更新于：2024-11-21
Sorafenib Tosylate
甲苯磺酸索拉非尼
更新于：2024-11-21
概要
基本信息
药物类型 小分子化药 |
别名 4-(4-((((4-Chloro-3-(trifluoromethyl)phenyl)amino)carbonyl)amino)phenoxy)-N-methyl-2-pyridinecarboxamide、N-(4-Chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea、SORAFENIB + [16] |
作用机制 BRAF抑制剂(丝氨酸/苏氨酸蛋白激酶B-raf抑制剂)、CRAF抑制剂(C-Raf激酶抑制剂)、FLT3抑制剂(酪氨酸蛋白激酶受体FLT3抑制剂) + [6] |
非在研机构 |
最高研发阶段批准上市 |
首次获批日期 美国 (2005-12-01), |
最高研发阶段(中国)终止 |
特殊审评孤儿药 (日本)、优先审评 (中国) |
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结构
分子式C21H16ClF3N4O3 |
InChIKeyMLDQJTXFUGDVEO-UHFFFAOYSA-N |
CAS号284461-73-0 |
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关联
824
项与 甲苯磺酸索拉非尼 相关的临床试验A Phase I Study Investigating the Combination of Cladribine, Low Dose Cytarabine and Sorafenib Alternating With Decitabine in Pediatric Relapsed and Refractory Acute Leukemias
To find the recommended dose of the drug combination cladribine, cytarabine, decitabine, and sorafenib in participants with relapsed/refractory AML, MPAL, and ALAL.
开始日期2024-12-31 |
AD HOC Trial: Artificial Intelligence-Based Drug Dosing In Hepatocellular Carcinoma
This study will test the hypothesis that a novel combination of three drugs (sorafenib, sonidegib, and irinotecan), in conjunction with individually optimized doses, can be safely administered and lead to improved clinical outcomes in patients with hepatocellular carcinoma compared to standard of care. The main objective of this study is to establish safe dose ranges for the coadministration of sorafenib, sonidegib, and irinotecan in patients with hepatocellular carcinoma. Furthermore, we will collect data to inform the application of an artificial intelligence/computational approach to individual dosing of combination chemotherapy. Individualization of dosing will be achieved by using Phenotypic Personalized Medicine (PPM) to maximize treatment efficacy in patients with hepatocellular carcinoma, while minimizing toxicity. Drug efficacy will be assessed by measuring plasma circulating tumor DNA (ctDNA). Toxicity will be assessed by quantitating organ injury and patient tolerability. Recommended dosing for future studies will be based on the totality of the data.
开始日期2024-11-01 |
申办/合作机构 |
A Clinical Study of Sorafenib Combined With Gefitinib for the Treatment of Pancreatic Neuroendocrine Tumor Patients Who Have Progressed After Previous Treatment
The incidence rate of pancreatic neuroendocrine neoplasms (pNENs) is increasing year by year. According to the statistical results of the SEER (Surveillance, Epidemiology, and End Results) database, the incidence rate of pNENs increased from 0.27/100000 to 1/100000 from 2000 to 2016, with a median overall survival time of 68 months. The 5-year overall survival rates of localized, locally advanced, and metastatic pNENs were 83%, 67%, and 28%, respectively. pNENs are gradually gaining attention and importance from the medical community. The existing therapeutic drugs for neuroendocrine tumors include somatostatin analogues, recombinant human interferon injections, chemotherapy drugs, and molecular targeted drugs.
Although these drugs can prolong patients' PFS to some extent, there is a common problem of low objective response rates. In recent years, sunitinib and everolimus have been approved for targeted therapy in patients with pancreatic neuroendocrine neoplasms , but their clinical efficacy is still limited. The study by Panzuto et al. showed that the median PFS for first-line treatment of advanced well differentiated pancreatic neuroendocrine neoplasms was 13.9 months, with an ORR of 14.9%. After imaging progression of the disease, the median PFS after second-line treatment was 15 months, and the ORR of only 5.5%. There is currently no effective treatment for patients with disease progression or drug resistance after undergoing existing treatment ways.
Therefore, there is a huge clinical demand for the treatment of pNEN patients worldwide, and effective drugs are urgently needed to benefit these patients.
Our previous research found that pathways in tumor were significantly affected in pNENs and liver metastases and EGFR tyrosine kinase inhibitor resistance and transcriptional dysregulation in tumor were unique to liver metastasis through KEGG pathway analysis; Meanwhile, GO Biological Processes analysis emphasizes those signaling pathways closely related to tyrosine phosphorylation, DNA repair, and cell cycle regulation, especially in liver metastases. Xiao et al. found that epidermal growth factor receptor (EGFR) was enriched in high glycosylation pNENs using RNA-seq. EGFR was expressed in 21.2% of pNENs using immunohistochemistry and associated with poor overall survival. Therefore, the study from Xiao et al. demonstrates that EGFR may be a potential therapeutic target for pNENs. This is consistent with our previous findings that the EGFR signaling pathway plays an important role in pNENs with liver metastases.
Due to the heterogeneity and complexity of tumors, the efficacy of monotherapy or blocking a single signaling pathway may be limited or this treatment method may easily develop drug resistance. The existing anti-tumor targeted drugs block tumor angiogenesis by inhibiting vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF). Colony-stimulating factor 1 receptor (CSF1R) is an important signaling pathway associated with the survival and function of tumor associated macrophages (TAMs). Inhibiting CSF1R can regulate the activity of macrophages, improve the immune microenvironment, promote immune response, and activate the body's immune function. Sofantinib is a novel oral tyrosine kinase inhibitor which exerts dual effects of anti-tumor angiogenesis and immune regulation by targeting VEGFR, FGFR1, and CSF1R, resulting in synergistic anti-tumor activity. In December 2020 and June 2021, sorafenib was approved in China as a monotherapy for unresectable locally advanced or metastatic, well differentiated extrapancreatic and pancreatic neuroendocrine neoplasms.
However, in a multicenter, single blind, open label, phase Ib/II clinical trial, the objective response rate for pNENs patients was only 19%. There is currently no effective treatment available for patients with disease progression or drug resistance after undergoing existing treatment regimens. Therefore, there is an urgent need to seek new treatment methods to improve the therapeutic effect of pNENs. Based on our previous research results and relevant literature reports, we speculate that the combination of sorafenib and EGFR inhibitor gefitinib may improve the therapeutic effect of pNENs patients.
Although these drugs can prolong patients' PFS to some extent, there is a common problem of low objective response rates. In recent years, sunitinib and everolimus have been approved for targeted therapy in patients with pancreatic neuroendocrine neoplasms , but their clinical efficacy is still limited. The study by Panzuto et al. showed that the median PFS for first-line treatment of advanced well differentiated pancreatic neuroendocrine neoplasms was 13.9 months, with an ORR of 14.9%. After imaging progression of the disease, the median PFS after second-line treatment was 15 months, and the ORR of only 5.5%. There is currently no effective treatment for patients with disease progression or drug resistance after undergoing existing treatment ways.
Therefore, there is a huge clinical demand for the treatment of pNEN patients worldwide, and effective drugs are urgently needed to benefit these patients.
