This is an open label, multi-center, Phase 1/2 study evaluating the safety, tolerability, PK, PD, and preliminary efficacy (antitumor activity) of BBT-207. It will consist of 3 parts; dose escalation, recommended phase 2 dose selection, and dose expansion.

开始日期2023-09-11

申办/合作机构

Bridge Biotherapeutics, Inc.

NCT05393466 / Not yet recruiting临床1/2期

A Phase I/II, Open-label Study to Evaluate the Safety, Pharmacokinetics, and Efficacy of BPI-361175 Tablets in Patients With Advanced Non-Small Cell Lung Cancer (NSCLC)

This is a three-stage study, consisting of Phase Ia dose-escalation, Phase Ib dose expansion, and a Phase II component.

开始日期2023-07-01

申办/合作机构

Xcovery Holding, Inc.

NCT05153408 / Terminated临床1期

A Phase 1/2 Study of the Highly Selective EGFR Inhibitor, BLU-701, in Patients With EGFR-Mutant Non-Small Cell Lung Cancer

This is a Phase 1/2, open-label, first-in-human (FIH) study is designed to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity of BLU-701 as monotherapy or in combination with either osimertinib or platinum-based chemotherapy in patients with EGFRm NSCLC.

开始日期2022-01-13

申办/合作机构

Blueprint Medicines Corp.

100 项与 EGFR L858R x EGFR C797S x EGFR-Ex19del 相关的临床结果

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100 项与 EGFR L858R x EGFR C797S x EGFR-Ex19del 相关的转化医学

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0 项与 EGFR L858R x EGFR C797S x EGFR-Ex19del 相关的专利（医药）

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项与 EGFR L858R x EGFR C797S x EGFR-Ex19del 相关的文献（医药）

2015-12-01·Translational lung cancer research2区 · 医学

Whacking a mole-cule: clinical activity and mechanisms of resistance to third generation EGFR inhibitors in EGFR mutated lung cancers with EGFR-T790M.

2区 · 医学

Article

作者: Costa, Daniel B ; Kobayashi, Susumu S

Epidermal growth factor receptor (EGFR) mutations, especially EGFR-exon 19 deletions and EGFR-L858R, are the most frequent actionable genomic events in lung adenocarcinomas. Tumors arise due to constitutively activated EGFR signaling and are susceptible to EGFR tyrosine kinase inhibitors (TKIs). First generation EGFR TKIs (gefitinib and erlotinib) and the second generation EGFR TKI afatinib are approved worldwide. Although targeted therapies against EGFR mutants induce dramatic initial responses, acquired resistance (through multiple biological mechanisms) to erlotinib, gefitinib and afatinib emerges within the first 1-2 years of continued monotherapy. EGFR-T790M accounts for more than half of acquired resistance to first or second generation EGFR TKIs by modifying ATP affinity and drug binding kinetics. Two new studies have shown that two covalent pyrimidine inhibitors-AZD9291 and rociletinib of EGFR-T790M (i.e., third generation EGFR TKIs) shown remarkable clinical activity in patients with acquired resistance to erlotinib, gefitinib and afatinib when the tumor carries EGFR-T790M in conjunction with an activating mutation. However, and regrettably, acquired resistance to these third generation EGFR TKIs has already been reported in preclinical models and clinical specimens; such as a tertiary mutation at EGFR-C797S that prevents covalent binding of EGFR TKIs. The experience with sequential EGFR TKI monotherapy highlights tumor heterogeneity and adaptability (i.e., relentless game of whack-a-mole played between TKIs and cancer), and will help shape future clinical development of novel combinatory approaches to manage EGFR mutated lung adenocarcinomas.

Frontiers in Oncology

Case Report: Durable Response to the Combination of Brigatinib and Cetuximab Plus Icotinib in a NSCLC Patient Harboring EGFR L858R-T790M-cis-G796S and L718Q Resistance Mutations Following Progression With Osimertinib

