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更新于：2025-03-28

Imlunestrant

更新于：2025-03-28

概要

概要

基本信息

药物类型

小分子化药

别名

Imlunestrant Tosylate、LY-3484356

靶点

作用方式

降解剂

作用机制

ERs降解剂(雌激素受体家族降解剂)

治疗领域

肿瘤皮肤和肌肉骨骼疾病消化系统疾病+ [1]

在研适应症

ER阳性/HER2阴性乳腺癌肝损伤晚期乳腺癌+ [4]

非在研适应症-

原研机构

Eli Lilly & Co.

在研机构

Eli Lilly & Co.

非在研机构-

最高研发阶段申请上市

首次获批日期-

最高研发阶段(中国)临床3期

特殊审评-

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结构/序列

分子式C29H24F4N2O3

InChIKeyUVBQMXOKKDCBJN-MUUNZHRXSA-N

CAS号2408840-26-4

关联

项与 Imlunestrant 相关的临床试验

CTR20231037

/ Terminated临床1期

一项LOXO-783单药治疗和与其他抗癌疗法联合治疗PIK3CA H1047R突变的晚期乳腺癌和其他实体瘤患者的研究

主要目的：确定在PIK3CA H1047R突变的晚期乳腺癌和其他实体瘤患者中 LOXO-783单药治疗和与其他抗癌疗法联合治疗的LOXO-783的MTD/RP2D

开始日期2023-11-27

申办/合作机构

礼来苏州制药有限公司

[+2]

CTR20230192

/ Recruiting临床3期

EMBER-4：一项在既往接受过2-5年辅助内分泌治疗的ER+、HER2-早期乳腺癌且具有较高复发风险的患者中比较Imlunestrant辅助治疗和标准辅助内分泌治疗的随机、开放性、III期研究

本研究的主要目的是在雌激素受体阳性（ER+）和人表皮生长因子受体2阴性（HER2-）早期乳腺癌受试者中评价Imlunestrant相比标准内分泌治疗的疗效。入组研究的受试者必须符合以下条件：既往接受过2-5年的内分泌治疗、具有较高的复发风险。受试者参与研究的持续时间可能长达10年。

开始日期2023-05-12

申办/合作机构

礼来苏州制药有限公司

[+2]

CTIS2022-501007-28-00

/ Recruiting临床3期

J2J-MC-JZLH EMBER-4: A Randomized, Open-Label, Phase 3 Study of Adjuvant Imlunestrant vs Standard Adjuvant Endocrine Therapy in Patients who have Previously Received 2 to 5 years of Adjuvant Endocrine Therapy for ER+, HER2- Early Breast Cancer with an Increased Risk of Recurrence - 18459

开始日期2023-04-27

申办/合作机构

Eli Lilly & Co.

100 项与 Imlunestrant 相关的临床结果

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100 项与 Imlunestrant 相关的转化医学

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100 项与 Imlunestrant 相关的专利（医药）

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项与 Imlunestrant 相关的文献（医药）

2025-03-27·NEW ENGLAND JOURNAL OF MEDICINE

Imlunestrant with or without Abemaciclib in Advanced Breast Cancer

Article

作者: Jhaveri, Komal L. ; Pradhan, Kamnesh R. ; Lim, Elgene ; Sohn, Joohyuk ; Llombart-Cussac, Antonio ; Saura, Cristina ; Ruíz Borrego, Manuel ; Mattar, André ; Harbeck, Nadia ; Cramer von Laue, Christoph ; Wang, Xuejing Aimee ; Carey, Lisa A. ; Barrett, Emily ; Neven, Patrick ; Nakamura, Rikiya ; O’Shaughnessy, Joyce ; Martinez Rodriguez, Jorge Luis ; Kim, Sung-Bae ; Tokunaga, Eriko ; Cao, Shanshan ; Huang, Chiun-Sheng ; Zhang, Qingyuan ; Bidard, François-Clément ; Smyth, Lillian M. ; Casalnuovo, Monica Lis ; Hung, Chih-Chiang ; Curigliano, Giuseppe ; García Tinoco, María de la Luz ; Aftimos, Philippe

BACKGROUND:

Imlunestrant is a next-generation, brain-penetrant, oral selective estrogen-receptor (ER) degrader that delivers continuous ER inhibition, even in cancers with mutations in the gene encoding ERα (ESR1).

METHODS:

In a phase 3, open-label trial, we enrolled patients with ER-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer that recurred or progressed during or after aromatase inhibitor therapy, administered alone or with a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor. Patients were assigned in a 1:1:1 ratio to receive imlunestrant, standard endocrine monotherapy, or imlunestrant-abemaciclib. Primary end points were investigator-assessed progression-free survival with imlunestrant as compared with standard therapy among patients with ESR1 mutations and among all patients and with imlunestrant-abemaciclib as compared with imlunestrant among all patients who had undergone randomization concurrently.