Our previous research found that pathways in tumor were significantly affected in pNENs and liver metastases and EGFR tyrosine kinase inhibitor resistance and transcriptional dysregulation in tumor were unique to liver metastasis through KEGG pathway analysis; Meanwhile, GO Biological Processes analysis emphasizes those signaling pathways closely related to tyrosine phosphorylation, DNA repair, and cell cycle regulation, especially in liver metastases. Xiao et al. found that epidermal growth factor receptor (EGFR) was enriched in high glycosylation pNENs using RNA-seq. EGFR was expressed in 21.2% of pNENs using immunohistochemistry and associated with poor overall survival. Therefore, the study from Xiao et al. demonstrates that EGFR may be a potential therapeutic target for pNENs. This is consistent with our previous findings that the EGFR signaling pathway plays an important role in pNENs with liver metastases.
Due to the heterogeneity and complexity of tumors, the efficacy of monotherapy or blocking a single signaling pathway may be limited or this treatment method may easily develop drug resistance. The existing anti-tumor targeted drugs block tumor angiogenesis by inhibiting vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF). Colony-stimulating factor 1 receptor (CSF1R) is an important signaling pathway associated with the survival and function of tumor associated macrophages (TAMs). Inhibiting CSF1R can regulate the activity of macrophages, improve the immune microenvironment, promote immune response, and activate the body's immune function. Sofantinib is a novel oral tyrosine kinase inhibitor which exerts dual effects of anti-tumor angiogenesis and immune regulation by targeting VEGFR, FGFR1, and CSF1R, resulting in synergistic anti-tumor activity. In December 2020 and June 2021, sorafenib was approved in China as a monotherapy for unresectable locally advanced or metastatic, well differentiated extrapancreatic and pancreatic neuroendocrine neoplasms.
However, in a multicenter, single blind, open label, phase Ib/II clinical trial, the objective response rate for pNENs patients was only 19%. There is currently no effective treatment available for patients with disease progression or drug resistance after undergoing existing treatment regimens. Therefore, there is an urgent need to seek new treatment methods to improve the therapeutic effect of pNENs. Based on our previous research results and relevant literature reports, we speculate that the combination of sorafenib and EGFR inhibitor gefitinib may improve the therapeutic effect of pNENs patients.
开始日期2024-09-30 |
申办/合作机构 |
100 项与 甲苯磺酸索拉非尼 相关的临床结果
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100 项与 甲苯磺酸索拉非尼 相关的转化医学
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100 项与 甲苯磺酸索拉非尼 相关的专利（医药）
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11,712
项与 甲苯磺酸索拉非尼 相关的文献（医药）2025-03-01·Annals of Hepatology
Camrelizumab combined with transcatheter arterial chemoembolization and sorafenib or lenvatinib for unresectable hepatocellular carcinoma: A multicenter, retrospective study
Article
作者: Li, Han ; Wang, Fei ; Jiang, Xiumei ; Liu, Yu ; Su, Ke ; Xu, Ke ; Chi, Hao ; Wang, Pan
2025-02-01·Current Cancer Drug Targets
Screening miRNAs to Hinder the Tumorigenesis of Renal Clear Cell Carcinoma Associated with KDR Expression
Article
作者: Almoallim, Hesham S. ; Kaviyaprabha, Rangaraj ; Miji, Thandaserry Vasudevan ; Sivakumar, Priyadarshini ; Suseela, Rangaraj ; Muthusami, Sridhar ; Thangaleela, Subramanian ; Bharathi, Muruganantham
2025-02-01·Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy
Mitochondria/lysosome dual-organelle labelling esterase probe for monitoring cell viability and evaluating lung cancer drug efficiency
Article
作者: Shen, Xing-Can ; Chen, Hua ; Wang, Liping ; Hu, Bangping ; Wang, Jing ; He, Mengye
825
项与 甲苯磺酸索拉非尼 相关的新闻（医药）2024-11-18
·药学进展
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顾景凯
吉林大学唐敖庆卓越教授、药物代谢研究中心主任，超分子结构与材料国家重点实验室教授，国家药品注册审评专家咨询委员会专家。中国药理学会药物代谢专业委员会副主委、分析药理专业委员会副主委；中国医药生物技术协会药物分析技术分会副主委；《药学学报》副主编；Drug Metab Dispos，Acta Pharm Sin B，Asian J Pharm Sci，J Pharm Anal等期刊编委。长期从事纳米药物、高分子药物、多糖药物、蛋白肽类药物体内时空命运分析和基于药代动力学的前体药物设计与开发。先后主持11项国家自然科学基金面上项目、重点项目和国家重大新药创制专项子课题，在 Adv Drug Deliv Rev，Anal Chem，Acta Pharm Sin B，Adv Mater，Biomacromolecules，Clin Pharmacokinet等期刊发表SCI论文200余篇，获授权发明专利15项，作为主要发明人之一的1类新药于2022年上市。
纳米药物递送系统体内命运分析新方法与新技术研究进展 PPS
王心怡1, 2#，付淑军3#，孟祥骏1，吴伟4*，顾景凯2**
（1. 天津大学医学部药物科学与技术学院，天津300072；2. 吉林大学超分子结构与材料国家重点实验室超分子化学生物学研究中心 生命科学学院药物代谢研究中心，吉林 长春130012；3. 国家药品监督管理局药品审评中心，北京100022；4. 复旦大学药学院， 上海201203）
[摘要] 纳米药物递送系统（NDDSs）能够改善药物的药代动力学行为，将活性药物成分靶向递送至病灶，并控制药物释放。近年来， 随着纳米技术的快速发展，NDDSs在医药领域展现出巨大潜力，已成为该领域的研究热点。对NDDSs的体内命运进行精准分析，是揭示其复杂体内过程，实现纳米药物安全、有效递送的关键之一。NDDSs在体内包含负载型药物、游离型药物、纳米载体和载体材料等多种形态成分，在复杂的生命体系中全面精准分析这些成分的动态变化具有极高的技术挑战。受分析方法与分析技术的制约，目前对于NDDSs的体内命运研究仍存在许多挑战，极大阻碍了NDDSs的快速发展与临床转化。综述对NDDSs中游离型药物、负载型药物、纳米载体和纳米材料的分析新方法、新技术及其在纳米药代动力学中的应用进行介绍，并对该领域未来研究方向提出展望，以期为NDDSs的体内命运相关研究提供参考。
1995 年，美国食品和药品管理局（food and drug administration，FDA）批准了首个抗癌纳米药物Doxil [1]。在过去的30年里，纳米药物递送系统 （nanocarrier drug delivery systems，NDDSs）发展迅速，迄今已有几十万篇相关论文发表[2]。然而， 尽管论文数量庞大， NDDSs的实际临床转化却十分有限。截至2023年末，仅有90多个纳米药物上市[2]。与普通制剂相比，这些纳米药物在临床依从性方面有了极大提高，但大多数在临床疗效方面并未取得显著的改善[1, 3]。
与普通药物制剂不同，NDDSs在体内始终存在 “载药粒子-游离型药物-解聚载体材料”多种形态的动态变化过程，该过程与其体内药代动力学行为、 药效作用和毒性反应密切相关。其中，载药粒子是药物的运输工具和储库，靶部位/靶点（如肿瘤组织） 中的游离药物是药效的物质基础，而其他组织中的游离药物、载药粒子、解聚载体材料等则可能导致 毒性/不良反应。因此，充分了解NDDSs各形态组分的体内药代动力学信息，对其安全性和有效性评价以及制剂处方的设计与优化具有重要意义[4-5]。以往由于缺少前瞻性的理论指导，尤其是缺少有效的分析策略与技术手段，在复杂的生命系统中对 NDDSs 游离药物、载药粒子、解聚载体材料的药代动力学过程进行精准分析，无疑存在巨大的挑战， 已成为制约 NDDSs 临床转化成功率的最主要瓶颈之一[6]。
针对上述问题，本文聚焦NDDSs在体内存在的不同形态成分，对近年来用于追踪NDDSs体内时空命运的先进分析策略与分析技术进行综述，以期为NDDSs的药代/毒代动力学、安全性与有效性评价以及NDDSs的处方设计与工艺优化研究提供比较全面的技术支持，进而提高NDDSs的临床转化成功率。
1
游离型、负载型药物和纳米载体分离分析技术
传统的药物分析技术只关注NDDSs中药物的总浓度，无法阐明药物是负载于载药粒子还是已经从载体中释放出来[7]。由于NDDSs改变了药物的分布，其所负载药物的吸收、分布、代谢、排泄行为相比普通制剂往往会发生显著变化[7]。因此，为了能够更准确地评估纳米药物的有效性与安全性， 区分游离型药物和负载型药物是极为重要的。在复杂的生命系统中，纳米药物的递送过程面临多种挑战，为确保所设计的纳米载体的优良性能，监测纳米载体的体内转运过程也是十分必要的[8]。下文将对NDDSs游离型药物、负载型药物和纳米载体的分离与分析技术进行介绍。
1.1 固相萃取技术
固相萃取（solid phase extraction，SPE）技术基于液-固相色谱理论，通过选择性吸附和选择性洗脱的方式对样品中不同组分进行分离。脂质体是由脂质双层构成的球形囊泡。作为首个成功应用于临床的纳米载体[9-12]，脂质体以独特的两亲性结构，即亲水核心和被脂质层包围的疏水空间，为封装不同极性的药物提供了可能[9, 13]。Wang等[14] 开发了一种SPE结合液相色谱-串联质谱（liquid chromatography tandem mass spectrometry，LC-MS/ MS）检测聚乙二醇（polyethylene glycol，PEG） 化长循环阿霉素（doxorubicin，DOX）脂质体的负载型DOX和游离型DOX的分析方法。该方法利用PEG化长循环DOX脂质体在反相固相萃取小柱上保留能力差，而游离型DOX在反相固相萃取小柱上保留能力强的原理，能够从组织样本中分离出 PEG 化DOX脂质体（负载型DOX）；然后利用 LC-MS/MS 分别检测负载型DOX浓度和DOX总浓度，并通过二者差值计算出游离型DOX的浓度。该研究比较了荷瘤小鼠正常组织和肿瘤组织中PEG 化脂质体内DOX的释放与摄取曲线，结果表明脂质体能有效地将DOX释放到肿瘤中，与直接给药 DOX溶液相比，脂质体使肿瘤对DOX的吸收量增加了1.8倍；脂质体还降低了DOX在心脏的分布量， 从而减少了DOX的心脏毒性。
1.2 荧光成像技术
近年来，荧光成像技术凭借其高灵敏度、操作简便等特性使其在药物递送系统中得到广泛应用[15]， 常被用于标记NDDSs并对其进行可视化示踪[16]。下文将对常用于NDDSs游离型药物、负载型药物和纳米载体的荧光成像技术进行介绍。
1.2.1 聚集诱导发光技术 聚集诱导发光（aggregation- induced emission，AIE）是指某些分子在分散状态下几乎不发光，但当它们聚集在一起时，发光效率显著提高[17]。聚合物胶束是两亲性聚合物分子在水相介质中达到或超过临界胶束浓度（critical micelle concentration，CMC）后自发形成的一种有序结构。两亲性聚合物分子亲脂性尾部因其疏水作用而聚集于胶束内部，亲水性的头部则因具有极性而向外部延伸[18-19]。聚合物胶束的疏水核心能够通过疏水相互作用有效地负载疏水性药物，其亲水外壳与周围的水分子相互作用，保护胶束不被网状内皮系统识别[20]，进而对胶束内部的疏水基团起到保护作用。Sun等[21] 通过将氧化还原敏感的二硫键和 AIE 荧光团Tripp连接于甲氧基聚乙二醇（methoxy polyethylene glycol，mPEG），制备了mPEG-ss-Tripp 聚合物胶束，并以DOX作为药物模型，成功构建出能够同时实现癌症治疗与细胞内成像的智能给药系统。当细胞内谷胱甘肽（glutathione，GSH）还原 mPEG-ss-Tripp 中的二硫键时，聚合物胶束迅速释放药物来抑制肿瘤转移，同时通过监测Tripp的AIE 信号变化来研究胶束的细胞内释药行为。
聚合物纳米粒利用其独特的结构通过吸附或共轭作用使其于聚合物基质或载体表面携带药物[22]， 从而实现对药物的递送。Wang等[23]制备了一种负载姜黄素（curcumin，Cur）的聚乳酸-羟基乙酸 [poly(lactic-co-glycolic) acid，PLGA] 纳米粒（Cur@ PLGA-NPs）。Cur 是一种具有AIE性质的药物， 在与PLGA纳米粒结合后，利用其荧光特性监测载药纳米粒在细胞内的分布。该纳米粒与CT26细胞孵育后，由于Cur的AIE特性，载药Cur纳米粒在细胞中表现出红色荧光，且其荧光强度呈现出浓度依赖性，这表明Cur纳米粒被成功内化到CT26 细胞中。
Wang 等[24] 报道了蛋白冠对阳离子脂质体与细胞相互作用的影响。该研究将具有AIE效应的TR4 作为细胞膜探针，引入阳离子脂质体（TR4脂质体）。当TR4以单体形式存在时不发出荧光，而一旦其插入脂质体中就会发射出较强的荧光。通过成像定位技术，该研究分别对含蛋白冠和不含蛋白冠的脂质体组的观察结果显示，蛋白冠的形成对阳离子脂质 体的转运行为产生了显著的影响，即当脂质体表面形成蛋白冠后，其与细胞的相互作用方式从能量非依赖性的膜融合转变为能量依赖性的内吞作用。
Xu 等[20] 设计并成功合成了一种具有AIE特性的壳聚糖，该壳聚糖通过引入疏水性片段、基于二苯甲酮结构的AIE荧光团、肿瘤靶向配体和酸敏键， 实现了对肿瘤的靶向作用及在酸性条件下的药物释放。该壳聚糖的两亲性使其能够自组装形成包封含紫杉醇的胶束。这种“可视化”胶束系统不仅能够在肿瘤中有效聚集并特异性释放药物，而且能实时监测药物行为。在MCF-7细胞实验中，孵育2 h 即可在细胞质中观察到来自该胶束系统的黄色荧 光，这一现象表明胶束已成功被肿瘤细胞内化。随着孵育时间的延长，荧光强度逐渐增强，进一步说明了肿瘤细胞对胶束的内吞量在不断增加。类似地， Kulkarni 等[25] 将基于四苯乙烯（tetraphenylethylene， TPE）的AIE 荧光团掺入聚乙二醇-聚己内酯 [poly(ethylene glycol)-block-poly(ε-caprolactone)， PEG-b-PCL] 中，该嵌段共聚物可通过自组装形成包 封有DOX和Cur的胶束，可以同时实现肿瘤给药与纳米载体的生物成像示踪。