作者: Zhu, Mengxiao ; He, Yong ; Wang, Yubo ; Han, Rui ; He, Tingting

The efficacy of osimertinib is severely limited by the emergence of EGFR C797S, which is detected in either the cis or trans position with T790M when osimertinib is used as a second-line treatment, and which is largely identified in combination with an EGFR 19 deletion. The EGFR T790M-cis-G796S mutation, which also occurs in exon 20 as C797S, participates in osimertinib resistance. To date, limited data for overcoming this resistance mutation have been reported. Here, we report data for an advanced NSCLC patient who developed EGFR L858R-T790M-cis-G796S and EGFR L718Q resistance co-mutations following progression with osimertinib. Such a case has rarely been reported, and under chemotherapy guidelines for this situation, no other effective treatment is recommended. The patient in our case experienced remarkable clinical improvement and good tolerance to the combination target therapy of brigatinib and cetuximab plus icotinib. At the time of our patient’s last follow-up and prior to publication, our patient had reached more than 9 months of progression-free survival (PFS) and felt very well. Our finding provides clinical evidence that the combined target therapy of brigatinib and cetuximab may potentially be an effective treatment strategy for patients with an acquired EGFR T790M-cis-G796S resistance mutation following osimertinib treatment.

Journal of Personalized Medicine3区 · 医学

Genomic Profiling on an Unselected Solid Tumor Population Reveals a Highly Mutated Wnt/β-Catenin Pathway Associated with Oncogenic EGFR Mutations

3区 · 医学

ArticleOA

作者: Russell, Meaghan ; Jiang, Jingrui ; Protopopov, Alexei ; Sun, Ruobai ; Lyle, Stephen

Oncogenic epidermal growth factor receptors (EGFRs) can recruit key effectors in diverse cellular processes to propagate oncogenic signals. Targeted and combinational therapeutic strategies have been successfully applied for treating EGFR-driven cancers. However, a main challenge in EGFR therapies is drug resistance due to mutations, oncogenic shift, alternative signaling, and other potential mechanisms. To further understand the genetic alterations associated with oncogenic EGFRs and to provide further insight into optimal and personalized therapeutic strategies, we applied a proprietary comprehensive next-generation sequencing (NGS)-based assay of 435 genes to systematically study the genomic profiles of 1565 unselected solid cancer patient samples. We found that activating EGFR mutations were predominantly detected in lung cancer, particularly in non-small cell lung cancer (NSCLC). The mutational landscape of EGFR-driven tumors covered most key signaling pathways and biological processes. Strikingly, the Wnt/β-catenin pathway was highly mutated (48 variants detected in 46% of the EGFR-driven tumors), and its variant number topped that in the TP53/apoptosis and PI3K-AKT-mTOR pathways. Furthermore, an analysis of mutation distribution revealed a differential association pattern of gene mutations between EGFR exon 19del and EGFR L858R. Our results confirm the aggressive nature of the oncogenic EGFR-driven tumors and reassure that a combinational strategy should have advantages over an EGFR-targeted monotherapy and holds great promise for overcoming drug resistance.

项与 EGFR L858R x EGFR C797S x EGFR-Ex19del 相关的新闻（医药）

2024-01-08

·PRNewswire

Blueprint Medicines Highlights 2024 Corporate Strategy and Business Priorities at 42nd Annual J.P. Morgan Healthcare Conference