RESULTS:

Overall, 874 patients underwent randomization, with 331 assigned to imlunestrant, 330 to standard therapy, and 213 to imlunestrant-abemaciclib. Among 256 patients with ESR1 mutations, the median progression-free survival was 5.5 months with imlunestrant and 3.8 months with standard therapy. The estimated restricted mean survival time at 19.4 months was 7.9 months (95% confidence interval [CI], 6.8 to 9.1) with imlunestrant and 5.4 months (95% CI, 4.6 to 6.2) with standard therapy (difference, 2.6 months; 95% CI, 1.2 to 3.9; P<0.001). In the overall population, the median progression-free survival was 5.6 months with imlunestrant and 5.5 months with standard therapy (hazard ratio for progression or death, 0.87; 95% CI, 0.72 to 1.04; P = 0.12). Among 426 patients in the comparison of imlunestrant-abemaciclib with imlunestrant, the median progression-free survival was 9.4 months and 5.5 months, respectively (hazard ratio, 0.57; 95% CI, 0.44 to 0.73; P<0.001). The incidence of grade 3 or higher adverse events was 17.1% with imlunestrant, 20.7% with standard therapy, and 48.6% with imlunestrant-abemaciclib.

CONCLUSIONS:

Among patients with ER-positive, HER2-negative advanced breast cancer, treatment with imlunestrant led to significantly longer progression-free survival than standard therapy among those with ESR1 mutations but not in the overall population. Imlunestrant-abemaciclib significantly improved progression-free survival as compared with imlunestrant, regardless of ESR1-mutation status. (Funded by Eli Lilly; EMBER-3 ClinicalTrials.gov number, NCT04975308.).

2025-03-01·Nature Reviews Clinical Oncology

Imlunestrant shows efficacy both with and without abemaciclib

Article

作者: Killock, David

2025-02-17·CANCER RESEARCH

Imlunestrant Is an Oral, Brain-Penetrant Selective Estrogen Receptor Degrader with Potent Antitumor Activity in ESR1 Wild-Type and Mutant Breast Cancer

Article

作者: Shen, Weihua ; Kindler, Lisa ; de Dios, Alfonso ; Garcia-Tapia, David ; Dowless, Michele S. ; Ortiz Ruiz, Maria Jesus ; Bastian, Jolie ; Rodrik-Outmezguine, Vanessa ; Rodriguez Cruz, Vivian ; Yu, Chunping ; Castanares, Mark A. ; Klippel, Anke ; Bhagwat, Shripad V. ; Marugán, Carlos ; Mattioni, Brian ; Fei, Dongling ; Vandekopple, Matthew ; Cohen, Jeff D. ; Ismail-Khan, Roohi ; Gong, Xueqian ; Stephens, Jennifer R. ; Peng, Sheng-Bin ; Capen, Andrew ; Bacchion, Francesca ; Puca, Loredana ; Zhao, Baohui ; Lallena, María Jose ; Yuen, Eunice ; Manro, Jason R. ; Baker, Thomas K. ; Pulliam, Nicholas ; Mur, Cecilia ; Huber, Lysiane

Abstract:

Targeting of the estrogen receptor (ER) by antiestrogens is the standard of care for patients with ER+ HER2− advanced/metastatic breast cancer. Although antiestrogens that degrade ERα (fulvestrant) or block estrogen production (aromatase inhibitors) have improved patient outcomes, clinically important challenges remain related to drug administration, limited bioavailability, lack of brain exposure, and acquired resistance due to ESR1 mutations. These limitations indicate a need for more robust ER-targeted therapies. Here, we discovered and characterized imlunestrant, a next-generation potent, brain-penetrant oral selective ER degrader. Imlunestrant degraded ERα and decreased ERα-mediated gene expression both in vitro and in vivo. Cell proliferation and tumor growth in ESR1 wild-type (WT) and mutant models were significantly inhibited by imlunestrant. Combining imlunestrant with abemaciclib (CDK4/6 inhibitor), alpelisib (PI3K inhibitor), or everolimus (mTOR inhibitor) further enhanced tumor growth inhibition, regardless of ESR1 mutational status. In an ER+ breast cancer intracranial tumor model, imlunestrant prolonged survival compared with vehicle or alternative selective ER degrader therapies. Together, these findings support the potential of imlunestrant to degrade ERα and suppress the growth of ESR1-WT and mutant breast cancer, including brain metastatic tumors.Significance: Imlunestrant, a next-generation, brain-penetrant oral ERα degrader, displays potent activity in ESR1 wild-type and mutant breast cancer, enhances combination activity with standard-of-care agents, and inhibits growth of ER+ intracranial tumors.

