This study is an open-label, international, multi-center, Phase 2 study in adult patients with recurrent, locally-advanced or metastatic solid tumors, which harbor the NRG1 gene fusion.

开始日期2024-02-28

申办/合作机构

Elevation Oncology, Inc.

NCT03241810

/ Terminated临床2期

Randomized Phase 2 Trial of Seribantumab Plus Fulvestrant in Postmenopausal Women With Hormone Receptor-positive, Heregulin Positive (HRG+), HER2 Negative Metastatic Breast Cancer (Merrimack Pharmaceuticals Inc.)

This study is a multi-center, randomized, double-blind, placebo-controlled, Phase 2 study in postmenopausal women with heregulin positive, hormone receptor positive, HER2 negative metastatic, unresectable breast cancer.

开始日期2017-08-15

申办/合作机构

Elevation Oncology, Inc.

NCT02538627

/ Terminated临床1期

A Phase 1 Multi Arm Study Evaluating the Safety, Pharmacology and Preliminary Activity of the Co-Administration of MM-151 With Seribantumab (MM-121), Istiratumab (MM-141), or Trametinib in Biomarker-selected Cancer Patients

This is a Phase 1 open-label, dose-escalation trial using "3+3" design, evaluating MM-151 co-administration with MM-121, MM-141, and trametinib at varying dose levels.

开始日期2015-08-01

申办/合作机构

Merrimack Pharmaceuticals, Inc.

100 项与 Seribantumab 相关的临床结果

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100 项与 Seribantumab 相关的转化医学

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100 项与 Seribantumab 相关的专利（医药）

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项与 Seribantumab 相关的文献（医药）

2025-01-01·Current medicinal chemistry

The Therapeutic Significance of HER3 in Non-small Cell Lung Cancer (NSCLC): A Review Study

Article

作者: Ding, Ke ; Zhang, Jinwei ; Trinder, Amelia

HER3 (Human Epidermal Growth Factor Receptor 3) is frequently overexpressed in various cancers, including non-small cell lung cancer (NSCLC), with a prevalence of 83% in primary tumors. Its involvement in tumorigenesis and resistance to targeted therapies makes HER3 a promising target for cancer treatment. Despite being initially considered “undruggable” due to its lack of catalytic activity, significant progress has been made in the development of anti-HER3 therapeutics. Monoclonal antibodies such as lumretuzumab, seribantumab, and patritumab have shown potential in targeting HER3 to overcome resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). Additionally, antibody-drug conjugates (ADCs) like HER3-DXd (patritumab deruxtecan) are new drug candidates that have demonstrated selective delivery of cytotoxic chemicals to NSCLC cells by exploiting HER3's widespread expression, minimizing cytotoxicity. This review aims to evaluate the efficacy of current HER3 therapeutics in development and their therapeutic potential in NSCLC, incorporating evidence from clinical trials.

2024-11-05·Circulation

ErbB3 Governs Endothelial Dysfunction in Hypoxia-Induced Pulmonary Hypertension

Article

作者: Zhang, Junting ; Chen, Yuan ; Yang, Xusheng ; Li, Yiying ; Chen, Rongchang ; Deng, Lin ; Nie, Xiaowei ; Bian, Jin-Song ; Tan, Jianxin ; Chen, Jingyu

BACKGROUND::

Pulmonary hypertension, characterized by vascular remodeling, currently lacks curative therapeutic options. The dysfunction of pulmonary artery endothelial cells plays a pivotal role in the initiation and progression of pulmonary hypertension (PH). ErbB3 (human epidermal growth factor receptor 3), also recognized as HER3, is a member of the ErbB family of receptor tyrosine kinases.

METHODS::

Microarray, immunofluorescence, and Western blotting analyses were conducted to investigate the pathological role of ErbB3. Blood samples were collected for biomarker examination from healthy donors or patients with hypoxic PH. The pathological functions of ErbB3 were further validated in rodents subjected to chronic hypoxia- and Sugen-induced PH, with or without adeno-associated virus-mediated ErbB3 overexpression, systemic deletion, or endothelial cell–specific ErbB3 knockdown. Primary human pulmonary artery endothelial cells and pulmonary artery smooth muscle cells were used to elucidate the underlying mechanisms.

RESULTS::

ErbB3 exhibited significant upregulation in the serum, lungs, distal pulmonary arteries, and pulmonary artery endothelial cells isolated from patients with PH compared with those from healthy donors. ErbB3 overexpression stimulated hypoxia-induced endothelial cell proliferation, exacerbated pulmonary artery remodeling, elevated systolic pressure in the right ventricle, and promoted right ventricular hypertrophy in murine models of PH. Conversely, systemic deletion or endothelial cell–specific knockout of ErbB3 yielded opposite effects. Coimmunoprecipitation and proteomic analysis identified YB-1 (Y-box binding protein 1) as a downstream target of ErbB3. ErbB3 induced nuclear translocation of YB-1 and subsequently promoted hypoxia-inducible factor 1/2α transcription. A positive loop involving ErbB3-periostin-hypoxia–inducible factor 1/2α was identified to mediate the progressive development of this disease. MM-121, a human anti-ErbB3 monoclonal antibody, exhibited both preventive and therapeutic effects against hypoxia-induced PH.

CONCLUSIONS::

Our study reveals, for the first time, that ErbB3 serves as a novel biomarker and a promising target for the treatment of PH.

