A Phase 0/1 Study of BDTX-1535 in Recurrent High-Grade Glioma (HGG) and Newly Diagnosed Glioblastoma (nGBM) Participants With EGFR Alterations or Fusions Scheduled for Resection to Evaluate Central Nervous System (CNS) Penetration With PK-triggered Expansion Cohort

This study will administer the investigational drug, BDTX-1535 to eligible patients with recurrent high-grade glioma (HGG) and newly-diagnosed glioblastoma (nGBM). BDTX-1535 was designed to block a growth signal important to some cancers. BDTX-1535 is being tested in this study to see if it can be given safely to people who have tumors that can be dependent on that growth signal because of changes in a protein called EGFR. These gene changes are called amplifications, mutations, fusions or alterations and are found only in the tumors.
The study design includes a Phase 0 component with PK/PD-trigger for participant enrollment into an Expansion Phase 1 component. The primary objective of the Phase 0 component is to evaluate the PK endpoints of BDTX-1535. The primary objective of the Phase 1 component is to establish the safe dose of BDTX-1535 to be used in participants with a specified treatment regimen, three of which include standard of care radiotherapy for nGBM participants.

开始日期2023-10-18

申办/合作机构

St. Joseph's Hospital

[+1]

NCT05256290

/ Active, not recruiting临床1/2期

A Phase 1/2 Study to Assess BDTX-1535, an Oral EGFR Inhibitor, in Patients With Glioblastoma or Non-Small Cell Lung Cancer

BDTX-1535-101 is an open-label, Phase 1 dose escalation and Phase 2 multiple cohort study designed to evaluate the safety, pharmacokinetics (PK), optimal dosage, central nervous system (CNS) activity, and antitumor activity of silevertinib (BDTX-1535). The study population comprises adults with either advanced/metastatic non-small cell lung cancer (NSCLC) with non-classical or acquired epidermal growth factor receptor (EGFR) resistance (EGFR C797S) mutations with or without CNS disease (in Phase 1 and Phase 2), or glioblastoma (GBM) expressing EGFR alterations (Phase 1 only). All patients will self-administer silevertinib (BDTX-1535) monotherapy by mouth in 21-day cycles.
Phase 1 enrollment is now complete. Phase 2 is currently ongoing.

开始日期2022-03-31

申办/合作机构

Black Diamond Therapeutics, Inc.

100 项与 Silevertinib 相关的临床结果

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100 项与 Silevertinib 相关的转化医学

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100 项与 Silevertinib 相关的专利（医药）

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项与 Silevertinib 相关的文献（医药）

2025-06-01·BIOORGANIC & MEDICINAL CHEMISTRY

A clinical review on third and fourth generation EGFR tyrosine kinase inhibitors for the treatment of non-small cell lung cancer

Review

作者: Patel, Harun M ; Patil, Chandragouda R ; Gawli, Chandrakant S

"Epidermal growth factor receptor (EGFR)" mutations are pivotal in the pathogenesis of "Non-Small Cell Lung Cancer (NSCLC)," which is associated with high morbidity and mortality rates. The advent of third and fourth-generation EGFR tyrosine kinase inhibitors (TKIs) has significantly advanced the therapeutic landscape for EGFR-mutant NSCLC, particularly in overcoming resistance mutations such as T790M and C797S. This review delves into the current clinical status, efficacy, safety profiles, and regulatory approvals of third-generation EGFR TKIs, including Osimertinib, Lazertinib, Furmonertinib, Aumolertinib, Rezivertinib, Befotertinib, Sunvozertinib. Furthermore, it explores emerging fourth-generation EGFR TKIs designed to address resistance mechanisms beyond those targeted by their predecessors. Notable fourth-generation candidates such as TQB3804, BPI-361175, BDTX-1535, WJ13404, QLH11811, H002, HS-10375, BBT-207, JIN-A02, and HS-10504 are highlighted for their potential to overcome the C797S mutation. The review emphasizes the importance of these advanced inhibitors in enhancing "progression-free survival and overall survival rates". By evaluating the therapeutic potential and limitations of these EGFR TKIs, this review aims to guide future research in the management of EGFR-mutant NSCLC. This acts as guiding beacon for the strategic design and development of third and fourth generation EGFR-TK inhibitors to overcome the drug resistance hurdles in the development of EGFR-TK inhibitors.

