AbstractThe effect of immune‐based therapies on patients with epidermal growth factor receptor (EGFR)-positive advanced non-small cell lung cancer (NSCLC) resistant to EGFR tyrosine kinase inhibitor (TKI) therapy remains unclear. The ALTER-L038 study aimed to evaluate efficacy and safety of a chemotherapy-free combination of benmelstobart, an anti-programmed cell death ligand 1 antibody, and anlotinib, a small-molecule multi-target anti-angiogenic TKI, in EGFR-positive advanced NSCLC patients who progressed after EGFR TKI therapy.

摘要基于免疫的治疗对EGFR酪氨酸激酶抑制剂（TKI）治疗耐药的表皮生长因子受体（EGFR）阳性晚期非小细胞肺癌（NSCLC）患者的影响尚不清楚。ALTER-L038研究旨在评估抗程序性细胞死亡配体1抗体benmelstobart和小分子多靶点抗血管生成TKI安洛替尼无化疗联合治疗EGFR阳性晚期NSCLC患者的疗效和安全性。EGFR TKI治疗后进展。

Patients were enrolled in a phase I/II study. In phase I (dose-escalation), patients received anlotinib (8, 10, 12 mg) plus benmelstobart (1200 mg). Recommended phase II dose, determined during phase I, was used in phase II dose-expansion cohort. Primary endpoints were maximum tolerable dose in phase I and progression-free survival (PFS) in phase II.

患者参加了I/II期研究。在I期（剂量递增），患者接受阿洛替尼（8,10,12mg）加benmelstobart（1200mg）。在I期确定的推荐II期剂量用于II期剂量扩展队列。主要终点是I期的最大耐受剂量和II期的无进展生存期（PFS）。

At the data cutoff date (March 10, 2024), 55 patients were enrolled in phase II dose-expansion cohort. Median PFS of patients included in phase II cohort was 9.0 months, median overall survival was 28.9 months, objective response rate was 25.5%, disease control rate was 87.3%, and median duration of response was 19.8 months.

在数据截止日期（2024年3月10日），55名患者被纳入II期剂量扩展队列。II期队列患者的中位PFS为9.0个月，中位总生存期为28.9个月，客观缓解率为25.5%，疾病控制率为87.3%，中位缓解时间为19.8个月。

Incidence of grade ≥3 treatment-related adverse events in study population was 25.5% (14/55), whereas grade ≥3 immune-related adverse events occurred in 10.9% (6/55) of patients. Benmelstobart plus anlotinib showed promising anti-tumor efficacy with tolerable safety profile, supporting the value of further development of this convenient chemotherapy-free regimen for patients with EGFR-positive advanced NSCLC who progressed after EGFR TKI therapy.

研究人群中≥3级治疗相关不良事件的发生率为25.5%（14/55），而≥3级免疫相关不良事件发生率为10.9%（6/55）。Benmelstobart加安洛替尼显示出良好的抗肿瘤疗效和可耐受的安全性，支持进一步开发这种方便的无化疗方案对于EGFR阳性晚期NSCLC患者在EGFR TKI治疗后进展的价值。

Trial Registration: ChiCTR1900026273..

