This clinical trial aims to investigate the efficacy of Calcipotriol ointment combined with 5-FU cream in Organ Transplant Recipients (OTRs) to determine if it can stimulate the immune cells against actinic keratoses precancerous skin lesions after transplantation and prevent cutaneous squamous cell carcinoma (SCC) in long-term.

开始日期2026-01-01

申办/合作机构

The General Hospital Corp.

[+1]

NCT04329221 / Not yet recruiting临床2期IIT

Calcipotriol Plus 5-Flourouracil Immunotherapy Before Transplantation for Skin Cancer Prevention in Organ Transplant Recipients

This clinical trial aims to investigate the efficacy of Calcipotriol ointment combined with 5-fluorouracil cream as an immunotherapy for actinic keratosis in Organ Transplant Recipients (OTRs) before transplantation and determine whether it can prevent cutaneous squamous cell carcinoma (SCC) in OTRs post-transplant.

开始日期2026-01-01

申办/合作机构

The General Hospital Corp.

[+1]

CTRI/2024/09/073579 / Not yet recruiting临床4期IIT

Comparative Evaluation of Post-Operative outcomes of Modified Carnoy’s Solution Versus 5-Flurouracial Used For Chemical Cauterization Following Enucleation And Peripheral Ostectomy In Patients With Odontogenickerato Cyst - Nil

开始日期2025-09-12

申办/合作机构-

100 项与氟尿嘧啶相关的临床结果

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100 项与氟尿嘧啶相关的转化医学

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100 项与氟尿嘧啶相关的专利（医药）

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49,886

项与氟尿嘧啶相关的文献（医药）

2025-12-01·Journal of Gastrointestinal Cancer

Network Meta-analysis of Randomized Controlled Trials in Patients with Previously Treated Advanced Gastric or Gastroesophageal Junction Cancer: Comparisons Involving Ramucirumab

Review

作者: Gupta, Palvi ; Taipale, Kaisa ; Goel, Rajat ; Earley-Valovic, Veronika ; D'yachkova, Yulia ; Paine, Abby ; Liepa, Astra M

PURPOSEWith relatively few direct comparisons among treatment options for previously treated advanced gastric cancer or gastroesophageal junction (GEJ) cancer, network meta-analysis (NMA) may inform evidence-based decision-making. Ramucirumab plus paclitaxel (RAM + PTX) is a preferred regimen in guideline recommendations. NMA of key outcomes may further characterize the relative clinical value of RAM + PTX.METHODSA systematic literature review of randomized controlled trials of adult patients with previously treated advanced gastric/GEJ cancer informed a NMA which compared overall survival, progression-free survival, and discontinuations due to adverse events. Comparisons were reported relative to placebo/best supportive care (BSC) when possible, otherwise relative to RAM + PTX.RESULTSThe base-case NMA focused on second-line treatment only, from 19 of 28 studies identified. For overall survival, seven of 16 regimens were favorable relative to placebo/BSC, with RAM + PTX as the most favorable. For progression-free survival, five of 14 regimens were unfavorable relative to RAM + PTX. For discontinuations due to adverse events, two of 13 regimens were similar to placebo/BSC: ramucirumab monotherapy and fluorouracil; relative to RAM-PTX, all regimens were similar except ramucirumab monotherapy which was favorable and irinotecan + cisplatin which was unfavorable.CONCLUSIONThis NMA of trials of previously treated gastric/GEJ cancer suggests that RAM + PTX has one of the more favorable clinical profiles.

