AbstractThis phase 2/3 trial (NCT04856787) assessed the efficacy and safety of SHR-1701, a bifunctional protein targeting PD-L1 and TGF-β, in combination with BP102 (a bevacizumab biosimilar) and XELOX (capecitabine plus oxaliplatin) as a first-line treatment for unresectable metastatic colorectal cancer (mCRC).

摘要本2/3期临床试验（NCT04856787）评估了靶向PD-L1和TGF-β的双功能蛋白SHR-1701联合BP102（贝伐单抗生物仿制药）和XELOX（卡培他滨联合奥沙利铂）作为不可切除转移性结直肠癌（mCRC）的一线治疗的有效性和安全性。

In this phase 2 study, a total of 62 patients with untreated, histologically confirmed colorectal adenocarcinoma and no prior systemic therapy for metastatic disease were enrolled. Patients received SHR-1701 (30 mg/kg), bevacizumab (7.5 mg/kg), and oxaliplatin (130 mg/m2) intravenously on day 1, along with oral capecitabine (1 g/m2 twice daily) on days 1–14 of 21-day cycles.

在这项2期研究中，共纳入了62例未经治疗，组织学证实为结直肠腺癌且未接受转移性疾病全身治疗的患者。患者在第1天静脉注射SHR-1701（30 mg/kg），贝伐单抗（7.5 mg/kg）和奥沙利铂（130 mg/m2），并在21天周期的第1-14天口服卡培他滨（1 g/m2，每日两次）。

Up to eight induction cycles were administered, followed by maintenance therapy for responders or those with stable disease. The primary endpoints were safety and objective response rate (ORR) per RECIST v1.1. The combination achieved an ORR of 59.7% and a disease control rate (DCR) of 83.9%. Median progression-free survival (PFS) was 10.3 months (95% CI: 8.3–13.7), with 6- and 12-month PFS rates of 77.2% and 41.3%, respectively.

给予多达八个诱导周期，然后对应答者或疾病稳定者进行维持治疗。主要终点是每个RECIST v1.1的安全性和客观缓解率（ORR）。该组合的ORR为59.7%，疾病控制率（DCR）为83.9%。。

The estimated 12-month overall survival (OS) rate was 67.7%. Grade ≥3 treatment-related adverse events (TRAEs) were reported in 59.7% of patients, with anemia and neutropenia (8.1% each) being the most common. Retrospective DNA sequencing revealed that high tumor mutational burden, neo-antigens, and SBS15 enrichment correlated with better responses.

。59.7%的患者报告了≥3级治疗相关不良事件（TRAEs），其中贫血和中性粒细胞减少症（各8.1%）最常见。回顾性DNA测序显示，高肿瘤突变负荷，新抗原和SBS15富集与更好的反应相关。

Elevated baseline lactate dehydrogenase was linked to shorter PFS. SHR-1701 combined with XELOX and bevacizumab demonstrated a manageable safety profile and potent antitumor activity in unresectable mCRC..

。SHR-1701联合XELOX和贝伐单抗在不可切除的mCRC中表现出可控的安全性和有效的抗肿瘤活性。。

IntroductionMetastatic colorectal cancer (mCRC) continues to pose a significant clinical challenge due to its high mortality rate and limited treatment options. The National Comprehensive Cancer Network (NCCN) guidelines recommend first-line chemotherapy regimens such as FOLFOX (fluorouracil, leucovorin, and oxaliplatin), FOLFIRI (fluorouracil, leucovorin, and irinotecan), and XELOX (capecitabine and oxaliplatin), administered either alone or in combination with targeted therapies like bevacizumab (an anti-VEGF antibody) or cetuximab (an anti-EGFR antibody), which enhance efficacy by targeting specific molecular pathways.1 Despite these therapeutic strategies, the prognosis for patients with mCRC remains poor, with a median overall survival (OS) of approximately 30 months even when receiving first-line chemotherapy.2 This underscores the urgent need for novel treatment approaches to improve patient outcomes.The advent of immunotherapy has revolutionized cancer treatment, offering new avenues for various malignancies, including colorectal cancer.