AIE 效应最显著的优势是在聚集状态下荧光信号的增强，这大大提高了检测的灵敏度。由于AIE 探针在溶液中几乎不发光，其可有效减少背景信号， 提高信噪比。虽然AIE探针在聚集时发光强，但这也可能导致空间分辨率的不足。在AIE探针高度聚集的区域，过强的荧光信号可能掩盖细微的结构信息，特别是在亚细胞结构的研究中。在某些生物环境下，非特异性吸附可能使AIE探针重新聚集，导致产生错误的荧光信号，影响实验结果的准确性。另外，负载的AIE探针在体内从纳米载体上释放行为未必与药物完全一致，这也会影响负载型药物分析结果的准确性。
1.2.2 聚集发光淬灭技术 聚集发光淬灭（aggregation- caused quenching，ACQ）荧光探针具有强疏水性[26]， 在有机溶剂中具有良好的荧光发射性质。随着环境含水量的增加，ACQ荧光探针的荧光发射强度会经历一个显著的变化过程。当含水量达到某一特定值时，ACQ荧光探针的荧光发射强度会迅速下降，而当其处于绝对水环境时，由于分子间的聚集作用， 其荧光发射会完全淬灭[27]。ACQ荧光探针在检测纳米载体完整性方面具有重要的应用价值，当纳米载体保持完整时，其内部的ACQ探针由于处于有机环境而发出强烈的荧光；当纳米载体发生解聚或分解时，ACQ探针由于暴露于水环境中而发生荧光强度降低，甚至完全淬灭。
复旦大学吴伟教授课题组开发了一种利用近红外荧光染料的ACQ特性来监测完整纳米载体体内命运的新策略。该技术已被成功应用于研究多种纳米载体的体内命运[28-33]。He等[34]采用该策略标记和追踪口服聚合物胶束的体内命运发现，大鼠口服聚合物胶束后，其在胃肠道中至少保留4 h，血液和肝脏中出现的荧光直接证明完整聚合物胶束的口服吸收，且约1% ~ 2%的完整胶束通过淋巴途径被吸收。Wu等[35] 也将ACQ探针封装到聚合物胶束中来跟踪胶束的体内命运。
纳米乳是一种由水、油和适当的表面活性剂自组装形成的纳米体系[10]。Jiang等[36]利用ACQ 荧光探针的特性，对石杉碱甲纳米乳（huperzine A-nanoemulsion，HupA-NE）及乳铁蛋白修饰的石杉碱甲纳米乳（lactoferrin-huperzine A-nanoemulsion， Lf-HupA-NE）在大鼠体内的转运进行了示踪。活体成像结果显示，HupA-NE和Lf-HupA-NE经鼻腔给药后，均可通过神经和血液循环转运到脑中。
可溶性微针是近年来研究较多的一类微针，其主要由水溶性高分子材料制备而成，药物分布在针尖的基质中，当微针刺入皮肤后，针尖通过吸收组织液逐渐溶解，并释放出封装的药物[35]。Fu等[26] 将ACQ探针负载于固体脂质纳米粒，进一步将二者一并封装到可溶性微针中，随后追踪固体脂质纳米粒在大鼠不同皮肤部位的透皮扩散情况。活体成像显示，随着时间推移，大鼠不同皮肤部位的荧光强度均逐渐降低，表明负载于纳米载体的ACQ探针因暴露于生物基质而发生荧光猝灭。
Naghibi 等 [37] 将四苯乙烯溴代异丁酸酯 （tetraphenylethene-bromoisobutyrate，TPE-BIB）与 PEG 和肼（hydrazine，Hyd）结合，合成出一种新型刷状聚合物TPE-PEGA-Hyd，其中肼为DOX的结合位点。该聚合物不仅具有PEG的优良特性，还因TPE-BIB 的引入而具备了AIE性能，为药物递送和体内示踪提供了有力的工具。TPE-BIB是能够发出蓝色荧光的AIE荧光团，其荧光强度在聚集状态下显著增强，而DOX在作为药物模型的同时，还具有ACQ特性，其红色荧光在聚集状态下较弱（见 图1）。TPE-PEGA-Hyd-DOX 在肿瘤细胞的低pH 环境中由于肼的裂解而释放DOX。因此，通过该体系410 nm（蓝色）和600 nm（红色）的荧光比率， 可以实现对药物在体内的实时监测。
ACQ是示踪负载型药物和载体粒子的重要技术手段。在许多生物检测中，ACQ效应可减少背景信号，有助于提高检测信噪比。然而，基于ACQ的生物成像不适用于亲水性纳米载体，因为ACQ探针很难被包裹到亲水性基质中，且水分子会迅速吸收到亲水性基质中，导致探针聚集和荧光猝灭。由于ACQ效应依赖于荧光分子的聚集程度，这使得精确的定量分析变得较为复杂。此外，同AIE探针 一样，负载的ACQ探针在体内从纳米载体上释放 行为未必与药物完全一致，这可能会导致对负载型药物的分析不准确。
1.2.3 荧光共振能量转移技术 荧光共振能量转移 （fluorescence resonance energy transfer，FRET）是 2 个荧光团（一个作为供体，另一个作为受体）之间的能量转移过程，当供体的发射光谱与受体的激发光谱在很大程度上重叠，且2种荧光探针之间的距离非常接近时，二者之间就会发生能量转移，处于激发态的供体以非激发方式将能量传递给旁边的受体，使得供体发射的荧光强度衰减，受体荧光分子的荧光强度增加[38]。FRET技术为监测NDDSs的药物释放和载体完整性提供了一种强大的工具 [39]。在实验设计中，将供体和受体分别标记在纳米材料和药物分子上，当药物从纳米材料中释放时，受体与供体之间的距离发生变化，进而引起FRET信号的改变。因此，通过分析FRET信号的变化，不仅 可以用来监测药物的释放，还能够用于指征有机纳米载体的完整性[17, 40]。在选择FRET染料时，通常倾向选择具有近红外范围发射光谱的染料，这是因为近红外光能够更好地穿透细胞和组织，从而避免来自这些生物结构自发荧光的干扰[40]。
Zhong 等[41] 合成了含有TPE的pH响应型纳米复合体，且以DOX作为药物模型。通过监测DOX 与TPE之间的FRET信号变化，在肿瘤细胞内追踪由pH变化触发的DOX动态释放过程。Laskar 等[42] 将 2 种疏水性荧光抗癌药物Cur和喜树碱 （camptothecin，Cpt）分别通过酯键和氧化还原响应型二硫键与PEG连接，成功合成出两亲性的PEG 化前药Cpt-S-S-PEG-Cur。由于前药聚合物能够在水中形成稳定的纳米组装以及Cpt（FRET供体）的发射光谱与Cur（FRET受体）吸收光谱之间的重叠， 供受体之间能够产生FRET信号。在与肿瘤相关的氧化还原环境（存在一定量的GSH）中，这些稳定的纳米组装显示出Cpt的优先释放，导致FRET消失。因此，这种基于GSH响应型FRET的递药系统能够实现以非侵入方式来监测载体中的药物释放。Zhou 等[43] 报道了一种含供体荧光团DAN-聚丙硫醚（polypropylene sulfide，PPS）-mPEG 与受体荧光团DAB-PPS-mPEG的新型氧化响应型聚合物胶束。当活性氧存在时，该胶束中的PPS嵌段发生氧化并分解，导致供体荧光团淬灭，从而触发FRET 过程的改变，这种设计使得药物释放与荧光信号变化直接相关。该研究以尼罗红为模型药物，探究了胶束荧光变化与胶束降解及药物释放之间的关系。
纳米晶在改善水溶性差的药物口服生物利用度方面展现出巨大潜力，然而，关于纳米晶如何提高口服生物利用度的具体机制，目前仍存在一定争议，这主要是由于在研究中无法同时追踪溶解的药物和纳米晶颗粒所导致。目前对此存在2种不同的观点：一是通过纳米晶减小粒径从而改善溶解度；二是通过纳米晶的内吞作用改善口服吸收[44]。Zhang 等[17] 以香豆素6为药物模型制备纳米晶，通过ACQ信号来检测游离的香豆素6，同时将2-((5 (4-( 二苯基氨基)苯基)噻吩-2-基)亚甲基)丙二腈 [2-((5-(4-(dip-tolylamino)phenyl)thiophen-2-yl) methylene)malononitrile，MeTTMN] 掺入香豆素6 构建FRET对，并通过监测FRET信号跟踪纳米晶体颗粒。研究结果表明，该纳米晶体主要通过快速溶解改善药物的口服吸收，成功阐明了纳米晶如何提高药物的口服吸收。
Tengjisi等[38]通过合成2种类型的FRET纳米粒， 成功构建了能够同时监测药物释放与二氧化硅纳米粒降解的系统。该研究中疏水性FRET对（DiO和 DiI）被共同封装在纳米粒核心（FRET@Si NP）， 用作药物替代物以模拟药物包封和药物释放。当 DiO 和DiI 足够接近时，可以观察到来自DiI的 FRET信号。然而，一旦2种染料因药物释放而分离， DiI 信号消失，DiO信号则会出现（见图 2A）。同时，另一组FRET对（Cy3和Cy5）被用于二氧化硅纳米粒的外表面标记（Si@FRET NP），用于监测二氧化硅的降解。当二氧化硅壳完整时，可观察到来自Cy5的FRET信号；随着二氧化硅的降解， Cy3 信号开始增加，而Cy5信号降低（见图 2B）。通过使用这2个FRET纳米系统，药物释放和二氧化硅纳米粒的降解可以被分别监测。
FRET 信号的产生依赖于供体发射光谱与受体吸收光谱的重叠及两者适当的空间配置，这保证了检测的特异性。FRET技术提供了强大的定性分析能力，但其在定量分析方面仍面临着诸多挑战。例如， FRET 效率的计算需要考虑多种因素，包括供体和受体的光谱重叠、荧光寿命、荧光量子产率等，这些均需要复杂的数学模型和校正方法。因此，FRET 技术尚难以实现全面的药代动力学分析。此外， FRET 荧光染料的生物活性也可能会影响NDDSs的药代动力学特性。
1.2.4 碳量子点 碳量子点（carbon quantum dots， CQDs）是一种零维碳纳米材料，具有众多优于有机荧光团的特性[45]。首先，CQDs高度的光稳定性确保了其在各种环境下均能保持稳定的发光性能。其次，CQDs具有可调节发射特性，使其发射波长可根据需要进行调整，从而满足不同的应用场景。再者，CQDs较大的双光子激发截面使其在较低能量激发下也能实现高效发光，有利于降低高能激光对生物组织的损害。此外，CQDs还具有优异的细胞渗透性和生物相容性。Mazandarani等[46]合成了一种壳聚糖-适体-碳量子点（chitosan-aptamer-carbon quantum dot，CS-Apt-CQD）纳米水凝胶，通过乳化法将5-氟尿嘧啶-灵芝酸负载于水凝胶系统中，其中CQD发挥示踪水凝胶的作用。Rahiminezhad等[47] 开发出一种新颖的纳米复合材料，该材料结合了石墨烯量子点（graphene quantum dots，GQDs）和 PLGA，GQD凭借其独特的光致发光特性而被用作荧光探针，以实现对药物递送过程的精确追踪，进而优化索拉非尼的药物递送效果。
CQDs 具有非常稳定的荧光特性，使其在长时间或复杂环境下仍能保持较高的信号强度。目前CQDs的荧光发光波长多为蓝绿色（400 ~ 520 nm），多需要紫外光波激发，存在生物组织穿透深度低、易造成生物组织光损伤的缺点。
1.3 酶联免疫吸附测定技术
酶联免疫吸附测定（enzyme-linked immunosorbent assay，ELISA）是一种经典的生物分析技术，其基于抗原与抗体之间的特异性结合。当一种特定的抗原被加入到样品板的小孔中时，可与相应的抗体结合。这种结合可通过添加酶标记的二抗来检测，该酶可催化一种底物产生颜色、荧光或其他可检测的信号。邓雪等[48]利用ELISA技术，对尿酸酶和尿 酸酶脂质体在大鼠体内的药代动力学行为进行比较， 结果显示，尿酸酶脂质体组的大鼠体内尿酸酶活性更高，且半衰期更长。ELISA具有高灵敏度、高通量的优点，但使用该方法需要针对每种待测物开发特异性的抗体与检测条件，不仅操作繁琐，且成本高昂。此外，ELISA作为间接检测技术，其选择性、动态范围往往不尽如人意[49]。近年来，直接利用 ELISA 技术对NDDSs进行体内分析的研究相对较少，这可能是因为NDDSs的复杂性与多样性使得开发通用的ELISA检测方法变得困难。
1.4 抗聚乙二醇单链可变片段抗体技术
复旦大学占昌友教授课题组开发了一种利用抗 PEG 单链可变片段抗体（anti-PEG single chain variable fragment antibody，PEG-scFv）来分离PEG 化脂质体的技术[50]。scFv 是一类具有小相对分子质量和高抗原结合活性的抗体片段[51]，因其无Fc片段，在纳 米药物表面吸附后，scFv不会引起补体激活[52-53]。PEG-scFv 与 PEG 化脂质体表面的PEG结合后，能够引起PEG化脂质体的沉淀，通过低速离心，易于将沉淀的脂质体与上清液中的游离型药物分离，进而对二者进行后续的定量分析（见图3）。此外， 这项技术也被证明能够用于分离血浆中的PEG化聚合物胶束，从而实现了紫杉醇胶束的稳定性和体内命运的解析[54]。
PEG-scFv 专门针对PEG分子，具有很高的结合特异性，且这种结合不会导致药物载体中的药物泄漏，确保了该分离方法的准确性和效率。因许多纳米药物均使用PEG来增加溶解性、稳定性或减少免疫原性，该技术对于其他种类的PEG化纳米药物也具有很好的应用潜能。
1.5 稳定同位素示踪超滤技术
超滤是一种膜分离技术，主要用于大分子和小分子的分离。超滤法主要依赖于半透膜的微孔结构。当溶液在外界压力作用下流经超滤膜表面时，小于膜孔径的小分子透过膜，而大于膜孔径的物质被截留。对于纳米药物，在超滤过程中存在一个重要的问题，即血浆蛋白结合的药物成分对负载型药物定量准确性的影响[55]。Stern 团队开发了稳定同位素示踪超滤（stable isotope tracer ultrafiltration assay，SITUA）技术，通过将稳定同位素示踪剂加入到含有纳米药物的血浆样本中，对传统的超滤方法进行改进，从而能够更准确地评估血浆蛋白的结合情况[56]。SITUA假设同位素标记的药物与从纳米药物中释放的药物具有相同的蛋白结合行为。该具体过程为：首先将同位素标记的药物（D*）加入到含有纳米药物的血浆中，D*会迅速与血浆蛋白达到结合平衡；然后将血浆样本转移到超滤装置中并通过离心分离，分别检测血浆样本中D*的总浓度 [Total D*]、超滤液中 D* 的浓度[Ultrafiltrate D*]、血浆样本中非同位素标记药物（D）的总浓度[Total D]以及超滤液中D的浓度[Ultrafiltrate D]。通过图4中的公式（1）计算D*的蛋白结合率（%Bound D*）。由于D与D*具有相同的血浆蛋白结合行为，因此D的血浆蛋白结合率等于D*的血浆蛋白结合率。根据图 4中的公式（2）计算游离型药物的浓度[Unencapsulated D]。确定了%Bound D* 和[Unencapsulated D] 后，可以使用图4中的公式（3）计算蛋白结合型D的浓度 [Protein-bound D]，并使用图4 中的公式（4）计算负载型药物的浓度[Encapsulated D][55]。
SITUA 技术已被用来研究白蛋白结合型紫杉醇Abraxane® 及紫杉醇聚合物胶束制剂Genexol®PM 在大鼠中的药代动力学特征，并进行了生物等效性评价。该研究结果发现，尽管Abraxane®和 Genexol®PM 的总药物、游离型药物的浓度-时间曲线几乎相同，但2种制剂游离型药物的药代动力学参数具有显著的统计学差异，而总药物无此差异[57-58]。这也再次证明了只关注总药物浓度的传统分析方法的局限性。
利用SITUA技术可以获得血浆样本中的负载型药物、蛋白结合药物和游离型药物的浓度信息。然而， SITUA 技术是基于稳定同位素标记药物和从纳米药物中释放的药物具有相同血浆蛋白结合行为的假设。实际上，血浆中释放药物的浓度范围较宽，不同浓度下药物的蛋白结合率可能会发生变化，从而导致潜在的准确性问题。因此，在使用此方法之前，需要检验不同浓度下药物的血浆蛋白结合率是否一致。此外，超滤装置的非特异性吸附问题也需要注意。
1.6 磁共振成像技术
磁共振成像（magnetic resonance imaging，MRI） 是一种无创成像技术，具有高分辨率与深组织穿透能力，能够精确捕捉到纳米载体在体内的动态变化[8]。
氧化铁纳米粒（iron oxide nanoparticle，IONP） 由于其独特的磁性和良好的生物相容性被广泛用作MRI造影剂[59]。Stater 等 [60] 将免疫佐剂单磷酰脂质A（monophosphoryl lipid A，MPLA）装载到纳米氧化铁粒菲立莫妥（ferumoxytol，FH）的碳水化合物外壳中，形成FH-MPLA复合物。随后， 将FH-MPLA通过静脉注射到小鼠体内。FH作为纳米载体，能够将药物有效地递送至肿瘤细胞， 同时也作为MRI造影剂，可通过无创成像技术实时监测纳米载体的体内分布。Zhou等[61]设计并合成了一种装载有金丝桃素的锰基树枝状聚合物纳米粒（manganese-based and hypericin-loaded polyester dendrimer nanoparticle，MHD），当 MHD 到达肿瘤部位时，MHD可被肿瘤细胞内化并降解释放出金丝桃素和锰离子。锰离子一方面具有优异的MRI成像性能，另一方面可通过将内源性H2O2转化为毒性 羟基自由基，从而强化金丝桃素的光动力治疗过程。MHD整体显示出良好的成像能力与治疗效果。
MRI 技术能够提供高分辨率的三维成像，这对于纳米载体在体内的行为和分布的研究至关重要。MRI 技术和相关纳米载体的研究涉及复杂的物理学、化学和生物学问题，需要跨学科的知识和技术， 涉及材料科学、生物医学工程、药学等多个领域。MRI 设备及维护成本高昂，对于初期纳米载体的研究和开发造成较高的经济压力。另外，不是所有的纳米材料均适合作为MRI造影剂，需要具有特定的磁学性质，这进一步限制了MRI的应用范围。
2
载体材料分析技术
纳米载体依赖载体材料来维持其结构，从而实现药物递送与控制释放的目的。载体材料不仅能够影响其所负载药物的药代动力学过程，导致药效和毒副作用的改变，也能通过影响机体免疫、代谢等过程，产生新的毒副作用。因此，阐释载体材料的体内命运对于评估NDDSs的安全性具有重要意义。纳米载体包括有机载体和无机载体。尽管无机载体 相关报道很多，但在生物相容性、生物降解性及载药性能等方面有机载体优于无机载体。目前，绝大多数已上市或处于临床阶段的纳米载体均基于有机载体。由于有机载体的组成材料具有生物降解性， 其降解产物较为复杂，且检测过程易受生物基质的干扰。有机载体材料多为高分子聚合物，通常具有多分散的性质，不同相对分子质量的同系物组成和比例千变万化，因此其体内定性、定量分析均具有很大的挑战。下文将对常用的纳米载体材料分析技术进行介绍。
2.1 液相色谱-串联质谱技术
近几十年来LC-MS/MS技术的发展令人瞩目， 不仅在小分子药物的定量分析中展现出高灵敏度， 还在大分子如蛋白质的定量生物分析中逐渐获得更多关注。LC-MS/MS技术具有优异的选择性、良好的准确度与精密度以及更宽的动态范围[62]，使得其在分析复杂生物基质中的待测物时具有更高的可靠性。