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

Introduction:This study delved into the role of Kinase Insert Domain Receptor (KDR) and its associated miRNAs in renal cell carcinoma through an extensive computational analysis. The potential of our findings to guide future research in this area is significant.Methods:Our methods, which included the use of UALCAN and GEPIA2 databases, as well as miRDB, MirDIP, miRNet v2.0, miRTargetLink, MiEAA v2.1, TarBase v8.0, INTERNET, and miRTarBass, were instrumental in identifying the regulation of miRNA associated with KDR expression. The predicted miRNA was validated with the TCGA-KIRC patients’ samples by implementing CancerMIRNome. The TargetScanHuman v8.0 was implemented to identify the associations between human miRNAs and KDR. A Patch Dock server analyzed the interactions between hsa-miR-200b-3p-KDR and hsa-miR-200b-3p with KDR.Results:The KDR expression rate was investigated in the Kidney Renal Cell Carcinoma (KIRC) samples, and adjacent normal tissues revealed that the expression rate was significantly higher than the normal samples, which was evident from the strong statistical significance (P = 1.63e-12). Likely, the KDR ex-pression rate was estimated as high at tumor grade 1 and gradually decreased till the metastasis grade, reducing the survival rate of the KIRC patients. To identify these signals early, we predicted a miRNA that could trigger the expression of KDR. Furthermore, we uncovered the potential associations between miR-200c-3p expressions by regulating KDR towards the progression of KIRC.Discussion:Upon examining the outcome, it became evident that miR-200c-3p was significantly down-regulated in KIRC compared to the normal samples. Moreover, the negative correlation was obtained for hsa-miR-200c-3p (R = - 0.276) along with the KDR expression describing that the increased rate of hsa-miR-200c-3p might reduce the KDR expression rate, which may suppress the KIRC initiation or progres-sion.Conclusion:The in-silico analysis indicated that the significant increase in KDR expression during the initiation of KIRC could serve as an early diagnostic marker. Moreover, KDR could be utilized to identify advancements in KIRC stages. Additionally, hsa-miR-200c-3p was identified as a potential regulator capable of downregulating and upregulating KDR expression among the 24 miRNAs screened. This find-ing holds promise for future research endeavors. Concurrent administration of the FDA-approved 5-fluor-ouracil with KIRC drugs, such as sorafenib, zidovudine, and everolimus, may have the potential to en-hance the therapeutic efficacy in downregulating hsa-miR-200c-3p. However, further in vitro studies are imperative to validate these findings and gain a comprehensive understanding of the intricate regulatory interplay involving hsa-miR-200c-3p, KDR, 5-fluorouracil, and other FDA-approved drugs for the treat-ment of KIRC. This will facilitate the identification of KIRC stage progression and its underlying pre-ventative mechanisms.

2025-01-01·Journal of Colloid and Interface Science

Facile fabrication of a thermal/pH responsive IPN hydrogel drug carrier based on cellulose and chitosan through simultaneous dual-click strategy

Article

作者: Li, Songmao ; Yu, Hui ; Wu, Yuxuan ; Hu, Chunwang ; Guo, Tao ; Wang, Gang ; Zhang, Bing ; Chen, Hongli ; Wei, Hongliang ; Wang, Mengyuan

Herein, an interpenetrating network hydrogel (IPN-Gel) based on cellulose and chitosan was synthesized via simultaneous amino-anhydride and azide-alkyne click reaction in water in one pot. The samples were characterized by various analytical methods including FTIR, SEM, XRD, XPS, ¹H NMR and so forth. The fabrication conditions were optimized by single factor experiments with water uptake (WU) and gel mass fraction (GMF) as two indexes. The WU and GMF of the IPN-Gel prepared under optimized conditions were 1192.37 % and 74.00 %, respectively. Its WU descended with the ascension in temperature, and first descended and then gradually ascended with the ascension in pH, confirming that the IPN-Gel had thermal/pH dual responsiveness. Using 5-Fu as a model drug, the release behavior of 5-Fu in IPN-Gel was explored. Its release behavior could be regulated by changing temperature and pH values, and it followed the Korsmeyer Peppas model. The viability of 4 T1 cells and HUVEC cells exceeded 80 % after 48 h of incubation at a high concentration of 200 μg/mL IPN-Gel, and hemolytic percentage was below the allowed limit of 5 %. The study provides a new strategy for the preparation of the IPN-Gel with biocompatibility, swelling reversibility and controllable drug release.

1,145

项与氟尿嘧啶相关的新闻（医药）

2024-11-18

·药学进展

独家原创 | 顾景凯教授：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

“ 点击蓝字关注我们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。参考文献： [1] Zingg R, Fischer M. 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DOI: 10.1107/S2052252517017912. 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。《药学进展》注重内容策划、加强组稿约稿、深度挖掘、分析药学信息资源、在药学学科进展、科研思路方法、靶点机制探讨、新药研发报告、临床用药分析、国际医药前沿等方面初具特色；特别是医药信息内容以科学前沿与国家战略需求相合，更加突出前瞻性、权威性、时效性、新颖性、系统性、实战性。根据最新统计数据，刊物篇均下载率连续三年蝉联我国医药期刊榜首，复合影响因子1.216，具有较高的影响力。《药学进展》编委会由国家重大专项化学药总师陈凯先院士担任主编，编委由新药研发技术链政府监管部门、高校科研院所、制药企业、临床医院、CRO、金融资本及知识产权相关机构近两百位极具影响力的专家组成。联系《药学进展》↓↓↓ 编辑部官网：pps.cpu.edu.cn；邮箱：yxjz@163.com；电话：025-83271227。欢迎投稿、订阅！往期推荐 “兴药为民·2023生物医药创新融合发展大会”盛大启幕！院士专家齐聚杭城，绘就生物医药前沿赛道新蓝图“兴药强刊”青年学者论坛暨《药学进展》第二届青年编委会议成功召开“兴药为民·2023生物医药创新融合发展大会”路演专场圆满收官！校企合作新旅程已启航我知道你在看哟

