BACKGROUNDAdvances in antibody engineering provide strategies to construct recombinant antibody-like molecules with modified pharmacokinetic properties. Multermerization is one strategy that has been used to produce antibody-like molecules with two or more antigen binding sites. Multimerization enhances the functional affinity (avidity) and can be used to optimize size and pharmacokinetic properties. Most multimerization strategies involve genetically fusing or non-covalently linking antibody fragments using oligomerization domains. Recent studies have defined guidelines for producing antibody-like molecules with optimal tumor targeting properties, which require intermediates size (70-120 kDa) and bi- or tri-valency.RESULTSWe described a highly modular antibody-engineering platform for rapidly constructing synthetic, trivalent single chain variable fragments (Tri-scFv) using the SpyCatcher/SpyTag protein ligase system. We used this platform to construct an anti-human epidermal growth factor receptor 3 (HER3) Tri-scFv. We generated the anti-HER3 Tri-scFv by genetically fusing a SpyCatcher to the C-terminus of an anti-HER3 scFv and ligating it to a synthetic Tri-SpyTag peptide. The anti-HER3 Tri-scFv bound recombinant HER3 with an apparent K_D of 2.67 nM, which is approximately 12 times lower than the K_D of monomeric anti-HER3 scFv (31.2 nM). Anti-HER3 Tri-scFv also bound endogenous cell surface expressed HER3 stronger than the monomer anti-HER3 scFv.CONCLUSIONWe used the SpyTag/SpyCatcher protein ligase system to ligate anti-HER3 scFv fused to a SpyCatcher at its C-termini to a Tri-SpyTag to construct Tr-scFv. This system allowed the construction of a Tri-scFv with all the scFv antigen-binding sites pointed outwards. The anti-HER3 Tri-scFv bound recombinant and endogenously expressed HER3 with higher functional affinity (avidity) than the monomeric anti-HER3 scFv. The Tri-scFv had the size, valency, and functional affinity that are desired for therapeutic and imaging applications. Use of the SpyTag/SpyCatcher protein ligase system allows Tri-scFvs to be rapidly constructed in a simple, modular manner, which can be easily applied to scFvs or other antibody fragments targeting other antigens.

2018-12-01·Breast Cancer Research1区 · 医学

Polyfunctional anti-human epidermal growth factor receptor 3 (anti-HER3) antibodies induced by HER3 vaccines have multiple mechanisms of antitumor activity against therapy resistant and triple negative breast cancers

1区 · 医学

ArticleOA

作者: Hobeika, Amy C ; Spector, Neil ; Osada, Takuya ; Clay, Timothy M ; Morse, Michael A ; Lyerly, H Kim ; Chen, Wei ; Hartman, Zachary C ; Diniz, Marcio A ; Gwin, William R ; Wei, Junping ; Lei, Gangjun

BACKGROUNDUpregulation of human epidermal growth factor receptor 3 (HER3) is a major mechanism of acquired resistance to therapies targeting its heterodimerization partners epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2), but also exposes HER3 as a target for immune attack. We generated an adenovirus encoding full length human HER3 (Ad-HER3) to serve as a cancer vaccine. Previously we reported the anti-tumor efficacy and function of the T cell response to this vaccine. We now provide a detailed assessment of the antitumor efficacy and functional mechanisms of the HER3 vaccine-induced antibodies (HER3-VIAs) in serum from mice immunized with Ad-HER3.METHODSSerum containing HER3-VIA was tested in complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC) assays and for its effect on HER3 internalization and degradation, downstream signaling of HER3 heterodimers and growth of metastatic HER2+ (BT474M1), HER2 therapy-resistant (rBT474), and triple negative (MDA-MB-468) breast cancers.RESULTSHER3-VIAs mediated CDC and ADCC, HER3 internalization, interruption of HER3 heterodimer-driven tumor signaling pathways, and anti-proliferative effects against HER2+ tumor cells in vitro and significant antitumor effects against metastatic HER2+ BT474M1, treatment refractory HER2+ rBT474 and triple negative MDA-MB-468 in vivo.CONCLUSIONSIn addition to the T cell anti-tumor response induced by Ad-HER3, the HER3-VIAs provide additional functions to eliminate tumors in which HER3 signaling mediates aggressive behavior or acquired resistance to HER2-targeted therapy. These data support clinical studies of vaccination against HER3 prior to or concomitantly with other therapies to prevent outgrowth of therapy-resistant HER2+ and triple negative clones.