项与 Imlunestrant 相关的新闻（医药）

2025-03-13

·PRNewswire

VERZENIO's Market Potential Soars as Demand for CDK4/6 Inhibitors Grows | DelveInsight

As VERZENIO gains traction in early-stage treatments and broadens its approved uses, its revenue is expected to keep growing. While the global CDK4/6 inhibitor market remains highly competitive, VERZENIO's distinct clinical advantages and ongoing studies could contribute to further market expansion. LAS VEGAS, March 13, 2025 /PRNewswire/ -- DelveInsight's " VERZENIO Market Size, Forecast, and Market Insight Report" highlights the details around VERZENIO, which is a targeted treatment known as a CDK4/6 inhibitor. The drug is a non-chemotherapy oral tablet. The report provides product descriptions, patent details, and competitor products (marketed and emerging therapies) of VERZENIO. The report also highlights the historical and forecasted sales from 2020 to 2034 segmented into 7MM [the United States, the EU4 (Germany, France, Italy, and Spain), the United Kingdom, and Japan]. Eli Lilly and Company's VERZENIO (abemaciclib) Overview VERZENIO (abemaciclib) is a prescription medication used to treat adults with HR-positive, HER2-negative breast cancer that has metastasized (spread to other parts of the body). It is administered orally and is prescribed in combination with an aromatase inhibitor as an initial endocrine-based therapy. Additionally, the drug is being developed for the treatment of prostate cancer. VERZENIO is approved for the following indications: In combination with endocrine therapy for the adjuvant treatment of adults with HR+/HER2-, node-positive, early-stage breast cancer at high risk of recurrence. In combination with an aromatase inhibitor as the initial endocrine-based therapy for adults with HR+/HER2- advanced or metastatic breast cancer. In combination with fulvestrant for adults with HR+/HER2- advanced or metastatic breast cancer that has progressed after prior endocrine therapy. As monotherapy for adults with HR+/HER2- advanced or metastatic breast cancer that has progressed following endocrine therapy and prior chemotherapy in the metastatic setting. Learn more about VERZENIO projected market size for breast cancer @ VERZENIO Market Potential HR+/HER2- breast cancer is the most common subtype of breast cancer, defined by the presence of estrogen and progesterone hormone receptors but lacking HER2 overexpression. This form of breast cancer generally has a favorable prognosis and is primarily managed with hormone therapy to suppress hormone-driven tumor growth. According to DelveInsight's estimates, around 211,000 new cases of HR+/HER2− breast cancer were reported in the US in 2024. Over the past decade, endocrine therapy has remained the cornerstone of treatment, including for cases with visceral involvement. The current preferred approach involves combining endocrine therapy—using aromatase inhibitors or fulvestrant—with CDK4/6 inhibitors. The approval of CDK4/6 inhibitors has significantly transformed the treatment landscape for HR+/HER2− breast cancer. Currently, five selective CDK4/6 inhibitors— ENHERTU, DATROWAY, IBRANCE, KISQALI, and VERZENIO—are used in combination with endocrine therapy. In November 2023, the FDA approved TRUQAP (capivasertib) in combination with FASLODEX for patients with advanced HR+/HER2− breast cancer harboring specific biomarker alterations (PIK3CA, AKT1, or PTEN). The NCCN Guidelines have designated KISQALI as the only Category 1 Preferred CDK4/6 inhibitor for first-line treatment in combination with an aromatase inhibitor, strengthening its position in the U.S. market. This led to KISQALI recovering its lost market share, with its U.S. revenue contribution rebounding to 50%, following declines to 46% in 2020, 36% in 2021, and 38% in 2022. In January 2025, the FDA approved DATROWAY for patients with unresectable or metastatic HR+/HER2- breast cancer (IHC 0, IHC 1+, or IHC 2+/ISH-) who had previously received endocrine-based therapy and chemotherapy. Additionally, ENHERTU was approved for patients with unresectable or metastatic HR+, HER2-low (IHC 1+ or IHC 2+/ISH-) or HER2-ultralow (IHC 0 with membrane staining) breast cancer that had progressed after at least one prior endocrine