This is a Phase 1/2, open-label first-in-human study of the safety, pharmacokinetics (PK), pharmacodynamics, and anti-tumor activity of BLU-451 monotherapy and BLU-451 in combination with platinum-based chemotherapy (carboplatin and pemetrexed). All participants will receive BLU-451 on a 21-day treatment cycle.

开始日期2022-03-04

申办/合作机构

Blueprint Medicines Corp.

100 项与 Pebezertinib 相关的临床结果

登录后查看更多信息

100 项与 Pebezertinib 相关的转化医学

登录后查看更多信息

100 项与 Pebezertinib 相关的专利（医药）

登录后查看更多信息

项与 Pebezertinib 相关的文献（医药）

MOLECULAR CANCER THERAPEUTICS

BLU-451, a CNS-Active, Potent, and Selective Small-Molecule Inhibitor against Uncommon EGFR Mutations

Article

作者: Murray, Brion W. ; Matsumoto, Shingo ; Keats, Jeffrey ; Baik, Christina S. ; Patel, Jyoti D. ; Le, Xiuning ; Yang, Tsung-Ying ; Millet, Yves A. ; Heymach, John V. ; Zalutskaya, Alena ; Nguyen, Danny ; Sun, Lova ; Shum, Elaine ; Leighl, Natasha B. ; Hong, Min Hee ; Hsieh, John ; Lee, Stephanie ; Spira, Alexander I. ; Nilsson, Monique B. ; Piotrowska, Zofia ; Jänne, Pasi A. ; Yoshida, Tatsuya

Abstract:

BLU-451 is a potent and selective tyrosine kinase inhibitor designed to target uncommon epidermal growth factor receptor (EGFR) mutations, spare wild-type (WT) EGFR, and be active in the central nervous system (CNS). In vitro EGFR enzyme assays and engineered cell line models revealed selectivity and antiproliferative potency of BLU-451 against a wide range of EGFR mutations in non–small cell lung cancer, including common mutations, atypical mutations, and exon 20 insertions. Particularly, BLU-451 demonstrated robust antitumor activity in EGFR exon 20 insertion cell-derived and patient-derived xenograft models and was well tolerated in animal studies. Pharmacokinetic and pharmacodynamic analyses showed that BLU-451 suppressed exon 20 insertion phosphorylated EGFR expression levels within tumor tissues but not in skin and intestinal tissues, potentially indicative of lower toxicity associated with WT EGFR. In intracranial tumor models with imaging-based analyses, BLU-451 showed CNS antitumor efficacy. Early clinical data from patients enrolled in the phase I portion of the phase I/II CONCERTO trial (NCT05241873) demonstrated the overall clinical potential of BLU-451, including its CNS antitumor activity in patients with EGFR exon 20 insertions and atypical mutations. Initial data suggest that BLU-451 is an active molecule. Further evaluation of the safety profile and pharmacokinetic properties of BLU-451 is needed.

项与 Pebezertinib 相关的新闻（医药）

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

2024-01-09

·FierceBiotech

JPM24, Day 2: GSK, Eli Lilly, Blueprint, SR One and more

Merger Monday lived up to its name, but Day 2 is also seeing deals at JPM 24. Welcome to Day 2 of the J.P. Morgan Healthcare Conference 2024 in San Francisco. Yesterday "Merger Monday" lived up to its name with deals for Novartis, J&J and Merck, and today, we’re also starting Tuesday with an early deal. Check out that deal and all the updates from JPM below. Want more? Fierce Biotech’s conference's kickoff Day 1 is available here, and Fierce Pharma’s can be found here. Tuesday 6:43 p.m. ET Jan. 9 Eli Lilly CEO David Ricks, speaking to the slow and steady progress that brought tirzepitide to the world, says the Indianapolis pharma is now ready to open up the chocolate factory. “I know a number of biotechs are in the room at this conference so it's worth mentioning: we're open for business on external innovation,” Ricks said at the J.P. Morgan Healthcare Conference Tuesday. Story Tuesday 6:10 p.m. ET Jan. 9 SR One CEO and managing partner Simeon George, M.D., said the firm was eyeing some investments in psychedelic-focused biotechs but is waiting on formally financing one to see how the space matures. He specifically pointed to the rollout of J&J's Spravato, an esketamine spray used to treat major depression. The treatment is currently one of J&J's fastest-growing products and is a pillar in the company's neuroscience portfolio. "We've been watching, obviously, how that has gone in terms of the launch and again, that product looks like it's starting to be on a nice ramp there," George said in an interview with Fierce Biotech on Tuesday. "My sense is there's going to be more than a couple of companies that will be interesting to look at from a fundraising perspective." George said there are probably "one or two" companies on the firm's shortlist, though he wouldn't specify which. Tuesday 3:45 p.m. ET Jan. 9 "We're seeing companies make investments in traditional pharma assets that are a little further along in the development pipeline," Sharon Flanagan, managing partner for global law firm Sidley's San Francisco office, told Fierce Biotech on the conference sidelines. "ADCs (antibody drug conjugates) are really interesting," she continued, citing Johnson & Johnson's $2 billion acquisition of ADC-focused Ambrx Biopharma. "So that's a way to do something that's still pharma, but with something novel and interesting, that has a spin to it. I do think in markets that are a little uncertain, sometimes the more truly novel types of products might get less interest." Tuesday 9:45 a.m. ET Jan. 9 Blueprint Medicines is pulling back from a core focus area, cutting two non-small lung cancer programs after getting a peak of early data. It was just a year ago that CEO Kate Haviland touted the EGFR tyrosine kinase inhibitors as the company's path to first-line treatment. The biotech says it will explore possible out-licensing deals to find a home for BLU-945 and BLU-451. Story Tuesday 3 a.m. ET Jan. 9 GSK is getting in on the M&A action as it snaps up respiratory biotech Aiolos Bio for $1 billion upfront and $400 million in biobucks. The deal sees GSK nab Aiolos’ leading asset AIO-001, a phase 2-ready mAb, with plans for the drug to also treat chronic rhinosinusitis with nasal polyps. Story.