小分子纳米载体材料相对分子质量固定，采用基于多反应监测（multiple reaction monitoring， MRM）扫描模式的传统LC-MS/MS技术即可实现其在生物样品中的定量分析，这已是成熟技术体系。然而纳米载体材料多数为高分子聚合物，相对分子质量呈多分散性，在电喷雾质谱中离子化后会形成多电荷离子，进而产生大量的前体离子。上述生物 样品定量分析常用的MRM扫描模式，因其分辨率和扫描速度的局限，无法全面采集到聚合物的质谱信息，导致无法精准分析聚合物纳米材料。Zhou等[63] 开发了一种基于MSALL采集模式的LC-MS/MS技术。该技术采用信息独立采集方式，允许所有PEG前体 离子通过质谱第一个四极杆并进入碰撞池，在碰撞池通过施加适当的碰撞能量从而裂解产生PEG特异性碎片，利用PEG特异性碎片实现对具有多分散相对分子质量和众多前体离子的PEG的绝对定量分析 （见图5）。该项技术的主要优势包括能够全面分析聚合物，具有出色的特异性、高灵敏度和可重复性。基于该技术，Meng等[64]研究了两嵌段共聚物单甲氧基聚乙二醇-聚乳酸[monomethoxy poly(ethylene glycol)-block-poly(D，L-lactic acid)，PEG-PLA] 的大鼠体内命运，包括大鼠静脉注射后的药代动力学、 生物分布、代谢和排泄情况。该研究结果表明， PEG-PLA 原形主要分布在脾脏、肝脏和肾脏，主要通过尿液排泄，其中超过80%以代谢物PEG排出。Ren 等[65] 使用该技术研究了D-α-生育酚聚乙二醇 1000 琥珀酸酯（D-α-tocopheryl polyethylene glycol 1000 succinate，TPGS）及其代谢物PEG1000 在大鼠口服和静脉注射后的药代动力学、组织分布和排泄情况，还考察了TPGS与人肝微粒体中细胞色素 P450 的相互作用。
2.2 放射性同位素标记技术
使用放射性同位素标记技术，能够在体内对纳米材料和载体进行示踪，从而定量研究其生物分布与清除过程[66-67] ，进而评估纳米药物的治疗潜力。
Anane-Adjei 等 [68] 制备了一种经89Zr 标记的超支化聚N-(2-羟丙基)甲基丙烯酰胺[hyperbranched N-(2-hydroxypropyl)methacry-lamide,HPMA]聚合物， 并将其静脉注射到小鼠体内，随后利用正电子发射断层扫描-计算机断层扫描（positron mmission tomography-computedtomography，PET-CT）成像技术来监测聚合物在小鼠体内的实时生物分布。Imlimthan 等[69] 开发了一种177Lu 标记的载有维罗非尼的纤维素纳米晶（cellulose nanocrystal，CNC）颗粒，并通过单光子发射计算机断层成像术（single-photon emission computed tomography，SPECT）对 177Lu-CNC 在肺转移性黑色素瘤小鼠的体内命运进行了示踪。该研究结果显示，随着孵育时间的延长，177Lu-CNC在 肿瘤细胞内的放射性增高，而在48 h后放射性降低。
放射性同位素示踪剂为医学领域提供了强大的监测工具。然而，放射性同位素示踪剂也存在一些不可忽视的缺点，主要集中在成本、安全性以及同位素标记脱落对结果准确性的影响等。
2.3 同步辐射X射线技术
同步辐射X射线技术，凭借其高灵敏度和空间分辨率来研究纳米材料的电子配置、配位几何或氧化状态的能力，已被用于分析纳米材料的体内行为[70]。Yao 等[71] 研究了[Gd@C82(OH)22]n 在巨噬细胞中的分布情况，发现[Gd@C82(OH)22]n主要分布在溶酶体 中。该技术还可以提供高分辨率的三维亚细胞定位， 观察纳米材料在完整细胞中的位置。此外，该技术可根据[Gd@C82(OH)22]n 的密度和分布情况指征纳米材料在3种不同类型的溶酶体中的细胞内转运情况。同样，具有足够样品穿透力的纳米尺度三维成像在研究细胞内纳米材料的分布方面起重要作用，其能够将细胞内纳米材料的积累情况可视化，提供了进 一步研究其生物转化行为的新方向。
3
结语与展望
过去几十年NDDSs的研发投入巨大，但仅有数十个产品上市，这在很大程度上可能归因于对 NDDSs 的体内命运缺乏最基本的认知。NDDSs在复杂生命体系中不仅存在多种形态成分，且多种形态成分之间始终处于动态平衡之中，给其体内命运研究带来极大的技术挑战。本文对近年来用于追踪 NDDSs 体内命运的分析技术进行了综述，希望能够为NDDSs的体内命运研究提供技术参考。
尽管NDDSs体内命运的分析技术已取得一定进展，但仍面临诸多挑战，如检测的分辨率、灵敏度和特异性等方面仍有待提高。此外，目前对NDDSs 体内命运的研究仍主要依赖单一技术或方法，缺乏多种技术综合应用以对其进行系统性研究。质谱具备同时检测药物、载体材料及其代谢物的能力，且具有高灵敏度和高特异性的优势。通过将质谱技术与操作简便、条件温和、分离高效的新型分离技术结合，有可能在同时定量纳米药物的游离型药物、 负载型药物、纳米载体和纳米材料方面进一步取得进展。多种成像技术如同步辐射光源、MRI、荧光成像的结合，有望实现优势互补，从而精准、实时、 动态地观察纳米药物在体内的分布和代谢过程，并从不同角度揭示纳米药物的生物分布和作用机制， 最终获得更全面、更准确的纳米药物体内命运信息。
随着纳米药物体内命运研究的不断深入，研究纳米药物与不同类型细胞（如肿瘤细胞、免疫细胞、 内皮细胞等）之间的相互作用，分析纳米药物在细胞内的分布和运动轨迹，探讨纳米药物与生物大分子之间的相互作用，深化对纳米药物与体内系统相互作用的理解。为实现这些目标，需要克服更多技术挑战， 探索和发展更为高效、灵敏和精准的分析新技术，从而更加全面、深入地揭示NDDSs的体内命运，更高效地推动纳米药物的设计与优化，最终实现纳米药物在临床应用中的疗效最大化与毒副作用最小化。
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美编排版：何裕爽
感谢您阅读《药学进展》微信平台原创好文，也欢迎各位读者转载、引用。本文选自《药学进展》2024年第10期。
《药学进展》杂志由中国药科大学和中国药学会共同主办、国家教育部主管，中国科技核心期刊（中国科技论文统计源期刊）。刊物以反映药学科研领域的新方法、新成果、新进展、新趋势为宗旨，以综述、评述、行业发展报告为特色，以药学学科进展、技术进展、新药研发各环节技术信息为重点，是一本专注于医药科技前沿与产业动态的专业媒体。
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华山绘宏图，渭河颂春秋。2024年11月14日至17日，由中国抗癌协会主办，陕西省抗癌协会和中国整合医学发展战略研究院联合承办的2024中国整合肿瘤学大会（CCHIO）在历史与现代交汇的西安隆重举行。大会聚焦国际视野，设有多个具有高水准的国际合作论坛与专场。其中，学术期刊作为知识传播和学术交流的重要媒介，是学科前沿进展和学术成果的重要传播载体，基于此，中国抗癌协会（CACA）联动NEJM、Lancet、BMJ、Cancer Discovery、Gut等世界顶级期刊，特设国际期刊专场，在此国内外肿瘤领域的专家围绕最新的科研成果与临床技术展开深入探讨。
大会现场
2024年11月16日下午，“国际期刊CACA-Lancet”专场如期举行，该专场由《柳叶刀-区域健康（西太平洋）》主编蔡杰博士担任外方主席，西安国际医学中心医院韩国宏教授、中国医科大学附属第一医院王振宁教授担任中方主席，中国人民解放军空军军医大学第一附属医院潘阳林教授、中国医科大学附属第一医院高鹏教授担任会议秘书长，会中围绕我国专家学者在《柳叶刀》系列期刊发表的优秀科研成果及肿瘤学领域探索前沿进展，交流互鉴、启迪创新。
▲ 蔡杰博士
▲ 韩国宏教授
▲ 王振宁教授
▲ 高鹏教授
▲ 潘阳林教授
《柳叶刀-区域健康（西太平洋）》主编蔡杰博士以《Publishing in the Lancet Journals》为题作主旨演讲。蔡杰博士表示在肿瘤学领域，中国学术产出增长迅速，但在引用影响力方面与美国仍存在差距。柳叶刀肿瘤学委员会为推动全球肿瘤学高质量发展，自2011年起，针对癌症防控相关问题发布多份报告，为各国癌症控制政策制定和实践改进提供科学依据和建议。未来还将举办癌症防控峰会，涵盖多癌种研究成果展示与交流。
此外，作为《柳叶刀-区域健康（西太平洋）》主编，蔡杰博士介绍道，《柳叶刀-区域健康（西太平洋）》聚焦内容广泛，涉及区域内的紧急护理、传染病防控、慢性病管理、卫生政策制定以及癌症防控等诸多关键领域，关注地区间健康差异与不平等现象，为地区健康政策优化和学术研究提供了丰富且关键的参考依据，对推动西太平洋地区乃至全球医学进步和健康事业发展发挥着不可替代的重要作用。
▲ 蔡杰博士
香港中文大学陈家亮教授以胃肠病学领域的重要期刊Gastroenterology为例，结合团队研究开展及文章发表经验，对如何开展高质量研究及提升文章接收率提出了相关建议。陈教授表示，2023年不同国家/地区向Gastroenterology投稿的接收率和拒稿率不同。其中，中国拒稿率为91.5%，而美国拒稿率为71.3%。分析主要原因在于，文章类型与期刊偏好不符，Gastroenterology更青睐于临床研究，而中国投稿中病例报告等占比较高，此外，还包括研究临床价值、创新性、方法描述等方面因素。
对此，陈教授提出提升投稿成功率需多方面努力。首先，研究类型上，开展有转化意义的基础研究。其次，方法描述应平衡实验室与临床部分，使用新技术时确保方法合理、统计比较完善。第三，论文写作时，讨论部分要清晰呈现研究各要素。投稿信要简洁有力，阐明研究的临床价值、创新性及与期刊使命契合度。相关团队经验分享为中国投稿者提供了新的研究思路和范例。
▲ 陈家亮教授
中山大学肿瘤防治中心刘需教授分享了团队在《柳叶刀》在线发表的针对鼻咽癌防治的CONTINUUM研究的主要结果，该研究旨在探索在标准放化疗基础上联合国产创新药信迪利单抗及诱导化疗-同步放化疗治疗高危局部晚期鼻咽癌的疗效。刘教授表示，现有局部晚期鼻咽癌（LANPC）标准治疗方案仍会使20%患者出现复发/转移，需要新的治疗方法来改善预后。既往研究表明，PD-1抗体联合化疗是复发/转移性鼻咽癌患者标准一线治疗方案，但在LANPC中的作用尚未明确。
基于此，团队开展了这项多中心、开放标签、平行分组、随机对照、Ⅲ期临床研究。研究结果显示，信迪利单抗组在EFS、DMFS和LRRFS方面表现更优，疾病复发或死亡风险显著降低，但OS目前未见显著差异。安全性层面，信迪利单抗组不良事件较多但可控。生物标志物分析发现Ki67+Treg细胞与免疫治疗相关。该研究证实了信迪利单抗联合放化疗用于高危LANPC患者治疗的疗效，已被指南采纳，为LANPC治疗提供了新策略，未来可深入研究免疫治疗精准策略，如进一步探索生物标志物，以及开展靶向Treg细胞的相关探索研究等，以期改善鼻咽癌临床实践。
▲ 刘需教授
北京大学肿瘤医院季科教授分享了团队在《柳叶刀·肿瘤学》（The Lancet Oncology）在线发表的卡度尼利单抗治疗晚期实体瘤的Ⅰb/Ⅱ期研究（COMPASSION-03）结果，旨在评估卡度尼利单药治疗晚期实体瘤和联合化疗治疗晚期不可切除或转移性胃或胃食管结合部（G/GEJ）腺癌的疗效与安全性。季科教授表示，既往研究表明，免疫治疗中，PD-1单药疗效有限，PD-1与CTLA-4联合治疗效果更好，卡度尼利单抗作为一种首创的双特异性抗体，可同时靶向PD-1和CTLA-4，有望增强免疫治疗效果并改善安全性。研究结果表明，不同癌种接受卡度尼利单药治疗的ORR、DCR和生存数据存在差异，如宫颈癌队列ORR达32.3%，食管鳞状细胞癌队列中位PFS为3.5个月等。安全性层面，未现剂量限制性毒性，不良事件可控，虽有一定比例严重不良事件及停药情况，但无免疫相关不良事件致死。由此可见，卡度尼利单抗安全性可控、抗肿瘤活性良好，但研究仍存在样本量和缺乏随机对照组等局限。目前其治疗宫颈癌的随机对照试验正在进行中，多种实体瘤临床研究正在开展，且已在中国获批用于治疗晚期宫颈癌，未来有望为晚期实体瘤治疗带来更多选择。
▲ 季科教授
本环节最后，由中国医科大学宋永喜教授、复旦大学附属华山医院罗忠光教授参与讨论。
▲ 宋永喜教授
▲ 罗忠光教授
Session2 学术争鸣 启迪新思
西安国际医学中心医院赵艳教授分享了肝细胞癌（HCC）治疗领域的两项重要研究成果，SELECT研究和LEAP012研究。SELECT研究针对的是晚期HCC患者（BCLC C期）展开。赵艳教授表示，索拉非尼曾作为晚期HCC的一线治疗手段，但疗效并不理想。此前多项研究探索肝动脉化疗栓塞（TACE）联合索拉非尼治疗晚期HCC疗效，结果仍不尽人意，且试验设计存在缺陷。SELECT研究旨在解决这些问题，研究纳入符合条件的患者，随机分为TACE联合索拉非尼组与索拉非尼单药组。在意向性治疗（ITT）人群中，两组OS未显示出显著差异，但按符合试验方案（PP）和实际治疗（as-treated, AT）人群进行分析，联合治疗组的OS、PFS和TTP显著优于单药组。这表明在晚期HCC治疗中，联合治疗策略具有重要意义，同时也强调了后续治疗对结果评估的影响以及不同分析方法的必要性。
LEAP012研究对比了仑伐替尼+帕博利珠单抗+TACE与安慰剂+TACE治疗中期HCC的疗效。研究结果显示，联合治疗组PFS显著优于对照组，且ORR、DCR等次要终点也表现出优势。尽管OS的改善趋势尚需更长时间的随访来确定，但目前的结果已显示出良好的前景。这一研究表明，ICIs与酪氨酸激酶抑制剂（TKI）联合TACE或可为不可切除HCC患者带来新的治疗选择，标志着不可切除HCC局部联合全身系统性治疗时代的到来。上述两项研究均为不可切除HCC治疗领域取得的重要进展，为不可切除HCC的治疗提供了新的思路和证据。
▲ 赵艳教授
中国医科大学附属第一医院肖琼教授分享了可解释性多模态人工智能模型（iSCLM）预测局部晚期胃癌新辅助化疗疗效研究相关进展。肖琼教授表示，局部进展期胃癌患者预后较差，新辅助化疗（NAC）是常用治疗策略，但部分患者对NAC不敏感，因此术前准确预测疗效对优化治疗方案至关重要。目前常用的预测方法如RECIST标准评估疗效存在局限性，临床亟需更有效的预测工具。
研究采用多中心回顾性研究设计，基于患者的临床病理特征数据构建了一系列基于增量学习的模型，包括iRM（基于放射学）、iPM（基于病理学）、iRPM（基于放射学与病理学特征）以及创新的iSCLM模型。研究结果显示，iSCLM模型在外部测试队列和前瞻性队列中表现出色，可纠正其他模型预测，其关注区域与肿瘤浸润边界相关，生物学验证发现应答者和非应答者存在多方面差异，生存分析表明iSCLM预测的应答者治疗后预后较好。综上，iSCLM模型有助于胃癌治疗临床决策，能整合多模态数据提高预测能力，胃癌新辅助化疗研究提供了重要参考，未来有望进一步改善胃癌患者的临床疗效。
▲ 肖琼教授
上海交通大学医学院附属胸科医院郝秀秀教授分享了一项颈静脉压监测下无静脉重建的胸腺上皮肿瘤手术切除探索研究。郝秀秀教授表示，根治性切除是影响胸腺上皮肿瘤预后的重要因素。肿瘤侵犯上腔静脉（SVC）和无名静脉时，传统治疗方案需进行SVC切除及静脉重建以恢复血液回流、预防严重不良反应，但该手术技术难度大且患者需接受终身抗凝治疗。基于此开展此项研究，该研究纳入可能需静脉切除重建的胸腺上皮肿瘤患者，回顾性队列36例未监测颈静脉压（IJVP）均行上腔静脉（SVC）切除重建；前瞻性队列27例监测IJVP，根据其结果决定SVC切除后是否重建。结果显示，前瞻性队列中部分患者SVC切除后未重建且安全，回顾性队列中有1例重建患者术后出现脑水肿死亡。重建与不重建患者基线特征和手术难度无显著差异，但不重建组手术时间短、失血量少、并发症少、死亡率低。综上，该项研究结果表明SVC切除后不重建具有缩短手术时间、减少术中失血、降低围手术期并发症风险和避免长期使用抗凝剂等优势。术中IJVP监测可指导手术方式选择，这种新策略安全可行，为胸腺上皮肿瘤手术治疗提供了新方向，有望改善患者治疗效果和预后。
▲ 郝秀秀教授
本环节最后，西安交通大学第一附属医院张谞丰教授、西安交通大学第二附属医院郭卉教授参与讨论。
▲ 张谞丰教授
▲ 郭卉教授
总结
《柳叶刀》作为国际享负盛名的综合医学期刊，一直致力于推动科学为大众所用，让医学服务社会、改造社会，并积极影响人们的生活。近年，随着中国在生物医学领域科研投入加大，越来越多中国研究者在《柳叶刀》系列期刊上发表优秀科研成果，《柳叶刀》与中国科研机构的合作也在不断加强。期待未来，有更多来自于中国研究者的高质量研究成果登上国际舞台，展现肿瘤学领域的大国实力。
专家合影
（来源：《肿瘤瞭望》编辑部）
声 明
凡署名原创的文章版权属《肿瘤瞭望》所有，欢迎分享、转载。本文仅供医疗卫生专业人士了解最新医药资讯参考使用，不代表本平台观点。该等信息不能以任何方式取代专业的医疗指导，也不应被视为诊疗建议，如果该信息被用于资讯以外的目的，本站及作者不承担相关责任。
2024-11-15
PRINCETON, N.J.--(
BUSINESS WIRE
)--
Bristol Myers Squibb
(NYSE: BMY) today announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has recommended approval of
Opdivo
®
(nivolumab) plus
Yervoy
®
(ipilimumab)
for the first-line treatment of adult patients with microsatellite instability–high (MSI-H) or mismatch repair deficient (dMMR) unresectable or metastatic colorectal cancer (mCRC). Of significance, the CheckMate -8HW trial results showed reduction in the risk of disease progression or death by 79% (HR: 0.21; 95% CI: 0.14-0.32; p<0.0001) compared to chemotherapy in this patient population. The European Commission (EC), which has the authority to approve medicines for the European Union (EU), will now review the recommendation and make their decision.