therapy in the metastatic setting. Also, in January 2025, Roche reported positive topline results from its Phase III INAVO120 trial, assessing ITOVEBI in combination with IBRANCE and fulvestrant for patients with PIK3CA-mutated HR+/HER2−, endocrine-resistant, locally advanced, or metastatic breast cancer. Among the seven major markets, the US accounted for the largest market share in HR+/HER2− breast cancer, generating USD 7.5 billion in revenue in 2023. The market is expected to experience substantial growth from 2025 to 2034, driven by the introduction of novel therapeutic options. Discover more about the breast cancer market in detail @ Metastatic HR+/HER2- Breast Cancer Market Report Emerging Competitors of VERZENIO Some of the competing emerging key players in HR+/HER2- breast cancer market are, Merck (KEYTRUDA), Arvinas (ARV-471 (vepdegestrant)), Olema Pharmaceuticals (OP1250 (palazestrant)), Celcuity (Gedatolisib), Roche (Giredestrant (RG6171, GDC-9545); Inavolisib), AstraZeneca and Daiichi Sankyo (Datopotamab Deruxtecan (Dato-DXd)), AstraZeneca (Camizestrant (AZD9833); Capivasertib), Eli Lilly (LY3484356/Imlunestrant), Sermonix Pharmaceuticals (Lasofoxifene), Veru Pharma (Enobosarm), DualityBio/BioNtech (DB-1303), Evgen Pharma (SFX-01), Carrick Therapeutics (Samuraciclib (CT-7001)), EQRx/G1 Therapeutics (Lerociclib), Immutep (Eftilagimod Alpha (LAG-3lg/IMP321)), and others. To know more about the number of competing drugs in development, visit @ VERZENIO Market Positioning Compared to Other Drugs Key Milestones of VERZENIO In 2024, Phase III trials did not meet primary endpoints or were terminated for futility. Negative Phase III CYCLONE-2 results, in which VERZENIO added to abiraterone did not meet the primary endpoint of improved radiographic progression-free survival (rPFS) in men with metastatic castration-resistant prostate cancer (mCRPC). In December 2023, Eli Lilly and Company presented results from the MONARCH 3 clinical trial at the 2023 San Antonio Breast Cancer Symposium (SABCS). Results from MONARCH 3 show a numerical improvement in overall survival (OS) of 13.1 months for women with HR+, HER2- metastatic breast cancer treated with VERZENIO plus an aromatase inhibitor in the intent-to-treat population and 14.9 months for women with visceral disease. In March 2023, the US FDA approved an expanded indication for VERZENIO in combination with endocrine therapy for the adjuvant treatment of adult patients with HR+/HER2−, node-positive, early breast cancer (EBC) at a high risk of recurrence. This expanded adjuvant indication removes the Ki-67 score requirement for patient selection. In February 2022, the CHMP adopted a positive opinion recommending a change to the terms of the marketing authorization for the medicinal product VERZENIO. VERZENIO, in combination with endocrine therapy, is indicated for the adjuvant treatment of adult patients with HR+/HER2− negative, node-positive early breast cancer at high risk of recurrence. In October 2021, the US FDA approved VERZENIO, in combination with endocrine therapy (tamoxifen or an aromatase inhibitor), for the adjuvant treatment of adult patients with HR+/HER2−, node-positive, early breast cancer at high risk of recurrence and a Ki-67 score of ≥20% as determined by an FDA-approved test. Ki-67 is a marker of cellular proliferation. In September 2018, VERZENIO was approved in Europe for treating advanced HR+ breast cancer in women if the cancer has already spread to other parts of the body or is locally advanced. In September 2018, VERZENIO was approved for the treatment of patients with HR+/HER2− unresectable or recurrent breast cancer in combination with fulvestrant or an aromatase inhibitor (AI) in Japan. In February 2018, the US FDA approved VERZENIO in combination with an aromatase inhibitor (AI) as initial endocrine-based therapy for the treatment of postmenopausal women with HR+/HER2− advanced or metastatic breast cancer In September 2017, the US FDA approved VERZENIO in combination with an endocrine therapy to treat adult patients who have HR+/HER2− advanced or metastatic breast cancer that has progressed after taking therapy that alters a patient's hormones (endocrine therapy). In October 2015, the US FDA