Ifinatamab deruxtecan

BASKING RIDGE, NJ & RAHWAY, NJ, USA I May 19, 2025 I The first patient has been dosed in the IDeate-Esophageal01 phase 3 trial evaluating the efficacy and safety of investigational ifinatamab deruxtecan (I-DXd) versus investigator’s choice of chemotherapy in patients with unresectable advanced or metastatic esophageal squamous cell carcinoma (ESCC) with disease progression following treatment with a platinum-containing systemic therapy and an immune checkpoint inhibitor. Ifinatamab deruxtecan is a specifically engineered, potential first-in-class B7-H3 directed DXd antibody drug conjugate (ADC) discovered by Daiichi Sankyo (TSE: 4568) and being jointly developed with Merck (NYSE: MRK), known as MSD outside of the United States and Canada. ESCC accounts for nearly 90% of esophageal cancers globally with a five-year overall survival rate around 15% to 20% and has a worse prognosis for those diagnosed at an advanced stage of the disease. 1,2 While the evolved landscape in the first-line metastatic setting of ESCC has helped to improve outcomes for patients, treatment options are limited for patients progressing after first-line therapy, reinforcing the need for new approaches. “Patients with metastatic esophageal squamous cell carcinoma continue to experience poor outcomes despite currently available treatments,” said Mark Rutstein, MD, Head, Therapeutic Area Oncology Development, Daiichi Sankyo. “The encouraging clinical activity seen in our early-phase signal finding trial supports further evaluation of ifinatamab deruxtecan as a potential treatment strategy for these patients.” “Advanced esophageal squamous cell carcinoma is a difficult-to-treat disease, and unfortunately overall survival remains low,” said Marjorie Green, MD, Senior Vice President and Head of Oncology, Global Clinical Development, Merck Research Laboratories. “The initiation of the pivotal phase 3 IDeate-Esophageal01 clinical trial demonstrates our shared commitment with Daiichi Sankyo to further expand our clinical development program evaluating this potentially first-in-class ADC across multiple solid tumors where there are unmet needs for new treatment options.” The initiation of IDeate-Esophageal01 is based on results from the IDeate-PanTumor01 phase 1/2 trial presented at both the 2022 and 2023 European Society of Medical Oncology (ESMO) where ifinatamab deruxtecan showed promising responses in heavily pretreated patients with ESCC. About the IDeate-Esophageal01 Trial IDeate-Esophageal01 is a global, multicenter, open-label, randomized phase 3 trial evaluating the safety and efficacy of ifinatamab deruxtecan (12 mg/kg) versus treatment of physician’s choice of chemotherapy (paclitaxel, docetaxel or irinotecan hydrochloride) in patients with advanced or metastatic ESCC with disease progression following treatment with platinum-based chemotherapy therapy and an immune checkpoint inhibitor. Eligible patients must have received no more than one prior line of systemic therapy in the advanced or metastatic setting. The primary endpoint of the trial is overall survival. Secondary endpoints include progression-free survival and objective response rate as assessed by blinded independent central review, and safety. IDeate-Esophageal01 will enroll approximately 510 patients across Asia, Europe and North America. For more information, please visit ClinicalTrials.gov . About Esophageal Squamous Cell Carcinoma More than half a million esophageal cancer cases were diagnosed in 2022, with nearly half a million deaths globally. 