 200 mg and platinum-doublet chemotherapy every 3 weeks (arm A) or those with PD-L1-positive tumors received neoadjuvant camrelizumab and apatinib 250 mg once daily (arm B), for 2–4 cycles, followed by surgery.

摘要这项多中心，双臂，2期研究旨在探讨新辅助卡美利珠单抗联合化疗或阿帕替尼治疗最初不可切除的II-III期非小细胞肺癌（NSCLC）患者的疗效和安全性。无论PD-L1表达如何，符合条件的患者每3周接受一次新辅助卡美利珠单抗200 mg和铂双联化疗（A组），或PD-L1阳性肿瘤患者每天一次接受新辅助卡美利珠单抗和阿帕替尼250 mg（B组），持续2-4个周期，然后进行手术。

The primary endpoint was major pathological response (MPR) rate. Thirty patients in arm A and 21 in arm B were enrolled. Surgery rates were 50.0% (15/30) in arm A and 42.9% (9/21) in arm B, with all patients achieving R0 resections. Of these patients, the MPR and pathological complete response rates were both 20.0% (95% CI 4.3–48.1) in arm A and were 55.6% (95% CI 21.2–86.3) and 11.1% (95% CI 0.3–48.2) in arm B, respectively.

主要终点是主要病理反应（MPR）率。招募了A组30名患者和B组21名患者。A组手术率为50.0%（15/30），B组手术率为42.9%（9/21），所有患者均实现R0切除。在这些患者中，A组的MPR和病理完全缓解率均为20.0%（95%CI 4.3-48.1），B组分别为55.6%（95%CI 21.2-86.3）和11.1%（95%CI 0.3-48.2）。

The corresponding objective response rates were 33.3% (95% CI 11.8–61.6) and 55.6% (95% CI 21.2–86.3). With a median follow-up of 22.4 months (95% CI 19.0–26.0), the median event-free survival was not reached (NR; 95% CI 13.6-NR) in arm A and 16.8 months (95% CI 8.6-NR) in arm B. Grade 3 or above treatment-related adverse events occurred in eight (26.7%) patients in arm A and three (14.3%) in arm B.

相应的客观缓解率分别为33.3%（95%CI 11.8-61.6）和55.6%（95%CI 21.2-86.3）。中位随访22.4个月（95%CI 19.0-26.0），a组未达到中位无事件生存期（NR；95%CI 13.6-NR），B组未达到16.8个月（95%CI 8.6-NR）。a组8例（26.7%）和B组3例（14.3%）发生3级或以上治疗相关不良事件。

Biomarker analysis showed baseline TYROBP expression was predictive of treatment response in arm B. Neoadjuvant camrelizumab plus chemotherapy or apatinib exhibits preliminary efficacy and manageable toxicity in patients with initially unresectable stage II–III NSCLC..

生物标志物分析显示，基线TYROBP表达可预测B组的治疗反应。新辅助卡美利珠单抗联合化疗或阿帕替尼对最初不可切除的II-III期NSCLC患者表现出初步疗效和可控的毒性。。

IntroductionLung cancer is the second most common malignancy and the leading cause of cancer-related death, with approximately 2.2 million new incidences and 1.8 million deaths worldwide in 2020.1 In China, it is estimated that lung cancer continues to be the most prevalent malignant disease with the highest incidence (1.06 million cases) and mortality (0.73 million deaths) in 2022 according to the latest statistics from the National Cancer Center of China.2 Non-small-cell lung cancer (NSCLC), which is the predominant pathological subtype of lung cancer, constitutes 85 to 90% of all cases.3 Nearly half of patients are initially diagnosed with early-stage, localized or regional NSCLC, which can be further classified as resectable, potentially resectable or initially unresectable disease according to the status of the tumor and lymph nodes.4,5 For these three disease classifications, treatment options vary.Over the last decade, immunotherapy with anti-programmed cell death-(ligand) 1 (PD-[L]1) antibodies have made breakthroughs and changed the comprehensive therapeutic paradigm for advanced driver-negative NSCLC.