granted Breakthrough Therapy Designation to abemaciclib for patients with refractory hormone-receptor-positive (HR+) advanced or metastatic breast cancer Discover how VERZENIO is shaping the breast cancer treatment landscape @ VERZENIO Breast Cancer VERZENIO Market Dynamics The oral administration of VERZENIO enhances patient convenience, while its expanded approval for the adjuvant treatment of adult patients with HR+/HER2- early breast cancer highlights its role as a differentiated CDK4/6 inhibitor in reducing the risk of recurrence. The rising prevalence of HR+/HER2- breast cancer is driving market demand for effective treatments like VERZENIO. Additionally, its demonstrated efficacy in combination with endocrine therapy and its ability to penetrate the central nervous system further strengthen its market position. Favorable reimbursement policies and increasing awareness among healthcare providers also contribute to its adoption. However, its adoption may be hindered by regulatory hurdles and potential side effects, including severe or life-threatening lung inflammation and serious liver problems. High treatment costs and access disparities in certain regions could also limit market penetration. Competition from other CDK4/6 inhibitors such as IBRANCE and KISQALI poses a challenge, along with concerns over long-term safety data. Additionally, the Phase III CYCLONE-2 trial failed to meet primary endpoints in mCRPC, which may impact its broader clinical prospects and investor confidence. Dive deeper to get more insight into VERZENIO's strengths & weaknesses relative to competitors @ VERZENIO Market Drug Report Table of Contents Related Reports CDK4/6 Inhibitor Market CDK4/6 Inhibitor Market Insights, Epidemiology, and Market Forecast – 2034 report deliver an in-depth understanding of the disease, historical and forecasted epidemiology, as well as the market trends, market drivers, market barriers, and key CDK4/6 inhibitor companies including Pfizer, Prelude Therapeutics, G1 Therapeutics, Pepper Bio, among others. Metastatic HR+/HER2− Breast Cancer Market Metastatic HR+/HER2− Breast Cancer Market Insights, Epidemiology, and Market Forecast – 2034 report deliver an in-depth understanding of the disease, historical and forecasted epidemiology, as well as the market trends, market drivers, market barriers, and key metastatic HR+/HER2− breast cancer companies including Pfizer, Novartis, Stemline Therapeutics, Olema Pharmaceuticals, Arvinas, Immutep, AstraZeneca, Roche, Genentech, Evexta Bio, EQRx, Sermonix Pharmaceuticals, Celcuity, Veru Pharma, Evgen Pharma, Eli Lilly, Biotheryx, among others. HR+/HER2− Breast Cancer Pipeline HR+/HER2− Breast Cancer Pipeline Insight – 2025 report provides comprehensive insights about the pipeline landscape, pipeline drug profiles, including clinical and non-clinical stage products, and the key HR+/HER2− breast cancer companies, including Regor Therapeuics, Seagen Inc., CytomX Therapeutics, Taizhou EOC Pharma, Chia Tai Tianqing Pharmaceutical Group, AstraZeneca, Daiichi Sankyo, Inc., Tyme, Inc., Seagen Inc., Context Therapeutics, Eisai Inc., Shanghai Hengrui Pharmaceutical Co., Ltd., Jiangsu Simcere Pharmaceutical Co., Kind Pharmaceuticals, Merus N.V., Atossa Therapeutics, Roche, among others. Breast Cancer Market Breast Cancer Market Insights, Epidemiology, and Market Forecast – 2034 report deliver an in-depth understanding of the disease, historical and forecasted epidemiology, as well as the market trends, market drivers, market barriers, and key breast cancer companies, including Veru, Sanofi, Roche, AstraZeneca, Eli Lilly, EQRx, Gilead, Sermonix Pharmaceuticals, Evgen Pharma, Tyme, Genentech, Daiichi Sankyo, among others. About DelveInsight DelveInsight is a leading Business Consultant and Market Research firm focused exclusively on life sciences. It supports pharma companies by providing comprehensive end-to-end solutions to improve their performance. Get hassle-free access to all the healthcare and pharma market research reports through our subscription-based platform PharmDelve . Contact Us Shruti Thakur [email protected] +14699457679 Logo: SOURCE DelveInsight Business Research, LLP WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