2022-11-01·JCO precision oncology

Clinical Response to Seribantumab, an Anti–Human Epidermal Growth Factor Receptor-3 Immunoglobulin 2 Monoclonal Antibody, in a Patient With Metastatic Pancreatic Ductal Adenocarcinoma Harboring an NRG1 Fusion

Article

作者: Thavaneswaran, Subotheni ; Deegan, Maegan ; Chan, Wei Yen ; Jansen, Valerie M. ; Grady, John P. ; Thomas, David M. ; Asghari, Ray

项与 Seribantumab 相关的新闻（医药）

2025-02-03

·精准药物

靶向NRG1融合肿瘤

NRG1基因编码神经调节蛋白 1（Neu Re Gulin 1，NRG1），是一种能够结合 HER3 和 HER4 并激活 ErbB 信号通路的神经调节生长因子。NRG1是表皮生长因子（EGF）配体家族的一员，NRG1基因框内融合可激活并保留NRG1蛋白的EFG样结构域，它可与 ERBB3 结合。ERBB3本身缺乏激酶域，但是它可以与ERBB2结合形成异二聚体，进而激活下游信号通路（MAPK和PI3K通路），导致细胞增殖或分化，并最终导致癌症的发生。 NRG1篇概要临床病理特征 1. 属于罕见靶点：很罕见、频率低（肺0.3%）、驱动基因、有药可用 2. NRG1融合常见因素：女性、不吸烟者、腺癌（黏液亚型） 3. 检测方法：RNA-seq NGS（优选）靶向治疗 4. Zenocutuzumab-zbco：后线，ORR为33%，DOR为7.4个月 5. 阿法替尼、吡咯替尼、Seribantumab等正在进行晚期泛癌种的NRG1融合试验 6. 目前临床个例报道疗效较多的药物有阿法替尼临床病理特点融合类型（泛瘤种） 2019年4月，《Clin Cancer Res》杂志上发表实体瘤中NRG1融合的数据0.19%（41/21858）[1]，非小细胞肺癌中25例中融合伙伴为CD74（15例），SLC3A2（1例），TNC（1例），MDK（1例），ATP1B1（1例），DIP2B（1例），RBPMS（1例），MRPL13（1例），ROCK1（1例），DPYSL2（1例），PARP8（1例）；卵巢癌3例中SETD4（1例），TSHZ2（1例），ZMYM2（1例）；胰腺导管癌3例中ATP1B1（1例），CDH1（1例），VTCN1（1例）；乳腺癌2例中ADAM9（1例），COX10-AS1（1例）；胆囊癌3例中ATP1B1（2例），NOTCH2（1例）；结直肠癌中POMK（1例）；肾细胞癌中RBPMS（1例）；尿路上皮癌中GDF14（1例）；肉瘤中WHC1L1（1例）；鼻咽神经内分泌肿瘤中HMOX1（1例）。 NRG1融合实体瘤非小细胞肺癌有研究纳入了117名携带NRG1融合的NSCLC患者[2]，并对他们的临床特征进行总结，最终观察到NRG1融合常见因素，包括：女性和从不吸烟者；发生NRG1融合最常见的肿瘤类型主要为腺癌和粘液亚型。 NSCLC基因融合谱检测方法目前，有多种方法可用于检测基因融合，比如RNA-seq NGS（优先），DNA-seq NGS，RT-PCR，FISH。NRG1融合一般与EGFR、ALK和ROS1等驱动基因不共存，TP53突变是其最常见的共存基因突变，见上右图。 RNA-seq NGS优势[3]：在对17,485例实体瘤的大规模分析中，所有肿瘤样本使用NGS（MSK-IMPACT）进行检测，对某些肿瘤采用靶向RNA测序（MSK-Fusion Solid Assay，Archer Fusion Plex）进行检测。测序发现在多个KRAS野生型IMA和一例胰腺腺癌中检测到NRG1融合，而之前仅靠NGS DNA测序是漏检的。这些发现表明，由于融合结构的复杂性和多样性以及NRG1具有较大的内含子区域，单NGS DNA测序可能会漏检一些NRG1融合，也就是说RNA测序可能比DNA NGS更可靠。可用于检测NRG1和其他基因融合的不同方法的优缺点靶向治疗根据NRG1融合致癌的原理，可发现抑制NRG1融合的潜在方法，主要有两大类：一类是针对 EGFR/HER2 的小分子TKIs（Tyrosine Kinase Inhibitors，酪氨酸激酶抑制剂）：比如阿法替尼，吡咯替尼，拉帕替尼，来那替尼，Tarloxitinib 等。一类是针对HER2或HER3的大分子mAb（monoclonal Antibody，单克隆抗体）/ADCs：比如针对HER2的曲妥珠单抗，Margetuximab等；针对HER3的 Patritumab，Seribantumab，Zenocutuzumab (MCLA-128)，Lumretuzumab，GSK2849330，U3-1402等。 NRG1融合阳性肿瘤患者使用ErbB靶向治疗的报道病例备注：Lung adenocarcinoma,肺腺癌；IMA，浸润性黏液腺癌；NSCLC，非小细胞肺癌；PDAC，胰腺导管腺癌 Zenocutuzumab[4-5]FDA加速批准首个NRG1基因融合靶向疗法，你了解多少？ Zenocutuzumab 是一种双特异性抗体，可与 HER2 和 HER3 的细胞外结构域结合。该药可通过阻断 NRG1/HER3 结合和 HER2/HER3 二聚化，从而通过 PI3KAKT-mTOR 致癌信号通路，抑制肿瘤细胞增殖和存活。生理→病理 eNRGy研究（NCT02912949）是一项多中心、开放标签、多队列的临床试验，共招募了64例NRG1融合阳性晚期或转移性NSCLC成人患者，以及30例NRG1融合阳性晚期或转移性胰腺癌成人患者，这些患者在接受标准治疗后出现疾病进展。NRG1融合阳性状态的确认由下一代测序（NGS）检测方法前瞻性确定。研究的主要终点包括经独立盲法中央审查依据RECIST v1.1标准评估的确认总体缓解率（ORR）和缓解持续时间（DOR）。结果显示，在NSCLC患者中，ORR为33%（95% CI：22%-46%），中位DOR为7.4个月（95% CI：4.0-16.6）。在胰腺癌患者中，ORR为40%（95% CI：23%-59%），DOR范围为3.7个月至16.6个月。安全性分析显示，在汇总的安全性人群中，最常见的不良反应（≥10%）包括腹泻、肌肉骨骼疼痛、疲劳、恶心、输液相关反应、呼吸困难、皮疹、便秘、呕吐、腹痛和水肿。