RET抑制剂SY-5007在晚期RET改变的实体瘤患者中的首次人体1期剂量递增和剂量扩大研究-动脉网

First-in-human, phase 1 dose-escalation and dose-expansion study of a RET inhibitor SY-5007 in patients with advanced RET-altered solid tumors

Nature 等信源发布 2024-11-04 08:54

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AbstractOncogenic RET alteration is an important, tissue-agnostic therapeutic target across diverse cancers. We conducted a first-in-human phase 1 study on SY-5007, a potent and selective RET inhibitor, in patients with RET-altered solid tumors. Primary endpoints were safety, maximum tolerated dose (MTD), and recommended phase 2 dose (RP2D).

摘要致癌RET改变是多种癌症中重要的组织不可知的治疗靶点。我们对RET改变的实体瘤患者进行了SY-5007（一种有效且选择性的RET抑制剂）的首次人体1期研究。主要终点是安全性，最大耐受剂量（MTD）和推荐的2期剂量（RP2D）。

Secondary endpoints included pharmacokinetics and preliminary anti-tumor activity. A total of 122 patients were enrolled (17 in dose-escalation phase and 105 in dose-expansion phase), including 91 with non-small cell lung cancer, 23 with medullary thyroid cancer, 7 with papillary thyroid cancer and 1 with gastric cancer.

次要终点包括药代动力学和初步抗肿瘤活性。共纳入122例患者（剂量递增期17例，剂量扩展期105例），其中非小细胞肺癌91例，甲状腺髓样癌23例，甲状腺乳头状癌7例，胃癌1例。

Treatment-related adverse events (TRAEs) were reported in 96.7% of patients, with the most common grade ≥ 3 TRAEs being hypertension (22.1%), diarrhea (16.4%), hypertriglyceridemia (6.6%), and neutropenia (6.6%). The exposure to SY-5007 was dose proportional. Among the 116 efficacy-evaluable patients, the overall objective response rate (ORR) was 57.8%, with 70.0% in treatment-naïve patients and 51.3% in previously treated patients.

96.7%的患者报告了治疗相关不良事件（TRAEs），最常见的≥3级TRAEs为高血压（22.1%），腹泻（16.4%），高甘油三酯血症（6.6%）和中性粒细胞减少症（6.6%）。暴露于SY-5007是剂量成比例的。在116名可评估疗效的患者中，总体客观缓解率（ORR）为57.8%，未接受治疗的患者为70.0%，先前接受治疗的患者为51.3%。

The median progression-free survival (PFS) was 21.1 months. Efficacy was observed regardless of tumor types and previous therapies. Biomarker analysis of 61 patients with circulating tumor DNA (ctDNA)-detectable RET alterations showed an ORR of 57.4% and median PFS of 13.8 months. Rapid ctDNA clearance of RET alteration correlated with faster responses and improved outcomes.

中位无进展生存期（PFS）为21.1个月。无论肿瘤类型和以前的治疗方法如何，都观察到疗效。对61例循环肿瘤DNA（ctDNA）可检测到的RET改变患者的生物标志物分析显示，ORR为57.4%，中位PFS为13.8个月。RET改变的快速ctDNA清除与更快的反应和改善的结果相关。

In relapsed patients, off-target induced resistance was observed in 57.1% (12/21), with no on-target RET alterations identified. In conclusion, SY-5007 was well-tolerated and showed promising efficacy in patients with RET-altered solid tumors. Serial ctDNA monitoring may unveil treatment response and potential resist.

在复发患者中，观察到脱靶诱导的耐药性为57.1%（12/21），未发现靶向RET改变。总之，SY-5007耐受性良好，在RET改变的实体瘤患者中显示出有希望的疗效。连续ctDNA监测可能揭示治疗反应和潜在的抵抗力。

IntroductionThe REarranged during Transfection (RET) gene encodes a vital transmembrane receptor tyrosine kinase that plays an essential role in various physiological processes. Upon stimulation by glial cell line-derived neurotrophic factor (GDNF) family ligands, specific tyrosine residues within the RET intracellular domain undergo autophosphorylation, creating docking sites for key adaptor proteins.