临床3期上市批准临床结果突破性疗法ASCO会议

2025-03-13

·生物制药小编

明星PROTAC，泯然众人矣

近日，辉瑞与Arvinas联合开发的雌激素受体（ER）靶向蛋白降解剂（PROTAC）vepdegestrant（ARV-471）在首个III期临床试验VERITAC-2中未能达到ITT（总体意向治疗）人群的主要终点，虽然辉瑞和Arvinas发现了ESR1m亚组患者的获批希望，市场的反馈却非常负面。消息发布后，Arvinas的股价截止当日收盘大跌52.73%。 vepdegestrant（ARV-471）的头上曾经有许多光环，例如全球首个进入III期临床的PROTAC，2021年数额最大的PROTAC交易，最有可能获批的PROTAC。现在，这些光环随着临床的失利而略显暗淡。为何市场也不接受亚组赛道 VERITAC-2试验针对的是624例接受过CDK4/6抑制剂和内分泌治疗的ER+/HER2-晚期或转移性乳腺癌患者，试验会比较vepdegestrant与阿斯利康的氟维司群（Faslodex）的疗效。被选择作为对照的Faslodex是目前ER+/HER2-乳腺癌的标准疗法，从机制上而言，虽然两者都是靶向雌激素受体α（ERα），但是Faslodex是通过竞争性结合雌激素受体并诱导其降解的，而且是通过肌肉注射油基制剂，这一点使得Faslodex在生物利用度上更差一些。而vepdegestrant则通过经典的PROTAC机制与ERα结合，招募E3泛素连接酶复合物（如CRBN），使ERα被泛素化标记，随后被细胞内的蛋白酶体识别并降解。由于vepdegestrant是口服药物，在便捷性上显然远胜Faslodex。2002年上市以来的Faslodex长期以来雄踞雌激素受体降解剂（SERD）宝座。如果vepdegestrant真的在ITT人群中取胜，是可以作为Faslodex平替的。问题是环境已经变了，随着众多二代三代的口服SERD疗法已经或即将上市，vepdegestrant作为口服药物的优势似乎正在消解。而这些口服SERD疗法在ESR1m亚组上似乎疗效也不弱。 2023年获批的elacestrant被发现在ESR1突变患者中也能降低45%的死亡率，而这次vepdegestrant的信息表明，在预设的ESR1突变亚组中，风险比（HR）超过预设目标0.6，超过0.6意味着至少能降低40%以上的死亡率，虽然没有公布实际数据，死亡率的降低可能不会和elacestrant的差太多。又例如礼来的Imlunestrant（LY3484356），这是一款可以穿透血脑屏障的SERD，在ESR1突变的患者中，Imlunestrant较标准内分泌治疗降低38%疾病进展或死亡风险，联合Verzenio（CDK4/6抑制剂，Abemaciclib）在全部人群中较单药Imlunestrant降低了43%进展或死亡风险。阿斯利康的camizestrant同样取得了积极的中期结果，Camizestrant作为一线治疗，在高度统计学意义和临床意义上显著改善了伴有新发ESR1肿瘤突变的晚期HR阳性乳腺癌患者的无进展生存期（PFS）。总结在这种情况下，vepdegestrant的未来市场前景不容乐观。vepdegestrant实际上并不能以PROTAC的技术特点在众多SERD中脱颖而出。参考来源： https://www.fiercebiotech.com/biotech/pfizer-arvinas-hormone-therapy-posts-mixed-survival-results-first-phase-3-test

蛋白降解靶向嵌合体临床3期临床结果

2025-03-11

·EndPoints

Arvinas, Pfizer’s PROTAC data fall short of hype in breast cancer

Arvinas and Pfizer’s targeted protein degrader has not managed to distinguish itself from other, similar breast cancer drugs, according to pivotal data released Tuesday. Results of the Phase 3 VERITAC-2 trial show that vepdegestrant extended progression-free survival in patients with mutated estrogen receptor genes, but not in the overall population. Arvinas’ shares $ARVN fell as much as 40% pre-market. The readout of VERITAC-2 was widely regarded as the first big test of a proteolysis-targeting chimera (PROTAC) drug. The hope was that a PROTAC would work in all comers, an achievement that has so far eluded the similar drugs known as SERDs — or selective estrogen receptor degraders. The Phase 3 trial assessed vepdegestrant monotherapy as a second-line treatment, following CDK4/6 inhibitors and hormone therapy, for estrogen receptor-positive, HER2-negative metastatic breast cancer. Arvinas and Pfizer said that vepdegestrant demonstrated a “statistically significant and clinically meaningful” improvement in progression-free survival over the hormone therapy Faslodex in the mutant population. The results in this cohort exceeded the prespecified target of a 40% cut in the risk of progression or death, though the partners did not give the actual figure. Significance was not reached in the intent-to-treat population, strongly suggesting that vepdegestrant has little effect in patients without mutations in the ESR1 gene, which codes for one of the two main types of estrogen receptors. Overall survival data were not mature at the time of the analysis, the companies said, with less than a quarter of the required number of events having occurred. Overall survival will continue to be monitored as a key secondary endpoint. The companies intend to present more VERITAC-2 results at a medical meeting later this year. They will also seek approval for the product, but a broad label encompassing wild-type patients is unlikely to be granted. If vepdegestrant is approved solely in mutant patients it would be on level terms with the only approved SERD, Menarini’s Orserdu. Analysts from Leerink wrote in a Feb. 3 note that if VERITAC-2 had demonstrated that best-in-class activity for vepdegestrant in both the mutants and in all comers, Arvinas’s market value could have tripled. Pfizer licensed vepdegestrant from Arvinas in 2021 for $1 billion upfront . Estrogen receptor degraders are intended to be more potent than inhibitors. Inhibitors bind transiently, blocking the action of the receptor only for a limited time. In contrast, degraders essentially destroy their target protein by co-opting the cell’s natural disposal systems. PROTACs, like vepdegestrant, bind to both the estrogen receptor and to what’s called the E3 ubiquitin. That recruits ubiquitin molecules to the receptor-PROTAC complex, which tags it for destruction by the proteasome. The proteasome is a complex of enzymes involved in breaking down intracellular proteins. This approach is distinct from SERDs, such as Eli Lilly’s imlunestrant and AstraZeneca’s camizestrant , both of which have scored recent Phase 3 successes in ESR1-mutant patients but have not been shown to work in wild-type subjects. SERDs enable receptor degradation via a more passive mechanism. Editor’s note: This article was updated to add Arvinas’ latest stock move.