最常见的3级或4级实验室异常（≥10%）包括γ-谷氨酰转移酶升高、血红蛋白降低、钠降低和血小板减少。经典报道(阿法替尼) 2014-01 CD74⁃NRG1融合基因首次由Fernandez⁃Cuesta等在《Cancer Discov》报道，通过对25例从未吸烟的KRAS和EGFR基因阴性的肺腺癌患者进行转录组测序，发现了CD74⁃NRG1融合基因占4%（1/25），随后作者运用逆转录聚合酶链式反应（RT⁃PCR）在15例浸润性黏液肺腺癌患者中，发现CD74⁃NRG1融合基因占27%（4/15），提示了CD74⁃NRG1融合基因与浸润性黏液肺腺癌有着密切的关系。 2014-06 Nakaoku等在《Clin Cancer Res》上首次报道了SLC3A2⁃NRG1融合基因，他们在从未吸烟的浸润性黏液肺腺癌患者中，发现6例患者拥有SLC3A2⁃NRG1融合基因，频率为17.6%（6/34）。 2014-07 Gow等在《Med Oncol》上也报道了台湾的一个小组在13 例浸润性黏液肺腺癌中发现了1例CD74⁃NRG1融合基因的病例（8%）。 2014-12 2014年12月，Dhanasekaran等在《Nat Commun》上报道了NRG1新的融合伙伴：RBPMS和SDC4。 2015-07 Jung等在《J Thorac Oncol》上首次报道了1例拥有VAMP2⁃NRG1融合基因的非小细胞肺癌，作者运用RNA测序技术分析了100多例非小细胞肺癌患者，发现了1例CD74⁃NRG1融合基因患者和1例VAMP2⁃NRG1融合基因患者，其中VAMP2⁃NRG1融合基因患者是1名67 岁从未吸烟的女性，基因测序没有发现EGFR、KRAS和BRAF基因突变和ALK、ROS1、RET等融合基因。 2016-09 Shin等也在《Oncotarget》上报道，通过二代测序检测59例浸润性黏液肺腺癌患者，NRG1融合为16例，融合伙伴SLC3A2占13例（81.25%），融合伙伴CD74⁃NRG1占3例（18.75%）。其中10例NRG1融合并发KRAS基因突变（62.5%），2 例NRG1 融合并发NRAS Q61L突变和EML4⁃ALK融合。 2017-05 Gay等在《J Thorac Oncol》上发表文章，报道了2个有趣的案例：2位NRG1融合的肺癌患者通过二代EGFR⁃TKI阿法替尼治疗，无进展生存时间分别为12个月和10个月。 2017-05 案例1 患者是一位42岁从不吸烟的男性白种人，肺腺癌伴随肝转移和颞骨转移，二代基因测序没有发现EGFR、ALK、ROS1、KRAS等突变，只有TP53突变。患者在接受了4个周期的培美曲塞联合铂类化疗后，进行了RNA测序，发现其具有SLC3A2⁃NRG1基因融合，随后应用了阿法替尼（40 mg qd）治疗，在服药2-3天后，患者咳嗽和气短症状便有了很大的改善。CT和MRI显示原发肿瘤和颞骨转移灶都发生了明显缩小，疗效评估达到部分缓解并维持了12个月。 2017-05 案例2 患者是一位62岁从不吸烟的男性白种人，诊断为早期肺癌，行右下肺切除术+淋巴结清扫。手术后几个月，发现了左肾上腺转移，二代测序显示只有TP53和 MYC基因突变，RNA测序发现患者具有CD74⁃NRG1基因融合，于是也应用了阿法替尼（40mg qd）治疗，疗效评估部分缓解并维持了10个月。 2017-10 Muscarella 等在《J Thorac Oncol》上报道了1例 CD74⁃NRG1融合基因与ALK基因融合基因同时存在的晚期肺腺癌病例，患者为65岁从不吸烟的男性白种人，2012年5月病理诊断为印戒细胞肺腺癌伴随淋巴结、脾脏、骨转移，二代基因测序显示CD74⁃NRG1融合基因与ALK基因突变同时存在，患者随后接受了化疗和克唑替尼、色瑞替尼等多重治疗，生存至今已5年。 2017-12 Cheema等也在《J Thorac Oncol》上报道了1例拥有CD74⁃NRG1融合基因的肺腺癌病例，患者为62岁从不吸烟的亚洲女性，没有远处转移，肺部肿块穿刺证实病理类型为浸润性黏液腺癌，且没有检测到常见的EGFR和ALK等基因状态改变，由于肿瘤多发且不可切除，该患者接受了培美曲塞联合铂类化疗，病情得到一定的缓解。但随后患者的病情恶化，二代测序检测显示该患者具有CD74⁃NRG1融合，随后应用了阿法替尼（40 mg qd）治疗，治疗2周后患者的症状得到了明显改善，影像学资料也显示肿瘤明显缩小，疗效评估为部分缓解并维持了26周。参考资料 [1]Jonna S, Feldman RA, Swensen J, et al. Detection of NRG1 Gene Fusions in Solid Tumors. Clin Cancer Res. 2019 Aug 15;25(16):4966-4972. doi: 10.1158/1078-0432.CCR-19-0160. [2]Duruisseaux M, Liu SV, Han JY, et al. NRG1 fusion-positive lung cancers: clinicopathologic profile and treatment outcomes from a global multicenter registry. J Clin Oncol. 2019;37. Abstract 9081. [3]Laskin J, Liu SV, Tolba K, et al. NRG1 fusion-driven tumors: biology, detection, and the therapeutic role of afatinib and other ErbB-targeting agents. Ann Oncol. 2020 Dec;31(12):1693-1703. doi: 10.1016/j.annonc.2020.08.2335. [4]https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-zenocutuzumab-zbco-non-small-cell-lung-cancer-and-pancreatic [5]https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/761352s001lbl.pdf 声明：发表/转载本文仅仅是出于传播信息的需要，并不意味着代表本公众号观点或证实其内容的真实性。据此内容作出的任何判断，后果自负。若有侵权，告知必删！长按关注本公众号粉丝群/投稿/授权/广告等请联系公众号助手觉得本文好看，请点这里↓