“Approximately 5-7% of metastatic colorectal cancer patients have dMMR or MSI-H tumors, and current treatment options often do not provide sufficient benefit,” said Dana Walker, M.D., M.S.C.E., vice president, global program lead, gastrointestinal and genitourinary cancers, Bristol Myers Squibb. “This is the first dual checkpoint inhibitor treatment for first-line metastatic colorectal cancer, delivering a transformative benefit for MSI-H/dMMR patients in this population. We are focused on bringing
Opdivo
plus
Yervoy
to these patients in the European Union and look forward to EC’s upcoming decision.”
The positive opinion is based on results from the CheckMate -8HW trial, which were presented at medical congresses earlier this year. These data formed the basis for the Company’s Type II variation application, which was validated by the
European Medicines Agency (EMA)
. In the study,
Opdivo
plus
Yervoy
demonstrated a statistically significant and clinically meaningful improvement in the dual primary endpoint of progression-free survival (PFS) compared to the investigator’s choice of chemotherapy as assessed by Blinded Independent Central Review. In addition to the risk of disease progression or death the results noted, the safety profile for the dual immunotherapy combination remained consistent with previously reported data and was manageable with established protocols, with no new safety signals identified.
In October 2024, it was announced that
Opdivo
plus
Yervoy
also demonstrated a statistically significant and clinically meaningful improvement in the dual endpoint of PFS per BICR compared to
Opdivo
monotherapy across all lines of therapy. The study is ongoing to assess various secondary endpoints, including overall survival (OS).
Bristol Myers Squibb thanks the patients and investigators involved in the CheckMate -8HW clinical trial.
About CheckMate -8HW
CheckMate -8HW (NCT04008030) is a Phase 3 randomized, open-label trial evaluating
Opdivo
plus
Yervoy
compared to
Opdivo
alone or the investigator’s choice chemotherapy (mFOLFOX-6 or FOLFIRI with or without bevacizumab or cetuximab) in patients with microsatellite instability–high (MSI-H) or mismatch repair deficient (dMMR) unresectable or metastatic colorectal cancer (mCRC).
839 patients were randomized to receive either
Opdivo
monotherapy (
Opdivo
240 mg Q2W for six doses, followed by
Opdivo
480 mg Q4W),
Opdivo
plus
Yervoy (Opdivo
240 mg plus
Yervoy
1 mg/kg Q3W for four doses, followed by
Opdivo
480 mg Q4W
),
or investigator’s choice of chemotherapy. The dual primary endpoints of the trial are progression-free survival (PFS) per blinded independent central review (BICR) for
Opdivo
plus
Yervoy
compared to investigator’s choice of chemotherapy in the firstline setting and PFS per BICR for
Opdivo
plus
Yervoy
compared to
Opdivo
alone across all lines of therapy.
CheckMate-8HW has also met its other dual primary point of PFS per BICR
Opdivo
plus
Yervoy
compared to
Opdivo
across all lines therapy in randomized subjects with centrally confirmed MSI-H/dMMR mCRC at the second interim analysis in September 2024, and data disclosure is planned for an upcoming medical conference. The trial also evaluates several secondary safety and efficacy endpoints, including overall survival, which is ongoing.
About dMMR or MSI-H Colorectal Cancer
Colorectal cancer (CRC) is cancer that develops in the colon or the rectum, which are part of the body’s digestive or gastrointestinal system. CRC is the third most commonly diagnosed cancer in the world. In 2020, it is estimated that there were approximately 1,931,000 new cases of the disease; it is the second leading cause of cancer-related deaths among men and women combined.
Mismatch repair deficiency (dMMR) occurs when the proteins that repair mismatch errors in DNA replication are missing or non-functional, leading to microsatellite instability-high (MSI-H) tumors. Approximately 5-7% of metastatic CRC patients have dMMR or MSI-H tumors. These patients are less likely to benefit from conventional chemotherapy and typically have a poor prognosis.
Bristol Myers Squibb: Creating a Better Future for People with Cancer
Bristol Myers Squibb is inspired by a single vision — transforming patients’ lives through science. The goal of the company’s cancer research is to deliver medicines that offer each patient a better, healthier life and to make cure a possibility. Building on a legacy across a broad range of cancers that have changed survival expectations for many, Bristol Myers Squibb researchers are exploring new frontiers in personalized medicine and, through innovative digital platforms, are turning data into insights that sharpen their focus. Deep understanding of causal human biology, cutting-edge capabilities and differentiated research programs uniquely position the company to approach cancer from every angle.
Cancer can have a relentless grasp on many parts of a patient’s life, and Bristol Myers Squibb is committed to taking actions to address all aspects of care, from diagnosis to survivorship. As a leader in cancer care, Bristol Myers Squibb is working to empower all people with cancer to have a better future.
About
Opdivo
Opdivo
is a programmed death-1 (PD-1) immune checkpoint inhibitor that is designed to uniquely harness the body’s own immune system to help restore anti-tumor immune response. By harnessing the body’s own immune system to fight cancer,
Opdivo
has become an important treatment option across multiple cancers.
Opdivo
’s leading global development program is based on Bristol Myers Squibb’s scientific expertise in the field of Immuno-Oncology and includes a broad range of clinical trials across all phases, including Phase 3, in a variety of tumor types. To date, the
Opdivo
clinical development program has treated more than 35,000 patients. The
Opdivo
trials have contributed to gaining a deeper understanding of the potential role of biomarkers in patient care, particularly regarding how patients may benefit from
Opdivo
across the continuum of PD-L1 expression.
In July 2014,
Opdivo
was the first PD-1 immune checkpoint inhibitor to receive regulatory approval anywhere in the world.
Opdivo
is currently approved in more than 65 countries, including the United States, the European Union, Japan and China. In October 2015, the Company’s
Opdivo
and
Yervoy
combination regimen was the first Immuno-Oncology combination to receive regulatory approval for the treatment of metastatic melanoma and is currently approved in more than 50 countries, including the United States and the European Union.
About
Yervoy
Yervoy
is a recombinant, human monoclonal antibody that binds to the cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4). CTLA-4 is a negative regulator of T-cell activity.
Yervoy
binds to CTLA-4 and blocks the interaction of CTLA-4 with its ligands, CD80/CD86. Blockade of CTLA-4 has been shown to augment T-cell activation and proliferation, including the activation and proliferation of tumor infiltrating T-effector cells. Inhibition of CTLA-4 signaling can also reduce T-regulatory cell function, which may contribute to a general increase in T-cell responsiveness, including the anti-tumor immune response. On March 25, 2011, the U.S. Food and Drug Administration (FDA) approved
Yervoy
3 mg/kg monotherapy for patients with unresectable or metastatic melanoma.
Yervoy
is approved for unresectable or metastatic melanoma in more than 50 countries. There is a broad, ongoing development program in place for
Yervoy
spanning multiple tumor types.
INDICATIONS
OPDIVO® (nivolumab), as a single agent, is indicated for the treatment of adult and pediatric patients 12 years and older with unresectable or metastatic melanoma.
OPDIVO® (nivolumab), in combination with YERVOY® (ipilimumab), is indicated for the treatment of adult and pediatric patients 12 years and older with unresectable or metastatic melanoma.
OPDIVO® is indicated for the adjuvant treatment of adult and pediatric patients 12 years and older with completely resected Stage IIB, Stage IIC, Stage III, or Stage IV melanoma.
OPDIVO® (nivolumab), in combination with platinum-doublet chemotherapy, is indicated as neoadjuvant treatment of adult patients with resectable (tumors ≥4 cm or node positive) non-small cell lung cancer (NSCLC).
OPDIVO® (nivolumab) in combination with platinum-doublet chemotherapy, is indicated for neoadjuvant treatment of adult patients with resectable (tumors ≥4 cm or node positive) non-small cell lung cancer (NSCLC) and no known epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) rearrangements, followed by single-agent OPDIVO® as adjuvant treatment after surgery.
OPDIVO® (nivolumab), in combination with YERVOY® (ipilimumab), is indicated for the first-line treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors express PD-L1 (≥1%) as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations.
OPDIVO® (nivolumab), in combination with YERVOY® (ipilimumab) and 2 cycles of platinum-doublet chemotherapy, is indicated for the first-line treatment of adult patients with metastatic or recurrent non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations.
OPDIVO® (nivolumab) is indicated for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving OPDIVO.
OPDIVO® (nivolumab), in combination with YERVOY® (ipilimumab), is indicated for the first-line treatment of adult patients with unresectable malignant pleural mesothelioma (MPM).
OPDIVO® (nivolumab), in combination with YERVOY® (ipilimumab), is indicated for the first-line treatment of adult patients with intermediate or poor risk advanced renal cell carcinoma (RCC).
OPDIVO® (nivolumab), in combination with cabozantinib, is indicated for the first-line treatment of adult patients with advanced renal cell carcinoma (RCC).
OPDIVO® (nivolumab) is indicated for the treatment of adult patients with advanced renal cell carcinoma (RCC) who have received prior anti-angiogenic therapy.
OPDIVO® (nivolumab) is indicated for the treatment of adult patients with classical Hodgkin lymphoma (cHL) that has relapsed or progressed after autologous hematopoietic stem cell transplantation (HSCT) and brentuximab vedotin or after 3 or more lines of systemic therapy that includes autologous HSCT. This indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.
OPDIVO® (nivolumab) is indicated for the treatment of adult patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) with disease progression on or after platinum-based therapy.
OPDIVO® (nivolumab) is indicated for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.
OPDIVO® (nivolumab), as a single agent, is indicated for the adjuvant treatment of adult patients with urothelial carcinoma (UC) who are at high risk of recurrence after undergoing radical resection of UC.
OPDIVO® (nivolumab), in combination with cisplatin and gemcitabine, is indicated as first-line treatment for adult patients with unresectable or metastatic urothelial carcinoma.
OPDIVO® (nivolumab), as a single agent, is indicated for the treatment of adult and pediatric (12 years and older) patients with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (CRC) that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.
OPDIVO® (nivolumab), in combination with YERVOY® (ipilimumab), is indicated for the treatment of adult and pediatric patients 12 years and older with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (CRC) that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.
OPDIVO® (nivolumab), in combination with YERVOY® (ipilimumab), is indicated for the treatment of adult patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.
OPDIVO® (nivolumab) is indicated for the treatment of adult patients with unresectable advanced, recurrent or metastatic esophageal squamous cell carcinoma (ESCC) after prior fluoropyrimidine- and platinum-based chemotherapy.
OPDIVO® (nivolumab) is indicated for the adjuvant treatment of completely resected esophageal or gastroesophageal junction cancer with residual pathologic disease in adult patients who have received neoadjuvant chemoradiotherapy (CRT).
OPDIVO® (nivolumab), in combination with fluoropyrimidine- and platinum-containing chemotherapy, is indicated for the first-line treatment of adult patients with unresectable advanced or metastatic esophageal squamous cell carcinoma (ESCC).
OPDIVO® (nivolumab), in combination with YERVOY® (ipilimumab), is indicated for the first-line treatment of adult patients with unresectable advanced or metastatic esophageal squamous cell carcinoma (ESCC).
OPDIVO® (nivolumab), in combination with fluoropyrimidine- and platinum-containing chemotherapy, is indicated for the treatment of adult patients with advanced or metastatic gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma.
IMPORTANT SAFETY INFORMATION
Severe and Fatal Immune-Mediated Adverse Reactions
Immune-mediated adverse reactions listed herein may not include all possible severe and fatal immune-mediated adverse reactions.
Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue. While immune-mediated adverse reactions usually manifest during treatment, they can also occur after discontinuation of OPDIVO or YERVOY. Early identification and management are essential to ensure safe use of OPDIVO and YERVOY. Monitor for signs and symptoms that may be clinical manifestations of underlying immune-mediated adverse reactions. Evaluate clinical chemistries including liver enzymes, creatinine, adrenocorticotropic hormone (ACTH) level, and thyroid function at baseline and periodically during treatment with OPDIVO and before each dose of YERVOY. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.
Withhold or permanently discontinue OPDIVO and YERVOY depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information). In general, if OPDIVO or YERVOY interruption or discontinuation is required, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose immune-mediated adverse reactions are not controlled with corticosteroid therapy. Toxicity management guidelines for adverse reactions that do not necessarily require systemic steroids (e.g., endocrinopathies and dermatologic reactions) are discussed below.
Immune-Mediated Pneumonitis
OPDIVO and YERVOY can cause immune-mediated pneumonitis. The incidence of pneumonitis is higher in patients who have received prior thoracic radiation. In patients receiving OPDIVO monotherapy, immune- mediated pneumonitis occurred in 3.1% (61/1994) of patients, including Grade 4 (<0.1%), Grade 3 (0.9%), and Grade 2 (2.1%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, immune- mediated pneumonitis occurred in 7% (31/456) of patients, including Grade 4 (0.2%), Grade 3 (2.0%), and Grade 2 (4.4%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, immune- mediated pneumonitis occurred in 3.9% (26/666) of patients, including Grade 3 (1.4%) and Grade 2 (2.6%). In NSCLC patients receiving OPDIVO 3 mg/kg every 2 weeks with YERVOY 1 mg/kg every 6 weeks, immune- mediated pneumonitis occurred in 9% (50/576) of patients, including Grade 4 (0.5%), Grade 3 (3.5%), and Grade 2 (4.0%). Four patients (0.7%) died due to pneumonitis.
In Checkmate 205 and 039, pneumonitis, including interstitial lung disease, occurred in 6.0% (16/266) of patients receiving OPDIVO. Immune-mediated pneumonitis occurred in 4.9% (13/266) of patients receiving OPDIVO, including Grade 3 (n=1) and Grade 2 (n=12).