-- AYVAKIT® (avapritinib) launch in indolent systemic mastocytosis to drive strong revenue growth in 2024, with ongoing U.S. launch and recent EU approval -- -- Expanding mast cell disease leadership with oral wild-type KIT inhibitor, BLU-808, advancing into clinical development; IND submission planned in Q2 2024 -- -- Maintaining durable cash position through focused investment and global commercial execution -- -- Kate Haviland, Chief Executive Officer, to present at J.P. Morgan conference today at 10:30 a.m. PT (1:30 p.m. ET) -- SAN FRANCISCO, Jan. 8, 2024 /PRNewswire/ -- Blueprint Medicines Corporation (Nasdaq: BPMC) today outlined its 2024 corporate strategy to deliver accelerated revenue growth, sustainable research and development, and a clear path to profitability. Kate Haviland, Chief Executive Officer of Blueprint Medicines, said: "As we enter 2024, AYVAKIT's early launch success in indolent systemic mastocytosis has grown our conviction that AYVAKIT has the potential to be a multi-billion-dollar therapy that will drive long-term growth into the next decade. We know that the first few quarters of a launch are critical in defining the trajectory of a new medicine, and we have built a strong foundation for success with AYVAKIT as we continue to drive growth in the U.S . and expand our launch in Europe this year. Throughout 2023, we also made significant progress across our research and development pipeline enabling us to focus investments on our most promising programs. A core component of our growth strategy is to build on our leadership position in SM by expanding to other allergic-inflammatory diseases where mast cells play a core role in the biology, and we have integrated infrastructure that we can efficiently scale. Across our portfolio, we are investing in our most compelling opportunities to deliver innovative, life-changing medicines to patients, while maintaining a strong and sustainable financial profile." Focused investment strategy in 2024 to drive long-term growth and maintain durable cash position Prioritized programs for investment Blueprint Medicines is building portfolio scale in therapeutic areas where there are significant medical needs in large patient populations and the company has a deep understanding of biological pathways, a potential to drive best-in-class efficacy and an ability to leverage expertise and infrastructure. Mast cell diseases Extend the company's leadership position in systemic mastocytosis with the ongoing launch of AYVAKIT in the U.S. and EU and continued development of the next-generation KIT D816V inhibitor elenestinib. Expand into larger patient populations with allergic-inflammatory diseases with BLU-808, an oral wild-type KIT inhibitor, including chronic urticaria and other diseases where mast cells are core to the biology. Breast cancer and other solid tumors Advance combination development of BLU-222, a highly selective CDK2 inhibitor with best-in-class potential, in HR+/HER2- breast cancer based on positive previously reported monotherapy clinical data. Progress ongoing strategic partnership discussions to maximize the potential of BLU-222 as a backbone combination therapy in HR+/HER2- breast cancer and other CDK2-vulnerable cancers. Advance additional programs including BLU-956, a next-generation CDK2 inhibitor development candidate nominated in 2023, and targeted protein degrader research programs for CDK2 and an undisclosed target to support long-term lifecycle management. De-prioritized programs Blueprint Medicines is discontinuing investment in specific programs, based on the evolving external landscape, emerging clinical data and partnering considerations. Lung cancer Discontinue further investment in the early clinical-stage therapies BLU-945 and BLU-451 for EGFR-mutant NSCLC and explore strategic options, including potential out-licensing, based on the evolving external landscape and emerging clinical data. In February 2023, Blueprint Medicines announced Roche's decision to terminate the global collaboration agreement for GAVRETO® (pralsetinib). Given Blueprint Medicines' lack of global infrastructure in lung and thyroid cancer, the company has decided to discontinue global development and marketing of GAVRETO in territories excluding the U.S. and Greater China. The companies will continue working on transition and wind-down activities anticipated to begin in the first quarter of 2024; further information on product discontinuation timing to be provided in the near future. Blueprint Medicines has identified a potential alternate partner for GAVRETO in the U.S. and is continuing to work with the involved parties to define a scenario that enables continued availability of GAVRETO in the U.S. Blueprint Medicines expects the wind-down of the Roche collaboration for GAVRETO will result in significantly lower year-over-year operating expenses related to GAVRETO in 2024 and will not affect the $175 million upfront payment received under a 2022 financing agreement with Royalty Pharma. As a result of continued strategic portfolio prioritization, Blueprint Medicines expects a year-over-year decline in operating expenses in 2024. The company plans to provide financial guidance for 2024, including anticipated AYVAKIT revenue, when it reports fourth quarter and full-year 2023 financial results in February 2024. 