申请上市临床1期临床研究

2025-01-13

·PRNewswire

Elevation Oncology Provides Updates on Differentiated ADC Programs and Upcoming Milestones

-- Initiated dosing in Phase 1 clinical trial cohort evaluating Claudin 18.2 ADC EO-3021 in combination with ramucirumab or dostarlimab in patients with advanced gastric/gastroesophageal junction (GEJ) cancer -- -- Expect to report initial data from combination cohort in 4Q 2025 or 1Q 2026 -- -- On-track to report additional monotherapy data from dose escalation and expansion cohorts of ongoing Phase 1 clinical trial in 1H 2025 -- -- Plan to present preclinical data for HER3 ADC EO-1022 in 1H 2025 and file an Investigational New Drug (IND) application in 2026 -- BOSTON, Jan. 13, 2025 /PRNewswire/ -- Elevation Oncology, Inc. (Nasdaq: ELEV), an innovative oncology company focused on the discovery and development of selective cancer therapies to treat patients across a range of solid tumors with significant unmet medical needs, today announced program updates and upcoming milestones. "We are rapidly advancing EO-3021 to address significant unmet needs in treating earlier lines of advanced gastric/GEJ cancer, where we believe we have a unique ability to improve on the standard of care," said Joseph Ferra, President and Chief Executive Officer of Elevation Oncology. "As we enter 2025, we are honing our focus, leveraging the competitive anti-tumor activity and differentiated safety profile of EO-3021 to explore combination approaches in the first- and second-line settings. With our Phase 1 clinical trial ongoing and now enrolling both monotherapy and combination cohorts, we are in a leading position to explore the compelling potential of EO-3021, our differentiated Claudin 18.2 ADC, to improve outcomes for people living with advanced gastric/GEJ cancer." Mr. Ferra continued, "We look forward to sharing additional data from our Phase 1 dose escalation and expansion study of EO-3021 in the first half of 2025. With this readout, we aim to build on the promising initial data reported in August 2024, reinforcing EO-3021's robust anti-tumor activity and potential better combinability, while garnering additional insights to inform our go-forward clinical development efforts. We are enthusiastic about the potential of EO-3021 in addressing meaningful market opportunities and look forward to a transformative 2025." Program Updates and Upcoming Milestones EO-3021: Elevation Oncology is developing EO-3021, a differentiated, potentially best-in-class antibody drug conjugate (ADC) for the treatment of patients with advanced, unresectable or metastatic solid tumors likely to express Claudin 18.2, including gastric/GEJ cancer. In August 2024, Elevation Oncology reported promising initial monotherapy data from the dose escalation portion of its ongoing Phase 1 clinical trial of EO-3021, demonstrating competitive efficacy, with a 42.8% confirmed overall response rate (ORR) in a biomarker-enriched population, and a differentiated safety profile, including minimal hematological toxicity and hepatotoxicity, and no peripheral neuropathy/hypoesthesia. Based on these data, Elevation Oncology is focusing the clinical development of EO-3021 on the first- and second-line treatment of advanced gastric/GEJ cancer, where EO-3021's key attributes can potentially provide differentiated benefits and address unmet needs in both patient outcomes and safety. Monotherapy : The dose expansion portion of Elevation Oncology's Phase 1 clinical trial of monotherapy EO-3021 is ongoing. As of January 2025, Elevation Oncology has implemented prospective Claudin 18.2 expression testing as part of the patient screening process, focusing enrollment on patients with ≥25% of tumor cells at IHC 1+/2+/3+. Elevation Oncology expects to report additional safety and efficacy data from the dose escalation and expansion portions of the study in the first half of 2025. Combination: Patient dosing is ongoing in the combination portion of Elevation Oncology's Phase 1 clinical trial of EO-3021. The combination cohorts are evaluating EO-3021 in combination with dostarlimab, a PD-1 inhibitor, in the first line setting and with ramucirumab, a VEGFR2 inhibitor, in the second line setting. By combining EO-3021 and dostarlimab, an immune checkpoint inhibitor, Elevation Oncology aims to deliver synergistic benefit, potentially offering patients improved outcomes beyond those seen with the existing combination of immunotherapy and chemotherapy. The combination of an immunotherapy and chemotherapy agent is the standard of care for the treatment of gastric/GEJ cancer in the front-line setting. With the EO-3021 and ramucirumab combination, Elevation Oncology aims to deliver improved tolerability and synergistic anti-tumor activity compared to the approved combination of ramucirumab and