2024-11-01·Translational Cancer Research

Targeting C797S mutations and beyond in non-small cell lung cancer—a mini-review

Review

作者: Fenchel, Klaus ; Dempke, Wolfram C M

Non-small cell lung cancer (NSCLC) represents over 80% of lung cancer cases and has a high mortality worldwide, however, targeting common epidermal growth-factor receptor (EGFR) alterations (i.e., del19, L858R) has provided a paradigm shift in the treatment of NSCLC. Uncommon EGFR mutations, however, show variable efficacy to EGFR-targeted drugs depending on the molecular alterations within exons 18-21 which underlying biological mechanism are far from being clear. The substitution mutations of G719X in exon 18, L861Q in exon 21, S768I in exon 20, and exon 20 insertions are the most frequent mutations among the uncommon mutations. The development of fourth-generation EGFR-tyrosine kinase inhibitor (TKIs) has gained increased interest as these drugs are able to inhibit resistance mutations (e.g., C797S) often detected in NSCLC patients' resistance to third-generation EGFR TKIs. BDTX-1535 is an orally bioavailable, brain-penetrating, mutation-selective, irreversible EGFR inhibitor with significant antitumour activity in NSCLCs and glioblastomas (phase I/II trials ongoing). It is a fourth-generation EGFR inhibitor that was found to overcome resistance to osimertinib in preclinical models and has shown promising activity in NSCLC patients harbouring C797S mutations. In experimental models BDTX-1535 was found to inhibit all common EGFR mutations and more than 50 of uncommon mutations including T790M, C797S, L718X, E709X, S784F, V834L and A289V, however, exon 20 insertions are inhibited to a much lesser extent. In addition, mutations in the extracellular domain of the EGF receptor (e.g., EGFRvII, III, IV) can be blocked as well. It should be noted that in up to 50% of all NSCLC patients who progress following osimertinib or other EGFR TKI therapy no underlying resistance mechanism can be identified suggesting that non-mutational signal transduction pathways may also be operative, and intratumoural heterogeneity has been found to be a major contributor to resistance and it consists of three main mechanisms: (I) drug-tolerant persister (DTP) cells, (II) chromosomal instability, and (III) extrachromosomal extracellular DNA (ecDNA) (seen in over 50% of NSCLCs) suggesting that novel EGFR TKIs will include many challenges in sufficiently targeting on-target resistance mechanisms. The development of novel drugs that can overcome TKI resistance in NSCLC patients harbouring the C797S mutation and beyond is, therefore, eagerly warranted.

2021-12-01·Cancer discovery1区 · 医学

BDTX-1535 Goes after Osimertinib Resistance

1区 · 医学

Article

Abstract:

According to a preclinical report, the investigational tyrosine kinase inhibitor BDTX-1535 may mitigate resistance to osimertinib, the standard of care for EGFR-mutant non–small cell lung cancer. It could also potentially treat central nervous system metastases, having shown preclinical efficacy in glioblastoma.

项与 Silevertinib 相关的新闻（医药）

2025-08-07

·GlobeNewswire-Health Care

Black Diamond Therapeutics Reports Second Quarter 2025 Financial Results and Provides Corporate Update