引言肺癌是第二大常见恶性肿瘤，也是癌症相关死亡的主要原因，2020年全球新增发病率约为220万，死亡人数约为180万。1根据中国国家癌症中心的最新统计数据，估计肺癌仍然是最常见的恶性疾病，2022年发病率（106万例）和死亡率（73万例死亡）最高。2非小细胞肺癌（NSCLC）是肺癌的主要病理亚型，占所有病例的85%至90%。3近一半的患者最初被诊断为早期，局部或区域性非小细胞肺癌，可以进一步分类根据肿瘤和淋巴结的状态，可切除，潜在可切除或最初不可切除的疾病[4,5]。对于这三种疾病分类，治疗选择各不相同。在过去的十年中，抗程序性细胞死亡-（配体）1（PD-[L]1）抗体的免疫治疗取得了突破，改变了晚期驱动阴性非小细胞肺癌的综合治疗模式。

Given the outstanding efficacy of immunotherapy in advanced disease and the association between high tumor burden and limited antigenic heterogeneity with improved efficacy of anti-PD-(L)1 antibodies, which indicates an optimal timing for immunotherapy possibly in the neoadjuvant setting,6 immunotherapy-based neoadjuvant strategies have been investigated in resectable or potentially resectable NSCLC.

鉴于免疫治疗在晚期疾病中的突出疗效以及高肿瘤负荷和有限的抗原异质性与抗PD-（L）1抗体的改善功效之间的关联，这表明可能在新辅助治疗中进行免疫治疗的最佳时机，已经在可切除或潜在可切除的NSCLC中研究了6种基于免疫治疗的新辅助策略。

Three randomized phase 3 trials evaluated the anti-PD-1 antibodies nivolumab (CheckMate 816),7 pembrolizumab (KEYNOTE-671)8 and toripalimab (Neotorch)9 and a fourth trial evaluated the anti-PD-L1 antibody durvalumab (AEGEAN)10 in combination with chemotherapy as neoa.

三项随机3期试验评估了抗PD-1抗体nivolumab（CheckMate 816），7 pembrolizumab（KEYNOTE-671）8和toripalimab（Neotorch）9，第四项试验评估了抗PD-L1抗体durvalumab（爱琴海）10与化疗联合作为neoa。

Data availability

数据可用性

We deposited the RNA-seq data in the Genome Sequence Archive database under accession number HRA005439. Only open-source software was used for this study, and no custom codes were generated for RNA-seq analysis. Deidentified individual data are available from the corresponding author on reasonable request..

我们将RNA-seq数据保存在基因组序列档案数据库中，登录号为HRA005439。这项研究仅使用开源软件，并且没有为RNA-seq分析生成自定义代码。通讯作者可根据合理要求提供身份不明的个人数据。。

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Download referencesAcknowledgementsThe study was supported by the National Natural Science Foundation of China (No. 82125001), the Innovation Program of Shanghai Municipal Education Commission (No. 2023ZKZD33), the Foundation of Shanghai Pulmonary Hospital (No. FKLY20004 and FKCX2304), the Beijing XiSiKe Clinical Oncology Research Foundation (No.

下载参考文献致谢本研究得到了国家自然科学基金（No.82125001），上海市教委创新计划（No.2023ZKZD33），上海市肺科医院基金（No.FKLY20004和FKCX2304），北京西斯克临床肿瘤研究基金（No。

Y-HR2019-0451), and Jiangsu Hengrui Pharmaceuticals Co., Ltd. We thank all the participants who made the study possible. We also thank Xiaojie Luo (a medical manager at Jiangsu Hengrui Pharmaceuticals Co., Ltd) for her input in data collection, Fengzhuo Cheng (a statistician at Hengrui) for his input in statistical analyses, and Yanhua Xu (a medical writer at Hengrui) for her input in medical writing assistance according to Good Publication Practice Guidelines.Author informationAuthor notesThese authors contributed equally: Haoran Xia, Han Zhang, Zheng Ruan, Huibiao Zhang, Liangdong SunAuthors and AffiliationsDepartment of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, ChinaHaoran Xia, Han Zhang, Liangdong Sun, Dongliang Bian, Xinsheng Zhu, Jing Zhang, Fenghuan Sun, Nan Song, Xiaogang Liu, Yuming Zhu, Wenxin He, Jian Chen, Jie Yang, Liang Duan, Deping Zhao, Peng Zhang & Gening JiangDepartment of Thoracic Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaZheng Ruan & Xiaomiao ZhangDepartment of Thoracic Surgery, Huadong Hospital Affiliated to Fudan University, Shanghai, ChinaHuibiao Zhang & Dongfang TangDepartment of Thoracic Surgery, Changhai Hospital, Naval Medical University, Shanghai, ChinaHezhong ChenDepartment of Thoracic-Cardiovascular Surgery, Tongji Hospital, Tongji University School of Medicine, Shanghai, .