2016-05-01·Cancer Chemotherapy and Pharmacology4区 · 医学

Population pharmacokinetic analysis of patritumab, a HER3 inhibitor, in subjects with advanced non-small cell lung cancer (NSCLC) or solid tumors

4区 · 医学

Article

作者: Chen, Shuquan ; Yoshiba, Satoshi ; Jansen, Mendel ; Mendell, Jeanne ; Matsushima, Nobuko

PURPOSEThe purpose of this analysis was to develop a population pharmacokinetic (PK) model for patritumab, a fully human monoclonal antibody that targets human epidermal growth factor receptor 3.METHODSA total of 833 serum concentrations were included in this analysis; serum concentrations were obtained from 145 subjects (136 with non-small cell lung cancer, nine with solid tumors) treated with patritumab [9 or 18 mg/kg intravenously every 3 weeks (q3w)] in one phase 1 and one phase 1b/2 study. Data were analyzed by nonlinear mixed-effect modeling.RESULTSPatritumab PKs were best described through a two-compartment model with first-order elimination and interindividual variability on clearance (CL), volume of the central compartment (V c), distributional clearance, and volume of the peripheral compartment. In the final model, CL and V c were estimated as 0.0238 L/h and 3.62 L, respectively. Body weight (BW) and baseline albumin were found to be covariates for CL and BW was a covariate for V c. Covariates associated with hepatic and renal impairment were not significant on CL. Simulations showed that BW-based dosing reduced interindividual variability in patritumab exposure compared with fixed dosing.CONCLUSIONSThe PK of patritumab was linear at the doses studied and well described by the two-compartment model. Hepatic and renal impairment did not appear to affect PK. Our results support BW-based dosing of patritumab on a q3w schedule.

项与 Anti-Her3 therapy(Band Therapeutics, LLC) 相关的新闻（医药）

2024-06-27

·FiercePharma

Daiichi's lung cancer ADC rejected by FDA in blow to first project under Merck partnership

The rejected drug, patritumab deruxtecan, was part of a $4 billion upfront ADC deal between Merck and Daiichi Sankyo. In the second setback for the HER3 field in days, the FDA has rejected Daiichi Sankyo’s Merck & Co.-partnered antibody-drug conjugate (ADC) patritumab deruxtecan. The drug, also known as HER3-DXd, was slated for an FDA decision Wednesday in EGFR-mutated non-small cell lung cancer following at least two systemic therapies until Daiichi and Merck delivered the bad news in the evening. Under a priority review, the drug was previously on track to be the first HER3 drug to reach the market and the first ADC launch for Merck. The FDA’s complete response letter is related to problems found during an inspection of a contractor’s manufacturing facility, rather than any issues with the efficacy or safety data, the two firms said. The identity of the contractor, as well as the nature of the production shortfalls, was not revealed. “We will work closely with the FDA and the third-party manufacturer to address the feedback as quickly as possible in order to bring the first HER3 directed medicine to patients with previously-treated EGFR-mutated non-small cell lung cancer,” Daiichi’s R&D head, Ken Takeshita, M.D., said in a statement. In a statement to Fierce Pharma, a Merck spokesperson said the New Jersey pharma is “working with Daiichi Sankyo and the third-party manufacturer to quickly resolve the issues identified by the FDA and will share more information about anticipated timing as available.” The FDA rejection for HER3-DXd comes only a few days after BioNTech said the FDA had put a partial clinical hold on a phase 1 trial of its rival HER3-targeted ADC, BNT326, following reports of three patients’ deaths. Shortly before the FDA’s move, BioNTech had decided to focus further development on dose levels below 4.0 mg/kg to balance the drug’s efficacy-safety profile. BioNTech got BNT326 from MediLink Therapeutics, which is running the phase 1 study. HER3-DXd is one of three ADC assets that Merck paid Daiichi $4 billion upfront last fall to co-develop and co-commercialize, and it’s the closest to market under the partnership. The other two programs target B7-H3 and CDH6, respectively. In the pivotal HERTHENA-Lung01 trial, patritumab deruxtecan led to a tumor shrinkage rate of 29.8%, with the median duration of response lasting 6.4 months in a group of EGFR-mutated NSCLC patients who had progressed following a tyrosine kinase inhibitor and chemotherapy. Among the 225 trial participants, one drug-related death was recorded as a result of interstitial lung disease, a known side effect of Daiichi’s DXd technology. Besides the phase 2 HERTHENA-Lung01 study, Daiichi is also running the phase 3 HERTHENA-Lung02 trial, which is pitting patritumab deruxtecan against platinum-based chemo as a second-line therapy following failure of an EGFR TKI. The pair is also evaluating the drug in breast cancer. Under the Merck deal, Daiichi is responsible for manufacturing. While still tapping outside manufacturers, the Japanese pharma has been investing in internal ADC production capabilities for years, beginning with a 15 billion yen investment in 2017 to build new and refurbish manufacturing lines at three of the company’s plants in Japan. This February, Daiichi unveiled a 1 billion euro ($1.1 billion) investment to expand its Pfaffenhofen site in Germany. Besides additional capacities to produce drugs for cardiovascular disease, ADCs are a key part of the upgrade.