引进/卖出细胞疗法

2024-11-17

·ioncology

CCHIO 2024丨沈琳教授：肿瘤精准治疗的关键要素与挑战

CCHIO&AOS微专辑扫描二维码可查看更多内容编者按 2024年11月14~17日，备受瞩目的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。此次大会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。《肿瘤瞭望消化时讯》记者深入大会现场，有幸深度对话北京大学肿瘤医院沈琳教授，就精准医学时代，消化肿瘤研究的热点与未来发展方向进行了专访。沈琳教授北京大学肿瘤医院消化肿瘤内科主任、Ⅰ期临床试验病房主任历任北京大学肿瘤医院副院长、北京市肿瘤防治研究所副所长北京学者中国抗癌协会肿瘤精准治疗专业委员会主任委员中国抗癌协会肿瘤药物临床研究专业委员会首届主任委员中国临床肿瘤学会临床研究专家委员会主任委员中国临床肿瘤学会胃癌专家委员会候任主任委员中国抗癌协会大肠癌专业委员会副主任委员中国女医师协会临床肿瘤专业委会主委肿瘤瞭望消化时讯：当前肿瘤治疗正逐步进入精准医学时代，能否请您谈谈实现精准医学的关键要素有哪些？沈琳教授：这实际上是大家都特别关心的一个议题，因为在临床治疗中，我们经常会被患者问到治疗是否有效。对此，医生通常会以概率大小来解答，而这个概率正是当前精准治疗能否实现的一个直接反映。若精准治疗能够实现，那么其成功的概率自然较高。我们固然期望能达到百分之百的成功率，但目前这显然还无法实现，有的患者成功率可能达到百分之六七十、三四十，甚至更低。因此，提高这一成功率，实现更精准的肿瘤治疗，一直是且将继续是大家共同努力的方向。当前为何难以实现理想的肿瘤精准治疗效果？原因在于肿瘤的“狡猾”远超人们的想象，尤其在实体瘤中，其免疫微环境非常复杂，外部影响因素也非常多。在本次大会中，从抗癌协会的主会场到各专委会的分会场，我们都可以看到大家在探讨肿瘤微环境、肿瘤发生发展及病因学。但是由于肿瘤本身处于持续动态变化之中，所以我们当前对其全面、实时的了解仍显不足。现有的靶向治疗和免疫治疗，虽然能够针对特定靶点或肿瘤生长微环境，但仍无法确保对所有患者有效，并且还存在复发情况。这背后的原因我们还尚未完全明晰，因此当前的研究均聚焦于这些挑战领域。但是尽管前路漫漫，我仍坚信未来精准治疗将不断进步。在这条道路上，我们需要探索新的治疗方法，包括新药、放疗、手术及其他局部治疗的精确选择与把控，以及不良反应的预防。正如中国抗癌协会所倡导的，未来应整合多学科优势，以患者为中心，制定个性化治疗策略，推动精准治疗的实现。这不仅是我们的研究方向，也是患者最深切的期盼。我相信，随着努力与时间的积累，这一天终将到来。肿瘤瞭望消化时讯：能否请您分享一下您在消化肿瘤精准诊疗领域的战略规划与布局，给业界同道提供一些参考？沈琳教授：我主要是做上消化道肿瘤的研究，这其中主要包括胃癌和食管癌。众所周知，这两种肿瘤是我国的高发肿瘤，其中食管癌病例占全球的53%以上，胃癌也占到了47%以上。面对如此高发的肿瘤，如何实现精准治疗，一直是我们努力的目标。起初，我们的治疗手段主要局限于化疗药物，如氟尿嘧啶类、铂类、紫杉类以及拓扑异构酶抑制剂等，选择相对有限。但如今，我们拥有了更多的治疗选项，包括针对EGFR、HER2的靶向治疗，PD-L1免疫治疗，以及针对Claudin、FGFR等新兴靶点的疗法。在探索这些治疗路径的过程中，我们更加深刻地认识到了消化系统肿瘤的复杂性和异质性。当然，与非小细胞肺癌和乳腺癌相比，我们在该领域的研究进展确实存在差距，因为全球对该类肿瘤研究的投入相对较少。但是，近年来得益于我国政府的支持和制药企业的快速发展，我们能够接触到的新型药物显著增加。加之国内众多科学家也致力于消化系统肿瘤的研究，所以我们能够在前人所提供的这些基础科研和新药的基础上，开展大量新药临床研究，这些研究可以说是涉及到现在胃癌和食管癌我们所发现的各个靶点，除了上面提到的靶点，还包括MET、HER3等等很多。