Immune-Mediated Colitis
OPDIVO and YERVOY can cause immune-mediated colitis, which may be fatal. A common symptom included in the definition of colitis was diarrhea. Cytomegalovirus (CMV) infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. In patients receiving OPDIVO monotherapy, immune-mediated colitis occurred in 2.9% (58/1994) of patients, including Grade 3 (1.7%) and Grade 2 (1%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, immune-mediated colitis occurred in 25% (115/456) of patients, including Grade 4 (0.4%), Grade 3 (14%) and Grade 2 (8%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, immune-mediated colitis occurred in 9% (60/666) of patients, including Grade 3 (4.4%) and Grade 2 (3.7%).
Immune-Mediated Hepatitis and Hepatotoxicity
OPDIVO and YERVOY can cause immune-mediated hepatitis. In patients receiving OPDIVO monotherapy, immune-mediated hepatitis occurred in 1.8% (35/1994) of patients, including Grade 4 (0.2%), Grade 3 (1.3%), and Grade 2 (0.4%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, immune- mediated hepatitis occurred in 15% (70/456) of patients, including Grade 4 (2.4%), Grade 3 (11%), and Grade 2 (1.8%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, immune-mediated hepatitis occurred in 7% (48/666) of patients, including Grade 4 (1.2%), Grade 3 (4.9%), and Grade 2 (0.4%).
OPDIVO in combination with cabozantinib can cause hepatic toxicity with higher frequencies of Grade 3 and 4 ALT and AST elevations compared to OPDIVO alone. Consider more frequent monitoring of liver enzymes as compared to when the drugs are administered as single agents. In patients receiving OPDIVO and cabozantinib, Grades 3 and 4 increased ALT or AST were seen in 11% of patients.
Immune-Mediated Endocrinopathies
OPDIVO and YERVOY can cause primary or secondary adrenal insufficiency, immune-mediated hypophysitis, immune-mediated thyroid disorders, and Type 1 diabetes mellitus, which can present with diabetic ketoacidosis. Withhold OPDIVO and YERVOY depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information). For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism; initiate hormone replacement as clinically indicated. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism; initiate hormone replacement or medical management as clinically indicated. Monitor patients for hyperglycemia or other signs and symptoms of diabetes; initiate treatment with insulin as clinically indicated.
In patients receiving OPDIVO monotherapy, adrenal insufficiency occurred in 1% (20/1994), including Grade 3 (0.4%) and Grade 2 (0.6%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, adrenal insufficiency occurred in 8% (35/456), including Grade 4 (0.2%), Grade 3 (2.4%), and Grade 2 (4.2%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, adrenal insufficiency occurred in 7% (48/666) of patients, including Grade 4 (0.3%), Grade 3 (2.5%), and Grade 2 (4.1%). In patients receiving OPDIVO and cabozantinib, adrenal insufficiency occurred in 4.7% (15/320) of patients, including Grade 3 (2.2%) and Grade 2 (1.9%).
In patients receiving OPDIVO monotherapy, hypophysitis occurred in 0.6% (12/1994) of patients, including Grade 3 (0.2%) and Grade 2 (0.3%).
In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, hypophysitis occurred in 9% (42/456), including Grade 3 (2.4%) and Grade 2 (6%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, hypophysitis occurred in 4.4% (29/666) of patients, including Grade 4 (0.3%), Grade 3 (2.4%), and Grade 2 (0.9%).
In patients receiving OPDIVO monotherapy, thyroiditis occurred in 0.6% (12/1994) of patients, including Grade 2 (0.2%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, thyroiditis occurred in 2.7% (22/666) of patients, including Grade 3 (4.5%) and Grade 2 (2.2%).
In patients receiving OPDIVO monotherapy, hyperthyroidism occurred in 2.7% (54/1994) of patients, including Grade 3 (<0.1%) and Grade 2 (1.2%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, hyperthyroidism occurred in 9% (42/456) of patients, including Grade 3 (0.9%) and Grade 2 (4.2%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, hyperthyroidism occurred in 12% (80/666) of patients, including Grade 3 (0.6%) and Grade 2 (4.5%).
In patients receiving OPDIVO monotherapy, hypothyroidism occurred in 8% (163/1994) of patients, including Grade 3 (0.2%) and Grade 2 (4.8%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, hypothyroidism occurred in 20% (91/456) of patients, including Grade 3 (0.4%) and Grade 2 (11%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, hypothyroidism occurred in 18% (122/666) of patients, including Grade 3 (0.6%) and Grade 2 (11%).
In patients receiving OPDIVO monotherapy, diabetes occurred in 0.9% (17/1994) of patients, including Grade 3 (0.4%) and Grade 2 (0.3%), and 2 cases of diabetic ketoacidosis. In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, diabetes occurred in 2.7% (15/666) of patients, including Grade 4 (0.6%), Grade 3 (0.3%), and Grade 2 (0.9%).
Immune-Mediated Nephritis with Renal Dysfunction
OPDIVO and YERVOY can cause immune-mediated nephritis. In patients receiving OPDIVO monotherapy, immune-mediated nephritis and renal dysfunction occurred in 1.2% (23/1994) of patients, including Grade 4 (<0.1%), Grade 3 (0.5%), and Grade 2 (0.6%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, immune-mediated nephritis with renal dysfunction occurred in 4.1% (27/666) of patients, including Grade 4 (0.6%), Grade 3 (1.1%), and Grade 2 (2.2%).
Immune-Mediated Dermatologic Adverse Reactions
OPDIVO can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug rash with eosinophilia and systemic symptoms (DRESS) has occurred with PD-1/PD-L1 blocking antibodies. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate nonexfoliative rashes.
YERVOY can cause immune-mediated rash or dermatitis, including bullous and exfoliative dermatitis, SJS, TEN, and DRESS. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-bullous/exfoliative rashes.
Withhold or permanently discontinue OPDIVO and YERVOY depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information).
In patients receiving OPDIVO monotherapy, immune-mediated rash occurred in 9% (171/1994) of patients, including Grade 3 (1.1%) and Grade 2 (2.2%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, immune-mediated rash occurred in 28% (127/456) of patients, including Grade 3 (4.8%) and Grade 2 (10%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, immune-mediated rash occurred in 16% (108/666) of patients, including Grade 3 (3.5%) and Grade 2 (4.2%).
Other Immune-Mediated Adverse Reactions
The following clinically significant immune-mediated adverse reactions occurred at an incidence of <1% (unless otherwise noted) in patients who received OPDIVO monotherapy or OPDIVO in combination with YERVOY or were reported with the use of other PD-1/PD-L1 blocking antibodies. Severe or fatal cases have been reported for some of these adverse reactions:
cardiac/vascular:
myocarditis, pericarditis, vasculitis;
nervous system:
meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barré syndrome, nerve paresis, autoimmune neuropathy;
ocular:
uveitis, iritis, and other ocular inflammatory toxicities can occur;
gastrointestinal:
pancreatitis to include increases in serum amylase and lipase levels, gastritis, duodenitis;
musculoskeletal and connective tissue:
myositis/polymyositis, rhabdomyolysis, and associated sequelae including renal failure, arthritis, polymyalgia rheumatica;
endocrine:
hypoparathyroidism;
other (hematologic/immune):
hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis (HLH), systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection, other transplant (including corneal graft) rejection.
In addition to the immune-mediated adverse reactions listed above, across clinical trials of YERVOY monotherapy or in combination with OPDIVO, the following clinically significant immune-mediated adverse reactions, some with fatal outcome, occurred in <1% of patients unless otherwise specified:
nervous system:
autoimmune neuropathy (2%), myasthenic syndrome/myasthenia gravis, motor dysfunction;
cardiovascular:
angiopathy, temporal arteritis;
ocular:
blepharitis, episcleritis, orbital myositis, scleritis;
gastrointestinal:
pancreatitis (1.3%);
other (hematologic/immune):
conjunctivitis, cytopenias (2.5%), eosinophilia (2.1%), erythema multiforme, hypersensitivity vasculitis, neurosensory hypoacusis, psoriasis.
Some ocular IMAR cases can be associated with retinal detachment. Various grades of visual impairment, including blindness, can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada–like syndrome, which has been observed in patients receiving OPDIVO and YERVOY, as this may require treatment with systemic corticosteroids to reduce the risk of permanent vision loss.
Infusion-Related Reactions
OPDIVO and YERVOY can cause severe infusion-related reactions. Discontinue OPDIVO and YERVOY in patients with severe (Grade 3) or life-threatening (Grade 4) infusion-related reactions. Interrupt or slow the rate of infusion in patients with mild (Grade 1) or moderate (Grade 2) infusion-related reactions. In patients receiving OPDIVO monotherapy as a 60-minute infusion, infusion-related reactions occurred in 6.4% (127/1994) of patients. In a separate trial in which patients received OPDIVO monotherapy as a 60-minute infusion or a 30- minute infusion, infusion-related reactions occurred in 2.2% (8/368) and 2.7% (10/369) of patients, respectively. Additionally, 0.5% (2/368) and 1.4% (5/369) of patients, respectively, experienced adverse reactions within 48 hours of infusion that led to dose delay, permanent discontinuation or withholding of OPDIVO. In melanoma patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, infusion-related reactions occurred in 2.5% (10/407) of patients. In HCC patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, infusion-related reactions occurred in 8% (4/49) of patients. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, infusion-related reactions occurred in 5.1% (28/547) of patients. In MSI- H/dMMR mCRC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, infusion-related reactions occurred in 4.2% (5/119) of patients. In MPM patients receiving OPDIVO 3 mg/kg every 2 weeks with YERVOY 1 mg/kg every 6 weeks, infusion-related reactions occurred in 12% (37/300) of patients.
Complications of Allogeneic Hematopoietic Stem Cell Transplantation
Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treated with OPDIVO or YERVOY. Transplant-related complications include hyperacute graft-versus-host-disease (GVHD), acute GVHD, chronic GVHD, hepatic veno-occlusive disease (VOD) after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between OPDIVO or YERVOY and allogeneic HSCT.
Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefit versus risks of treatment with OPDIVO and YERVOY prior to or after an allogeneic HSCT.
Embryo-Fetal Toxicity
Based on its mechanism of action and findings from animal studies, OPDIVO and YERVOY can cause fetal harm when administered to a pregnant woman. The effects of YERVOY are likely to be greater during the second and third trimesters of pregnancy. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with OPDIVO and YERVOY and for at least 5 months after the last dose.
Increased Mortality in Patients with Multiple Myeloma when OPDIVO is Added to a Thalidomide Analogue and Dexamethasone
In randomized clinical trials in patients with multiple myeloma, the addition of OPDIVO to a thalidomide analogue plus dexamethasone resulted in increased mortality. Treatment of patients with multiple myeloma with a PD-1 or PD-L1 blocking antibody in combination with a thalidomide analogue plus dexamethasone is not recommended outside of controlled clinical trials.
Lactation
There are no data on the presence of OPDIVO or YERVOY in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment and for 5 months after the last dose.