试用注册：ChiCTR1900026273。。

IntroductionA high epidermal growth factor receptor (EGFR) mutation rate of 51.4% has been reported in Asian patients with advanced non-small cell lung cancer (NSCLC).1 Platinum-based chemotherapy with or without bevacizumab has become the standard treatment for patients with EGFR-positive advanced NSCLC resistant to EGFR tyrosine kinase inhibitors (TKIs).2,3 Previous studies have shown the preliminary efficacy of immunochemotherapy with or without bevacizumab in this population.3 Considering the high toxicity and poor treatment compliance of chemotherapy, there remains an unmet clinical need for a safer, more convenient, and comparably effective chemotherapy-free regimen for patients with NSCLC after TKIs resistance.4A phase I study on a first-line chemotherapy-free regimen (sintilimab plus anlotinib) presented at the 2019 World Conference on Lung Cancer showed anti-tumor efficacy (objective response rate [ORR], 77.3%; 6-month progression-free survival [PFS], 93.8%),5,6 indicating the synergy of immunotherapy and anti-angiogenic therapy in patients with EGFR-negative advanced NSCLC.7 The median PFS (mPFS) of 15 months observed in the updated analysis supports the value of this chemotherapy-free regimen as a potential treatment option,6 comparable to that of immunochemotherapy (mPFS, 6–8 months).8,9,10,11 Inspired by the regimen of immune checkpoint inhibitors (ICIs) and anti-angiogenic agents, we designed a chemotherapy-free combination therapy for patients with EGFR-positive advanced NSCLC.Benmelstobart (also known as TQ-B2450), a novel humanized anti-programmed cell death ligand 1 (PD-L1) antibody, has shown preliminary efficacy in patients with advanced solid tumors, including NSCLC (ORR, 32.8%; disease control rate [DCR], 81.8%).12 Anlotinib, an oral multi-target T.

引言据报道，亚洲晚期非小细胞肺癌（NSCLC）患者的表皮生长因子受体（EGFR）突变率高达51.4%。1含或不含贝伐单抗的铂类化疗已成为EGFR阳性晚期NSCLC患者对EGFR酪氨酸激酶抑制剂（TKIs）耐药的标准治疗方法[2,3]。先前的研究表明，在该人群中，含或不含贝伐单抗的免疫化疗的初步疗效[3]。考虑到化疗的高毒性和较差的治疗依从性，对于TKIs耐药后的NSCLC患者，仍然需要更安全，更方便，相对有效的无化疗方案2019年世界肺癌会议上提出的一线无化疗方案（辛迪单抗加阿洛替尼）显示出抗肿瘤疗效（客观缓解率[ORR]，77.3%；6个月无进展生存率[PFS]，93.8%），5,6表明EGFR阴性晚期NSCLC患者的免疫治疗和抗血管生成治疗具有协同作用[7]。在最新分析中观察到的15个月的中位PFS（mPFS）支持这种无化疗方案作为潜在治疗选择的价值，6与免疫化疗（mPFS，6-8个月）相当[8,9,10,11]。受免疫检查点抑制剂（ICIs）和抗血管生成药物方案的启发，我们为EGFR阳性晚期NSCLC患者设计了无化疗联合治疗。Benmelstobart（也称为TQ-B2450）是一种新型人源化抗程序性细胞死亡配体1（PD-L1）抗体，已在包括NSCLC在内的晚期实体瘤患者中显示出初步疗效（ORR，32.8%；疾病控制率[DCR]，81.8%）。12安洛替尼是一种口服多靶点T。

Data availability

数据可用性

The datasets used and/or analyzed in the current study are available from the corresponding author upon reasonable request.

本研究中使用和/或分析的数据集可根据合理要求从通讯作者处获得。

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Download referencesAcknowledgementsThis study was funded by the Chia Tai Tianqing Pharmaceutical Group Co., Ltd., Jiangsu, China. We would like to express our sincere gratitude to all the patients and their families who participated in this trial, as well as to all the research personnel and site staff who were involved in this work.

下载参考文献致谢本研究由中国江苏正大天青制药集团有限公司资助。我们要衷心感谢所有参与这项试验的患者及其家属，以及所有参与这项工作的研究人员和现场工作人员。

Funding: Not applicable.Author informationAuthors and AffiliationsDepartment of Medical Oncology, Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research and The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, ChinaMeiqi Shi & Li WangDepartment of Oncology, Yancheng NO.1 People’s Hospital, Yancheng, ChinaPing ChenDepartment of Oncology, Ji’nan Zhangqiu District People’s Hospital, Zhangqiu, ChinaBin CuiDepartment of Radiotherapy, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, ChinaYuanhu YaoDepartment of Oncology, Hanzhong 3201 Hospital, Hanzhou, ChinaJuanyi WangDepartment of Oncology, Changzhou Cancer Hospital, Changzhou, ChinaTong ZhouAuthorsMeiqi ShiView author publicationsYou can also search for this author in.