3 ESCC accounts for nearly 90% of esophageal cancers globally with a five-year overall survival rate around 15% to 20% and has a worse prognosis for those diagnosed at an advanced stage of the disease. 1,2 ESCC is most prevalent in Eastern Asia where mortality rates are also the highest. 1,2 While the evolved landscape in the first-line metastatic setting of ESCC has helped to improve outcomes for patients, treatment options are limited for patients progressing after first-line therapy, reinforcing the need for new approaches. About B7-H3 B7-H3 is a transmembrane protein that belongs to the B7 family of proteins which bind to the CD28 family of receptors that includes PD-1. 4,5 B7-H3 is overexpressed in a wide range of cancer types, including ESCC, and its overexpression has been shown to correlate with poor prognosis, making B7-H3 a promising therapeutic target. 6-9 There are currently no B7-H3 directed medicines approved for the treatment of any cancer. About Ifinatamab Deruxtecan Ifinatamab deruxtecan is an investigational potential first-in-class B7-H3 directed ADC. Designed using Daiichi Sankyo’s proprietary DXd ADC Technology, ifinatamab deruxtecan is comprised of a humanized anti-B7-H3 IgG1 monoclonal antibody attached to a number of topoisomerase I inhibitor payloads (an exatecan derivative, DXd) via tetrapeptide-based cleavable linkers. In addition to IDeate-Esophageal01 , ifinatamab deruxtecan is being evaluated in a global development program that includes IDeate-Lung01 , a phase 2 monotherapy trial in patients with previously treated extensive-stage small cell lung cancer (ES-SCLC); IDeate-Lung02 , a phase 3 trial in patients with relapsed SCLC versus investigator’s choice of chemotherapy; IDeate-Lung03 , a phase 1b/2 trial in patients with ES-SCLC in combination with atezolizumab with or without carboplatin as first-line induction or maintenance therapy; IDeate-PanTumor02 , a phase 2 monotherapy trial in patients with recurrent or metastatic solid tumors; and, IDeate-PanTumor01 , a phase 1/2 first-in-human monotherapy trial in patients with advanced solid malignant tumors in collaboration with Sarah Cannon Research Institute (SCRI) with study operational oversight and delivery provided through SCRI’s early phase oncology clinical research organization, SCRI Development Innovations in Nashville, TN. Ifinatamab deruxtecan has been granted orphan drug designation in the EU, Japan, Taiwan and US for the treatment of SCLC. About the Daiichi Sankyo and Merck Collaboration Daiichi Sankyo and Merck entered into a global collaboration in October 2023 to jointly develop and commercialize