抗体药物偶联物临床1期临床2期临床3期优先审批

2024-03-12

·Insight数据库

恒瑞、信达…国内药企全力出击 ADC！超 50 款新药闪耀 AACR

2024 年美国癌症研究协会（AACR）年会将于 4 月 5 日～10 日在美国圣地亚哥召开，目前，官网已经公布了部分摘要信息，Insight 数据库也已收录了 800+ 数据。鉴于临床结果相关的摘要正文将在会议开始当天公布，本文从已公布摘要中选取了部分国内企业的 ADC 项目进行分享。这其中不少是首次披露的新项目，或是首次公布已有项目的靶点、载荷信息等。开篇之前，先通过 Insight 数据库窥视一下当前全球 ADC 药物热门靶点 Top20，以辅助了解本文所述国内企业 ADC 靶点竞争程度。ADC 药物热门靶点 Top20来自：Insight 数据库网页版（下文如无特殊标注，为统一来源）以下，笔者主要从靶点的角度，选取竞争不是非常激烈的项目做简要介绍。恒瑞医药：5 款 ADC 亮相，4 个新项目首次公开恒瑞医药亮相 2024AACR 项目 DP03923-000-9106；靶点：LIV-1LIV-1 是锌转运蛋白家族的成员，因为其在肿瘤中表达广泛，而正常组织表达有限，使 LIV-1 成为 ADC 研发的有希望靶点。目前，该靶点全球在研 ADC 药物只有 7 款，进展最快的是 Seagen/默沙东的 Ladiratuzumab vedotin，已进入 II 期临床。初步临床结果显示，Ladiratuzumab vedotin 在 TNBC 中有很好的疗效（ORR = 32%），但 HR+/HER2-乳腺癌没有反应（ORR = 0%），且观察到典型的 MMAE 相关不良事件。SDP03923-000-9106 则是恒瑞研发的一款靶向 LIV-1 ADC，采用了可裂解的 linker 加上恒瑞自主研发的强效拓扑异构酶 I 抑制剂依沙替康衍生物（推测为 DXh），DAR 为 6。在 LIV-1 高表达乳腺癌细胞系中，SDP03923-000-9106 表现出较强的抑制作用，IC50 为 5.36 nM。在 LIV-1 高表达患者来源的乳腺癌模型中，3 mg/kg 和 10 mg/kg 剂量下均显示出明显的肿瘤消退，并且 3 mg/kg 剂量下，SDP03923-000-9106 显示出比 BMK-MMAE（恒瑞根据公开的 Ladiratuzumab vedotin 结构合成）更强的抗肿瘤活性 (TGI: 109%)。这些临床前的研究结果支持该药物进入临床研究，恒瑞在 AACR 摘要中表示已经向 NMPA 提交 IND 申请。 HRA00130-C004；靶点：DLL3DLL3 在 SCLC 和其他高级别神经内分泌肿瘤细胞表面上调和异常表达，而在正常组织中的表达有限，因此，DLL3 被认为是治疗 SCLC 等肿瘤的潜力靶点。其实，在很早的时候艾伯维就布局了靶向 DLL3 的 ADC 药物 Rovalpituzumab tesirine（Rova-T，引进自 Stemcentrx，载荷：DNA 交联剂），但在 2019 年宣布停止开发，原因是 Rova-T 作为晚期 SCLC 一线维持治疗的一项 3 期试验显示，与安慰剂相比，Rova-T 并没有显示出生存获益。业内认为 Rova-T 失败的原因之一可能是毒素，而不是靶点问题，因此纷纷进行了改毒素、用新的偶联技术继续探索向 DLL3 的 ADC 药物。全球同靶点在研 ADC 项目共 8 个，除艾伯维的项目外，进展最快的是宜联生物，已进入 I 期临床。HRA00130-C004 是一款具有旁观者效应、高 DAR 值的 DLL3 ADC 药物，将恒瑞自研的拓扑异构酶 I 抑制剂 DXh 通过一个可裂解的 Linker 与人源化 IgG1 抗体连接。在旁观者杀伤体内实验中，HRA00130-C004 在 DLL3 高表达和 DLL3 低表达异种移植模型中产生了显著和持续的肿瘤生长抑制。