引言转染过程中重排（RET）基因编码一种重要的跨膜受体酪氨酸激酶，在各种生理过程中起着至关重要的作用。在神经胶质细胞系衍生的神经营养因子（GDNF）家族配体的刺激下，RET细胞内结构域内的特定酪氨酸残基经历自磷酸化，为关键衔接蛋白产生对接位点。

This process triggers critical signaling pathways, including RAS/MAPK, PI3K/AKT, and JAK/STAT, which are integral to cellular functions such as migration, proliferation, survival, and differentiation. These pathways are particularly important during embryogenesis, nervous system development, and renal morphogenesis.1,2 Dysregulation of RET through somatic gene alterations, such as fusions and activating mutations, can lead to its constitutive activation, which result in heightened downstream signaling activation.

该过程触发关键的信号传导途径，包括RAS/MAPK，PI3K/AKT和JAK/STAT，它们是细胞功能如迁移，增殖，存活和分化所不可或缺的。这些途径在胚胎发生，神经系统发育和肾脏形态发生过程中尤为重要。1,2通过体细胞基因改变（例如融合和激活突变）导致RET失调，可导致其组成型激活，从而导致下游信号激活增强。

This persistent activation over-activates downstream signaling, promoting uncontrolled cell growth, resistance to apoptosis, and ultimately contributing to tumorigenesis and metastasis. Consequently, RET has garnered considerable attention as a significant target for therapeutic intervention in various malignancies.3,4,5In non-small cell lung cancer (NSCLC), RET fusions are found in approximately 1–2% of cases.

这种持续激活过度激活下游信号传导，促进不受控制的细胞生长，抵抗细胞凋亡，并最终促进肿瘤发生和转移。因此，RET作为各种恶性肿瘤治疗干预的重要靶点引起了人们的广泛关注。3,4,5在非小细胞肺癌（NSCLC）中，约有1-2%的病例发现RET融合。

These fusions typically result from the juxtaposition of the RET gene with other genes, such as KIF5B, CCDC6, and NCOA4, producing fusion proteins that exhibit constitutive kinase activity. This persistent activation promotes increased cell proliferation, survival, and invasion, contributing to the aggressive nature of RET fusion-positive NSCLC.

这些融合通常是由RET基因与其他基因（例如KIF5B，CCDC6和NCOA4）并置产生的，产生了具有组成型激酶活性的融合蛋白。这种持续激活促进细胞增殖，存活和侵袭的增加，有助于RET融合阳性NSCLC的侵袭性。

Such fusions mark a distinct molecular subtype that is associated with poor clinical outcomes and aggressive tum.

这种融合标志着一种独特的分子亚型，与不良的临床结果和侵袭性tum相关。

Data availability

数据可用性

The raw sequencing data reported in this paper have been deposited in the Genome Sequence Archive in National Genomics Data Center, China National Center for Bioinformation/Beijing Institute of Genomics, Chinese Academy of Sciences (https://ngdc.cncb.ac.cn/gsa-human). These data are accessible under the accession number: HRA008677.

本文报道的原始测序数据已保存在中国国家生物信息中心/中国科学院北京基因组研究所国家基因组数据中心的基因组序列档案中(https://ngdc.cncb.ac.cn/gsa-human)。这些数据可以通过登录号HRA008677访问。

These data are under controlled access by human privacy regulations and are only available for research purposes. Access to the data can be granted following approval from the Data Access Committee of the GSA-human database. Shouyao Holdings (Beijing) Co., Ltd, Beijing, China, is the owner of SY-5007 and is dedicated to ensuring data transparency.

这些数据受人类隐私法规的控制，只能用于研究目的。在获得GSA人类数据库数据访问委员会的批准后，可以授予对数据的访问权限。中国北京首耀控股（北京）有限公司是SY-5007的所有者，致力于确保数据的透明度。