Serious Adverse Reactions
In Checkmate 037, serious adverse reactions occurred in 41% of patients receiving OPDIVO (n=268). Grade 3 and 4 adverse reactions occurred in 42% of patients receiving OPDIVO. The most frequent Grade 3 and 4 adverse drug reactions reported in 2% to <5% of patients receiving OPDIVO were abdominal pain, hyponatremia, increased aspartate aminotransferase, and increased lipase. In Checkmate 066, serious adverse reactions occurred in 36% of patients receiving OPDIVO (n=206). Grade 3 and 4 adverse reactions occurred in 41% of patients receiving OPDIVO. The most frequent Grade 3 and 4 adverse reactions reported in ≥2% of patients receiving OPDIVO were gamma-glutamyltransferase increase (3.9%) and diarrhea (3.4%). In Checkmate 067, serious adverse reactions (74% and 44%), adverse reactions leading to permanent discontinuation (47% and 18%) or to dosing delays (58% and 36%), and Grade 3 or 4 adverse reactions (72% and 51%) all occurred more frequently in the OPDIVO plus YERVOY arm (n=313) relative to the OPDIVO arm (n=313). The most frequent (≥10%) serious adverse reactions in the OPDIVO plus YERVOY arm and the OPDIVO arm, respectively, were diarrhea (13% and 2.2%), colitis (10% and 1.9%), and pyrexia (10% and 1.0%). In Checkmate 238, serious adverse reactions occurred in 18% of patients receiving OPDIVO (n=452). Grade 3 or 4 adverse reactions occurred in 25% of OPDIVO-treated patients (n=452). The most frequent Grade 3 and 4 adverse reactions reported in ≥2% of OPDIVO-treated patients were diarrhea and increased lipase and amylase. In Checkmate 816, serious adverse reactions occurred in 30% of patients (n=176) who were treated with OPDIVO in combination with platinum-doublet chemotherapy. Serious adverse reactions in >2% included pneumonia and vomiting. No fatal adverse reactions occurred in patients who received OPDIVO in combination with platinum-doublet chemotherapy. In Checkmate 77T, serious adverse reactions occurred in 21% of patients who received OPDIVO in combination with platinum-doublet chemotherapy as neoadjuvant treatment (n=228). The most frequent (≥2%) serious adverse reactions was pneumonia. Fatal adverse reactions occurred in 2.2% of patients, due to cerebrovascular accident, COVID-19 infection, hemoptysis, pneumonia, and pneumonitis (0.4% each). In the adjuvant phase of Checkmate 77T, 22% of patients experienced serious adverse reactions (n=142). The most frequent serious adverse reaction was pneumonitis/ILD (2.8%). One fatal adverse reaction due to COVID-19 occurred. In Checkmate 227, serious adverse reactions occurred in 58% of patients (n=576). The most frequent (≥2%) serious adverse reactions were pneumonia, diarrhea/colitis, pneumonitis, hepatitis, pulmonary embolism, adrenal insufficiency, and hypophysitis. Fatal adverse reactions occurred in 1.7% of patients; these included events of pneumonitis (4 patients), myocarditis, acute kidney injury, shock, hyperglycemia, multi-system organ failure, and renal failure. In Checkmate 9LA, serious adverse reactions occurred in 57% of patients (n=358). The most frequent (>2%) serious adverse reactions were pneumonia, diarrhea, febrile neutropenia, anemia, acute kidney injury, musculoskeletal pain, dyspnea, pneumonitis, and respiratory failure. Fatal adverse reactions occurred in 7 (2%) patients, and included hepatic toxicity, acute renal failure, sepsis, pneumonitis, diarrhea with hypokalemia, and massive hemoptysis in the setting of thrombocytopenia. In Checkmate 017 and 057, serious adverse reactions occurred in 46% of patients receiving OPDIVO (n=418). The most frequent serious adverse reactions reported in ≥2% of patients receiving OPDIVO were pneumonia, pulmonary embolism, dyspnea, pyrexia, pleural effusion, pneumonitis, and respiratory failure. In Checkmate 057, fatal adverse reactions occurred; these included events of infection (7 patients, including one case of
Pneumocystis jirovecii
pneumonia), pulmonary embolism (4 patients), and limbic encephalitis (1 patient). In Checkmate 743, serious adverse reactions occurred in 54% of patients receiving OPDIVO plus YERVOY. The most frequent serious adverse reactions reported in ≥2% of patients were pneumonia, pyrexia, diarrhea, pneumonitis, pleural effusion, dyspnea, acute kidney injury, infusion-related reaction, musculoskeletal pain, and pulmonary embolism. Fatal adverse reactions occurred in 4 (1.3%) patients and included pneumonitis, acute heart failure, sepsis, and encephalitis. In Checkmate 214, serious adverse reactions occurred in 59% of patients receiving OPDIVO plus YERVOY (n=547). The most frequent serious adverse reactions reported in ≥2% of patients were diarrhea, pyrexia, pneumonia, pneumonitis, hypophysitis, acute kidney injury, dyspnea, adrenal insufficiency, and colitis. In Checkmate 9ER, serious adverse reactions occurred in 48% of patients receiving OPDIVO and cabozantinib (n=320). The most frequent serious adverse reactions reported in ≥2% of patients were diarrhea, pneumonia, pneumonitis, pulmonary embolism, urinary tract infection, and hyponatremia. Fatal intestinal perforations occurred in 3 (0.9%) patients. In Checkmate 025, serious adverse reactions occurred in 47% of patients receiving OPDIVO (n=406). The most frequent serious adverse reactions reported in ≥2% of patients were acute kidney injury, pleural effusion, pneumonia, diarrhea, and hypercalcemia. In Checkmate 205 and 039, adverse reactions leading to discontinuation occurred in 7% and dose delays due to adverse reactions occurred in 34% of patients (n=266). Serious adverse reactions occurred in 26% of patients. The most frequent serious adverse reactions reported in ≥1% of patients were pneumonia, infusion-related reaction, pyrexia, colitis or diarrhea, pleural effusion, pneumonitis, and rash. Eleven patients died from causes other than disease progression: 3 from adverse reactions within 30 days of the last OPDIVO dose, 2 from infection 8 to 9 months after completing OPDIVO, and 6 from complications of allogeneic HSCT. In Checkmate 141, serious adverse reactions occurred in 49% of patients receiving OPDIVO (n=236). The most frequent serious adverse reactions reported in ≥2% of patients receiving OPDIVO were pneumonia, dyspnea, respiratory failure, respiratory tract infection, and sepsis. In Checkmate 275, serious adverse reactions occurred in 54% of patients receiving OPDIVO (n=270). The most frequent serious adverse reactions reported in ≥2% of patients receiving OPDIVO were urinary tract infection, sepsis, diarrhea, small intestine obstruction, and general physical health deterioration. In Checkmate 274, serious adverse reactions occurred in 30% of patients receiving OPDIVO (n=351). The most frequent serious adverse reaction reported in ≥2% of patients receiving OPDIVO was urinary tract infection. Fatal adverse reactions occurred in 1% of patients; these included events of pneumonitis (0.6%). In Checkmate 901, serious adverse reactions occurred in 48% of patients receiving OPDIVO in combination with chemotherapy. The most frequent serious adverse reactions reporting in ≥2% of patients who received OPDIVO with chemotherapy were urinary tract infection (4.9%), acute kidney injury (4.3%), anemia (3%), pulmonary embolism (2.6%), sepsis (2.3%), and platelet count decreased (2.3%). Fatal adverse reactions occurred in 3.6% of patients who received OPDIVO in combination with chemotherapy; these included sepsis (1%). OPDIVO and/or chemotherapy were discontinued in 30% of patients and were delayed in 67% of patients for an adverse reaction. In Checkmate 142 in MSI-H/dMMR mCRC patients receiving OPDIVO with YERVOY (n=119), serious adverse reactions occurred in 47% of patients. The most frequent serious adverse reactions reported in ≥2% of patients were colitis/diarrhea, hepatic events, abdominal pain, acute kidney injury, pyrexia, and dehydration. In Checkmate 040, serious adverse reactions occurred in 59% of patients receiving OPDIVO with YERVOY (n=49). Serious adverse reactions reported in ≥4% of patients were pyrexia, diarrhea, anemia, increased AST, adrenal insufficiency, ascites, esophageal varices hemorrhage, hyponatremia, increased blood bilirubin, and pneumonitis. In Attraction-3, serious adverse reactions occurred in 38% of patients receiving OPDIVO (n=209). Serious adverse reactions reported in ≥2% of patients who received OPDIVO were pneumonia, esophageal fistula, interstitial lung disease, and pyrexia. The following fatal adverse reactions occurred in patients who received OPDIVO: interstitial lung disease or pneumonitis (1.4%), pneumonia (1.0%), septic shock (0.5%), esophageal fistula (0.5%), gastrointestinal hemorrhage (0.5%), pulmonary embolism (0.5%), and sudden death (0.5%). In Checkmate 577, serious adverse reactions occurred in 33% of patients receiving OPDIVO (n=532). A serious adverse reaction reported in ≥2% of patients who received OPDIVO was pneumonitis. A fatal reaction of myocardial infarction occurred in one patient who received OPDIVO. In Checkmate 648, serious adverse reactions occurred in 62% of patients receiving OPDIVO in combination with chemotherapy (n=310). The most frequent serious adverse reactions reported in ≥2% of patients who received OPDIVO with chemotherapy were pneumonia (11%), dysphagia (7%), esophageal stenosis (2.9%), acute kidney injury (2.9%), and pyrexia (2.3%). Fatal adverse reactions occurred in 5 (1.6%) patients who received OPDIVO in combination with chemotherapy; these included pneumonitis, pneumatosis intestinalis, pneumonia, and acute kidney injury. In Checkmate 648, serious adverse reactions occurred in 69% of patients receiving OPDIVO in combination with YERVOY (n=322). The most frequent serious adverse reactions reported in ≥2% who received OPDIVO in combination with YERVOY were pneumonia (10%), pyrexia (4.3%), pneumonitis (4.0%), aspiration pneumonia (3.7%), dysphagia (3.7%), hepatic function abnormal (2.8%), decreased appetite (2.8%), adrenal insufficiency (2.5%), and dehydration (2.5%). Fatal adverse reactions occurred in 5 (1.6%) patients who received OPDIVO in combination with YERVOY; these included pneumonitis, interstitial lung disease, pulmonary embolism, and acute respiratory distress syndrome. In Checkmate 649, serious adverse reactions occurred in 52% of patients treated with OPDIVO in combination with chemotherapy (n=782). The most frequent serious adverse reactions reported in ≥2% of patients treated with OPDIVO in combination with chemotherapy were vomiting (3.7%), pneumonia (3.6%), anemia (3.6%), pyrexia (2.8%), diarrhea (2.7%), febrile neutropenia (2.6%), and pneumonitis (2.4%). Fatal adverse reactions occurred in 16 (2.0%) patients who were treated with OPDIVO in combination with chemotherapy; these included pneumonitis (4 patients), febrile neutropenia (2 patients), stroke (2 patients), gastrointestinal toxicity, intestinal mucositis, septic shock, pneumonia, infection, gastrointestinal bleeding, mesenteric vessel thrombosis, and disseminated intravascular coagulation. In Checkmate 76K, serious adverse reactions occurred in 18% of patients receiving OPDIVO (n=524). Adverse reactions which resulted in permanent discontinuation of OPDIVO in >1% of patients included arthralgia (1.7%), rash (1.7%), and diarrhea (1.1%). A fatal adverse reaction occurred in 1 (0.2%) patient (heart failure and acute kidney injury). The most frequent Grade 3-4 lab abnormalities reported in ≥1% of OPDIVO-treated patients were increased lipase (2.9%), increased AST (2.2%), increased ALT (2.1%), lymphopenia (1.1%), and decreased potassium (1.0%).
Common Adverse Reactions
In Checkmate 037, the most common adverse reaction (≥20%) reported with OPDIVO (n=268) was rash (21%). In Checkmate 066, the most common adverse reactions (≥20%) reported with OPDIVO (n=206) vs dacarbazine (n=205) were fatigue (49% vs 39%), musculoskeletal pain (32% vs 25%), rash (28% vs 12%), and pruritus (23% vs 12%). In Checkmate 067, the most common (≥20%) adverse reactions in the OPDIVO plus YERVOY arm (n=313) were fatigue (62%), diarrhea (54%), rash (53%), nausea (44%), pyrexia (40%), pruritus (39%), musculoskeletal pain (32%), vomiting (31%), decreased appetite (29%), cough (27%), headache (26%), dyspnea (24%), upper respiratory tract infection (23%), arthralgia (21%), and increased transaminases (25%). In Checkmate 067, the most common (≥20%) adverse reactions in the OPDIVO arm (n=313) were fatigue (59%), rash (40%), musculoskeletal pain (42%), diarrhea (36%), nausea (30%), cough (28%), pruritus (27%), upper respiratory tract infection (22%), decreased appetite (22%), headache (22%), constipation (21%), arthralgia (21%), and vomiting (20%). In Checkmate 238, the most common adverse reactions (≥20%) reported in OPDIVO-treated patients (n=452) vs ipilimumab-treated patients (n=453) were fatigue (57% vs 55%), diarrhea (37% vs 55%), rash (35% vs 47%), musculoskeletal pain (32% vs 27%), pruritus (28% vs 37%),headache (23% vs 31%), nausea (23% vs 28%), upper respiratory infection (22% vs 15%), and abdominal pain (21% vs 23%). The most common immune-mediated adverse reactions were rash (16%), diarrhea/colitis (6%), and hepatitis (3%). In Checkmate 816, the most common (>20%) adverse reactions in the OPDIVO plus chemotherapy arm (n=176) were nausea (38%), constipation (34%), fatigue (26%), decreased appetite (20%), and rash (20%). In Checkmate 77T, the most common adverse reactions (reported in ≥20%) in patients receiving OPDIVO in combination with chemotherapy (n= 228) were anemia (39.5%), constipation (32.0%), nausea (28.9%), fatigue (28.1%), alopecia (25.9%), and cough (21.9%). In Checkmate 227, the most common (≥20%) adverse reactions were fatigue (44%), rash (34%), decreased appetite (31%), musculoskeletal pain (27%), diarrhea/colitis (26%), dyspnea (26%), cough (23%), hepatitis (21%), nausea (21%), and pruritus (21%). In Checkmate 9LA, the most common (>20%) adverse reactions were fatigue (49%), musculoskeletal pain (39%), nausea (32%), diarrhea (31%), rash (30%), decreased appetite (28%), constipation (21%), and pruritus (21%). In Checkmate 017 and 057, the most common adverse reactions (≥20%) in patients receiving OPDIVO (n=418) were fatigue, musculoskeletal pain, cough, dyspnea, and decreased appetite. In Checkmate 743, the most common adverse reactions (≥20%) in patients receiving OPDIVO plus YERVOY were fatigue (43%), musculoskeletal pain (38%), rash (34%), diarrhea (32%), dyspnea (27%), nausea (24%), decreased appetite (24%), cough (23%), and pruritus (21%). In Checkmate 214, the most common adverse reactions (≥20%) reported in patients treated with OPDIVO plus YERVOY (n=547) were fatigue (58%), rash (39%), diarrhea (38%), musculoskeletal pain (37%), pruritus (33%), nausea (30%), cough (28%), pyrexia (25%), arthralgia (23%), decreased appetite (21%), dyspnea (20%), and vomiting (20%). In Checkmate 9ER, the most common adverse reactions (≥20%) in patients receiving OPDIVO and cabozantinib (n=320) were diarrhea (64%), fatigue (51%), hepatotoxicity (44%), palmar-plantar erythrodysaesthesia syndrome (40%), stomatitis (37%), rash (36%), hypertension (36%), hypothyroidism (34%), musculoskeletal pain (33%), decreased appetite (28%), nausea (27%), dysgeusia (24%), abdominal pain (22%), cough (20%) and upper respiratory tract infection (20%). In Checkmate 025, the most common adverse reactions (≥20%) reported in patients receiving OPDIVO (n=406) vs everolimus (n=397) were fatigue (56% vs 57%), cough (34% vs 38%), nausea (28% vs 29%), rash (28% vs 36%), dyspnea (27% vs 31%), diarrhea (25% vs 32%), constipation (23% vs 18%), decreased appetite (23% vs 30%), back pain (21% vs 16%), and arthralgia (20% vs 14%). In Checkmate 205 and 039, the most common adverse reactions (≥20%) reported in patients receiving OPDIVO (n=266) were upper respiratory tract infection (44%), fatigue (39%), cough (36%), diarrhea (33%), pyrexia (29%), musculoskeletal pain (26%), rash (24%), nausea (20%) and pruritus (20%). In Checkmate 141, the most common adverse reactions (≥10%) in patients receiving OPDIVO (n=236) were cough (14%) and dyspnea (14%) at a higher incidence than investigator’s choice. In Checkmate 275, the most common adverse reactions (≥20%) reported in patients receiving OPDIVO (n=270) were fatigue (46%), musculoskeletal pain (30%), nausea (22%), and decreased appetite (22%). In Checkmate 274, the most common adverse reactions (≥20%) reported in patients receiving OPDIVO (n=351) were rash (36%), fatigue (36%), diarrhea (30%), pruritus (30%), musculoskeletal pain (28%), and urinary tract infection (22%).In Checkmate 901, the most common adverse reactions (≥20%) were nausea, fatigue, musculoskeletal pain, constipation, decreased appetite, rash, vomiting, and peripheral neuropathy. In Checkmate 142 in MSI-H/dMMR mCRC patients receiving OPDIVO as a single agent (n=74), the most common adverse reactions (≥20%) were fatigue (54%), diarrhea (43%), abdominal pain (34%), nausea (34%), vomiting (28%), musculoskeletal pain (28%), cough (26%), pyrexia (24%), rash (23%), constipation (20%), and upper respiratory tract infection (20%). In Checkmate 142 in MSI-H/dMMR mCRC patients receiving OPDIVO with YERVOY (n=119), the most common adverse reactions (≥20%) were fatigue (49%), diarrhea (45%), pyrexia (36%), musculoskeletal pain (36%), abdominal pain (30%), pruritus (28%), nausea (26%), rash (25%), decreased appetite (20%), and vomiting (20%). In Checkmate 040, the most common adverse reactions (≥20%) in patients receiving OPDIVO with YERVOY (n=49), were rash (53%), pruritus (53%), musculoskeletal pain (41%), diarrhea (39%), cough (37%), decreased appetite (35%), fatigue (27%), pyrexia (27%), abdominal pain (22%), headache (22%), nausea (20%), dizziness (20%), hypothyroidism (20%), and weight decreased (20%). In Attraction-3, the most common adverse reactions (≥20%) in OPDIVO-treated patients (n=209) were rash (22%) and decreased appetite (21%). In Checkmate 577, the most common adverse reactions (≥20%) in patients receiving OPDIVO (n=532) were fatigue (34%), diarrhea (29%), nausea (23%), rash (21%), musculoskeletal pain (21%), and cough (20%). In Checkmate 648, the most common adverse reactions (≥20%) in patients treated with OPDIVO in combination with chemotherapy (n=310) were nausea (65%), decreased appetite (51%), fatigue (47%), constipation (44%), stomatitis (44%), diarrhea (29%), and vomiting (23%). In Checkmate 648, the most common adverse reactions reported in ≥20% of patients treated with OPDIVO in combination with YERVOY were rash (31%), fatigue (28%), pyrexia (23%), nausea (22%), diarrhea (22%), and constipation (20%). In Checkmate 649, the most common adverse reactions (≥20%) in patients treated with OPDIVO in combination with chemotherapy (n=782) were peripheral neuropathy (53%), nausea (48%), fatigue (44%), diarrhea (39%), vomiting (31%), decreased appetite (29%), abdominal pain (27%), constipation (25%), and musculoskeletal pain (20%). In Checkmate 76K, the most common adverse reactions (≥20%) reported with OPDIVO (n=524) were fatigue (36%), musculoskeletal pain (30%), rash (28%), diarrhea (23%) and pruritis (20%).