HRA00130-C004 在给药剂量为 3 mg/kg 和 10 mg /kg 的动物试验中表现出良好的 PK 谱和分子完整性。此外，HRA00130-C004 在大鼠和食蟹猴中耐受性良好，无相关不良反应，具有良好的安全性。综上所述，利用恒瑞 DXh 平台，HRA00130-C004 表现出了强大的疗效潜力和良好的安全性。这些数据支持 HRA00130-C004 的未来临床研究。除上述两款 ADC 新药外，恒瑞此次还公布了靶向 PSMA、tissue factor (TF) 的 ADC 新药，据 Insight 数据库显示，目前恒瑞布局的 ADC 药物超过 20 款。信达生物：3 款 ADC 亮相，2 个新项目首次公开信达生物亮相 2024AACR 项目靶向 Trop2 的免疫刺激抗体偶联物（ISAC）本次 AACR 大会摘要中，信达公布了一款靶向 Trop2 抗体偶联 TLR7/8 激动剂。在体内，该分子有效地抑制了不同 TROP2+ 异种移植肿瘤的生长，并增强了 ADC 的杀伤能力，在动物模型中表现出可接受的安全性。布局 Trop2 靶向的 ISAC 药物并不多，除了信达生物，第一三共也发表过相关专利；此外，启德医药和博瑞医药在本次 AACR 摘要中也披露布局了该靶点的 ISAC，不过药物形式是偶联双药的 ADC，其中一个是细胞毒药物，另一个是免疫激动剂。这些新药目前都处于早期阶段，具体临床疗效，值得持续追踪。据 Insight 数据库显示，目前信达生物共有 9 款 ADC 药物，ISAC 类药物除了 Trop2 这个靶点外，还有一款 CLDN-18.2 抗体偶联 TLR7/8 激动剂，用于治疗胃癌，目前也处在临床前阶段。 IBI3001；靶点：B7-H3/EGFRIBI3001 是一款 B7-H3/EGFR 双抗 ADC 药物，采用了定点偶联的方法，该研究入选了 2024AACR「突破性研究」。信达是最早布局 B7-H3/EGFR 双抗的企业（代号：IBI334），目前正在开展一项实体瘤的 I/II 期临床，进度最快；本次的 ADC 也是在双抗基础上做的进一步延伸，是一款潜在的 FIC 药物，具体摘要内容会在 4 月 5 日公布。多禧生物：6 个 ADC 新药披露靶点/载荷信息多禧生物亮相 2024AACR 项目 DXC006；靶点：NCAM1CD56，也称神经细胞黏附分子 1（NCAM1），几乎在所有的神经母细胞瘤、95% 的小细胞肺癌和 78% 的多发性骨髓瘤患者中都过度表达，而在正常组织表达量低，使其成为肿瘤治疗的潜在靶点。DXC006 是人源化抗 CD56 抗体通过可裂解的多肽连接子与拓扑异构酶 I 抑制剂 CPT113 相连。体外对多个类型癌细胞表现出强效抗肿瘤活性，IC50 为 0.0046～0.061 nmol/L。在大鼠和猕猴表现出中良好的药代动力学和安全性，有望在临床应用中进行探索。目前，全球共有 4 款靶向 CD56 的 ADC 药物在研，进展最快的是 ImmunoGen/Vernalis Researchy 研发的 Lorvotuzumab mertansine，目前正在开展用于多种实体瘤的 II 期临床。多禧生物的 DXC006 正在开展血液瘤和实体瘤的 I 期临床，进度全球第二。 DXC008；靶点：STEAP1STEAP1 属于前列腺六跨膜上皮抗原（STEAP）家族，是一种在前列腺癌中经常表达的细胞表面蛋白，在非前列腺组织表达有限。第一个布局该靶点 ADC 药物的是罗氏旗下基因泰克 Vandortuzumab Vedotin，已经完成 I 期临床，用于治疗表达 STEAP1 的去势抵抗性前列腺癌，显示出可接受的安全性。然而，由于靶标表达水平低和常见的与 MMAE 相关的不良反应，许多患者对 Vandortuzumab Vedotin 不响应。