AbstractAdvanced biliary tract cancer (BTC) and pancreatic ductal adenocarcinoma (PDAC) have poor prognoses and limited treatment options. Here, we conducted this first-in-class phase II study to evaluate the efficacy and safety of SHR-1701, a bifunctional fusion protein targeting programmed death-ligand 1 (PD-L1) and transforming growth factor-beta (TGF-β), combined with famitinib, a multi-targeted receptor tyrosine kinase inhibitor, in patients with advanced BTC or PDAC who failed previous standard treatment (trial registration: ChiCTR2000037927).

摘要晚期胆道癌（BTC）和胰腺导管腺癌（PDAC）预后差，治疗选择有限。在这里，我们进行了这项首次II期研究，以评估SHR-1701（一种靶向程序性死亡配体1（PD-L1）和转化生长因子β（TGF-β）的双功能融合蛋白）与famitinib（一种多靶向受体酪氨酸激酶抑制剂）联合用于先前标准治疗失败的晚期BTC或PDAC患者的疗效和安全性（试验注册：ChiCTR2000037927）。

Among 51 enrolled patients, the BTC cohort showed an objective response rate (ORR) of 28% (including 2 complete responses) and a disease control rate (DCR) of 80%, with a median progression-free survival (mPFS) of 5.1 months and a median overall survival (mOS) of 16.0 months. In the PDAC cohort, the ORR was 15% (2 complete responses), with a DCR of 60%, and the mPFS and mOS were 2.1 months and 5.3 months, respectively.

在51名入选患者中，BTC队列显示客观缓解率（ORR）为28%（包括2个完全缓解），疾病控制率（DCR）为80%，中位无进展生存期（mPFS）为5.1个月，中位总生存期（mOS）为16.0个月。在PDAC队列中，ORR为15%（2个完全缓解），DCR为60%，mPFS和mOS分别为2.1个月和5.3个月。

Grade 3 or 4 treatment-related adverse events (TRAEs) occurred in 29.4% of patients, with no grade 5 TRAEs reported. Exploratory analyses revealed that primary tumor resection history, peripheral blood immunophenotype changes, and distinct immune-metabolic profiles were associated with treatment benefits.

29.4%的患者发生3级或4级治疗相关不良事件（TRAEs），未报告5级TRAEs。探索性分析显示，原发性肿瘤切除史，外周血免疫表型变化和不同的免疫代谢谱与治疗益处相关。

An immune/metabolism score integrating the features of six genes was developed as a predictive biomarker for immunotherapy response in multiple cohorts, allowing for the selection of patients most likely to experience positive outcomes from this therapy regimen. In conclusion, our study provides proof-of-concept data supporting the potential of SHR-1701 plus famitinib as an effective and safe subsequent-line therapy for refractory BTC and PDAC, highlighting the promise of targeting PD-L1, TGF-β, and angiogene.

整合了六个基因特征的免疫/代谢评分被开发为多个队列中免疫治疗反应的预测性生物标志物，从而可以选择最有可能从该治疗方案中获得积极结果的患者。总之，我们的研究提供了概念验证数据，支持SHR-1701加法米替尼作为难治性BTC和PDAC的有效和安全的后续一线治疗的潜力，突出了靶向PD-L1，TGF-β和血管生成的前景。

IntroductionBiliary tract cancer (BTC), which includes cholangiocarcinoma, gallbladder cancer, and ampullary cancer, accounts for approximately 0.6% of all new cancer diagnoses in 2023, while the more common pancreatic ductal adenocarcinoma (PDAC) comprises nearly 3%.1 Both BTC and PDAC are aggressive malignancies with poor prognoses, often diagnosed at an advanced stage.2,3,4 Despite initial treatment with standard chemotherapy, disease progression is almost inevitable.