2024 Corporate Milestones The company's anticipated 2024 corporate milestones include: Mast cell diseases Present long-term safety and efficacy data from the PIONEER trial of AYVAKIT in indolent SM (ISM) in the first half of 2024. Submit an investigational new drug (IND) application for BLU-808 in the second quarter of 2024. Initiate the registration-enabling Part 2 of the HARBOR trial of elenestinib in ISM in the second half of 2024. Breast cancer and other solid tumors Continue ongoing strategic business development discussions. Present data for BLU-222 in combination with ribociclib and fulvestrant in patients with HR+/HER2- breast cancer in the first half of 2024. Provide update on BLU-222 registration plan in HR+/HER2- breast cancer in the second half of 2024. J.P. Morgan Healthcare Conference Presentation Information Kate Haviland, Chief Executive Officer of Blueprint Medicines, will present a company overview and 2024 outlook at the 42nd Annual J.P. Morgan Healthcare Conference on Monday, January 8 at 10:30 a.m. PT / 1:30 p.m. ET. A live webcast of the presentation and Q&A breakout session will be available by visiting the "Events and Presentations" section of Blueprint Medicines' website at . A replay of the webcast will be archived on Blueprint Medicines' website for 30 days following the presentation. About Blueprint Medicines Blueprint Medicines is a global precision therapy company that invents life-changing medicines. Applying an approach that is both precise and agile, we create therapies that selectively target the root cause of disease, with the goal of staying one step ahead across stages of disease. Since 2011, we have leveraged our research platform, including expertise in molecular targeting and world-class drug design capabilities, to rapidly and reproducibly translate science into a broad pipeline of precision therapies. Today, we have brought our approved medicines to patients in the United States and Europe, and we are globally advancing multiple programs for mast cell disorders, including systemic mastocytosis and chronic urticaria, breast cancer and other solid tumors. For more information, visit and follow us on X (formerly Twitter; @BlueprintMeds) and LinkedIn. Cautionary Note Regarding Forward-Looking Statements  This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, as amended, including, without limitation, statements regarding Blueprint Medicines' views with respect to AYVAKIT's potential to be a multi-billion-dollar therapy; the continued growth of AYVAKIT in the U.S. and the expansion of AYVAKYT's launch in Europe; the expansion of Blueprint Medicines' mast cell disease franchise with the development of BLU-808; the advancement of its clinical development of BLU-222, preclinical development of BLU-956 and progression of targeted protein degrader research programs for CDK2; plans, strategies, timelines and expectations for Blueprint Medicines' current or future approved drugs and drug candidates; the potential benefits of any of Blueprint Medicines' current or future approved drugs or drug candidates in treating patients; and Blueprint Medicines' financial performance, strategy, goals and anticipated milestones, business plans, outlook and focus. The words "aim," "may," "will," "could," "would," "should," "expect," "plan," "anticipate," "intend," "believe," "estimate," "predict," "project," "potential," "continue," "target" and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. Any forward-looking statements in this press release are based on management's current expectations and beliefs and are subject to a number of risks, uncertainties and important factors that may cause actual events or results to differ materially from those expressed or implied by any forward-looking statements contained in this press release, including, without limitation: preliminary activity and safety data may not be representative of more mature data; the risk of delay of any current or planned clinical trials or the development of Blueprint Medicines' current or future drug candidates; risks related to Blueprint Medicines' ability to successfully demonstrate the safety and efficacy of its drug candidates and gain approval of its drug candidates on a timely basis, if at all; preclinical and clinical results for Blueprint Medicines' drug candidates may not support further development of such drug candidates either as monotherapies or in combination with other agents or may impact the anticipated timing of data or regulatory submissions; the timing of the initiation of clinical trials and trial cohorts at clinical trial sites and patient enrollment rates may be delayed or slower than anticipated; actions of regulatory agencies may affect the initiation, timing and progress of clinical trials; the success of Blueprint Medicines' current and future collaborations, financing arrangements, partnerships or licensing arrangements may impact Blueprint Medicines' ability to capitalize on the market potential of its approved drugs and drug candidates; and risks related to Blueprint Medicines' ability to obtain, maintain and enforce patent and other intellectual property protection for its products and current or future drug candidates it is developing. These and other risks and uncertainties are described in greater detail in the section entitled "Risk Factors" in Blueprint Medicines' filings with the Securities and Exchange Commission (SEC), including Blueprint Medicines' most recent Annual Report on Form 10-K, as supplemented by its most recent Quarterly Report on Form 10-Q and any other filings that Blueprint Medicines has made or may make with the SEC in the future. Any forward-looking statements contained in this press release represent Blueprint Medicines' views only as of the date hereof and should not be relied upon as representing its views as of any subsequent date. Except as required by law, Blueprint Medicines explicitly disclaims any obligation to update any forward-looking statements. Trademarks Blueprint Medicines, AYVAKIT, AYVAKYT, GAVRETO and associated logos are trademarks of Blueprint Medicines Corporation. SOURCE Blueprint Medicines Corporation