这些探索不仅推动了治疗进展，也让我们发现了新的问题，如患者耐药性的产生及其原因。为了克服这一问题，我们正在研究一些新型的治疗手段，如不同的药物组合、细胞和基因治疗等。大家可以看到，当前在国际消化系统肿瘤细胞治疗领域，我们起到了引领作用。当然这一选择的背后，也是源于患者迫切的治疗需求，因为当前这些肿瘤的治疗效果尚未达到理想状态。在探索新型治疗手段的过程中，我们发现了诸多能够为患者带来长期生存益处的创新疗法。这些疗法有时仅需单次治疗，即可实现疾病的长期稳定，甚至为患者提供治愈的可能。这正是我们在临床上追求精准治疗的结果，通过临床试验不断发现问题，进行转化研究，再回到临床进行验证。正是这样的循环迭代，不断推动着临床实践的变革。我坚信，在未来的日子里，我们定能满足中国胃癌和食管癌患者的治疗需求，进而惠及全球患者。我也相信，中国的医生和科学家将在这一领域引领全球的发展潮流。肿瘤瞭望消化时讯：若将精准医学时代的完全实现视为100%，您认为我们当前已进展至哪个百分比阶段？沈琳教授：虽然我们在通往100%实现精准医学的路上可能还有很长的路要走，但我认为我们已经完成了大约30%的进程。我们已经见证了一些革命性的进步，例如免疫药物的使用，特别是抗PD-1单抗，使得高度微卫星不稳定的患者甚至可以不手术即可达到治愈。同时，抗HER2治疗与靶向免疫疗法的结合也为患者带来了长期生存的希望。当我们尝试将这种疗法应用于围手术期，发现其病理完全缓解率提高了2.5~3倍，即治愈的可能性提升了两倍以上。此外，免疫治疗在围手术期的食管癌和胃癌治疗中也展现出良好的前景。当前我们正在进行Ⅲ期随机对照研究，来进一步评估这些治疗能否提高患者的五年生存率和治愈率。只有逐步将治疗从晚期推向治愈的平台，我们才能进一步解决这个领域内的治疗难题，即提高患者的五年生存率和治愈率，这些都是我们一直在努力的工作方向。往期推荐沈琳教授：新型ADC引领HER2阳性胃癌的精准治疗格局沈琳教授团队研究证实免疫联合化疗作为局部晚期食管癌新辅助治疗疗效值得期待丨AACR 2024中国之声 ASCO 2024丨斩获7项口头报告！沈琳教授全面精准战略布局，引领消化肿瘤治疗新篇章 CGOG 主席专访丨沈琳教授：聚焦创新靶点，深入转化研究，助力消化系统肿瘤健康发展沈琳教授：打破壁垒，融合创新，构筑中国特色消化肿瘤精准治疗新格局 ESMO中国之声丨聚焦临床热点问题，沈琳教授三项研究荣登ESMO壁报展示（来源：肿瘤瞭望消化时讯）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。

免疫疗法

2024-11-15

·Business Wire

Bristol Myers Squibb Receives Positive CHMP Opinion for Opdivo® (nivolumab) plus Yervoy® (ipilimumab) for the First-Line Treatment of Adult Patients with Microsatellite Instability–High or Mismatch Repair Deficient Metastatic Colorectal Cancer

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 BMS.com or follow us on LinkedIn , X (formerly Twitter), YouTube , Facebook and Instagram . 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. corporatefinancial-news

临床结果免疫疗法上市批准临床3期加速审批

100 项与氟尿嘧啶相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D00584	氟尿嘧啶	L01BC02	DB00544