在此背景下，多禧生物开发了 DXC008，它是通过可裂解的多肽连接子将抗 STEAP1 抗体与 Tubulysin B 类似物链接而成。DXC008 不仅对 STEAP1 具有良好的亲和力，还对 PSMA 具有适度的亲和力。DXC008 对多种前列腺肿瘤细胞具有几十～ 100 皮摩尔浓度 (pM) 的抑癌活性，体外 90 分钟内化率超过 60%。在体内，在 STEAP1 和 PSMA 高表达和中等表达的异种移植物模型中，低剂量 1 mg/kg 单次注射显示出持久抗肿瘤反应。在小鼠体内单次注射最大耐受剂量 (MTD) 在 120 mg/kg 以上。DXC008 已被推进到 NHP 毒性研究阶段，有望成为对前列腺癌具有更宽治疗窗口的 STEAP1/ PSMA 靶向 ADC。普方生物：两个 ADC 披露靶点信息普方生物亮相 2024AACR 项目 PRO1106；靶点：SLITRK6SLITRK6 在某些上皮性肿瘤中高表达，包括尿路上皮、肺部、乳腺癌和胶质母细胞瘤，而在正常组织中表达微弱。目前布局该靶点的只有安斯泰来/Seagen 的 ADC 药物 Sirtratumab vedotin，已经在膀胱癌和尿路上皮癌中进行了概念验证，其中尿路上皮癌 I 期临床已完成，结果发表在 2016 年 ASCO 上，整体 ORR 为 30%。PRO1106 是由靶向 SLITRK6 的人源化 IgG1 和基于拓扑异构酶 1 抑制剂的连接子-载荷 sesutecan 组成，该链接子-载荷已经在之前多个新药的临床研究中经过验证。体外试验显示，PRO1106 的靶标结合能力优于 Sirtratumab；在膀胱癌和食管鳞癌细胞来源异种移植模型中，PRO1106 显示出强大的肿瘤生长抑制作用。在动物模型中，表现出比 Sirtratumab vedotin 更稳定的 PK，循环中毒素释放极小，且未观察到明显毒性。总之，PRO1106 是建立在经临床验证的连接子-载荷基础上、针对经临床验证的靶点的 ADC，且在临床前药理学研究中显示出有希望的数据。由于皮肤中 SLITRK6 的表达几乎可以忽略不计，与当前膀胱癌标准 ADC 疗法（enfortumab vedotin）在患者中导致显著的皮肤相关毒副作用相比，PRO1106 可能为该类患者提供一种新的选择。另一款 PRO1286，靶点为 EGFR/MET，目前同靶点 ADC 药物共有 9 款，进展最快的是阿斯利康/BSP Pharmaceuticals 的 AZD9592，已进入临床 I 期，其余 8 款均为国内企业研发，且均处于临床前阶段。除上述企业外，另有不少国内企业公布了 ADC 新项目、靶点信息、载荷信息等，鉴于篇幅有限，统一汇总到如下表格中。2024 AACR 国内企业 ADC 项目来自：Insight 人工整理（如有纰漏请指正）综上可以看出，中国企业在 ADC 领域的新药研发如火如荼，很多靶点组合的布局处于全球前列；除了传统的 ADC 药物很多企业也在积极布局下一代 ADC，比如双抗 ADC、免疫刺激抗体偶联物（ISAC）、双药 ADC 等，相信越来越多国内企业会乘着 ADC 的东风飞起。本次 AACR 大会上还会有多家企业公布 ADC 最新的临床结果，比如，科伦将公布 SKB264 用于晚期 NSCLC 的最新疗效和安全性数据；康宁杰瑞将公布 JSKN003 晚期实体瘤 1 期临床研究结果；映恩生物将公布 B7-H3 和 HER3 两项 ADC 的最新临床结果。相关信息将在 4 月 5 日公布，我们拭目以待。封面来源：站酷海洛 Plus免责声明：本文仅作信息分享，不代表 Insight 立场和观点，也不作治疗方案推荐和介绍。如有需求，请咨询和联系正规医疗机构。编辑：HebePR 稿对接：微信 insightxb投稿：微信 insightxb；邮箱 insight@dxy.cn