引进/卖出

2023-06-19

·SYNAPSE

EGFR新进展：谁先解决耐药问题？

自从针对EGFR突变的酪氨酸激酶抑制剂（EGFR-TKI）问世以来，大大延长了肺癌患者的生存时间，已成为EGFR突变肺癌一线治疗的最佳选择。然而，其耐药问题一直是肺癌靶向治疗的难点。为克服耐药，EGFR-TKI不断更新迭代，从一代到三代，再到即将上市的四代，“打补丁”式地进行完善。然而，耐药难题仍然存在。那么如何提升药效并降低耐药性，成为药企思考的关键。除了小分子药物外，在攻克EGFR靶点的征途上，还有哪些新兴技术已经呈现？下面我们从EGFR靶点出发，来浅谈一下其研发进展。 EGFR，即表皮生长因子受体（又称ErbB-1或HER1），是HER家族成员之一。该家族包括HER1（erbB1，EGFR）、HER2（erbB2，NEU）、HER3（erbB3）及HER4（erbB4）。EGFR广泛分布于哺乳动物上皮细胞、成纤维细胞、胶质细胞等细胞表面。EGFR信号通路对细胞的生长、增殖和分化等生理过程发挥重要的作用：EGFR受体激活后会发生二聚化，并启动RAS-RAF-MEK-MAPK、PI3K-PTEN-AKT、STAT多种重要信号通路，与肿瘤发生发展密切相关。基于此作用机制，科学家们开始设计酪氨酸激酶抑制剂（TKI）。 EGFR-TKI三代同堂，奥希替尼占市场主流 2003年，第一代EGFR-TKI吉非替尼的获批，被认为是肺癌治疗的一个里程碑式事件。第一代EGFR-TKI主要针对EGFR 21号外显子L858R点突变或19号外显子缺失exon19 del突变，除吉非替尼外，其代表药物还有厄洛替尼和埃克替尼。与接受标准化疗的患者相比，EGFR-TKI一线治疗致敏性EGFR突变可延长无进展生存期（PFS），改善与健康相关的生活质量并减少与治疗相关的严重副作用。随后，以阿法替尼为代表的第二代EGFR-TKI获批上市。尽管第一、二代EGFR-TKI显著改善了NSCLC患者的PFS，但与对照组相比，OS均没有显著获益。而且，几乎所有使用前两代EGFR-TKI的患者最终都会进展，并产生明显的耐药性，主要与EGFR 20号外显子T790M耐药突变有关。于是科学家们开始探索针对T790M突变的第三代EGFR-TKI。2015年11月，奥希替尼获FDA批准用于EGFR T790M突变的NSCLC患者，它成功地创造了EGFR-TKI史上最长PFS和OS，分别达到18.9个月和38.6个月，为NSCLC治疗史上的新高峰。 2020年，奥希替尼又获FDA批准用于早期EGFR突变NSCLC患者的术后辅助治疗。在名为ADAURA的奥希替尼辅助治疗研究中，结果显示，奥希替尼组和安慰剂组的5年OS率分别为88%和78%，奥希替尼组显著降低了死亡风险（HR=0.49, 95%CI 0.34-0.70，P＜0.0001）。卓越的疗效让奥希替尼成为EGFR-TKI的风向标。国内已上市三款自研第三代EGFR-TKI，分别是翰森制药的阿美替尼、艾力斯的伏美替尼以及贝达药业的贝福替尼。它们均是奥希替尼的me too产品，疗效与奥希替尼相差并不大。第四代EGFR-TKI呼之欲出即便强如奥希替尼，依然逃不掉耐药的命运。EGFR基因20号外显子C797S的突变再次成为EGFR抑制剂所面对的新难题，如何开发新的针对性药物成为第四代EGFR-TKI研发的主要思路。目前，国内布局四代EGFR-TKI的药企主要包括贝达药业的BPI-361175、再鼎医药/BlueprintMedicines的BLU-945、正大天晴的TQB3804等。 BPI-361175 贝达药业的BPI-361175是一种强效、选择性第四代EGFR-TKI，拟开发用于治疗携带EGFR C797S突变及其他EGFR相关突变的晚期NSCLC等实体瘤。临床前研究显示，BPI-361175体内外生物学活性一致，能有效抑制携带EGFR C797S突变肿瘤细胞的增殖。 BBT-176 BBT-176是一种可逆的ATP竞争性抑制剂，可靶向复杂的EGFR突变，在临床前研究中已显示出较好的抗肿瘤活性。在2022年的世界肺癌大会上，BridgeBiotherapeutics公布了BBT-176的I期临床研究初步数据。结果显示：在18例接受BBT-176治疗的NSCLC患者中，5例患者存在EGFR耐药三重突变（外显子 19 del/T790M/C797S 或 L858R/T790M/C797S）。接受BBT-176治疗后，2例患者的肿瘤缩小，2例携带外显子19 del/T790M/C797S 三重突变的患者的靶病灶和非靶病灶均有缓解。 