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

本研究中使用和/或分析的其他数据集可根据合理要求从通讯作者处获得。。

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Download referencesAcknowledgementsThis work was supported by Shouyao Holdings (Beijing) Co., Ltd, Beijing, China. The authors thank the patients, their families and all investigators and their personnel, for their participation in the study.Author informationAuthor notesThese authors contributed equally: Wei Li, Yongsheng Wang, Anwen XiongAuthors and AffiliationsDepartment of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, Shanghai, ChinaWei Li, Anwen Xiong, Fei Zhou & Caicun ZhouDepartment of Thoracic Oncology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, ChinaYongsheng Wang, Ge Gao, Zhihui Li & Jiaye LiuDepartment of Thoracic Oncology, Zhejiang Cancer Hospital, Hangzhou, ChinaZhengbo Song, Yiping Zhang & Chunwei XuLung Cancer Department, Tianjin Medical University Cancer Institute & Hospital, Tianjin, ChinaDingzhi HuangDepartment of Medical Oncology, The First Affiliated Hospital of Xiamen University, Fujian, ChinaFeng YeDepartment of Internal Medicine, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, ChinaQiming WangShouyao Holdings (Beijing) Co., Ltd, Beijing, ChinaYinghui Sun & Xijie LiuAuthorsWei LiView author publicationsYou can also search for this author in.

下载参考文献致谢这项工作得到了中国北京首耀控股（北京）有限公司的支持。作者感谢患者，他们的家人以及所有研究人员和他们的工作人员参与了这项研究。作者信息作者注意到，这些作者做出了同样的贡献：李伟，王永胜，熊安文作者和附属机构上海市肺部医院，同济大学医学院癌症研究所，同济大学医学院，上海，中国李伟，熊安文，周飞和周蔡村四川大学华西医院生物治疗与癌症中心国家重点实验室和协同创新中心，中国成都王永胜，高格，李志辉和刘嘉业浙江省肿瘤医院，杭州，宋正波，张一平和徐春伟肺癌科，天津医科大学肿瘤研究所和医院中国天津黄定志厦门大学第一附属医院肿瘤内科，福建，中国叶峰内科，郑州大学附属肿瘤医院，河南省肿瘤医院，郑州，中国启明王守尧控股（北京）有限公司，北京，中国孙英辉和刘西杰作者Wei LiView作者出版物您也可以在中搜索这位作者。

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PubMed Google ScholarContributionsW.L., Y.W., and A.X. contributed equally to this work. C.Z., W.L., Y.W., F.Z., and Y.S. conceived and designed the study. C.Z., W.L., Y.W., F.Z., G.G., Z.S., Y.Z., D.H., F.Y., Q.W., Z.L., J.L., and C.X. enrolled and treated patients and gathered data.

PubMed谷歌学术贡献软件。五十、，Y.W.和A.X.对这项工作做出了同样的贡献。C.Z.，W.L.，Y.W.，F.Z。和Y.S.构思并设计了这项研究。C、 Z.，W.L.，Y.W.，F.Z.，G.G.，Z.S.，Y.Z.，D.H.，F.Y.，Q.W.，Z.L.，J.L。和C.X.登记并治疗患者并收集数据。

Data were analyzed and interpreted by all authors. All authors participated in the writing and review of this manuscript, and approved the final submitted version.Corresponding authorsCorrespondence to.

。所有作者都参与了这份手稿的撰写和审查，并批准了最终提交的版本。通讯作者通讯。

Fei Zhou or Caicun Zhou.Ethics declarations

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Y.S. and X.L. are employees of Shouyao Holdings (Beijing) Co., Ltd, Beijing, China. All other authors declare no competing interests.

Y、 S.和X.L.是中国北京首耀控股（北京）有限公司的员工。所有其他作者都声明没有利益冲突。

Supplementary informationFigures. S1 to S5, Tables S1 to S7Study protocolRights and permissions

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Reprints and permissionsAbout this articleCite this articleLi, W., Wang, Y., Xiong, A. et al. First-in-human, phase 1 dose-escalation and dose-expansion study of a RET inhibitor SY-5007 in patients with advanced RET-altered solid tumors.

转载和许可本文引用本文Li，W.，Wang，Y.，Xiong，A。等人首次在人类中进行RET抑制剂SY-5007在晚期RET改变实体瘤患者中的1期剂量递增和剂量扩展研究。

Sig Transduct Target Ther 9, 300 (2024). https://doi.org/10.1038/s41392-024-02006-9Download citationReceived: 09 April 2024Revised: 12 September 2024Accepted: 30 September 2024Published: 04 November 2024DOI: https://doi.org/10.1038/s41392-024-02006-9Share 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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