patritumab deruxtecan (HER3-DXd), ifinatamab deruxtecan (I-DXd) and raludotatug deruxtecan (R-DXd), except in Japan where Daiichi Sankyo will maintain exclusive rights. Daiichi Sankyo will be solely responsible for manufacturing and supply. In August 2024 , the global co-development and co-commercialization agreement was expanded to include gocatamig (MK-6070/DS3280), which the companies will jointly develop and commercialize worldwide, except in Japan where Merck will maintain exclusive rights. Merck will be solely responsible for manufacturing and supply for gocatamig. About the ADC Portfolio of Daiichi Sankyo The Daiichi Sankyo ADC portfolio consists of seven ADCs in clinical development crafted from two distinct ADC technology platforms discovered in-house by Daiichi Sankyo. The ADC platform furthest in clinical development is Daiichi Sankyo’s DXd ADC Technology where each ADC consists of a monoclonal antibody attached to a number of topoisomerase I inhibitor payloads (an exatecan derivative, DXd) via tetrapeptide-based cleavable linkers. The DXd ADC portfolio currently consists of ENHERTU ® , a HER2 directed ADC, and DATROWAY ® , a TROP2 directed ADC, which are being jointly developed and commercialized globally with AstraZeneca. Patritumab deruxtecan (HER3-DXd), a HER3 directed ADC, ifinatamab deruxtecan (I-DXd), a B7-H3 directed ADC, and raludotatug deruxtecan (R-DXd), a CDH6 directed ADC, are being jointly developed and commercialized globally with Merck. DS-3939, a TA-MUC1 directed ADC, is being developed by Daiichi Sankyo. The second Daiichi Sankyo ADC platform consists of a monoclonal antibody attached to a modified pyrrolobenzodiazepine (PBD) payload. DS-9606, a CLDN6 directed PBD ADC, is the first of several planned ADCs in clinical development utilizing this platform. Ifinatamab deruxtecan, patritumab deruxtecan, raludotatug deruxtecan, DS-3939 and DS-9606 are investigational medicines that have not been approved for any indication in any country. Safety and efficacy have not been established. About Daiichi Sankyo Daiichi Sankyo is an innovative global healthcare company contributing to the sustainable development of society that discovers, develops and delivers new standards of care to enrich the quality of life around the world. With more than 120 years of experience, Daiichi Sankyo leverages its world-class science and technology to create new modalities and innovative medicines for people with cancer, cardiovascular and other diseases with high unmet medical needs. For more information, please visit www.daiichisankyo.com . Merck’s Focus on Cancer Every day, we follow the science as we work to discover innovations that can help patients, no matter what stage of cancer they have. As a leading oncology company, we are pursuing research where scientific opportunity and medical need converge, underpinned by our diverse pipeline of more than 25 novel mechanisms. With one of the largest clinical development programs across more than 30 tumor types, we strive to advance breakthrough science that will shape the future of oncology. By addressing