BLU-945 BLU-945可靶向常见的EGFR突变和T790M以及C797X耐药突变，同时对EGFR野生型(WT)具有选择性。临床前研究显示，BLU-945与奥希替尼联合使用较单用奥希替尼可增强L858R的药效，延长抗肿瘤疗效的持续性。在今年的ASCO会议上，Blueprint Medicines公布了BLU-945单药或联合奥希替尼治疗既往接受过≥1线EGFR-TKI治疗耐药的晚期NSCLC患者。其中，既往接受过奥希替尼治理的患者，入组后接受BLU-945+奥希替尼治疗。BLU-945单药组入组了112例患者；BLU-945+奥希替尼组入组了55例患者。结果显示，单药治疗队列中，大部分的治疗相关不良反应（TRAEs）为1-2级，共有12例患者出现剂量限制性毒性，最常见的不良反应为3级ALT和AST升高。疗效方面，4例患者部分缓解（PR）（其中2例已经确认）。在BLU-945联合奥希替尼的队列中，≥3级TRAEs发生率为10.9%，3例患者发生剂量限制毒性。在疗效方面，10例患者达到PR，其中4例已确认。总之，在多线治疗后的EGFR突变NSCLC患者中，BLU-945单药治疗展现出一定的疗效，安全性可耐受，不过疗效持续时间有待提高。而BLU-945联合奥希替尼在安全性良好的情况下，奥希替尼耐药患者的疗效可观。 EGFR-PROTAC：另辟蹊径以上四代EGFR-TKI，均是靶向EGFR三磷酸腺苷 (ATP) 结合位点的类似药物设计策略，该策略既有优势又有劣势，这些化合物可能始终难以避免遭受药物诱导的EGFR突变。因此需要一种新的药物设计策略来开发具有不同作用机制的化合物。蛋白降解靶向嵌合体（PROTAC）是一种杂合双功能小分子化合物，结构中含有两种不同配体，一个是E3泛素连接酶的配体，另一个是与细胞中目标靶蛋白结合的配体，两个配体之间通过 Linker 相连，从而形成“三体”聚合物——靶蛋白配体-Linker-E3 配体。PROTAC通过拉近靶蛋白和E3配体之间的距离，利用泛素-蛋白酶体系统同时结合靶蛋白和E3配体复合物，进而引起泛素转移并启动，最终使靶蛋白被蛋白酶体降解。其独特的降解机制可以有效避免耐药性突变的产生，而其独特的三元复合物结构形式更是可以从现有的EGFR抑制剂出发来设计相应分子结构。近年来，PROTAC 技术在肿瘤药物开发领域深受欢迎，不过国内布局的企业还比较少，且大部分处于早期阶段。国内海思科、贝达药业、百济神州、先导药物等布局了EGFR PROTAC项目。其中海思科药业的PROTAC药物HSK40118于今年3月15日获NMPA批准开展临床试验，拟用于治疗不可手术的、携带EGFR突变的晚期NSCLC患者。这是全球首款申报临床的EGFR靶向PROTAC药物。临床前研究表明，HSK40118在体外对突变型EGFR蛋白具有良好的抑制以及降解活性，对EGFR L858R-T790M双突变、ex19del(或L858R)-T790M-C797S三突变体内移植瘤的生长具有显著的抑制效果，提示HSK40118对3代EGFR-TKI诱导的获得性耐药突变患者将产生显著疗效，有望延缓甚至克服由于长期使用EGFR-TKI导致的EGFR耐药突变问题。 EGFR-ADC：崭露头角抗体偶联药物（ADC）是近年来研发火热的赛道之一，对于EGFR突变NSCLC患者来说，ADC药物的出现也为奥希替尼进展后的临床需求提供了支持。事实上，针对EGFR开发ADC药物已有很长时间，艾伯维先后开发了ABBV-221、ABT-414等多款EGFR ADC药物。尽管在临床前和早期临床研究中，ABBV-221、ABT-414具有强大的抗肿瘤活性，但在III期临床试验中两者均以失败告终。无独有偶，Forbius公司的AVID100是一种高效力的EGFR靶向ADC，在临床前研究中，AVID100在对已上市EGFR抑制剂耐药的EGFR过表达肿瘤模型中显示出显著的抗癌活性，而且仅观察到了轻微的皮肤毒性。但在Ia / IIa期临床试验中，由于缺乏疗效，Forbius于2021年终止了AVID100的临床研究。国内方面，虽然布局EGFR-ADC的药企较多。不过在NSCLC治疗领域进入临床阶段的仅有乐普生物、石药集团等。乐普生物的MRG003，作为一种新型ADC药物，能特异性识别并结合肿瘤细胞表面的EGFR，然后通过EGFR介导的内吞作用而内化至肿瘤细胞中。连接子被溶酶体蛋白酶裂解后，细胞毒有效载荷释放到细胞质中，发挥抗肿瘤作用。MRG003目前正在国内进行II期临床试验。