临床3期临床结果

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研发状态

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适应症	最高研发状态	国家/地区	公司	日期
ER阳性/HER2阴性乳腺癌	申请上市	加拿大	Eli Lilly & Co.	2025-02-01
肝损伤	临床1期	美国	Eli Lilly & Co.	2022-07-05
晚期乳腺癌	临床1期	美国	Eli Lilly & Co.	2019-12-10
晚期乳腺癌	临床1期	日本	Eli Lilly & Co.	2019-12-10
晚期乳腺癌	临床1期	澳大利亚	Eli Lilly & Co.	2019-12-10
晚期乳腺癌	临床1期	比利时	Eli Lilly & Co.	2019-12-10
晚期乳腺癌	临床1期	法国	Eli Lilly & Co.	2019-12-10
晚期乳腺癌	临床1期	西班牙	Eli Lilly & Co.	2019-12-10
晚期乳腺癌	临床1期	中国台湾	Eli Lilly & Co.	2019-12-10
子宫内膜样腺癌	临床1期	美国	Eli Lilly & Co.	2019-12-10

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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


NCT04975308 (EMBER-3, Pubmed \| N Engl J Med)	临床3期	晚期乳腺癌	874	Imlunestrant	醖壓遞顧夢醖製顧範艱(憲顧鏇窪憲鹽醖積膚膚) = 選齋糧鑰淵鹹鹹艱選網憲壓膚餘窪鏇醖構衊製 (繭願構醖鹹壓願構艱醖 ) 更多	积极	2025-03-27
				Standard Therapy	醖壓遞顧夢醖製顧範艱(憲顧鏇窪憲鹽醖積膚膚) = 鬱蓋繭鏇窪廠選夢鬱鹽憲壓膚餘窪鏇醖構衊製 (繭願構醖鹹壓願構艱醖 ) 更多
NCT04975308 (EMBER-3, Pubmed \| SABCS2024) 人工标引	临床3期	晚期乳腺癌	874	Imlunestrant	鹹積壓窪鬱鬱鑰積膚廠(齋顧遞選鏇廠遞鬱鬱獵) = 獵繭構網壓願衊積鑰鏇觸壓鹹積製淵遞鑰遞鹽 (積艱觸糧憲鬱憲廠壓糧 ) 更多	积极	2024-12-11
				Standard therapy	鹹積壓窪鬱鬱鑰積膚廠(齋顧遞選鏇廠遞鬱鬱獵) = 膚願遞鹹糧廠蓋壓鬱鬱觸壓鹹積製淵遞鑰遞鹽 (積艱觸糧憲鬱憲廠壓糧 ) 更多
NCT04188548 (EMBER, Pubmed \| J Clin Oncol) 人工标引	临床1期	ER阳性/HER2阴性乳腺癌 HER2 Negative \| Estrogen receptor	262	Imlunestrant monotherapy	鬱範獵網範觸鏇獵糧簾(糧鹹鏇蓋獵觸築願鹽願) = 廠襯鬱襯鹹遞觸糧製餘壓鏇醖窪顧願鹹顧願鏇 (鑰鏇壓鹽壓鑰衊鏇鑰鑰 ) 更多	积极	2024-09-06
				Imlunestrant + abemaciclib	膚襯窪衊憲艱鬱衊選壓(憲鬱鑰選餘網簾廠鹹鬱) = 願網艱襯淵範鏇簾淵膚壓築願範齋鑰簾壓憲選 (夢壓壓簾廠鏇餘顧憲構, 13.8 ~ NA)
NCT04188548 (EMBER, ASCO2024) 人工标引	临床1期	ER阳性/HER2阳性乳腺癌 HER2 Positive	45	Imlunestrant + Trastuzumab	糧糧憲衊選廠鏇鹽觸願(艱蓋齋膚製衊壓鹹淵鹹) = 鹽憲築範憲壓憲憲壓夢範襯齋膚簾獵範製衊獵 (獵繭鹽鏇構糧蓋廠觸鏇 ) 更多	积极	2024-05-24