paclitaxel. The combination of ramucirumab and paclitaxel is the standard of care for the treatment of second-line gastric/GEJ cancer. Elevation Oncology expects to report initial data from the combination cohorts in the fourth quarter of 2025 or the first quarter of 2026. EO-1022: Elevation Oncology is developing EO-1022, a differentiated HER3 ADC for the treatment of patients with HER3-expressing solid tumors, including breast cancer, EGFR-mutant non-small cell lung cancer, and pancreatic cancer. EO-1022 combines seribantumab, a fully human anti-HER3 monoclonal antibody, and a monomethyl auristatin E (MMAE) payload with site-specific conjugation to glycan. It is designed to leverage seribantumab's desirable internalization capability and the latest site-specific ADC technology to deliver a safe, effective option for patients living with solid tumors that express HER3. Elevation Oncology expects to present preclinical data for EO-1022 in the first half of 2025 and to file an IND application in 2026. Financial Guidance Elevation Oncology expects that its cash, cash equivalents and marketable securities as of September 30, 2024, will be sufficient to fund its current operations into 2026. About Elevation Oncology, Inc. Elevation Oncology is an innovative oncology company focused on the discovery and development of selective cancer therapies to treat patients across a range of solid tumors with significant unmet medical needs. We are leveraging our ADC expertise to advance a novel pipeline, initially targeting two clinically validated targets in oncology, Claudin 18.2 and HER3. Our lead candidate, EO-3021, is a potential best-in-class, Claudin 18.2 ADC and is currently being evaluated in a Phase 1 trial (NCT05980416) as a monotherapy, and in combinations with dostarlimab or ramucirumab, in patients with advanced, unresectable or metastatic gastric/gastroesophageal adenocarcinoma that express Claudin 18.2. We are also advancing EO-1022, a HER3 ADC for the treatment of patients living with solid tumors that express HER3, through preclinical development. For more information, visit . Forward-Looking Statements This press release contains forward-looking statements within the meaning of the "safe harbor" provisions of the Private Securities Litigation Reform Act of 1995, including, but not limited to, anticipated clinical and preclinical development activities, expected timing of announcements of clinical and preclinical results, potential benefits of product candidates, potential market opportunities for product candidates, the ability of product candidates to treat their targeted indications and Elevation Oncology's expectations about its cash runway. All statements other than statements of historical fact are statements that could be deemed forward-looking statements. These forward-looking statements may be accompanied by such words as "aim," "anticipate," "believe," "could," "estimate," "expect," "forecast," "goal," "intend," "may," "might," "plan," "possible," "potential," "will," "would," and other words and terms of similar meaning. Although Elevation Oncology believes that the expectations reflected in such forward-looking statements are reasonable, Elevation Oncology cannot guarantee future events, results, actions, levels of activity, performance or achievements, and the timing and results of biotechnology development and potential regulatory approval are inherently uncertain. Forward-looking statements are subject to risks and uncertainties that may cause Elevation Oncology's actual activities or results to differ significantly from those expressed in any forward-looking statement, including risks and uncertainties related to Elevation Oncology's ability to advance its product candidates, the timing and results of preclinical studies and clinical trials, approvals and commercialization of product candidates, the receipt and timing of potential regulatory designations, Elevation Oncology's ability to fund development activities and achieve development goals, Elevation Oncology's ability to protect intellectual property, Elevation Oncology's ability to establish and maintain collaborations with third parties, and other risks and uncertainties described under the heading "Risk Factors" in documents Elevation Oncology files from time to time with the Securities and Exchange Commission. These forward-looking statements speak only as of the date of this press release, and Elevation Oncology undertakes no obligation to revise or update any forward-looking statements to reflect events or circumstances after the date hereof. Elevation Oncology Investor and Media Contact Gracie Tong Senior Director, Investor Relations and Corporate Communications [email protected] SOURCE Elevation Oncology WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