barriers to clinical trial participation, screening and treatment, we work with urgency to reduce disparities and help ensure patients have access to high-quality cancer care. Our unwavering commitment is what will bring us closer to our goal of bringing life to more patients with cancer. For more information, visit https://www.merck.com/research/oncology . About Merck At Merck, known as MSD outside of the United States and Canada, we are unified around our purpose: We use the power of leading-edge science to save and improve lives around the world. For more than 130 years, we have brought hope to humanity through the development of important medicines and vaccines. We aspire to be the premier research-intensive biopharmaceutical company in the world – and today, we are at the forefront of research to deliver innovative health solutions that advance the prevention and treatment of diseases in people and animals. We foster a diverse and inclusive global workforce and operate responsibly every day to enable a safe, sustainable and healthy future for all people and communities. For more information, visit www.merck.com and connect with us on X (formerly Twitter) , Facebook , Instagram , YouTube and LinkedIn . SOURCE: Daiichi Sankyo

在肿瘤治疗领域，历经20年沉寂的DLL3靶点，正以颠覆性姿态重塑小细胞肺癌（SCLC）等神经内分泌肿瘤的治疗格局。作为Notch通路的抑制性配体，DLL3凭借其高表达于肿瘤细胞、近乎零表达的“干净”正常组织分布，以及独立于PD-L1等传统靶点的调控机制，成为精准治疗的新星。2024年安进塔拉妥单抗的加速获批，不仅验证了DLL3靶向治疗的临床价值，更点燃了全球药企对这一领域的研发热情，短短两年内超10项重磅交易、超40款在研管线喷涌而出，昭示着DLL3靶点从“冷门”向“必争之地”的跃迁。2025年4月24日，再鼎医药宣布靶向DLL3的ADC ZL-1310用于治疗小细胞肺癌的全球1期临床研究数据将在2025年美国临床肿瘤学会（ASCO）年会上公布。而深究之下，除ZL-1310之外，本次ASCO大会上安进的Tarlatamab、Gensun的ZG-006、勃林格殷格翰的BI-764532、Phanes的Peluntamig以及诺华的LB2102等诸多DLL靶向新药均不约而同地选择在此大会上露脸。短短几年，DLL3到底是如何走进研究者的视野中？又是如何转瞬间成为ASCO的热门？更关键的是，在上述管线之外，现阶段的DLL3靶向药领域究竟是怎样的格局？20年沉寂DLL3靶点负重而行所谓DLL3，即Notch信号通路的抑制性配体，属于DLL家族（包括DLL1、DLL3、DLL4），近年来因其在肿瘤治疗中的独特潜力逐渐成为较为创新的潜力靶点。而其之所以能成为肿瘤治疗的关键靶点，主要原因有四：高表达特性：作为靶向性的载体，DLL3在部分肿瘤中的高表达特性决定了其主要潜力，比如研究表明，其在85%的SCLC患者肿瘤细胞中高度表达，使其成为一个广泛适用的治疗靶点。高特异性：由于靶向治疗过程中，需要严格区分肿瘤与非肿瘤环境，因此DLL3在正常组织中几乎不表达的特性，使其成为部分肿瘤的精准治疗靶点，可以极大地减少正常组织的损伤。独立的作用机制：由于DLL3表达水平由ASCL1转录因子调控，其独立于如PD-L1等疗法，且疾病过程中相对稳定，这使其可作为PD-L1阴性或对免疫检查点抑制剂等疗法无效患者的替代治疗选择。潜在影响足：高表达DLL3的患者在BiTEs和ADC研究中的疗效可能更佳，但具体的生物标志物作用仍需进一步研究，以明确DLL3表达水平与治疗反应的直接相关性。数据来源：公开数据整理而纵观历史，从2006年Ayyanan揭示了DLL3在肿瘤发生中的作用以来，到2024年全球首款DLL3靶向获得FDA加速批准上市，可以发现DLL3靶点的研究开发历史明显不及PD-1、GLP-1等绝大多数热门疗法。但是，就是如此一个新生代靶点反向却又有何魅力引得市场青睐，以至于诸多MNC不惜失败也要接连入局？一款产品引发领域频繁交易近年以来，随着DLL3作为抗肿瘤靶点的潜力显现，其作为靶向疗法得以在当下快速发展，抗体偶联药物（ADC）、双特异性T细胞接合器（BiTE）、嵌合抗原受体T细胞疗法（CAR-T）以及RDC/PDC等不同的技术方向，通过不同的机制，实现对肿瘤的精准打击。2024年，安进自主研发的塔拉妥单抗（Tarlatamab）DLL3靶向疗法成功获FDA批准上市，其技术方向选用的则是双特异性T细胞接合器（BiTE），通过连接DLL3阳性癌细胞和CD3阳性 T 细胞，引发MHC-I非依赖性 T 细胞活化，促进肿瘤细胞裂解。市场表现方面，自2024年5月上市后，Tarlatamab仅用半年时间，销售额就已达到1.15亿美元。而随着其适应逐渐从二线向一线扩展，资本市场预测其销售峰值可能会达到15-20亿美元，之后则需要依靠多维度适应症扩展来进一步提高市场天花板。适应症方面，Tarlatamab率先获批上市的适应症为“小细胞肺癌”（源于在85%的SCLC患者中高表达）；其次是“非小细胞肺癌”适应症，目前已进入注册申请阶段；前列腺癌、神经内分泌前列腺癌等适应症临床进度则相对靠前，尚处于临床I期阶段。图注：SCLC临床常用治疗方案数据来源：2025 CACA小细胞肺癌诊治指南针对已获批的“小细胞肺癌”适应症，Tarlatamab主要用于铂类化疗后疾病进展的广泛期小细胞肺癌成人患者，目前尚处于ES-SCLC的二线疗法，其疗法最大突破性意义有二，一者一定程度上解决了经治ES-SCLC患者的耐药问题；二者取得了前所未有的持久临床缓解及超长的生存获益，将已治ES-SCLC患者的中位无进展生存期，从平均4.9个月提升到了17.9个月，甚至比很多一线治疗还长（下图）。