				Imlunestrant + Trastuzumab + Abemaciclib	糧糧憲衊選廠鏇鹽觸願(艱蓋齋膚製衊壓鹹淵鹹) = 繭夢鹽窪鹽廠窪範夢壓範襯齋膚簾獵範製衊獵 (獵繭鹽鏇構糧蓋廠觸鏇 ) 更多
NCT04188548 (EMBER, ASCO2024) 人工标引	临床1期	子宫内膜癌 ER+	72	Imlunestrant 400mg po daily	齋構鏇網餘糧積積艱憲(蓋鏇網網淵獵繭醖襯淵) = 襯蓋遞淵衊蓋築窪餘壓壓積選餘簾餘壓網糧憲 (獵廠艱蓋艱夢鹽積繭襯 ) 更多	积极	2024-05-24
				Imlunestrant 400mg po daily + Abemaciclib 150mg po twice daily	齋構鏇網餘糧積積艱憲(蓋鏇網網淵獵繭醖襯淵) = 鹽築醖夢衊襯簾醖襯襯壓積選餘簾餘壓網糧憲 (獵廠艱蓋艱夢鹽積繭襯 ) 更多
NCT04188548 (EMBER, ESMO_BC2024) 人工标引	临床1期	ER阳性/HER2阴性乳腺癌 HER2 Negative \| ER Positive	109	Imlunestrant	鏇鏇鹹夢網鏇顧醖窪壓(衊衊簾廠蓋淵築積憲網) = 獵範網網願醖範簾廠淵築窪憲齋選顧願鹽艱鏇 (鹹獵獵顧網製鹽廠鬱齋, 32 ~ 52)	不佳	2024-05-14
				Imlunestrant (without baseline detectable ctDNA)	鏇鏇鹹夢網鏇顧醖窪壓(衊衊簾廠蓋淵築積憲網) = 網簾窪齋顧膚餘憲醖膚築窪憲齋選顧願鹽艱鏇 (鹹獵獵顧網製鹽廠鬱齋 )
EMBER (Biospace) 人工标引	临床1期	ER阳性/HER2阴性乳腺癌末线 ER Positive \| HER2 Negative	-	Imlunestrant + Verzenio + AI	遞鑰膚糧網製齋淵壓選(糧夢膚範獵膚衊壓製選) = 壓鏇構築糧蓋選觸選壓鏇遞醖簾簾廠廠構廠鬱 (鑰鹹淵網蓋製簾積遞膚 ) 更多	积极	2023-12-05
				Imlunestrant + Verzenio	遞鑰膚糧網製齋淵壓選(糧夢膚範獵膚衊壓製選) = 醖鹽繭積壓鹹艱夢衊選鏇遞醖簾簾廠廠構廠鬱 (鑰鹹淵網蓋製簾積遞膚 ) 更多
NCT04188548 (EMBER, ESMO 12023 \| ESMO 22023) 人工标引	临床1期	ER阳性/HER2阴性乳腺癌 HER2 Negative \| ER Positive	177	Imlunestrant	襯餘鬱範蓋獵積鹹鏇餘(築鹽艱蓋夢範廠選蓋鏇) = Imlunestrant monotherapy (Nausea 40%,Fatigue 32%,Diarrhea 31%);Imlunestrant + everolimus ( Diarrhea 55%,Fatigue 45%, AST increase 38%);Imlunestrant + alpelisib (Diarrhea 86%,Rash 67 %,Hyperglycaemia 62%) 淵襯蓋獵積積簾鬱餘窪 (衊膚鏇網壓齋觸鏇艱壓 )	积极	2023-10-22
				Imlunestrant + everolimus
NCT04188548 (EMBER, ASCO2022)	临床1期	子宫内膜样腺癌 \| ER阳性乳腺癌	138	Imlunestrant	憲願範齋鬱鹽憲鑰遞選(鏇鏇糧夢願獵餘糧簾鏇) = 選簾築鏇範獵衊醖築淵顧醖鑰夢艱積衊艱製餘 (範鬱衊觸鏇觸簾鏇鹽衊 ) 更多	-	2022-06-02
NCT04188548 (EMBER, ASCO 12021 \| ASCO 22021) 人工标引	临床1期	子宫内膜样腺癌 \| ER阳性乳腺癌 ER Positive	28	LY3484356	襯繭繭窪鑰遞淵築鹹築(鬱積網淵積膚繭鹹鏇糧) = 鏇壓衊繭壓壓遞構積壓簾衊網艱蓋壓遞餘網蓋 (鬱膚襯窪膚築糧簾餘範 ) 更多	积极	2021-05-20