临床1期免疫疗法抗体药物偶联物临床结果

2024-12-25

·CPHI制药在线

HER3靶点进展浅谈，Zenocutuzumab率先获批

关注并星标CPHI制药在线 2024年10月，默沙东注射用MK-1022在国内获得临床试验默示许可，用于治疗胃肠道肿瘤。MK-1022（HER3-DXd，Patritumab deruxtecan）是采用第一三共技术设计的潜在首创HER3靶向ADC，由全人源化抗HER3 IgG1单克隆抗体通过可裂解四肽连接子与拓扑异构酶I抑制剂有效载荷（一种依喜替康衍生物，DXd）连接组成。（点击小图看大图） 2021年12月，MK-1022被FDA授予突破性疗法认定，用于治疗EGFR突变的局部晚期或转移性非小细胞肺癌（NSCLC）患者，这些患者在接受第三代酪氨酸激酶抑制剂（TKI）和铂类药物治疗期间或治疗后出现疾病进展。 2023年10月，第一三共和默沙东就包括MK-1022在内的三款ADC签订全球开发和商业化协议，潜在交易总金额约220亿美元。据协议，默沙东获得这些产品在日本之外的全球开发及商业化权益。 2023年12月，MK-1022治疗既往接受过两种或两种以上全身治疗的局部晚期或转移性EGFR突变成人NSCLC的BLA获FDA受理，并被授予优先审查。该BLA是基于II期研究HERTHENA-Lung01的结果。 HERTHENA-Lung01研究在225例EGFR突变的局部晚期或转移性NSCLC患者中开展，这些患者既往接受过EGFR-TKI和含铂化疗后发生疾病进展。结果显示：接受MK-1022治疗患者的客观缓解率（ORR）为29.8%，中位缓解持续时间为6.4个月。安全性方面，HERTHENA-Lung01研究安全性扩展结果显示，MK-1022安全性可控，与既往报告一致。血液学和消化道TEAE通常发生在中位治疗（TX）周期的早期，未观察到其他安全信号。遗憾的是，2024年6月，第一三共和默沙东收到了FDA就该BLA发出的完整回复函（CRL），原因是第三方生产设施的问题。 2024年9月，默沙东/第一三共宣布MK-1022的III期研究HERTHENA-Lung02 达到主要终点PFS。该研究是一项全球性、多中心、开放标签试验，旨在评估每三周一次5.6 mg/kg MK-1022与四个周期的培美曲塞和铂类化疗相比，在转移性或局部晚期NSCLC患者中的疗效和安全性，这些患者携带EGFR激活突变（外显子19缺失或L858R）并接受过第三代EGFR TKI（包含奥希替尼、拉泽替尼、奥莫替尼、阿氟替尼）治疗后发生疾病进展。数据显示：与铂联合培美曲塞诱导化疗后再接受培美曲塞维持化疗相比，MK-1022治疗后患者实现显著的PFS统计学改善，达到主要终点。但在进行分析时，次要终点总生存期（OS）数据还不成熟。安全性方面，研究中观察到的安全性与之前临床试验中的安全性一致，没有发现新的安全信号。默沙东计划与全球监管单位就该研究结果进行进一步的讨论。 MK-1022是默沙东研发管线中进展最快的一款ADC，期待其可以早日通过监管批准，造福EGFR-TKI耐药的NSCLC患者。 ! HER3靶向药进展 HER3是EGFR/HER家族成员之一，没有或几乎没有细胞内酪氨酸激酶活性。虽然有报道称HER3具有一些激酶活性，但它比完全激活的EGFR激酶活性弱1000倍。与其他家族成员相比，HER3单独过表达时不具有致癌作用，但当其与神经调节蛋白（NRG）配体结合后，便会与其他RTK（受体酪氨酸激酶）形成异源二聚体。特别是HER3与HER2结合时，更是会形成HER2：HER3异源二聚体，导致PI3K/AKT和MEK/MAPK信号通路会被激活，促进细胞的分裂、增殖与分化，促进癌细胞的存活和发展。 HER3在正常成人的胃肠道、生殖系统、皮肤、神经系统、泌尿道等系统中均有表达，而其过度表达与前列腺癌、膀胱癌和乳腺癌等多种癌症相关。而且，已有研究证明HER3与EGFR、HER2疗法的耐药机制有关。鉴于HER2、EGFR耐药的广泛发生，HER3被认为可能是破解EGFR以及HER2靶点耐药性，进一步提升临床治疗潜力的关键所在。目前，全球监管机构仅批准一款HER3靶向药，即Zenocutuzumab。 Zenocutuzumab是Merus开发的一款靶向HER2/HER3的双抗，2023年6月被FDA授予突破性治疗认定，用于治疗既往全身治疗进展后或没有令人满意的替代治疗方案的NRG1+胰腺癌。2023年7月，该药被FDA授予第二项突破性治疗认定，用于NRG1融合阳性NSCLC。 ESMO 2023大会上公布的数据显示：在晚期NRG1+ NSCLC患者中，研究者根据RECIST 1.1版评估的ORR为37.2%，mDOR为14.9个月；在晚期NRG1+胰腺导管腺癌中，研究者根据RECIST 1.1版评估的ORR为42.4%，mDOR为9.1个月。安全性方面，研究中观察到61%的患者出现任何级别的TRAEs，包括5%的3/4级TRAEs。最常见的任何级别的TRAEs包括腹泻（21%）、乏力/疲劳（12%）、输液相关反应（15%）和恶心（10%）。此外，不到1%的患者因毒性而停止治疗。 2024年5月，FDA受理Zenocutuzumab治疗NRG1+ NSCLC和胰腺癌的BLA，同时授予该BLA优先审评资格。