引言胆道癌（BTC）包括胆管癌，胆囊癌和壶腹癌，约占2023年所有新诊断癌症的0.6%，而更常见的胰腺导管腺癌（PDAC）占近3%。BTC和PDAC都是侵袭性恶性肿瘤，预后较差，常被诊断为晚期[2,3,4]。尽管最初用标准化疗治疗，但疾病进展几乎是不可避免的。

For BTC, second-line treatment options include FOLFOX (folinic acid, fluorouracil, and oxaliplatin) chemotherapy following first-line cisplatin and gemcitabine, as well as targeted therapy for a subset of patients with specific genetic alterations.2,3 Advanced PDAC patients unresponsive to first-line treatment face constrained options, with nanoliposomal irinotecan in combination with fluorouracil and folinic acid (Nal-IRI with 5-FU/LV) as recommended.4 Current subsequent-line chemotherapies offer disappointing efficacy, with a median overall survival (mOS) of about 6.2 months for BTC and even lower for PDAC,4,5 and the modest survival benefit often comes at the cost of severe toxicities.Although immunotherapy has revolutionized the treatment landscape for various solid tumors, immune checkpoint inhibitor (ICI) monotherapy has not yielded significant advantages in advanced BTC (objective response rates [ORR]: 3–20%) and PDAC ( ≤ 10%) due to the immunosuppressive tumor microenvironment (TME),6,7 with only specific subgroups being eligible.8,9 One of the key factors negatively shaping the TME is transforming growth factor-beta (TGF-β), a pleiotropic cytokine that promotes immune evasion by inhibiting cytotoxic T and NK lymphocytes, while inducing the differentiation of regulatory T cells (Tregs) and myelo.

对于BTC，二线治疗选择包括一线顺铂和吉西他滨后的FOLFOX（亚叶酸，氟尿嘧啶和奥沙利铂）化疗，以及针对一部分具有特定基因改变的患者的靶向治疗。2,3对一线治疗无反应的晚期PDAC患者面临着有限的选择，推荐使用纳米脂质体伊立替康联合氟尿嘧啶和亚叶酸（Nal IRI联合5-FU/LV）。4目前的后续一线化疗疗效令人失望，BTC的中位总生存期（mOS）约为6.2个月，PDAC的中位总生存期（mOS）甚至更低，4,5和适度的生存获益通常以严重毒性为代价。。

Data availability

数据可用性

The RNA-seq data generated in this study have been deposited in the NCBI Sequence Read Archive under BioProject accession number PRJNA1173873. All other data supporting our findings of this work are available from the corresponding authors upon reasonable request.

本研究中产生的RNA-seq数据已保存在NCBI序列读取档案中，生物项目登录号为PRJNA1173873。根据合理的要求，通讯作者可以提供所有其他支持我们这项工作发现的数据。

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Download referencesAcknowledgementsThe work was supported by the National Cancer Center Fund (NCC201909B04) and the National Natural Science Foundation of China (Grant Number: 82074202). The authors express their gratitude to the collaborative group members for their commitment, as well as to all of the patients and their families who took part in this experiment.

下载参考文献致谢这项工作得到了国家癌症中心基金（NCC201909B04）和国家自然科学基金（批准号：82074202）的支持。作者对合作小组成员的承诺，以及所有参与该实验的患者及其家属表示感谢。

We are appreciative of Jiangsu Hengrui Pharmaceuticals Co., Ltd. for providing SHR1701 and famitinib. We thank Prof. Zhen Chen, Prof. Zhentian Wang, Dr. Fei Luo (Hengrui Pharmaceuticals Co., Ltd.), Sijia Gu, Wenqian Yu, Yingcheng Wu (Fudan University), Anyi Jiang (Tongji University), Ke Tong (Imperial College London) and Guanhua Yi (Sichuan University).

我们感谢江苏恒瑞制药有限公司提供SHR1701和法米替尼。我们感谢陈振教授、王振田教授、罗飞博士（恒瑞制药有限公司）、顾思嘉、余文倩、吴应成（复旦大学）、江安忆（同济大学）、柯彤（伦敦帝国理工学院）和易冠华（四川大学）。