Enrollment completed for the Phase 2 trial of silevertinib (BDTX-1535) in 1L patients with non-classical EGFRm NSCLC (n=43); ORR and preliminary DOR data on track for Q4 2025Exploring partnership opportunities to advance pivotal development of silevertinib in NSCLC and GBMPlan to meet with FDA regarding 1L NSCLC development path in 1H 2026, when PFS data becomes availableCash, cash equivalents, and investments of $142.8 million as of June 30, 2025; expected to be sufficient to fund operations into Q4 of 2027 CAMBRIDGE, Mass., Aug. 07, 2025 (GLOBE NEWSWIRE) -- Black Diamond Therapeutics, Inc. (Nasdaq: BDTX), a clinical-stage oncology company developing MasterKey therapies that target families of oncogenic mutations in patients with cancer, today reported financial results for the second quarter ended June 30, 2025, and provided a corporate update. “With enrollment completed in our silevertinib Phase 2 trial for the treatment of newly diagnosed patients with EGFRm NSCLC, we look forward to sharing a clinical update in the fourth quarter of 2025,” said Mark Velleca, M.D., Ph.D., President and Chief Executive Officer of Black Diamond Therapeutics. “Given the evolving competitive and regulatory landscape, we are also exploring partnership opportunities to advance silevertinib into pivotal development and bring this potential best-in-class treatment to patients as quickly as possible.” Recent Developments & Upcoming Milestones: Silevertinib (BDTX-1535): In July 2025, Black Diamond completed enrollment (n=43) in the Phase 2 trial of silevertinib in frontline non-small cell lung cancer (NSCLC) patients with non-classical EGFR mutations.In the fourth quarter of 2025, Black Diamond expects to disclose objective response rate (ORR) and preliminary duration of response (DOR) data from all patients (n=43) in the Phase 2 trial of silevertinib in frontline NSCLC with non-classical EGFR mutations.Black Diamond is exploring partnership opportunities in NSCLC and glioblastoma (GBM) to advance silevertinib into pivotal development.The Company plans to solicit U.S. Food and Drug Administration (FDA) feedback on a potential registrational path in frontline EGFRm NSCLC in 1H 2026, when progression free survival (PFS) data from the ongoing Phase 2 trial becomes available. Financial Highlights Cash Position: Black Diamond ended the second quarter of 2025 with approximately $142.8 million in cash, cash equivalents, and investments compared to $98.6 million as of December 31, 2024. Net cash used in operations was $9.2 million for the second quarter of 2025 compared to net cash used in operations of $14.7 million for the second quarter of 2024.Research and Development Expenses: Research and development (R&D) expenses were $9.3 million for the second quarter of 2025, compared to $12.6 million for the same period in 2024. The decrease in R&D expenses was primarily due to workforce efficiencies and outlicensing of BDTX-4933 to increase focus on the development of silevertinib.General and Administrative Expenses: General and administrative (G&A) expenses were $4.1 million for the second quarter of 2025, compared to $9.6 million for the same period in 2024. The decrease in G&A expenses was primarily due to the restructuring announced in October 2024.Net Income/Loss: Net loss for the second quarter of 2025 was $10.6 million, as compared to a net loss of $19.9 million for the same period in 2024. Financial Guidance Black Diamond ended the second quarter of 2025 with approximately $142.8 million in cash, cash equivalents and investments, which the Company believes is sufficient to fund its anticipated operating expenses and capital expenditure requirements into the fourth quarter of 2027. About Black Diamond Therapeutics Black Diamond Therapeutics is a clinical-stage oncology company developing MasterKey therapies that target families of oncogenic mutations in patients with cancer. The Company’s MasterKey therapies are designed to address a broad spectrum of genetically defined tumors, overcome resistance, minimize wild-type mediated toxicities, and be brain penetrant to treat central nervous system disease. The Company is advancing a Phase 2 NSCLC trial of silevertinib, a brain-penetrant fourth-generation EGFR MasterKey inhibitor targeting EGFR-mutant NSCLC and GBM. For