引言转移性结直肠癌（mCRC）由于其高死亡率和有限的治疗选择，继续构成重大的临床挑战。国家综合癌症网络（NCCN）指南推荐一线化疗方案，如FOLFOX（氟尿嘧啶，亚叶酸钙和奥沙利铂），FOLFIRI（氟尿嘧啶，亚叶酸钙和伊立替康）和XELOX（卡培他滨和奥沙利铂），单独或联合靶向治疗，如贝伐单抗（抗VEGF抗体）或西妥昔单抗（抗EGFR抗体），通过靶向特定分子途径增强疗效。尽管有这些治疗策略，mCRC患者的预后仍然很差，即使接受一线化疗，中位总生存期（OS）约为30个月。2强调迫切需要新的治疗方法来改善患者的预后。免疫疗法的出现彻底改变了癌症治疗，为包括结直肠癌在内的各种恶性肿瘤提供了新的途径。

Immune checkpoint inhibitors (ICIs), such as pembrolizumab and nivolumab, have shown remarkable efficacy in tumors exhibiting high microsatellite instability (MSI-H) or deficient mismatch repair (dMMR) due to their high mutational burden that enhances tumor immunogenicity.3,4 By inhibiting checkpoints such as PD-1/PD-L1 or CTLA-4, ICIs bolster T-cell-mediated immune responses against cancer cells.

免疫检查点抑制剂（ICI），如pembrolizumab和nivolumab，在表现出高微卫星不稳定性（MSI-H）或错配修复缺陷（dMMR）的肿瘤中显示出显着的功效，因为它们具有增强肿瘤免疫原性的高突变负荷。通过抑制PD-1/PD-L1或CTLA-4等检查点，ICI增强了T细胞介导的针对癌细胞的免疫应答。

Consequently, several ICIs have received approval from the U.S. Food and Drug Administration (FDA) for use in both first-line and subsequent treatment for mCRC patients with MSI-H/dMMR status.4 However, MSI-H/dMMR tumors constitute only about 5% of advanced mCRC cases, leaving the majority of patients with proficient mismatch repair (p.

因此，一些ICI已获得美国食品和药物管理局（FDA）的批准，可用于MSI-H/dMMR状态的mCRC患者的一线和后续治疗。然而，MSI-H/dMMR肿瘤仅占晚期mCRC病例的约5%，大多数患者具有熟练的错配修复（p。

Data availability

数据可用性

Deidentified individual participant data underlying the results reported in this article will be made available upon request, starting 24 months after the study’s completion. Researchers interested in accessing the data must submit a proposal to the corresponding author, detailing the purpose and justification for their request.

本文报告的结果所依据的身份不明的个人参与者数据将根据要求提供，从研究完成后24个月开始。有兴趣访问数据的研究人员必须向通讯作者提交一份提案，详细说明其请求的目的和理由。

The leading clinical site and study sponsor will review the proposal to ensure compliance with any applicable intellectual property or confidentiality obligations. Access to the data will require a signed data access agreement with the sponsor. The study protocol is included in the supplementary materials..

领先的临床站点和研究赞助商将审查该提案，以确保遵守任何适用的知识产权或保密义务。访问数据需要与赞助商签署数据访问协议。研究方案包含在补充材料中。。

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Download referencesAcknowledgementsThis study was supported by Jiangsu Hengrui Pharmaceuticals and the following grants: the National Natural Science Foundation of China (NSFC: 82321003, 82173128, 82073377, 81930065), the Natural Science Foundation of Guangdong (2021A1515012439), Guangdong Basic and Applied Basic Research Foundation (2024B1515020120), and the CAMS Innovation Fund for Medical Sciences (CIFMS: 2019-I2M-5-036).

下载参考文献致谢本研究得到了江苏恒瑞制药有限公司和以下基金的支持：国家自然科学基金（NSFC:82321003、82173128、82073377、81930065），广东省自然科学基金（2021A1515012439），广东省基础与应用基础研究基金（2024B151502 0120）和中国医学科学院医学科学创新基金（CIFMS:2019-I2M-5-036）。

Additional funding was provided by the Cancer Innovative Research Program of Sun Yat-sen University Cancer Center (CIRP-SYSUCC-0004). We extend our sincere gratitude to all patients and their families, as well as to the members of the collaborative team involved in this trial. Editorial support was provided by Lin Dong, PhD (medical writer at Jiangsu Hengrui Pharmaceuticals), in compliance with Good Publication Practice Guidelines.Author informationAuthors and AffiliationsDepartment of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University, Guangzhou, PR ChinaMiao-Zhen Qiu, Yu-kun Chen, Rui-Hua Xu & Hui-Yan LuoResearch Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou, PR ChinaMiao-Zhen Qiu, Yu-kun Chen, Rui-Hua Xu & Hui-Yan LuoDepartment of Gastroenterology 1, Harbin Medical University Cancer Hospital, Harbin, PR ChinaYuxian BaiDepartment of Medical Oncology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, PR ChinaJufeng WangOncology Ward 1, The First Affiliated Hospital of Anhui Medical University, Hefei, PR ChinaKangsheng GuGastroenterology Ward (2), Shanxi Provincial Cancer Hospital, Taiyuan,.