AACR会议抗体药物偶联物临床3期临床结果临床申请

2023-09-10

·BioSpace

Patritumab Deruxtecan Demonstrated Clinically Meaningful and Durable Responses in Patients with EGFR-Mutated Metastatic Non-Small Cell Lung Cancer in HERTHENA-Lung01 Phase 2 Trial

An objective response rate of 29.8% was observed with patritumab deruxtecan in heavily pretreated patients BLA submission in U.S. planned for the second half of fiscal year 2023 TOKYO & BASKING RIDGE, N.J.--(BUSINESS WIRE)-- Results from the HERTHENA-Lung01 phase 2 trial showed that patritumab deruxtecan (HER3-DXd) demonstrated clinically meaningful and durable responses in patients with EGFR-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC) following disease progression with an EGFR TKI and platinum-based chemotherapy. These data were presented today during an oral presentation (OA05.03) at the 2023 World Conference on Lung Cancer (#WCLC23) and simultaneously published in the Journal of Clinical Oncology. Patritumab deruxtecan is a specifically engineered potential first-in-class HER3 directed antibody drug conjugate (ADC) designed using Daiichi Sankyo’s (TSE: 4568) proprietary DXd ADC technology. NSCLC accounts for approximately 85% of all lung cancers – 55% having distant spread at diagnosis – with EGFR-activating mutations occurring in 14% to 38% of all NSCLC tumors worldwide.1,2,3 After disease progression following treatment with an EGFR TKI and platinum-based chemotherapy, currently available therapies offer limited efficacy, highlighting the need for new approaches to improve outcomes.3,4 A confirmed objective response rate (ORR) of 29.8% (95% CI: 23.9-36.2) was observed with patritumab deruxtecan (5.6 mg/kg) in 225 patients with EGFR-mutated NSCLC as assessed by blinded independent central review (BICR). One complete response (CR), 66 partial responses (PRs) and 99 cases of stable disease (SD) were seen. A median duration of response (DOR) of 6.4 months (95% CI: 4.9-7.8) and a disease control rate (DCR) of 73.8% (95% CI: 67.5-79.4) were observed. Median progression-free survival (PFS) was 5.5 months (95% CI: 5.1-5.9) and median overall survival (OS) was 11.9 months (95% CI: 11.2-13.1) as of snapshot data cutoff of May 18, 2023. Efficacy outcomes were consistent across subgroups including a subset of 209 patients previously treated with a third-generation EGFR TKI and platinum-based chemotherapy. Anti-tumor activity with patritumab deruxtecan was observed across diverse mechanisms of EGFR TKI resistance and across a broad range of pretreatment tumor HER3 membrane expression. In a subset of 30 patients with brain metastases at baseline and no prior radiotherapy treatment, an intracranial ORR of 33.3% (95% CI: 17.3-52.8%) was observed as assessed by central nervous system (CNS) BICR. In these patients, nine intracranial CRs, one intracranial PR and 13 cases of SD were seen. A CNS DOR of 8.4 months (95% CI: 5.8-9.2) was observed. “The results from HERTHENA-Lung01 provide compelling evidence of efficacy of patritumab deruxtecan in heavily pretreated patients with advanced EGFR-mutated non-small cell lung cancer,” said Helena Yu, MD, Associate Attending Physician, Memorial Sloan Kettering Cancer Center. “The clinically meaningful efficacy observed across a broad range of HER3 expression and diverse mechanisms of EGFR TKI resistance as well as the anti-tumor activity seen in patients with brain metastases, underscore the potential of patritumab deruxtecan to become an important treatment option for a population of patients with lung cancer who have limited treatment options.” “Disease progression is inevitable in patients with previously treated and relapsed metastatic EGFR-mutated non-small cell lung cancer, reinforcing the need for new and innovative treatments across diverse mechanisms of resistance,” said Ken Takeshita, MD, Global Head, R&D, Daiichi Sankyo. “The results from HERTHENA-Lung01, coupled with early trial results, show that patritumab deruxtecan demonstrates clinically meaningful and durable responses, illustrating the potential of this HER3 directed antibody drug conjugate to become a new standard of care for this patient population with high unmet medical need. These data will support our ongoing discussions with health authorities including our planned submission in the U.S.” The safety pro patritumab deruxtecan observed in HERTHENA-Lung01 was consistent with