more information, please visit www.blackdiamondtherapeutics.com. From time to time, we may use our website or our LinkedIn profile at www.linkedin.com/company/black-diamond-therapeutics to distribute material information. Our financial and other material information is routinely posted to and accessible on the Investors section of our website, available at www.blackdiamondtherapeutics.com. Investors are encouraged to review the Investors section of our website because we may post material information on that site that is not otherwise disseminated by us. Information that is contained in and can be accessed through our website or our LinkedIn page is not incorporated into, and does not form a part of, this press release. Forward-Looking Statements Statements contained in this press release regarding matters that are not historical facts are “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995. Because such statements are subject to risks and uncertainties, actual results may differ materially from those expressed or implied by such forward-looking statements. Such statements include, but are not limited to, statements regarding: the continued development and advancement of silevertinib, including the ongoing Phase 2 clinical trial and the timing of clinical updates for silevertinib in patients with NSCLC and in patients with GBM, enrollment in the investigator sponsored Phase 0/1 clinical trial of silevertinib of newly diagnosed GBM patients with EGFR alterations, the expected timing for regulatory feedback and the disclosure of a potential registrational pathway for silevertinib in NSCLC, the potential of silevertinib to address the unmet medical need for newly diagnosed NSCLC patients with non-classical EGFR mutations and benefit patients with NSCLC across multiple lines of therapy, the potential future development plans for silevertinib in NSCLC and GBM, a potential partnership for silevertinib, and the Company’s expected cash runway. Any forward-looking statements in this press release are based on management’s current expectations of future events and are subject to a number of risks and uncertainties that could cause actual results to differ materially and adversely from those set forth in or implied by such forward-looking statements. Risks that contribute to the uncertain nature of the forward-looking statements include those risks and uncertainties set forth in its Annual Report on Form 10-K for the year ended December 31, 2024, filed with the United States Securities and Exchange Commission and in its subsequent filings filed with the United States Securities and Exchange Commission. All forward-looking statements contained in this press release speak only as of the date on which they were made. The Company undertakes no obligation to update such statements to reflect events that occur or circumstances that exist after the date on which they were made. Black Diamond Therapeutics, Inc.Condensed Consolidated Balance Sheet Data (Unaudited)(in thousands) June 30, 2025 December 31, 2024 (in thousands)Cash, cash equivalents, and investments$142,829 $98,575 Total assets$166,385 $122,640 Accumulated deficit$(441,126) $(487,107)Total stockholders’ equity$132,610 $83,285 Black Diamond Therapeutics, Inc.Consolidated Statements of Operations (Unaudited)(in thousands, except per share data) Three Months EndedJune 30, Six Months EndedJune 30, 2025 2024 2025 2024 License revenue$— $— $70,000 $— Operating expenses: Research and development$9,319 $12,556 $19,825 $26,101 General and administrative 4,101 9,574 9,065 16,275 Total operating expenses 13,420 22,130 28,890 42,376 Income (loss) from operations (13,420) (22,130) 41,110 (42,376)Other income (expense): Interest income 1,118 464 1,713 1,101 Other income (expense) 1,741 1,757 3,158 3,141 Total other income (expense), net 2,859 2,221 4,871 4,242 Net income (loss)$(10,561) $(19,909) $45,981 $(38,134) Net income (loss) per share - basic$(0.19) $(0.36) $0.81 $(0.71)Net income (loss) per share - diluted$(0.19) $(0.36) $0.80 $(0.71) Weighted average common shares outstanding - basic 56,803,450 55,155,220 56,734,010 53,482,034 Weighted average common shares outstanding - diluted 56,803,450 55,155,220 57,474,118 53,482,034 Contact For Investors:investors@bdtx.com For Media:media@bdtx.com