2024年12月，FDA批准Zenocutuzumab用于治疗NRG1+胰腺癌和非小细胞肺癌，商品名为Bizengri。此外，据不完全统计全球还有几款HER3靶向药，详见下表。HER3靶向药药物类型多样，涉及单抗、ADC和双抗ADC。（点击小图看大图） HER3靶向单抗中的Seribantumab可抑制NRG1融合蛋白启动的信号传导，从而引导癌细胞生长和增殖。临床前数据表明，Seribantumab可阻止携带NRG1基因融合的细胞中HER3信号的激活，并破坏ERBB家族信号传导途径的稳定性，其中包括HER2、EGFR和HER4的激活。2024年4月，Seribantumab被FDA授予快速通道指定，用于治疗携带NRG1基因融合的晚期实体瘤。 HER3靶向ADC中的YL202/BNT326是基于宜联生物的TMALIN®技术所开发的一款靶向人HER3的下一代ADC。2023年10月，宜联生物与BioNTech就YL202达成战略合作和全球许可协议。 ASCO 2024年会上公布的YL202首次临床研究数据显示：截至2024年4月16日，该项中、美同步开展的I期临床爬坡共计入组55人（NSCL 40人，BC 15人），累计爬坡7个剂量组（0.5 – 5.5 mg/kg Q3W）。全部剂量下共51例可评估病例，ORR为42.3%，DCR为94.2%，mPFS为6.0月，mDOR为5.8月。其中3.0mg/kg剂量组ORR为60.0%，DCR为100%。在EGFRm NSCLC末线人群中，全部爬坡剂量下ORR为39.4%（15/38）；在HR+/HER2- BC末线人群中，全部爬坡剂量下ORR为53.8%（7/13）。安全性方面，常见治疗相关安全事件包括白细胞计数减少、中性粒细胞减少等血液学副作用。在爬坡过程中，5.5mg/kg剂量组下出现一例DLT事件（三级粒缺伴发热）。在回填过程中，4.0mg/kg和5.5mg/kg剂量组下分别出现2例（中性粒和血细胞减少）和1例受试者死亡（新冠感染后间质性肺炎）。考虑到YL202在较高剂量下，可能会使人类受试者面临不合理和重大的疾病或伤害风险，6月17日，FDA对由MediLink赞助的YL202/BNT326多中心、开放标签、首次人体1期临床（NCT05653752）试验进行部分临床搁置。不过8月，FDA解除了该部分临床搁置。 SHR-A2009是恒瑞医药自主研发的一款以HER3为靶点的ADC，由全人抗HER3 IgG1 mAb、可切割肽接头和 DNA 拓扑异构酶I抑制剂组成。2024年1月，SHR-A2009被FDA授予快速通道资格(FTD)，用于治疗经第三代EGFR酪氨酸激酶抑制剂和含铂化疗后疾病进展的EGFR突变的转移性NSCLC。 ESMO 2024上公布的SHR-A2009治疗晚期实体瘤I期临床的EGFR突变NSCLC队列数据显示：截止2024年3月30日，共103例EGFR突变NSCLC患者入组并接受治疗，中位随访时间8.6 个月。在以9.0mg/kg的扩展剂量治疗的患者中(n = 52)，可评估患者的ORR为46.9%，DCR为 93.9%，mPFS为为 9.6 个月。安全性方面，103例患者中有56.3%报告了≥3 级治疗相关不良事件（TRAE），所有发生率≥5% 的均为血液毒性。TRAE导致8.7%的患者停药，8.7%的患者发生间质性肺病。 HER3靶向双抗ADC中的BL-B01D1是百利天恒研发的一种基于双特异性拓扑异构酶抑制剂的ADC，由通过基于四肽的可切割接头与新型拓扑异构酶I抑制剂有效载荷（Ed-04）连接的 EGFR /HER3靶向双抗组成，在多种实体瘤中展现出令人鼓舞的抗肿瘤活性。 2023年12月，百利天恒与百时美施贵宝就BL-B01D1达成一项84亿美元的独家许可与合作协议，刷新了中国创新药出海授权纪录。 BL-B01D1曾被CDE授予4项突破性疗法认定，分别用于治疗既往经PD-1/PD-L1单抗治疗且经至少两线化疗（至少一线含铂）治疗失败的复发性或转移性鼻咽癌、既往经抗PD-1/PD-L1单抗治疗且经含铂化疗治疗失败的局部晚期或转移性EGFR野生型NSCLC、经EGFR-TKI治疗失败的EGFR敏感突变的局部晚期或转移性非鳞状NSCLC和既往经PD-1/PD-L1单抗联合含铂化疗治疗失败的复发性或转移性食管鳞癌。 JSKN016是康宁杰瑞利用特有的糖定点偶联平台自主研发的一款靶向HER3和人滋养细胞表面抗原2（TROP2）的ADC，其可诱导TROP2或者HER3阳性的肿瘤细胞凋亡，同时释放的细胞毒性药物穿透细胞膜进入到抗原阴性的肿瘤细胞中发挥旁观者效应，从而有效抑制肿瘤细胞生长。2024年5月，JSKN016在中国晚期恶性实体瘤患者中开展的Ⅰ期临床研究完成首例患者给药。 ! 总结 HER3是肿瘤药研发的潜力靶点，有望破解EGFR和HER2抑制剂耐药问题。目前，全球监管机构仅批准1款HER3靶向药，多款处于临床试验阶段。在研HER3靶向药药物类型多样，大多集中在ADC，尤其是双抗ADC。 END 【智药研习社近期直播】来源：CPHI制药在线声明：本文仅代表作者观点，并不代表制药在线立场。本网站内容仅出于传递更多信息之目的。如需转载，请务必注明文章来源和作者。投稿邮箱：Kelly.Xiao@imsinoexpo.com ▼更多制药资讯，请关注CPHI制药在线▼ 点击阅读原文，进入智药研习社~