资金：不适用。作者信息作者和附属机构江苏省肿瘤医院和江苏省肿瘤研究所肿瘤内科南京医科大学附属肿瘤医院南京市梅奇石和李旺中国盐城市第一人民医院肿瘤科陈平中国章丘市济南章丘区人民医院肿瘤科崔斌徐州徐州医科大学附属医院放射治疗科姚元虎汉中3201医院肿瘤科王娟怡中国常州市常州肿瘤医院肿瘤科作者梅奇希维作者出版物您也可以在中搜索此作者。

PubMed Google ScholarPing ChenView author publicationsYou can also search for this author in

PubMed Google ScholarPing ChenView作者出版物您也可以在

PubMed Google ScholarBin CuiView author publicationsYou can also search for this author in

PubMed谷歌学术评论作者出版物您也可以在

PubMed Google ScholarYuanhu YaoView author publicationsYou can also search for this author in

PubMed Google ScholarYuanhu YaoView作者出版物您也可以在

PubMed Google ScholarJuanyi WangView author publicationsYou can also search for this author in

PubMed Google ScholarJuanyi WangView作者出版物您也可以在

PubMed Google ScholarTong ZhouView author publicationsYou can also search for this author in

PubMed Google ScholarTong ZhouView作者出版物您也可以在

PubMed Google ScholarLi WangView author publicationsYou can also search for this author in

PubMed Google ScholarLi WangView作者出版物您也可以在

PubMed Google ScholarContributionsConception and design: Meiqi Shi; Provision of study materials or patients: All authors; Collection and assembly of data: All authors; Data analysis and interpretation: Meiqi Shi; Manuscript writing: All authors; All authors have read and approved the article.Corresponding authorCorrespondence to.

PubMed谷歌学术贡献概念与设计：Meiqi Shi；提供研究材料或患者：所有作者；数据的收集和汇编：所有作者；数据分析和解释：Meiqi Shi；手稿写作：所有作者；所有作者都阅读并批准了这篇文章。对应作者对应。

Meiqi Shi.Ethics declarations

梅奇石。道德宣言

Competing interests

相互竞争的利益

This study was funded by the Chia Tai Tianqing Pharmaceutical Group Co., Ltd., Jiangsu, China. The authors declare no competing interests.

这项研究由中国江苏正大天青制药集团有限公司资助。作者声明没有利益冲突。

Ethical approval

道德认可

The study protocol was reviewed and approved by the Ethics Committee of Jiangsu Cancer Hospital (approval no.: 2019 [053]). Written informed consent was obtained from all patients before enrolment.

该研究方案经江苏省肿瘤医院伦理委员会审查批准（批准号：2019[053]）。入组前已获得所有患者的书面知情同意书。

Supplementary informationSigtrans_Supplementary_MaterialsClinical Study ProtocolRights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made.

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Reprints and permissionsAbout this articleCite this articleShi, M., Chen, P., Cui, B. et al. Benmelstobart plus anlotinib in patients with EGFR-positive advanced NSCLC after failure of EGFR TKIs therapy: a phase I/II study.

转载和许可本文引用本文Shi，M.，Chen，P.，Cui，B。等人Benmelstobart加anlotinib治疗EGFR阳性晚期非小细胞肺癌EGFR TKIs治疗失败后的患者：I/II期研究。

Sig Transduct Target Ther 9, 283 (2024). https://doi.org/10.1038/s41392-024-01982-2Download citationReceived: 25 April 2024Revised: 06 September 2024Accepted: 16 September 2024Published: 10 October 2024DOI: https://doi.org/10.1038/s41392-024-01982-2Share 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.

Sig Transduct Target Ther 9283（2024）。https://doi.org/10.1038/s41392-024-01982-2Download引文收到日期：2024年4月25日修订日期：2024年9月6日接受日期：2024年9月16日发布日期：2024年10月10日OI：https://doi.org/10.1038/s41392-024-01982-2Share本文与您共享以下链接的任何人都可以阅读此内容：获取可共享链接对不起，本文目前没有可共享的链接。复制到剪贴板。

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Subjects

CancerCancer therapy

癌症治疗