previous clinical trials with a low rate (7.1%) of treatment discontinuation due to treatment-emergent adverse events (TEAEs) at the time of primary data cutoff of November 21, 2022. Grade 3 or higher TEAEs occurred in 64.9% of patients. The most common (>5%) grade 3 or higher TEAEs were thrombocytopenia (21%), neutropenia (19%), anemia (14%), leukopenia (10%), fatigue (6%), hypokalemia (5%) and asthenia (5%). Twelve patients (5.3%) had confirmed treatment-related interstitial lung disease (ILD) as determined by an independent adjudication committee. The majority of ILD events were low grade with one grade 1 event and eight grade 2 events. Two grade 3, zero grade 4 and one grade 5 ILD event were observed. In HERTHENA-Lung01, 51% of patients (n=115) had a history of CNS metastases; 32% (n=72) and 33% of patients (n=75) had brain or liver metastases at baseline by BICR, respectively. In the trial, 63% (n=142) and 36% (n=82) of patients had either an EGFR exon 19 deletion or exon 21 L858R mutation detected at baseline, respectively, and one patient had both. Patients were heavily pretreated receiving a median of three prior lines of systemic therapy in the locally advanced/metastatic setting (range, 1-11), including platinum-based chemotherapy (100%), third generation EFGR TKI (93%) and immunotherapy (40%). As of the snapshot data cutoff of May 18, 2023, the median trial duration was 18.9 (14.9-27.5) months, and 13 patients were continuing to receive patritumab deruxtecan. Summary of HERTHENA-Lung01 Results Efficacy Measure Prior treatment with any EGFR TKI and platinum-based chemotherapy n=225 Subset with prior treatment with third-generation EGFR TKI and platinum-based chemotherapy n=209 Confirmed ORR, % (95% CI) 29.8% (23.9-36.2) 29.2.% (23.1-35.9) CR, n (%) 1 (0.4%) 1 (0.5%) PR, n (%) 66 (29.3%) 60 (28.7%) SD, n (%) 99 (44.0%) 91 (43.5%) PD, n (%) 43 (19.1%) 41 (19.6%) NE, n (%) 16 (7.1%) 16 (7.7%) DCR (95% CI), % 73.8% (67.5-79.4) 72.7% (66.2-78.6) DOR, median (95% CI), months 6.4 months (4.9-7.8) 6.4 months (5.2-7.8) PFS, median (95% CI), months 5.5 months (5.1-5.9) 5.5 months (5.1-6.4) OS, median (95% CI), months 11.9 months (11.2-13.1) 11.9 months (10.9-13.1) CR, complete response; DCR, disease control rate; DOR, duration of response; NE, not evaluable; ORR, objective response rate; OS, overall survival; PR, partial response; PFS, progression-free survival; PD, progressive disease; SD, stable disease. About HERTHENA-Lung01 HERTHENA-Lung01 is a global, multicenter, open-label, two-arm phase 2 trial evaluating the safety and efficacy of patritumab deruxtecan in patients with EGFR-mutated locally advanced or metastatic NSCLC following disease progression with an EGFR TKI and platinum-based chemotherapy. Patients were randomized 1:1 to receive 5.6 mg/kg (n=225) or an uptitration regimen (n=50). The uptitration arm was discontinued as the dose of 5.6 mg/kg of patritumab deruxtecan was selected following a risk-benefit analysis conducted from the phase 1 trial assessing the doses in a similar patient population. The primary endpoint of HERTHENA-Lung01 was ORR as assessed by BICR. Secondary endpoints included duration of response, PFS, disease control rate, and time to response – all assessed by both BICR and investigator assessment – as well as investigator-assessed ORR, OS, safety and tolerability. The data presented at WCLC is from the first arm and based on the fixed-dose (5.6 mg/kg) regimen. HERTHENA-Lung01 enrolled patients in Asia, Europe, North America and Oceania. For more information about the trial, visit ClinicalTrials.gov. About EGFR-Mutated Non-Small Cell Lung Cancer Lung cancer is the second most common cancer and the leading cause of cancer-related deaths worldwide.5 NSCLC accounts for approximately 85% of all lung cancers – 55% having distant spread at diagnosis – with EGFR mutations occurring in 14% to 38% of all NSCLC tumors worldwide.1,2,3 The introduction of targeted therapies has improved the treatment landscape for patients with EGFR-mutated locally advanced or metastatic NSCLC. Targeted therapy with EGFR TKIs offers higher response rates, PFS and potential OS advantage, compared to chemotherapy, with third generation EGFR TKIs demonstrating superior efficacy compared to earlier generation inhibitors.1 However, disease progression from resistance to EGFR TKIs inevitably occurs one to two years