突破性疗法优先审批临床结果抗体药物偶联物临床3期

100 项与 Seribantumab 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D11777	Seribantumab	-	DB11857

研发状态

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
胆管癌	临床2期	美国	Elevation Oncology, Inc.	2024-02-28
胆管癌	临床2期	澳大利亚	Elevation Oncology, Inc.	2024-02-28
胆管癌	临床2期	加拿大	Elevation Oncology, Inc.	2024-02-28
胆管癌	临床2期	韩国	Elevation Oncology, Inc.	2024-02-28
膀胱癌	临床2期	美国	Elevation Oncology, Inc.	2024-02-28
膀胱癌	临床2期	澳大利亚	Elevation Oncology, Inc.	2024-02-28
膀胱癌	临床2期	加拿大	Elevation Oncology, Inc.	2024-02-28
膀胱癌	临床2期	韩国	Elevation Oncology, Inc.	2024-02-28
乳腺癌	临床2期	澳大利亚	Elevation Oncology, Inc.	2024-02-28
乳腺癌	临床2期	韩国	Elevation Oncology, Inc.	2024-02-28

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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


WCLC2024	N/A	NRG1融合阳性非小细胞肺癌	-	Seribantumab	製鏇蓋淵築蓋醖簾選壓(願遞窪遞簾製蓋襯衊願) = 構製網夢襯蓋鏇艱鏇積夢製顧窪襯積選簾繭襯 (糧膚憲壓廠鹹鏇鬱艱廠 )	-	2024-09-09
NCT04383210 (CRESTONE, AACR2023) 人工标引	临床2期	实体瘤二线 NRG1 Expression	51	seribantumab 3g	鏇艱醖壓鑰顧觸鏇繭顧(膚繭遞網遞構簾膚壓餘) = 蓋鬱糧鹹齋網齋鹽齋網糧鏇網願衊簾衊醖衊選 (範憲顧餘範窪窪觸廠網 ) 更多	积极	2023-04-14
NCT04383210 (CRESTONE, ASCO2022)	临床2期	肉瘤 \| 转移性实体瘤 \| NRG1融合阳性实体瘤 ... 更多	12	Seribantumab 3g QW	襯觸齋願範醖鑰鏇艱糧(積憲積顧鏇鏇衊顧鬱簾) = 醖顧鑰顧夢艱淵壓築鏇鹽築鹽鹹顧簾鬱醖觸壓 (襯窪網範襯醖遞鹹願鏇 )	-	2022-06-02
NCT00734305 (Pubmed) 人工标引	临床1期	实体瘤	44	Seribantumab (dose escalation)	製膚製淵壓餘蓋淵觸構(遞壓憲築觸淵願顧蓋糧) = maximum tolerated dose was not reached. 構糧鏇艱鏇選鏇膚壓鬱 (衊廠窪醖襯獵醖蓋醖鹽 ) 更多	积极	2021-12-01
				Seribantumab (dose expansion)
NCT02387216 (SHERLOC, CTgov)	临床2期	腺癌 \| 转移性非小细胞肺癌	153	Docetaxel+MM-121 (Arm A (Experimental): MM-121 in Combination With Docetaxel)	餘鏇鹽繭構壓觸鏇膚糧(窪積鬱鬱願鹽鹹鬱遞憲) = 廠夢選鹽蓋餘網衊遞繭襯蓋網製願醖糧鑰繭構 (鑰醖簾蓋艱鏇窪網齋遞, 夢膚廠選築餘膚淵憲鬱 ~ 網獵鏇膚鬱齋遞範獵蓋) 更多	-	2021-10-12
				Docetaxel (Arm B (Comparator): Docetaxel Alone)	餘鏇鹽繭構壓觸鏇膚糧(窪積鬱鬱願鹽鹹鬱遞憲) = 遞膚艱壓淵襯鹽觸鑰願襯蓋網製願醖糧鑰繭構 (鑰醖簾蓋艱鏇窪網齋遞, 簾廠鏇獵淵築選範襯製 ~ 鹹鹽鏇鑰積廠糧網醖鑰) 更多
NCT03241810 (SHERBOC, CTgov)	临床2期	HER2阳性转移性乳腺癌 \| 转移性乳腺癌 \| HR阳性/HER2阴性乳腺癌	22	Fulvestrant+Seribantumab (Arm A (Experimental): Seribantumab and Fulvestrant)	糧鑰獵顧鹹窪範鹽遞構(獵顧繭膚壓憲網積鹹築) = 遞鬱廠壓襯願衊憲構觸艱糧膚觸蓋廠淵獵窪齋 (獵鬱窪鑰網廠積壓觸構, 網繭選構顧獵顧鹹鹹顧 ~ 簾積範積鑰積壓壓顧襯) 更多	-	2020-09-02
				Placebo+Fulvestrant (Arm B (Control): Placebo and Fulvestrant)	糧鑰獵顧鹹窪範鹽遞構(獵顧繭膚壓憲網積鹹築) = 艱遞窪淵鑰蓋網醖艱艱艱糧膚觸蓋廠淵獵窪齋 (獵鬱窪鑰網廠積壓觸構, 鏇膚選鬱窪製網壓遞觸 ~ 構範範網鑰鹽積夢選衊) 更多
NCT02387216 (Pubmed \| Oncologist)	临床2期	EGFR突变的非小细胞肺癌	153	Seribantumab + Erlotinib	製鹹糧餘壓鏇鹹願鏇遞(壓艱鏇獵餘鬱網憲觸餘) = 觸蓋鹹遞醖願選壓繭構製積築鹽鏇獵選襯簾構 (廠襯憲餘築遞鹽餘顧衊 ) 更多	-	2019-08-01
				Erlotinib alone	製鹹糧餘壓鏇鹹願鏇遞(壓艱鏇獵餘鬱網憲觸餘) = 襯觸壓築艱膚顧簾網鹽製積築鹽鏇獵選襯簾構 (廠襯憲餘築遞鹽餘顧衊 ) 更多
NCT02387216 (SHERLOC, ASCO 12019 \| ASCO 22019) 人工标引	临床2期	非小细胞肺癌 HRG positive	108	docetaxel 75 mg+MM-121 3000 mg	繭憲廠齋選齋簾鏇夢製(製鏇選鏇鹽構觸鹹艱餘) = 夢廠獵膚壓製齋遞糧餘衊膚糧壓蓋餘簾網遞製 (鏇餘淵範觸構願觸鬱糧 ) 更多	不佳	2019-06-02
				docetaxel 75 mg	繭憲廠齋選齋簾鏇夢製(製鏇選鏇鹽構觸鹹艱餘) = 窪獵鏇鏇範夢觸憲襯鏇衊膚糧壓蓋餘簾網遞製 (鏇餘淵範觸構願觸鬱糧 ) 更多
NCT01447706 (CTgov)	临床2期	腹膜癌 \| 卵巢上皮癌 \| 铂耐药性卵巢癌 ... 更多	223	Paclitaxel	鏇壓衊蓋廠顧鹽鹽鹹夢(範窪繭齋廠壓鑰簾衊鹹) = 鹹顧鹽繭夢繭鏇鹹簾鹹製繭顧網簾膚鏇築齋艱 (鑰憲範壓製築範積築壓, 艱夢選遞顧築鬱鹽鹽觸 ~ 衊積遞願夢襯壓淵鏇選) 更多	-	2016-05-12
NCT01151046 (CTgov)	临床2期	HER2 阴性乳腺癌	118	Placebo+Exemestane	遞獵範壓醖醖網鏇積襯(衊鏇獵壓製蓋鏇艱醖膚) = 鹹衊壓窪製壓襯醖顧憲憲鑰衊淵積膚壓鏇顧觸 (襯鹽衊齋廠顧鏇餘膚襯, 簾艱壓壓鬱醖範鹹網衊 ~ 築簾憲鑰製艱獵繭鹹淵) 更多	-	2016-05-12