ES-SCLC的抗癌疗法数据对比疗法阶段分级ORRmPFSmOS铂类+依托泊苷（EP方案或EC方案）上市一线-＜6月10月阿替利珠单抗+化疗上市一线--12月斯鲁利单抗+化疗上市一线-5.7月15.4月贝莫苏拜单抗+化疗上市一线-6.9月19.3月安罗替尼+化疗上市一线-4.2月11.8月卡瑞利珠单抗+阿帕替尼+化疗-二线34%3.6月8.4月芦比替丁（新型化疗药物）上市二线35%3.5月9.3月Tarlatamab单药上市二线40.40%4.3月15.2月DS-7300临床Ⅲ期二线52.40%5.6月12.2月注：非头对头，数据仅做参考数据来源：公开数据整理并且，Tarlatamab作为DLL3靶向疗法的代表产品，其并未止步于二线疗法，相反，其还同时还开展了一系列联合疗法与一线疗法的头对头实验。如果Tarlatamab最终能拿出惊艳的结果，或将带领整个DLL3靶向药领域迈入一个全新的阶段。很明显，Tarlatamab无论是ORR、mPFS与mOS方面均明显优于同类二线疗法，甚至超越部分一线联合疗法。侧面预示着DLL3靶向药在SCLC领域的强大竞争优势，未来甚至有望成为该领域中的颠覆性疗法类型。而事实上，市场层面已有不少企业开始注意到了DLL3靶点的潜在优势，两年时间内已有超过10项BD交易集中于此，其中不乏体量巨大的MNC药企。部分DLL3靶点管线交易情况数据来源：药智数据（点击查看大图）2016年6月，艾伯维以58亿美元收购Stemcentrx，将其重要资产Rova-T（DLL-3 ADC）收入囊中，可惜Rova-T在后来的Ⅲ期中表现不尽如人意，被迫终止。2023年11月，诺华以1亿美元首付款+10.1亿美元里程碑付款，获得传奇生物处于Ⅰ期临床的靶向DLL3 CAR-T疗法，再度将DLL3靶点拉到了舞台中央。2024年1月，默沙东通过6.8亿美元的整体收购拿下Harpoon Therapeutics公司，由此获得后者一款DLL3/CD3/Albumin三抗MK-6070（HPN328），又在7个月后将该管线除日本外的全球权益授权给了日本药企巨头第一三共，仅首付款已达1.7亿美元。2024年5月，诺华斥资10亿美元收购了Mariana Oncology及其前景广阔的产品线，其核心是MC-339，这是一种正在小细胞肺癌（SCLC）中进行研究的基于锕的治疗药物。2024年12月，恒瑞医药宣布将其DLL3 ADC（SHR-4849）的海外权益以7500万美元首付及超10亿美元的总额授权给美国IDEAYA Biosciences公司。SHR-4849于2024年6月获批临床并于12月公布早期临床数据，在小细胞肺癌（SCLC）的1期临床研究中展现了73%（8/11）的总应答率（ORR）。2025年1月，信达生物宣布与罗氏达成DLL3 ADC（IBI3009）的全球独家许可协议，首付款8千万美元，总额约10亿美元。IBI3009目前已在澳大利亚、中国和美国获得临床申请（IND）批准，并于2024年12月完成1期临床研究首例患者给药。很明显，从全球首款DLL靶向药因表现不佳而被迫终止，到塔拉妥单抗成为全球首款获批上市的DLL3靶向药物，该领域的受关注程度正在有目共睹的提升，兼具成药性与商业化可能的潜力也让越来越多制药企业加入竞争，未来可期。40种新药ADC、BiTE已为在研主导在全球制药企业紧锣密鼓入局DLL3靶向药的同时，该领域的全球在研管线数量也水涨船高，截至目前全球在研DLL3管线超过40款，其中活跃管线占比超60%（共计26款）。就临床阶段而言，26款活跃DLL3管线中，绝大多数均处于临床前期阶段，其中活跃临床Ⅲ期管线仅Rova-T一款（终止）、活跃临床Ⅱ期管线6款、临床I期管线9款、临床申请与临床前管线9款。数据来源：药智数据就技术方向而言，ADC、TCE（包括BiTE与TiTE）是现阶段DLL3靶向药领域最主要的技术方向，其中TCE数量最多，可分为BiTE（双特异性T细胞衔接器）与TiTE（三特异性T细胞衔接器）两类，分别有6款与7款新药管线；之后是ADC技术领域，共有8款活跃管线在研，占比30%；最后，CAR-T、RDC、普通双抗虽数量不多，但也是DLL3靶点的重要潜力方向之一。数据来源：药智数据在BiTE（双特异性T细胞衔接器）技术方向上，作为DLL3靶向药领域最早诞生的类型，是早期企业布局的主要方向，但目前该技术层面已有安进的塔拉妥单抗获批上市，这对后续在研管线研发有一定不利影响，目前在研管线分别有勃林格殷格翰的BI-764532（临床Ⅱ期）、齐鲁制药的QLS-31904（临床I期）、信达生物的IBI115（临床申请）等。在TiTE（三特异性T细胞衔接器）技术方向上，作为迭代技术，其理论上可具备更灵活的靶向策略，实现多种作用机制并存的同时，有利于将药物重定向至肿瘤局部，增加结合特异性，提升药物靶向肿瘤细胞的准确性，降低脱靶毒性，增强抗肿瘤能力。目前全球领域尚无任何三抗获批上市，更别提DLL3的TiTE层面，目前活跃TiTE层面临床进展最快的为Gensun的ZG-006、Harpoon的HPN-823与默沙东的HPN-328，三者均处于临床Ⅱ期阶段。在ADC技术方向，其作为国内优势领域，与TiTE中国产药企管线数量稀少有所不同，在该领域中国内管线占据主要，再鼎医药的ZL-1310（临床Ⅱ期）、信达生物的IBI-3009（临床I期）、恒瑞医药的SHR-4849（临床I期）与复旦张江的FZ-AD005（临床I期）均是极具代表性的管线。总体来看，Tarlatamab作为行业的颠覆者，其为整个DLL3靶向药领域带来了全新的市场格局，打破了ES-SCLC原有患者临床仅PD-1+化疗可用的窘境等各方面的成就值得肯定。但同时，其也并非完全不可超越，相反，在目前不同技术方向的数十款新药中，也有不少潜力管线有望在疗效、安全性以及给药便利性方面，做出巨大的改善。结语从BiTE、ADC到三抗与CAR-T，很明显DLL3靶向治疗的技术迭代正以前所未有的速度推进，而跨国药企的频繁BD与管线布局，更凸显其商业化潜力。尽管挑战犹存——如生物标志物验证不足、脱靶毒性风险等，但以塔拉妥单抗为代表的DLL靶向药在LS-SCLC领域的疗效突破已为行业注入强心剂。未来，随着前线治疗数据的揭晓、多技术路径的协同探索，DLL3靶点或将从“潜力股”蜕变为肿瘤精准治疗的新支柱，为患者带来更高效、更低毒的治疗选择。而对于更关键的“DLL3竞争格局”而言，其三大特征有望继续延续：‌技术路径百花齐放‌：ADC（如再鼎ZL-1310的73%ORR5）、三抗（默沙东HPN328的精准靶向设计）等创新机制持续突破，形成对BiTE疗法的补充与超越。‌临床价值纵深拓展‌：安进Tarlatamab向一线治疗迈进，若验证其对PD-L1阴性患者的替代价值，或将重构SCLC全程治疗体系。‌全球化研发竞速‌：恒瑞、信达等中国药企通过BD快速切入赛道，诺华、默沙东等MNC则通过收购加速技术整合，形成跨国跨技术平台的立体竞争网络。展望未来，DLL3靶向药的真正潜力或许还未完全释放，SCLC某种层面来看更像是DLL3靶向药全面进军的敲门砖，这场靶向革命有望向着更宏伟的经内分泌肿瘤疆域延伸。来源 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