临床2期财报临床1期

2025-06-23

·CPHI制药在线

老靶点EGFR在肺癌领域的创新韧性

关注并星标CPHI制药在线近日，翰森制药宣布，其第三代EGFR-TKI阿美替尼（Aumseqa）的上市许可申请，已获英国药品和健康产品管理局 (MHRA）批准，作为单药治疗成人局部晚期或转移性非小细胞肺癌（NSCLC）且具有激活的EGFR突变的患者的一线治疗，以及成人局部晚期或转移性EGFR T790M突变阳性NSCLC患者的治疗，成为首个出海欧洲的中国原研三代EGFR-TKI。从NDA受理到获批，阿美替尼历经了三年的漫长等待。阿美替尼的成功出海，再次彰显了EGFR这一老靶点的创新韧性。EGFR的作用机制EGFR（表皮生长因子受体）是一个跨膜酪氨酸激酶受体，对于细胞增殖、迁移、分化等都发挥着关键作用。当EGFR与表皮生长因子（EGF）结合后，可参与细胞正常生长和分裂，是人体表皮细胞的调控开关。TKI（酪氨酸激酶抑制剂）是一组通过多种抑制模式破坏蛋白激酶信号转导通路的药物。EGFR-TKI可通过竞争性抑制EGFR的ATP结合位点，阻断EGFR的自磷酸化和下游信号通路的激活，实现抑制肿瘤细胞的增殖、存活和诱导肿瘤细胞凋亡的治疗目的。EGFR基因在非小细胞肺癌（NSCLC）中的总体发生率为17.2%。但在包括中国在内的东南亚地区，其发生率则高达40%-60%。因此，EGFR-TKI成为NSCLC领域的主流治疗药物。从EGFR发现至今，EGFR-TKI已历经三代更迭。如今，第四代已箭在弦上，另外还有其他技术路线产品正在临床阶段。EGFR-TKI的造富能力有多强？2002年，阿斯利康的吉非替尼（Gefitinib）在日本获批上市，开启了EGFR-TKI时代。目前，已经历三代更迭，代表产品分别是：第一代：吉非替尼、厄洛替尼、埃克替尼；第二代：阿法替尼、达可替尼；第三代：奥希替尼、阿美替尼、伏美替尼、贝福替尼、奥莫替尼、兰泽替尼、瑞齐替尼。吉非替尼上市首年销售额便达到6700万美元，2003年获FDA批准上市，销售额暴涨240%，高达2.28亿美元。罗氏的厄洛替尼于2004年获得FDA批准后，销售额也一路高涨，2013年达到销售额巅峰13.39亿法郎（14.58亿美元）。2015年11月，阿斯利康的奥希替尼（Tagrisso）获FDA批准上市，用于单药一线治疗外显子19缺失（EGFR ex19del）或外显子21 L858R突变（EGFR ex21 L858R）的局部晚期或转移性非小细胞肺癌（NSCLC）患者，开启了三代EGFR-TKI治疗时代。目前，该药物已获批5项适应症。奥希替尼自上市以来销售额稳步上升，2018年被批准一线疗法后销售额突飞猛进，2021年首次突破50亿美元大关，2023年全球销售额达到57.99亿美元，2024年全球销售额达到65.80亿美元，成为阿斯利康第二大畅销药。成立于2003年的贝达药业，更是凭借中国第一个自主研发的EGFR-TKI-盐酸埃克替尼（商品名：凯美纳），成为国内首个销售额破十亿的创新药。目前成为主流的三代EGFR-TKI依然面临着严峻的肿瘤耐药挑战，在经奥希替尼二线治疗后出现耐药的NSCLC患者中，大约10%-26%的患者存在EGFR C797S耐药性突变。EGFR-TKI与肺癌的对抗之战已然来到第四阶段。"后EGFR时代"之战目前第四代EGFR-TKI大战已经打响，全球约有20多款四代EGFR-TKI进入临床，其中以Black Diamond Therapeutics的BDTX-1535的数据最为亮眼。BDTX-1535是一种中枢神经系统渗透剂第四代不可逆（共价）EGFR抑制剂，可靶向第三代EGFR TKI获得性和内在耐药性突变，对野生型EGFR有选择性，同时有很好的渗脑作用。在II期研究中，接受每日1次200mg BDTX-1535治疗的EGFR突变型NSCLC患者有42%（8/19）实现了客观缓解（ORR）。为了克服EGFR-TKI耐药难题，行业还开发了EGFR抗体、EGFR ADC、EGFR PROTAC等方向产品。EGFR抗体的研发很早就开始了，但在肺癌治疗领域一直未能成功，这是因为EGFR信号通路的激活依赖于配体介导的EGFR受体二聚化，EGFR单抗可以与EGFR胞外区结合，抑制配体介导的受体二聚化，从而抑制EGFR信号传递。而EGFR突变发生在胞内区，因此EGFR单抗无法阻止EGFR信号传递。2015年，首款EGFR单抗necitumumab获批用于治疗NSCLC，不过疗效非常有限。2021年5月，强生的EGFR/cMET双抗埃万妥单抗以I期试验结果获得FDA加速批准，用于治疗铂化疗后进展的EGFR 20ins突变的局部晚期或转移性NSCLC，成为首个成功进入肺癌领域的EGFR抗体疗法。在EGFR单抗的基础上，ADC技术带来了新的突破。乐普生物的EGFR ADC新药维贝柯妥塔单抗（MRG003）是国内进展最快的，由EGFR靶向单抗与强效的微管抑制剂MMAE分子通过vc链接体偶联而成，维贝柯妥塔单抗针对肺癌的适应症正在临床研究中。PROTAC作为一种具有新结构新机制的肿瘤靶向药物，可以降解整个蛋白而不仅仅是抑制酶活性，因此可能克服耐药性问题，是EGFR赛道一个理想的成药方向。全球已有20多个PROTAC药物进入临床研究，包括海思科的EGFR PROTAC药物HSK40118和贝达药业/C4 Therapeutics的EGFR PROTAC药物CFT8919，正在开展临床试验，用于治疗不可手术的、携带EGFR突变的晚期NSCLC患者。历久弥新的EGFR靶点，在一代代技术更迭下，演绎着属于自己的创新韧性。参考来源： 1.翰森制药公告 2.Dawei Hong, Bizhong Zhou, Bei Zhang, Hao Ren, Liquan Zhu, Guowan Zheng, Minghua Ge, Jingyan Ge, Recent advances in the development of EGFR degraders: PROTACs and LYTACs, European Journal of Medicinal Chemistry Volume 239, 5 September 2022, 114533. 3.Specific non-genetic IAP-based protein erasers (SNIPERs) as a potential therapeutic strategy. Eur J Med Chem 2021;216:113247.END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~