石药集团的CPO301于今年6月12日获FDA授予快速通道资格，用于治疗复发/难治性或EGFR靶向治疗(包括奥希替尼)无效的转移性EGFR突变NSCLC患者。临床前研究显示，CPO301在含有针对第三代EGFR-TKI奥希替尼耐药的EGFR三重突变(Exon19Del、T790M及C797S)的人源化NSCLC PDX模型中显示出很强的抗肿瘤效果。临床前毒理学和安全药理学研究中已显示良好的安全性和耐受性。目前其I期剂量递增及剂量扩展临床研究正在美国和加拿大开展，拟评估CPO301用于治疗晚期NSCLC的安全性和疗效。除了ADC药物外，今年的ASCO年会上，百利天恒公布了其新型EGFR/HER3双抗ADC——BL-B01D1在治疗EGFR突变NSCLC患者中的I期临床数据。BL-B01D1的载荷为新型 TOP1 抑制剂ED04（属于一种喜树碱类物质），其通过阻止肿瘤细胞的DNA复制和RNA合成，破坏DNA的结构，实现对肿瘤细胞的直接杀伤。BL-B01D1的单抗部分SI-B001针对EGFR和HER3两个不同的靶点，更强的特异性增加了药物的安全性；同时通过交联作用促进两个靶点的协同内吞，提高毒素进入肿瘤细胞的效率，并进一步通过减少受体蛋白在细胞膜上的表达量来抑制肿瘤细胞生长信号，实现更好的治疗效果。 BL-B01D1结合双抗和小分子毒素实现了对EGFR依赖肿瘤的靶向杀伤并防止HER3引起的耐药，既精准杀伤肿瘤细胞，又减少毒素对体内正常细胞的破坏。在今年ASCO大会上公布的I期临床数据显示，BL-B01D1治疗经治的EGFR突变NSCLC的客观缓解率（ORR）达63.2%，不同耐药突变均有疗效，治疗经治的EGFR野生型NSCLC的ORR也达44.9%，且未见间质性肺病报告。 EGFR突变作为中国NSCLC患者的第一大驱动基因，已成为NSCLC药物开发的热点。目前针对第三代EGFR-TKI耐药，已经开发出了多种类型的药物，如第四代EGFR-TKI、PROTAC、ADC、双抗（此文未涉及）、双抗ADC等，均已进入攻坚阶段。相信随着对耐药机制认识的愈加清晰，EGFR靶点将老而弥新，未来会有更加多样化形式的药物上市，为肺癌慢病化再添一臂之力。参考资料： 1.Liu X, Wang P, Zhang C, Ma Z. Epidermal growth factor receptor (EGFR): A rising star in the era of precision medicine of lung cancer. Oncotarget. 2017 Jul 25;8(30):50209-50220. doi: 10.18632/oncotarget.16854. 2.Cantor, A. J., et al. Deep mutational analysis reveals functional trade-offs in the sequences of EGFR autophosphorylation sites. Proc. Natl Acad. Sci. USA. 115, E7303-E7312(2018). 3.BLU-945 monotherapy and in combination with osimertinib in previously treated patients with advanced EGFR-mutant NSCLC in the phase 1/2 SYMPHONY study. 4.Zhang H, Zhao HY, Xi XX, Liu YJ, Xin M, Mao S, Zhang JJ, Lu AX, Zhang SQ. Discovery of potent epidermal growth factor receptor (EGFR) degraders by proteolysis targeting chimera (PROTAC). Eur J Med Chem. 2020 Mar 1;189:112061. 5.Zhao HY, Yang XY, Lei H, Xi XX, Lu SM, Zhang JJ, Xin M, Zhang SQ. Discovery of potent small molecule PROTACs targeting mutant EGFR. Eur J Med Chem. 2020 Dec 15;208:112781. 6.2023 ASCO Abstract 3001.