研发状态

批准上市

10 条最早获批的记录,

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适应症	国家/地区	公司	日期
食管癌	日本	Kyowa Kirin Co., Ltd.	2021-11-25
鲍恩病	澳大利亚	iNova Pharmaceuticals (Australia) Pty Ltd.	1991-08-23
皮肤肿瘤	日本	Kyowa Kirin Co., Ltd.	1972-08-26
晚期胃癌	日本	Kyowa Kirin Co., Ltd.	1967-07-24
乳腺癌	日本	Kyowa Kirin Co., Ltd.	1967-07-24
结直肠癌	日本	Kyowa Kirin Co., Ltd.	1967-07-24
子宫内膜癌	日本	Kyowa Kirin Co., Ltd.	1967-07-24
肝癌	日本	Kyowa Kirin Co., Ltd.	1967-07-24
肺癌	日本	Kyowa Kirin Co., Ltd.	1967-07-24
卵巢癌	日本	Kyowa Kirin Co., Ltd.	1967-07-24
胰腺腺泡癌	日本	Kyowa Kirin Co., Ltd.	1967-07-24
复发性胃癌	日本	Kyowa Kirin Co., Ltd.	1967-07-24
宫颈癌	日本	Kyowa Kirin Co., Ltd.	1967-07-24
光化性角化病	加拿大	Hill Dermaceuticals, Inc.	-

未上市

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
胃腺癌	临床2期	美国	Spectrum Pharmaceuticals, Inc.	1962-04-25
肿瘤转移	药物发现	美国	National Cancer Institute	1996-01-01
直肠癌	药物发现	加拿大	National Cancer Institute	1994-03-01
III期结肠癌	药物发现	-	National Cancer Institute	1977-09-01
乳腺癌	药物发现	美国	Spectrum Pharmaceuticals, Inc.	1962-04-25
胃腺癌	药物发现	美国	Spectrum Pharmaceuticals, Inc.	1962-04-25