上市批准申请上市医药出海

2025-06-04

·E药经理人

AZ“腹背受敌”！30+管线“围剿”奥希替尼，谁能成功？

EGFR不是“过去完成式”，而是“现在进行时”与“未来进行时”，尤其是在面对异质性极强的耐药机制时，新一代靶向技术正变得至关重要。撰文| Kathy2025年ASCO年会如火如荼，EGFR，一个“老”靶点依旧屹立潮头。作为非小细胞肺癌（NSCLC）精准治疗的起点，EGFR靶向治疗已经走过近二十年的进化与迭代。从第一代吉非替尼、厄洛替尼，到第二代阿法替尼，再到第三代奥希替尼，这条路径见证了分子靶向治疗从尝试到成熟的蜕变。然而，“耐药”这个问题是连头顶“重磅炸弹”与“诊疗金标准”光环的奥希替尼都无法逾越的鸿沟。也正因如此，谁能成为下个奥希替尼，这一悬而未决的挑战，倒逼着行业前赴后继投身于此，寻找突破口。本次ASCO上与EGFR相关的口头报告、壁报及摘要展示依然有数十项，涵盖小分子、ADC、双抗、蛋白降解剂（PROTAC）等多个技术路径，EGFR这个“老靶点”正经历一场从传统小分子药物向新兴技术融合的转型升级。而这场新竞赛，中国药企的活跃度要是称第二，几乎再无药企称第一。奥希替尼之后，EGFR-TKI尚无王者EGFR-TKI的发展史堪称是一部不断“破而后立”的演进史。第一代EGFR-TKI如吉非替尼、厄洛替尼，首次实现对EGFR敏感突变患者的精准打击，却在T790M突变面前折戟；第二代药物如阿法替尼强化了不可逆结合，却因毒性和选择性问题未能实现大规模替代；直到第三代EGFR-TKI奥希替尼的横空出世，通过特异性靶向T790M突变，才真正延长了生存时间与无进展生存期（mPFS）。奥希替尼凭借对T790M耐药突变的精准抑制，成为三代EGFR-TKI家族的“标杆”，在FLAURA研究中，其mPFS达到18.9个月，mOS更是刷新纪录至38.6个月，堪称EGFR治疗史上的高光时刻。据阿斯利康公布2024年业绩，奥希替尼已上市近10年时间，但作为治疗非小细胞肺癌的重要药物，其全球年销售额实现了16%的同比增长，达65.80亿美元，稳居“肺癌药王”宝座。然而，C797S突变、EGFR变构改变、旁路激活等复杂耐药机制，依旧在治疗中期悄然酝酿。强如奥希替尼，也未能终结这场“追逐战”，在经奥希替尼二线治疗后出现耐药的NSCLC患者中，大约10%-26%的患者存在EGFR C797S耐药性突变。在国内市场，已经有7款三代EGFR-TKI被批准用于治疗伴有EGFR 19外显子缺失、21外显子L858R以及20外显子T790M突变的非小细胞肺癌，分别是奥希替尼、阿美替尼、伏美替尼、贝福替尼、瑞齐替尼、瑞厄替尼和利厄替尼。在研并且进入III期临床的三代EGFR-TKI，也已经超过了10款。迭代升级之路，在浩浩荡荡的研发大军里延伸出来。能够看到，第四代EGFR-TKI已经呼之欲出。贝达的BPI-43487、正大天晴的TQB3804、齐鲁的QLH11811……一众中国药企均已布局四代EGFR-TKI，直指奥希替尼耐药的C797S突变。在这一背景下，如何绕开C797S等耐药突变、同时延长疾病控制时间，成为全球创新药企正面临的技术挑战。值得一提的是，Blueprint的BLU-945，曾是近两年最受关注的四代EGFR-TKI药物。2020年ESMO，BLU945迎来首秀高光时刻。BLU945在体外实验中对T790M/C797S共突变展现出抑制作用，前期研究的成功推动了I/II期SYMPHONY研究启动。2022 AACR年会上报道的I/II期SYMPHONY 研究的成果初步证实了其临床获益，因此彼时BLU-945被寄予厚望。然而到了2024年1月初，在第42届JPM年会上，Blueprint表示停止对BLU-945和BLU-451进一步投资。明星管线被放弃的原因也很简单：安全性问题。研究显示，高剂量BLU-945组（400-600mg/天）患者中出现12例剂量限制性毒性，主要是肝功能异常，联合治疗组起效剂量高过限制性毒性剂量，限制它的临床使用。从2020年ESMO的高光到2024年JPM的折戟，短短4年，新星便陨落。不过，“九死一生”的残酷现实并未让后来者却步。Black Diamond Therapeutics研发的BDTX-1535“接力”而来。BDTX-1535是第四代不可逆脑渗透性EGFR-TKI，可靶向NSCLC一系列经典/非经典EGFR驱动基因突变和耐药突变（包括C797S、G719X和S768I等）。重要的是，I期临床前研究显示，BDTX-1535穿过血脑屏障能力优秀，或可填补中枢神经系统（CNS）转移患者治疗的空白。临床前研究数据显示，BDTX-1535对C797S和多种罕见EGFR突变具有较低的半数抑制浓度（IC50），而对野生型EGFR的IC50极高。这意味着BDTX-1535在抑制耐药突变的同时，对正常细胞的损伤较小，从而降低了相关不良反应的发生。如火如荼召开的2025 ASCO年会上，也不乏四代EGFR-TKI的身影。像DZD6008、CM-205、CCM-308、WSD0922-FU片和JIN-A02等多款第四代EGFR抑制剂亮相。DZD6008是迪哲医药在研的一款第四代EGFR-TKI，可靶向EGFR敏感突变(L858R/del19)、耐药双突变（T790M+L858R/del19）及三突变（C797X+T790M+L858R/del19），可完全穿透血脑屏障（BBB），能有效抑制多种EGFR突变细胞及肿瘤动物模型的生长，对多种EGFR 突变具有广谱活性。