中山大学癌症中心癌症创新研究计划（CIRP-SYSUCC-0004）提供了额外的资金。我们衷心感谢所有患者及其家属，以及参与本试验的合作团队成员。编辑支持由Lin Dong博士（江苏恒瑞制药的医学作家）提供，符合良好出版实践指南。作者信息作者和附属机构中山大学肿瘤中心肿瘤内科，华南肿瘤学国家重点实验室，广东省肿瘤临床研究中心，中山大学，广州，中华人民共和国缪振秋，陈玉坤，徐瑞华和许惠燕研究中国医学科学院广州市胃肠道癌症精确诊断与治疗研究室缪振秋，陈玉坤，徐瑞华和许惠燕罗哈尔滨医科大学肿瘤医院消化内科1，中华人民共和国盂县白医学肿瘤科，郑州大学附属肿瘤医院和河南省肿瘤医院，郑州市巨峰王肿瘤病区1，安徽医科大学第一附属医院，合肥，中国康生胃肠病区（2），山西省肿瘤医院，太原，。

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PubMed Google ScholarContributionsConception and design: R.X., H.L., M.Q., Y.J., and C.H.; Provision of study materials or patients: RX, HL, MQ, YB, JW, KG, MY, YH, CY, YJ, BL, FW; Collection and assembly of data: R.X., M.Q., H.L., Y.B., J.W., K.G., M.Y., Y.H., C.Y., Y.J., B.L., F.W., Y.C.; Statistical analysis: W.D.; Data interpretation: all authors; Data verification: R.X., M.Q., H.L., Y.J., and C.H.

PubMed谷歌学术贡献概念和设计：R.X.，H.L.，M.Q.，Y.J。和C.H。；提供研究材料或患者：RX，HL，MQ，YB，JW，KG，MY，YH，CY，YJ，BL，FW；数据的收集和组装：R.X.，M.Q.，H.L.，Y.B.，J.W.，K.G.，M.Y.，Y.H.，C.Y.，Y.J.，B.L.，F.W.，Y.C。；统计分析：W.D。；数据解释：所有作者；数据验证：R.X.，M.Q.，H.L.，Y.J。和C.H。

Manuscript writing and revision: All authors. All authors have read and approved the article.Corresponding authorsCorrespondence to.

稿件撰写和修订：所有作者。所有作者都阅读并批准了这篇文章。通讯作者通讯。

Miao-Zhen Qiu, Rui-Hua Xu or Hui-Yan Luo.Ethics declarations

缪振秋、徐瑞华或罗慧艳。道德宣言

Competing interests

相互竞争的利益

W.D., Y.J., and C.H. are employees of Jiangsu Hengrui Pharmaceuticals. The remaining authors declare no conflicts of interest.

W、 D.，Y.J.和C.H.是江苏恒瑞制药的员工。其余作者声明没有利益冲突。

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Reprints and permissionsAbout this articleCite this articleQiu, MZ., Bai, Y., Wang, J. et al. Addition of SHR-1701 to first-line capecitabine and oxaliplatin (XELOX) plus bevacizumab for unresectable metastatic colorectal cancer.

转载和许可本文引用本文Qiu，MZ.，Bai，Y.，Wang，J。等人将SHR-1701添加到一线卡培他滨和奥沙利铂（XELOX）加贝伐单抗治疗不可切除的转移性结直肠癌。

Sig Transduct Target Ther 9, 349 (2024). https://doi.org/10.1038/s41392-024-02063-0Download citationReceived: 18 April 2024Revised: 11 November 2024Accepted: 13 November 2024Published: 16 December 2024DOI: https://doi.org/10.1038/s41392-024-02063-0Share 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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胃肠道肿瘤免疫学