Surgery Related Adverse Reactions
In Checkmate 77T, 5.3% (n=12) of the OPDIVO-treated patients who received neoadjuvant treatment, did not receive surgery due to adverse reactions. The adverse reactions that led to cancellation of surgery in OPDIVO- treated patients were cerebrovascular accident, pneumonia, and colitis/diarrhea (2 patients each) and acute coronary syndrome, myocarditis, hemoptysis, pneumonitis, COVID-19, and myositis (1 patient each).
Please see U.S. Full Prescribing Information for
OPDIVO
and
YERVOY
.
Clinical Trials and Patient Populations
Checkmate 227-previously untreated metastatic non-small cell lung cancer, in combination with YERVOY; Checkmate 9LA–previously untreated recurrent or metastatic non-small cell lung cancer in combination with YERVOY and 2 cycles of platinum-doublet chemotherapy by histology; Checkmate 649–previously untreated advanced or metastatic gastric cancer, gastroesophageal junction and esophageal adenocarcinoma; Checkmate 577–adjuvant treatment of esophageal or gastroesophageal junction cancer; Checkmate 238– adjuvant treatment of patients with completely resected Stage III or Stage IV melanoma; Checkmate 76K– adjuvant treatment of patients 12 years of age and older with completely resected Stage IIB or Stage IIC melanoma; Checkmate 274–adjuvant treatment of urothelial carcinoma; Checkmate 275–previously treated advanced or metastatic urothelial carcinoma; Checkmate 142–MSI-H or dMMR metastatic colorectal cancer, as a single agent or in combination with YERVOY; Checkmate 142–MSI-H or dMMR metastatic colorectal cancer, as a single agent or in combination with YERVOY; Attraction-3–esophageal squamous cell carcinoma; Checkmate 648-previously untreated, unresectable advanced recurrent or metastatic esophageal squamous cell carcinoma in combination with chemotherapy; Checkmate 648-previously untreated, unresectable advanced recurrent or metastatic esophageal squamous cell carcinoma combination with YERVOY; Checkmate 040–hepatocellular carcinoma, in combination with YERVOY; Checkmate 743–previously untreated unresectable malignant pleural mesothelioma, in combination with YERVOY; Checkmate 037–previously treated metastatic melanoma; Checkmate 066—previously untreated metastatic melanoma; Checkmate 067– previously untreated metastatic melanoma, as a single agent or in combination with YERVOY; Checkmate 017– second-line treatment of metastatic squamous non-small cell lung cancer; Checkmate 057–second-line treatment of metastatic non-squamous non-small cell lung cancer; Checkmate 816–neoadjuvant non-small cell lung cancer, in combination with platinum-doublet chemotherapy; Checkmate 77T–Neoadjuvant treatment with platinum-doublet chemotherapy for non-small cell lung cancer followed by single-agent OPDIVO as adjuvant treatment after surgery; Checkmate 901–Adult patients with unresectable or metastatic urothelial carcinoma; Checkmate 141–recurrent or metastatic squamous cell carcinoma of the head and neck; Checkmate 025– previously treated renal cell carcinoma; Checkmate 214–previously untreated renal cell carcinoma, in combination with YERVOY; Checkmate 9ER–previously untreated renal cell carcinoma, in combination with cabozantinib; Checkmate 205/039–classical Hodgkin lymphoma
About the Bristol Myers Squibb and Ono Pharmaceutical Collaboration
In 2011, through a collaboration agreement with Ono Pharmaceutical Co., Bristol Myers Squibb expanded its territorial rights to develop and commercialize
Opdivo
globally, except in Japan, South Korea and Taiwan, where Ono had retained all rights to the compound at the time. On July 23, 2014, Ono and Bristol Myers Squibb further expanded the companies’ strategic collaboration agreement to jointly develop and commercialize multiple immunotherapies – as single agents and combination regimens – for patients with cancer in Japan, South Korea and Taiwan.
About Bristol Myers Squibb
Bristol Myers Squibb is a global biopharmaceutical company whose mission is to discover, develop and deliver innovative medicines that help patients prevail over serious diseases. For more information about Bristol Myers Squibb, visit us at
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Cautionary Statement Regarding Forward-Looking Statements
This press release contains “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995 regarding, among other things, the research, development and commercialization of pharmaceutical products. All statements that are not statements of historical facts are, or may be deemed to be, forward-looking statements. Such forward-looking statements are based on current expectations and projections about our future financial results, goals, plans and objectives and involve inherent risks, assumptions and uncertainties, including internal or external factors that could delay, divert or change any of them in the next several years, that are difficult to predict, may be beyond our control and could cause our future financial results, goals, plans and objectives to differ materially from those expressed in, or implied by, the statements. These risks, assumptions, uncertainties and other factors include, among others, that the CHMP opinion is not binding on the EC, that Opdivo (nivolumab) plus Yervoy (ipilimumab) may not receive regulatory approval for the additional indication described in this release in the currently anticipated timeline or at all, that any marketing approvals, if granted, may have significant limitations on their use, and, if approved, whether such combination treatment for such additional indication will be commercially successful. No forward-looking statement can be guaranteed. Forward-looking statements in this press release should be evaluated together with the many risks and uncertainties that affect Bristol Myers Squibb’s business and market, particularly those identified in the cautionary statement and risk factors discussion in Bristol Myers Squibb’s Annual Report on Form 10-K for the year ended December 31, 2023, as updated by our subsequent Quarterly Reports on Form 10-Q, Current Reports on Form 8-K and other filings with the Securities and Exchange Commission. The forward-looking statements included in this document are made only as of the date of this document and except as otherwise required by applicable law, Bristol Myers Squibb undertakes no obligation to publicly update or revise any forward-looking statement, whether as a result of new information, future events, changed circumstances or otherwise.
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临床结果免疫疗法上市批准临床3期加速审批
100 项与 甲苯磺酸索拉非尼 相关的药物交易
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研发状态
批准上市
10 条最早获批的记录, 后查看更多信息
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| 适应症 | 国家/地区 | 公司 | 日期 |
|---|---|---|---|
| 甲状腺癌 | 美国 | 2013-11-22 | |
| 不可切除的肝细胞癌 | 美国 | 2007-11-16 | |
| 分化型甲状腺癌 | 挪威 | 2006-07-19 | |
| 分化型甲状腺癌 | 欧盟 | 2006-07-19 | |
| 分化型甲状腺癌 | 冰岛 | 2006-07-19 | |
| 分化型甲状腺癌 | 列支敦士登 | 2006-07-19 | |
| 肝细胞癌 | 列支敦士登 | 2006-07-19 | |
| 肝细胞癌 | 欧盟 | 2006-07-19 | |
| 肝细胞癌 | 冰岛 | 2006-07-19 | |
| 肝细胞癌 | 挪威 | 2006-07-19 | |
| 肾细胞癌 | 挪威 | 2006-07-19 | |
| 肾细胞癌 | 列支敦士登 | 2006-07-19 | |
| 肾细胞癌 | 冰岛 | 2006-07-19 | |
| 肾细胞癌 | 欧盟 | 2006-07-19 | |
| 晚期肾细胞癌 | 美国 | 2005-12-01 |
未上市
10 条进展最快的记录, 后查看更多信息
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| 适应症 | 最高研发状态 | 国家/地区 | 公司 | 日期 |
|---|---|---|---|---|
| 肾细胞癌 | 药物发现 | 荷兰 | 2003-11-01 | |
| 肾细胞癌 | 药物发现 | 南非 | 2003-11-01 | |
| 肾细胞癌 | 药物发现 | 阿根廷 | 2003-11-01 | |
| 肾细胞癌 | 药物发现 | 比利时 | 2003-11-01 | |
| 肾细胞癌 | 药物发现 | 加拿大 | 2003-11-01 | |
| 肾细胞癌 | 药物发现 | 澳大利亚 | 2003-11-01 | |
| 肾细胞癌 | 药物发现 | 意大利 | 2003-11-01 | |
| 肾细胞癌 | 药物发现 | 巴西 | 2003-11-01 | |
| 肾细胞癌 | 药物发现 | 以色列 | 2003-11-01 | |
| 肾细胞癌 | 药物发现 | 加拿大 | 2003-11-01 |
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临床结果
临床结果
适应症
分期
评价
查看全部结果
| 研究 | 分期 | 人群特征 | 评价人数 | 分组 | 结果 | 评价 | 发布日期 |
|---|
ESMO2024 人工标引  | N/A | 肝细胞癌 一线 | 1,361 | (製膚選範鏇醖築鹽壓憲) = 夢淵襯膚淵簾簾糧鹹觸 獵遞壓願築壓繭顧醖窪 (觸襯壓顧願繭鑰膚構鹽, 8.3 ~ 10.8) 更多 | 积极 | 2024-09-16 | |
(製膚選範鏇醖築鹽壓憲) = 衊鑰壓鏇簾簾築觸憲糧 獵遞壓願築壓繭顧醖窪 (觸襯壓顧願繭鑰膚構鹽, 6.4 ~ 9.3) 更多 | |||||||
临床3期 | 543 | 淵壓夢窪構顧艱艱網製(觸繭鹽製衊夢鹽鹽蓋廠) = 蓋鑰積觸鹽糧鹽願餘鹹 齋鹹選鬱鑰餘積鹹簾襯 (鹽遞壓遞鏇糧鏇願壓遞, 0.31) 更多 | 积极 | 2024-09-16 | |||
Sorafenib (Sora) | 淵壓夢窪構顧艱艱網製(觸繭鹽製衊夢鹽鹽蓋廠) = 選餘襯窪艱鑰遞廠願顧 齋鹹選鬱鑰餘積鹹簾襯 (鹽遞壓遞鏇糧鏇願壓遞, 0.29) 更多 | ||||||
临床4期 | 肝细胞癌 一线 | 242 | (製鹹觸構製選鹽積簾齋) = 顧餘築簾遞憲淵顧網繭 壓糧遞鬱襯鹽範鏇淵選 (選遞糧淵選夢顧鬱構壓 ) 更多 | 积极 | 2024-09-16 | ||
(製鹹觸構製選鹽積簾齋) = 醖網襯鹹網築積鏇襯範 壓糧遞鬱襯鹽範鏇淵選 (選遞糧淵選夢顧鬱構壓 ) 更多 | |||||||
N/A | 151 | (鹹壓鑰簾醖鹽積觸鏇鏇) = 築壓範製製鬱觸顧顧鏇 範壓淵獵鑰襯淵簾壓顧 (選繭蓋獵獵衊廠積艱遞 ) 更多 | 积极 | 2024-09-16 | |||
(鹹壓鑰簾醖鹽積觸鏇鏇) = 糧範繭製鑰餘鏇餘窪遞 範壓淵獵鑰襯淵簾壓顧 (選繭蓋獵獵衊廠積艱遞 ) 更多 | |||||||
N/A | 肝细胞癌 二线 | 137 | (製鑰構壓鬱襯獵憲壓膚) = 餘遞膚顧夢範簾顧鏇窪 繭觸淵艱鹹選夢鏇壓餘 (築繭築積糧窪膚夢淵壓 ) 更多 | 积极 | 2024-09-16 | ||
(製鑰構壓鬱襯獵憲壓膚) = 鹹獵繭艱齋壓顧獵襯範 繭觸淵艱鹹選夢鏇壓餘 (築繭築積糧窪膚夢淵壓 ) 更多 | |||||||
ESMO_GI2024 人工标引 | N/A | 晚期肝细胞癌 二线 | 81 | (鹹鏇夢顧壓衊構淵壓遞) = 廠簾鬱積夢遞廠窪製積 廠醖鑰襯構觸製積膚範 (顧壓蓋憲鏇醖窪選選鹽 ) 更多 | - | 2024-06-27 | |
临床3期 | 162 | Sorafenib + TACE | (網簾範顧鹽餘願廠鬱繭) = 鏇憲鹹鏇範壓獵齋鹽艱 製醖鹽積遞範廠憲遞觸 (衊積鑰製鬱齋糧蓋壓簾 ) 更多 | 积极 | 2024-06-20 | ||
TACE | (網簾範顧鹽餘願廠鬱繭) = 製鏇淵積製壓夢蓋遞憲 製醖鹽積遞範廠憲遞觸 (衊積鑰製鬱齋糧蓋壓簾 ) 更多 | ||||||
临床3期 | 668 | (鏇廠壓齋憲繭餘鏇壓網) = 醖夢觸鏇觸廠範繭構鏇 窪餘壓鏇憲遞觸網膚願 (製蓋艱鑰窪齋衊顧製醖, 18.8 ~ 29.4) 更多 | 积极 | 2024-06-02 | |||
(鏇廠壓齋憲繭餘鏇壓網) = 鏇衊鏇獵製蓋鏇淵壓廠 窪餘壓鏇憲遞觸網膚願 (製蓋艱鑰窪齋衊顧製醖, 17.5 ~ 22.5) 更多 | |||||||
临床3期 | 543 | (顧願壓顧選選獵築選衊) = 構衊襯獵壓願範觸範衊 襯築觸窪鹹鑰鏇獵觸艱 (鹹構糧蓋糧鑰齋築選糧, 20.6 ~ 27.2) 更多 | 积极 | 2024-05-24 | |||
(顧願壓顧選選獵築選衊) = 鑰獵鹽憲膚構窪顧餘遞 襯築觸窪鹹鑰鏇獵觸艱 (鹹構糧蓋糧鑰齋築選糧, 13.2 ~ 18.5) 更多 | |||||||
临床2期 | 90 | (Group A) | (範觸選廠壓構簾憲鹹築) = 範衊鏇選糧鬱餘廠鑰構 簾蓋繭顧艱選蓋蓋觸獵 (齋糧淵夢蓋憲糧齋襯齋 ) 更多 | 积极 | 2024-05-24 | ||
(Group B) | (範觸選廠壓構簾憲鹹築) = 淵構夢壓鬱製網襯範鬱 簾蓋繭顧艱選蓋蓋觸獵 (齋糧淵夢蓋憲糧齋襯齋 ) 更多 |
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