We thank the computing platform of the Medical Research Data Center of Shanghai Medical College Fudan University. We thank Biotrainee and Bioinfo Composer for sharing their codes.Author informationAuthor notesThese authors contributed equally: Lixia Yi, Haoqi PanAuthors and AffiliationsDepartment of Integrative Oncology, Fudan University Shanghai Cancer Center, Shanghai, ChinaLixia Yi, Zhouyu Ning, Litao Xu, Hena Zhang, Yifan Yang, Waimei Si, Xiaoyan Zhu, Shenglin Huang, Zhiqiang Meng & Jing XieDepartment of Minimally Invasive Therapy Center, Fudan University Shanghai Cancer Center, Shanghai, ChinaLixia Yi, Zhouyu Ning, Litao Xu, Yifan Yang, Waimei Si, Xiaoyan Zhu, Zhiqiang Meng & Jing XieDepartment of Oncology, Shanghai Medical College, Fudan University, Shanghai, ChinaLixia Yi, Haoqi Pan, Zhouyu Ning, Litao Xu, Yaowu Liu, Yifan Yang, Xiaoyan Zhu, Shenglin Huang, Zhiqiang Meng & Jing XieShanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, Fudan University, Shanghai, ChinaHena Zhang & Shenglin HuangSuzhou Institute .

我们感谢复旦大学上海医学院医学研究数据中心的计算平台。我们感谢Biotrainee和Bioinfo Composer分享他们的代码。作者信息作者注意到，这些作者做出了同样的贡献：易丽霞，郝琦作者和附属机构复旦大学上海癌症中心综合肿瘤学系，上海，中国易丽霞，周玉宁，徐丽涛，张海娜，杨一凡，斯外梅，朱晓燕，黄盛林，孟志强和谢静复旦大学上海癌症中心微创治疗中心，上海，易丽霞，周玉宁，徐丽涛，杨一凡，斯外梅，朱晓燕，孟志强和谢静复旦大学上海医学院肿瘤学系，易丽霞，中国潘浩琦，周玉宁，徐立涛，刘耀武，杨一凡，朱晓燕，黄生林，孟志强，谢尚海复旦大学生物医学研究所医学表观遗传学重点实验室，上海，中国。张和黄生林苏州研究所。

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PubMed Google ScholarContributionsJ.X. and Z.Q.M. conceptualized the study and provided overall supervision. L.X.Y. analyzed the data and took the lead in drafting the manuscript. H.Q.P. was dominantly in charge of experiment validation. S.L.H., L.T.X. and Z.Y.N. provided guidance on the statistical analysis.

。十、 Z.Q.M.将研究概念化并提供全面监督。五十、 X.Y.分析了数据，并率先起草了手稿。H、 Q.P.主要负责实验验证。S、 L.H.，L.T.X.和Z.Y.N.提供了统计分析的指导。

H.N.Z. helped with the RNA-seq data processing. L.F.P. assisted in the collection of tissue samples. Y.W.L. and Y.F.Y. helped with the refinement of the writing essays. W.M.S. and Y.W. contributed to the acquisition and interpretation of the data the interpretation of the results. X.Y.Z. recommended the patient’s participation in the clinical trial at the time of initial diagnosis.

H、 N.Z.帮助进行RNA-seq数据处理。五十、 F.P.协助收集组织样本。Y、 W.L.和Y.F.Y.帮助改进了论文的写作。W、 M.S.和Y.W.为数据的获取和解释以及结果的解释做出了贡献。十、 Y.Z.建议患者在初次诊断时参加临床试验。

All authors have read and approved the article.Corresponding authorsCorrespondence to.

所有作者都阅读并批准了这篇文章。通讯作者通讯。

Shenglin Huang, Zhiqiang Meng or Jing Xie.Ethics declarations

黄生林、孟志强或谢静。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。

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Reprints and permissionsAbout this articleCite this articleYi, L., Pan, H., Ning, Z. et al. Clinical and biomarker analyses of SHR-1701 combined with famitinib in patients with previously treated advanced biliary tract cancer or pancreatic ductal adenocarcinoma: a phase II trial.

转载和许可本文引用本文Yi，L.，Pan，H.，Ning，Z。等人。SHR-1701联合法米替尼治疗先前治疗的晚期胆道癌或胰腺导管腺癌患者的临床和生物标志物分析：II期试验。

Sig Transduct Target Ther 9, 347 (2024). https://doi.org/10.1038/s41392-024-02052-3Download citationReceived: 09 July 2024Revised: 21 October 2024Accepted: 05 November 2024Published: 13 December 2024DOI: https://doi.org/10.1038/s41392-024-02052-3Share 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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