Y-HR2019-0451）和江苏恒瑞制药有限公司。我们感谢所有使研究成为可能的参与者。我们还要感谢罗晓洁（江苏恒瑞制药有限公司的医疗经理）在数据收集方面的投入，感谢程凤卓（恒瑞的统计学家）在统计分析方面的投入，感谢徐燕华（恒瑞的医学作家）根据良好出版规范指南在医学写作协助方面的投入。作者信息作者注意到，这些作者做出了同样的贡献：夏浩然，张汉，郑阮，张惠彪，孙良东作者和附属机构上海同济大学医学院上海肺科医院胸外科，中国夏浩然，张汉，孙良东，孙东良边，朱新生，张静，孙凤欢，南松，刘晓刚，朱玉明，何文新，陈健，杨杰，梁端，赵德平，张鹏和江根宁上海交通大学医学院上海总医院胸外科，上海郑阮和张晓淼华东医院胸外科中国上海复旦大学附属上海海军医科大学长海医院胸外科张惠彪和唐东方，中国陈和忠同济大学医学院同济医院胸心血管外科，上海。

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PubMed Google ScholarContributionsLian Duan, Deping Zhao, Qinchuan Li, Peng Zhang, and Gening Jiang contributed to the conception and design of the study. Haoran Xia, Zheng Ruan, Huibiao Zhang, Qinchuan Li, Hezhong Chen, Yongxin Zhou, Liang Duan, Deping Zhao, Lele Zhang, Dongliang Bian, Yuming Zhu, Jing Zhang, Fenghuan Sun, Huansha Yu, Nan Song, Xiaogang Liu, Xinsheng Zhu, Haiping Zhang, Wenxin He, Jian Chen, Jie Yang, Guohan Chen, Shiliang Xie, Dongfang Tang and Xiaomiao Zhang collected and interpreted data.

PubMed谷歌学术贡献段连斌，赵德平，李秦川，张鹏和江根宁为这项研究的概念和设计做出了贡献。夏浩然、郑阮、张惠彪、李秦川、陈和忠、周永新、梁端、赵德平、张乐乐、董良边、朱玉明、张静、孙凤焕、余欢沙、南宋、刘晓刚、朱新生、张海平、何文欣、陈健、杨洁、陈国汉、谢世良、东方堂和张晓淼收集并解释了数据。

Haoran Xia, Han Zhang, and Liangdong Sun performed statistical analysis. Haoran Xia, Han Zhang, Zheng Ruan, Huibiao Zhang, and Liangdong Sun drafted the manuscript; All authors revised the manuscript. Lian Duan, Deping Zhao, Qinchuan Li, Peng Zhang, and Gening Jiang had full access to the data in the study and final responsibility for the decision to submit for publication.

夏浩然，张汉和孙良东进行了统计分析。夏浩然，张汉，郑阮，张惠标和孙良东起草了手稿；所有作者都修改了手稿。连端，赵德平，李秦川，张鹏和江根宁可以完全访问研究中的数据，并对提交出版的决定承担最终责任。

All authors have read and approved the final version.Corresponding authorsCorrespondence to.

所有作者都阅读并批准了最终版本。通讯作者通讯。

Deping Zhao, Qinchuan Li, Peng Zhang or Gening Jiang.Ethics declarations

赵德平、李秦川、张鹏或江根宁。道德宣言

Competing interests

相互竞争的利益

The authors declare no competing interests.

作者声明没有利益冲突。

Supplementary informationSupplementary MaterialsSupplementary Information for Resectability Before and After Neoadjuvant TherapyProtocolRights and permissions

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Reprints and permissionsAbout this articleCite this articleXia, H., Zhang, H., Ruan, Z. et al. Neoadjuvant camrelizumab (an anti-PD-1 antibody) plus chemotherapy or apatinib (a VEGFR-2 inhibitor) for initially unresectable stage II–III non-small-cell lung cancer: a multicentre, two-arm, phase 2 exploratory study..

转载和许可本文引用本文Xia，H.，Zhang，H.，Ruan，Z。等人。新辅助卡美利珠单抗（一种抗PD-1抗体）加化疗或阿帕替尼（一种VEGFR-2抑制剂）治疗最初不可切除的II-III期非小细胞肺癌：一项多中心，双臂，2期探索性研究。。

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临床试验肺癌