following initial treatment.6 After failure of EGFR TKI and platinum-based chemotherapy, currently available therapies offer limited efficacy.3,4 A recent real-world analysis of the treatment of patients in this setting showed that the median PFS in this setting is 3.3 months (95% CI: 2.8-4.4) and median OS is 8.6 months (95% CI: 7.4-9.8). An estimated real-world ORR of 14.1% (95% CI: 3.7%-33.1%) also has been observed.7,8 New treatment approaches are needed to help improve clinical outcomes in patients with EGFR-mutated NSCLC. About HER3 HER3 is a member of the EGFR family of receptor tyrosine kinases.9 It is estimated that about 83% of primary NSCLC tumors and 90% of advanced EGFR-mutated tumors express HER3 after prior EGFR TKI treatment.10,11 There is currently no HER3 directed therapy approved for the treatment of any cancer. About Patritumab Deruxtecan Patritumab deruxtecan (HER3-DXd) is an investigational HER3 directed ADC. Designed using Daiichi Sankyo’s proprietary DXd ADC technology, patritumab deruxtecan is composed of a fully human anti-HER3 IgG1 monoclonal antibody attached to a number of topoisomerase I inhibitor payloads (an exatecan derivative, DXd) via tetrapeptide-based cleavable linkers. Patritumab deruxtecan was granted Breakthrough Therapy Designation by the U.S. Food and Drug Administration in December 2021 for the treatment of patients with EGFR-mutated locally advanced or metastatic NSCLC with disease progression on or after treatment with a third-generation TKI and platinum-based therapies. Patritumab deruxtecan is currently being evaluated as both a monotherapy and in combination with other therapies in a global development program, which includes HERTHENA-Lung02, a phase 3 trial versus platinum-based chemotherapy in patients with EGFR-mutated locally advanced or metastatic NSCLC following disease progression on or after treatment with a third-generation EGFR TKI; a phase 1 trial in combination with osimertinib in EGFR-mutated locally advanced or metastatic NSCLC; and a phase 1 trial in previously treated patients with advanced NSCLC. A phase 1/2 trial in HER3 expressing metastatic breast cancer also has been completed. About the DXd ADC Portfolio of Daiichi Sankyo The DXd ADC portfolio of Daiichi Sankyo currently consists of six ADCs in clinical development across multiple types of cancer. ENHERTU, a HER2 directed ADC, and datopotamab deruxtecan (Dato-DXd), a TROP2 directed ADC, are being jointly developed and commercialized globally with AstraZeneca. Four additional Daiichi Sankyo DXd ADCs include patritumab deruxtecan (HER3-DXd), a HER3 directed ADC, ifinatamab deruxtecan (I-DXd; DS-7300), a B7-H3 directed ADC, raludotatug deruxtecan (R-DXd; DS-6000), a CDH6 directed ADC, and DS-3939, a TA-MUC1 directed ADC. Designed using Daiichi Sankyo’s proprietary DXd ADC technology to target and deliver a cytotoxic payload inside cancer cells that express a specific cell surface antigen, 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. Datopotamab deruxtecan, ifinatamab deruxtecan, patritumab deruxtecan, raludotatug deruxtecan and DS-3939 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 . Disclosure: Dr. Yu has a consulting relationship with Daiichi Sankyo. ______________________ References: 1 Economopoulou P, et al. Ann Transl Med. 2018; 6(8):138. 2 Chen R, et al. J Hematol Oncol. 2020; 13(1):58. 3 Zhang Y-L, et al. Oncotarget. 2016; 7(48):78985-78993. 4 Janne PA, et al. Cancer Discov. 2022; 12(1):74-89. 5 World Health Organization. International Agency for Research on Cancer. Lung Fact Sheet. Accessed January 2023. 6 Janne PA, et al. N Engl J Med 2015; 372:1689-1699. 7 Patel JD, et al. AACR 2023. Poster 6754. 8 Patel JD, et al. IASLC 2023 WCLC. Abstract 2201. 9 Mishra R, et al. Oncol Rev. 2018; 12(355):45-62. 10 Scharpenseel H, et al. Scientific Reports. 2019; 9:7406. 11 Yonesaka K, et al. Clin Cancer Res. 2022; 15:28(2):390-403. View source version on businesswire.com: Contacts Global/US: Jennifer Brennan Daiichi Sankyo, Inc. jbrennan2@dsi.com +1 908 900 3183 (mobile) Japan: Koji Ogiwara Daiichi Sankyo Co., Ltd. ogiwara.koji.ay@daiichisankyo.co.jp +81 3 6225 1126 (office) Investor Relations Contact: DaiichiSankyoIR@daiichisankyo.co.jp Source: Daiichi Sankyo View this news release online at:

临床结果临床1期临床2期突破性疗法临床3期

100 项与 Anti-Her3 therapy(Band Therapeutics, LLC) 相关的药物交易

登录后查看更多信息