CM-205和CCM-308是CCM Biosciences 的新型第四代EGFR抑制剂，能够靶向EGFR敏感突变（如L858R/19外显子缺失）、T790M耐药突变以及C797S三重突变，且对野生型EGFR的选择性较高，减少脱靶毒性。临床前研究表明，它们通过不可逆结合突变型EGFR的ATP结合位点，抑制肿瘤细胞增殖。另外两款在研第四代靶向口服抑制剂正在进行的临床研究也在海报会议上进行了报告。WSD0922-FU片是威尚生物医药研发的一款口服、可穿透中枢神经系统(CNS)、保留野生型、ATP 非竞争性、可逆的 EGFR/EGFRvIII 第四代口服小分子靶向抑制剂，可有效抑制非小细胞肺癌(NSCLC)和高级别星形细胞瘤(HGA)特异性的 EGFR 突变，以及其他肿瘤的神经中枢转移。JIN-A02是J INTS BIO在研的一种新型口服的第四代EGFR-TKI 靶向药物，可以选择性和可逆性地与EGFR突变结合，尤其是导致对奥希替尼治疗产生耐药性的C797S突变。全球超30+管线竞逐于此，谁能率先跨越耐药这道天堑？迭代为下一个奥希替尼？甚至攻下EGFR这座“碉堡”？推荐阅读 * EGFR打不动了？中国药企抄出底牌* 1000亿魔幻“赌局”：中国双抗“完”了？换个战场，新机制卷翻天了随着对耐药机制研究的深入，开发能够覆盖C797S等新突变的第四代EGFR-TKI之外的另一个策略是——换战场。面对耐药的困境，研发者将目光投向了新兴技术，期望能从中找到攻克 EGFR 靶点的新途径，双抗、ADC、PROTAC技术，都成了这场战疫里的新兵。如通过PROTAC降解EGFR蛋白、利用ADC靶向EGFR表达细胞、或者构建EGFR/MET双靶向药物，绕过传统机制路径。这些新技术平台试图重塑EGFR这一“老靶点”的治疗新范式。强生的埃万妥单抗成功破茧。埃万妥单抗是一种靶向EGFR-MET的双特异性抗体。2021年，FDA批准其用于治疗铂类化疗治疗中或之后疾病进展的携带EGFR外显子20插入突变的局部晚期或转移性NSCLC成人患者。今年2月，埃万妥单抗在国内获批用于联合化疗治疗接受奥希替尼治疗期间或之后疾病进展的EGFR突变NSCLC患者。EGFR ADC则算得上是靶向EGFR的新机制中，开发起步较早的。早在2008年，雅培与Life Science Pharma达成一项合作协议，获得了后者4款靶向EGFR产品的全球开发和商业化许可权益，其中包括了两款EGFR ADC：ABBV-321和ABBV-414，不过这两款药物落入艾伯维的管线后研发并不顺利，相继折戟。有意思的是，从目前布局来看，EGFR ADC赛道的几乎都是来自中国的药企。靶向EGFR的ADC药物，如乐普生物的维贝柯妥塔单抗（MRG003），目前已在国内申报上市。另外，MRG003与PD-1抑制剂普特利单抗的联合治疗也取得了积极进展。百利天恒和BMS合作的靶向EGFR/HER3的双抗ADC产品BL-B01D1，目前已在六大瘤种中开展了III期研究，包括EGFR突变型和野生型非小细胞肺癌、鼻咽癌、食管鳞癌、三阴性乳腺癌以及HER2-/HR+乳腺癌。石药的SYS6010、基石药业的CS5007、百力司康的BB-1705等等一众ADC竞逐其中……值得注意的是，石药集团/新诺威的SYS6010，于2025年3月在CDE登记了一项既往EGFR-TKI治疗失败的EGFR突变局部晚期或转移性NSCLC，成为了首个国产冲击肺癌适应症三期注册临床的EGFR ADC。随着研究的深入，对于EGFR-TKI耐药难题，PROTAC或许也是一个有效的解决方案。PROTAC可以降解整个蛋白，而不仅仅是抑制酶活性，因此EGFR是一个理想的PROTAC靶标。目前海思科的EGFR PROTAC药物HSK40118和贝达药业/C4 Therapeutics的EGFR PROTAC药物CFT8919，分别已获批开展临床试验，用于治疗不可手术的、携带EGFR突变的晚期NSCLC患者。如今再提起EGFR，无论是数十条管线盘踞的三代、四代EGFR-TKI，抑或是PROTAC、ADC、双抗的前沿路径，所有竞逐者都在向同一个目标迈进——试图重构奥希替尼耐药后的EGFR治疗新秩序，并且打破研发追着耐药跑的被动“耐药-研发-再耐药”的循环。而由此带来的下一代EGFR下一代竞赛，或许是未来三到五年最值得关注的赛道。一审| 黄佳二审| 李芳晨三审| 李静芝精彩推荐大事件 | IPO | 融资&交易 | 财报季 | 新产品 | 研发日 | 里程碑 | 行业观察 | 政策解读 | 深度案例 | 大咖履新 | 集采&国谈 | 出海 | 高端访谈 | 技术&赛道 | E企谈 | 新药生命周期 | 市值 | 新药上市 | 商业价值 | 医疗器械 | IND | 周年庆大药企 | 竞争力20强 | 恒瑞 | 石药 | 中生制药 | 齐鲁 | 复星 | 科伦 | 翰森 | 华润 | 国药 | 云南白药 | 天士力 | 华东 | 上药创新药企 | 创新100强 | 百济 | 信达 | 君实 | 复宏汉霖 | 康方 | 和黄 | 荣昌 | 亚盛｜康宁杰瑞｜贝达｜微芯｜再鼎｜亚虹跨国药企｜ＭＮＣ卓越｜辉瑞｜AZ｜诺华｜罗氏｜BMS｜默克｜赛诺菲｜GSK｜武田｜礼来｜诺和诺德｜拜耳供应链｜赛默飞｜药明｜凯莱英｜泰格｜思拓凡｜康龙化成｜博腾｜晶泰｜龙沙｜三星启思会 | 声音·责任 | 创百汇 | E药经理人理事会 | 微解药直播 | 大国新药 | 营销硬观点 | 投资人去哪儿 | 分析师看赛道 | 药事每周谈 | 中国医药手册