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临床结果

适应症

分期

评价

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT03512756 (TYME-88-Panc Part 1, CTgov)	临床2/3期	胰腺癌	130	SM-88 (Part 1: SM-88 460 mg)	醖簾簾簾選積觸顧構繭(繭窪鹹鏇淵觸鹽襯築壓) = 範觸積網淵憲鑰衊範構網襯壓遞夢選膚積醖衊 (鏇艱衊構夢蓋鏇膚製醖, 選積構製廠襯鏇顧膚築 ~ 齋糧憲齋鏇膚築衊膚選) 更多	-	2024-11-06
				SM-88 (Part 1: SM-88 920 mg)	醖簾簾簾選積觸顧構繭(繭窪鹹鏇淵觸鹽襯築壓) = 網餘鏇網顧糧獵窪鏇鹽網襯壓遞夢選膚積醖衊 (鏇艱衊構夢蓋鏇膚製醖, 遞獵築壓糧淵觸襯鏇鹽 ~ 憲築遞鑰衊窪構壓壓觸) 更多
NCT04731467 (FW-2020-01, Company_Website) 人工标引	临床1/2期	胰腺导管腺癌二线	-	CM24 + nivolumab + irinotecan/fluoropyrimidine based chemotherapy	(衊鑰範鬱網鏇廠繭餘糧) = 廠餘齋廠餘願範繭鬱膚壓構鏇鹽鬱鬱鹹鏇壓醖 (餘齋窪蓋糧積構艱築觸 ) 更多	积极	2024-11-04
				Chemotherapy alone	(製淵網醖積繭淵齋築範) = 艱鏇膚鹽壓製夢膚蓋衊衊醖獵積觸夢蓋鹽糧網 (鬱簾網鏇糧鏇餘齋夢鏇 )
NCT01013649 (NRG Oncology/RTOG 0848 \| NRG/RTOG 0848, CTgov)	临床3期	胰腺导管内肿瘤 \| 胰腺导管腺癌	548	Chemotherapy+Gemcitabine Hydrochloride (Arm I (Gemcitabine Hydrochloride or Combination Chemotherapy))	齋餘繭糧膚襯製範鑰齋(鹽齋鏇鏇餘繭齋繭衊餘) = 鏇醖鬱觸鬱願淵鑰衊鹽憲願窪壓廠範願選衊蓋 (夢範夢積築淵糧鹹鑰廠, 鬱觸鹽鹽艱鏇構繭築簾 ~ 繭網製糧襯齋膚鑰鑰糧) 更多	-	2024-10-24
				Erlotinib Hydrochloride+Gemcitabine Hydrochloride (Arm II (Gemcitabine Hydrochloride, Erlotinib Hydrochloride))	齋餘繭糧膚襯製範鑰齋(鹽齋鏇鏇餘繭齋繭衊餘) = 選齋鬱餘鏇鹽遞餘窪鹽憲願窪壓廠範願選衊蓋 (夢範夢積築淵糧鹹鑰廠, 窪齋艱齋鹽繭襯選廠膚 ~ 廠壓艱蓋鹹糧淵簾獵鑰) 更多
NCT03259035 (CCTG CO.28 \| NEO \| CO.28, CTgov)	临床2期	直肠癌	58	folinic acid+oxaliplatin+capecitabine+fluorouracil	獵糧窪鏇鬱鏇觸選範蓋(蓋築鏇選構窪醖廠鑰憲) = 鹽積壓築衊製夢餘獵鑰壓糧獵夢築觸範夢製製 (鹽觸膚鏇膚獵鹹獵衊餘, 築顧顧選鹽壓鬱構遞憲 ~ 鑰壓夢蓋鏇糧積壓觸蓋) 更多	-	2024-10-10
GlobeNewswire 人工标引	临床2期	转移性微卫星稳定结直肠癌一线	104	GRANITE+ immune checkpoint inhibitors + fluoropyrimidine+bevacizumab	(餘顧遞膚廠廠繭顧簾衊) = 糧蓋鹽鏇鏇鑰壓鑰齋襯鹽遞壓繭壓繭選鏇淵窪 (憲築顧餘簾窪鑰艱簾網 ) 更多	积极	2024-09-30
				Fluoropyrimidine+bevacizumab	(餘顧遞膚廠廠繭顧簾衊) = 選製憲觸衊壓鬱製簾憲鹽遞壓繭壓繭選鏇淵窪 (憲築顧餘簾窪鑰艱簾網 )
NCT03483038 (NEO-Nal-IRI, CTgov)	临床2期	胰腺腺癌	45	LEUCOVORIN CALCIUM+Liposomal Irinotecan+Oxaliplatin+Fluorouracil	範壓選糧壓選製膚鏇淵(夢鏇築繭襯憲鏇鹽構願) = 遞鬱壓夢餘顧繭鑰遞糧簾鹽夢夢遞窪觸鑰構簾 (夢遞鬱淵範選鹽顧鬱淵, 鏇窪範窪獵窪鑰廠蓋齋 ~ 製鑰淵鹹廠選廠鹽繭壓) 更多	-	2024-09-23
JPRN-UMIN000048143 (JON 2109-P, ESMO2024) 人工标引	临床3期	胰腺癌二线	446	S-1 monotherapy	(製觸廠糧範夢淵繭繭蓋) = 艱衊夢憲夢構廠構襯積淵齋憲淵餘獵壓鑰鹽鏇 (壓蓋糧獵淵鑰網衊廠憲 ) 更多	积极	2024-09-16
				Nanoliposomal irinotecan plus 5-fluorouracil/leucovorin regimen	(製觸廠糧範夢淵繭繭蓋) = 窪鏇簾糧獵壓齋顧網窪淵齋憲淵餘獵壓鑰鹽鏇 (壓蓋糧獵淵鑰網衊廠憲 ) 更多
NCT02355379 (ADAGE, ESMO2024) 人工标引	临床3期	III期结肠癌辅助	757	Oxaliplatin + Fluoropyrimidine	(衊製製構憲製壓鹹襯鏇) = 淵構鑰窪觸願廠繭網願願願餘鬱齋糧襯廠積遞 (憲窪淵齋襯構鏇構簾鹹 ) 更多	不佳	2024-09-16
				Fluoropyrimidine	(衊製製構憲製壓鹹襯鏇) = 網窪醖膚淵憲蓋願遞鏇願願餘鬱齋糧襯廠積遞 (憲窪淵齋襯構鏇構簾鹹 ) 更多
NCT05947201 (CAPITAL, ESMO2024) 人工标引	临床2期	局部晚期食管鳞状细胞癌新辅助	21	Cadonilimab+albumin-paclitaxel+cisplatin+fluorouracil	(衊憲構網醖願繭衊選構) = 糧餘範鏇齋糧鑰鹽簾衊願製鏇製壓選齋鏇鹹觸 (鑰顧壓醖鹽選齋夢鑰襯 ) 更多	积极	2024-09-16
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