抗体药物偶联物ASCO会议临床3期蛋白降解靶向嵌合体

100 项与 Silevertinib 相关的药物交易

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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
晚期鳞状非小细胞肺癌	临床2期	美国	Black Diamond Therapeutics, Inc.	2022-03-31
晚期鳞状非小细胞肺癌	临床2期	加拿大	Black Diamond Therapeutics, Inc.	2022-03-31
EGFR阳性非小细胞肺癌	临床2期	美国	Black Diamond Therapeutics, Inc.	2022-03-31
EGFR阳性非小细胞肺癌	临床2期	加拿大	Black Diamond Therapeutics, Inc.	2022-03-31
多形性胶质母细胞瘤	临床2期	美国	Black Diamond Therapeutics, Inc.	2022-03-31
多形性胶质母细胞瘤	临床2期	加拿大	Black Diamond Therapeutics, Inc.	2022-03-31
转移性非小细胞肺癌	临床2期	美国	Black Diamond Therapeutics, Inc.	2022-03-31
转移性非小细胞肺癌	临床2期	加拿大	Black Diamond Therapeutics, Inc.	2022-03-31
继发性肺恶性肿瘤	临床2期	美国	Black Diamond Therapeutics, Inc.	2022-03-31
继发性肺恶性肿瘤	临床2期	加拿大	Black Diamond Therapeutics, Inc.	2022-03-31

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临床结果

适应症

分期

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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


NCT05256290 (GlobeNewswire) 人工标引	临床2期	复发性非小细胞肺癌二线 EGFR C797S	27	BDTX-1535 200 mg	網獵選構選夢製糧夢窪(構製蓋鏇醖鏇獵膚鑰餘) = 夢簾糧膚淵蓋餘網簾顧簾憲襯願膚淵網餘鹽壓 (艱夢窪襯顧窪餘築願顧 ) 更多	积极	2024-09-23
NCT05256290 (GlobeNewswire) 人工标引	临床2期	复发性非小细胞肺癌二线 EGFR C797S	27	BDTX-1535 200 mg (either C797S or P-loop alpha-C helix compressing (PACC, a major subset of NCMs))	網獵選構選夢製糧夢窪(構製蓋鏇醖鏇獵膚鑰餘) = 鹽網構餘鬱襯鏇積蓋醖簾憲襯願膚淵網餘鹽壓 (艱夢窪襯顧窪餘築願顧 )	积极	2024-09-23
NCT05256290 (BDTX-1535-101, ASCO2024)	临床1期	复发性胶质母细胞瘤 EGFR alterations \| EGFRvIII \| missense mutations	54	BDTX-1535 15mg QD	膚簾選醖淵製齋觸鑰鹹(積鏇築築鏇獵糧範夢獵) = Gr 3 TRAEs ≥ 10% included rash (19%) reported at 300 or 400 mg QD doses 艱鏇製願觸壓壓範觸壓 (鑰蓋製願選願憲獵窪襯 ) 更多	积极	2024-05-24
NCT06072586 (Phase 0/1 trigger trial of BDTX-1535, ASCO2024)	早期临床1期	复发性恶性胶质瘤 EGFR alterations \| EGFR fusions	7	BDTX-1535 200 mg	鹽積築夢鏇蓋顧構壓鏇(窪鹹鏇鏇窪襯網築繭蓋) = No serious adverse events were observed among patients in the Phase 1 component of the study 淵膚壓願繭蓋築艱蓋願 (鹽艱衊壓鏇製遞網獵衊 )	积极	2024-05-24
NCT06072586 (GlobeNewswire) 人工标引	临床1期	复发性胶质母细胞瘤二线	22	BDTX-1535	壓窪壓艱觸鏇網網齋淵(積齋衊選繭艱鹹壓醖簾) = consistent with the EGFR tyrosine kinase inhibitor (TKIs) class of drugs, including primarily Grade 1 and 2 diarrhea and rash 憲願膚範鑰構鹽鑰蓋築 (淵顧糧糧鹹窪餘夢齋鬱 )	积极	2023-12-13
Corporate Publications 人工标引	临床1期	非小细胞肺癌	-	BDTX-1535	鏇鏇構觸繭鹹襯餘夢襯(鑰夢糧醖衊繭窪淵壓壓) = No patients experienced dose limiting toxicity at 15-200 mg QD doses. One of 15 patients treated at the 300 mg QD dose experienced dose limiting diarrhea and 5 of 12 patients at the 400 mg QD dose experienced dose limiting toxicity (diarrhea, 2 patients; rash, stomatitis, fatigue and decreased appetite, 1 patient each). 廠鬱夢鹹艱壓襯襯窪膚 (廠鏇觸顧餘鹽憲鹹顧願 ) 更多	积极	2023-06-27