2024-01-09

·FierceBiotech

Blueprint tears up plans, dropping 2 lung cancer programs after seeing early clinical data

Blueprint disclosed the news alongside an update on its plans for Gavreto. Blueprint Medicines is pulling back from one of its three areas of focus, dropping two non-small cell lung cancer (NSCLC) programs in response to early clinical data on the EGFR tyrosine kinase inhibitors. One year ago, Blueprint CEO Kate Haviland used a presentation at the J.P. Morgan Healthcare Conference to explain how the company designed a phase 1 EGFR-driven lung cancer study to give “the confidence that we can win in first line.” The decision to spend 2023 gathering data to inform a go/no-go decision reflected Haviland’s recognition that lung cancer was an ambitious and potentially “expensive endeavor.” Now, Blueprint has early evidence of whether its two drug candidates, BLU-945 and BLU-451, can deliver on its aim to develop best-in-class molecules capable of replacing the standard of care in frontline, EGFR lung cancer. Haviland pulled investment in the programs after getting a look at the data. “Combining this emerging data, from both the BLU-945 and the BLU-451 programs, with the evolving EGFR landscape, we have decided to deprioritize continued investment in EGFR-driven non-small cell lung cancer and to focus our R&D investments in the most compelling and highest value programs,” the CEO said at a JPM presentation this week. Blueprint’s interest in EGFR-driven lung cancer was built on evidence that the first three generations of TKIs had failed to address the need for a molecule that maintains activity against sensitizing mutations, notably L858R. The L858R mutation is associated with worse outcomes on the current standard of care. Blueprint believed a combination with AstraZeneca’s Tagrisso could provide more durable benefits. While the biotech has opted against spending its own cash to pursue that belief, it will “explore strategic options, including potential out-licensing” to support further development of BLU-945 and BLU-451. Blueprint disclosed the news alongside an update on its plans for Gavreto, the approved RET inhibitor that Roche decided to drop 11 months ago. Lacking global infrastructure in lung and thyroid cancer, the approved indications for Gavreto, Blueprint is stopping global development and marketing of the drug outside of the U.S. and China. CStone Pharmaceuticals owns the rights to Gavreto in China. In the U.S., Blueprint has found “a potential alternate partner” and “is continuing to work with the involved parties to define a scenario that enables continued availability of Gavreto.” Winding down work on Gavreto outside of those markets will reduce operating expenses without affecting the $175 million Blueprint received from Royalty Pharma in 2022.

临床1期引进/卖出上市批准

100 项与 Pebezertinib 相关的药物交易

登录后查看更多信息

外链

KEGG	Wiki	ATC	Drug Bank
D12859	-	-	-

研发状态

10 条进展最快的记录,

后查看更多信息

适应症	最高研发状态	国家/地区	公司	日期
腺癌	临床2期	韩国	Blueprint Medicines Corp.	2022-03-04
支气管癌	临床2期	韩国	Blueprint Medicines Corp.	2022-03-04
EGFR 20号外显子插入突变非小细胞肺癌	临床2期	韩国	Blueprint Medicines Corp.	2022-03-04
EGFR阳性肿瘤	临床2期	韩国	Blueprint Medicines Corp.	2022-03-04
转移性非小细胞肺癌	临床2期	美国	Blueprint Medicines Corp.	2022-03-04
神经组织肿瘤	临床2期	美国	Blueprint Medicines Corp.	2022-03-04
晚期癌症	临床1期	美国	Blueprint Medicines Corp.	2022-03-04
晚期癌症	临床1期	日本	Blueprint Medicines Corp.	2022-03-04
晚期癌症	临床1期	加拿大	Blueprint Medicines Corp.	2022-03-04
晚期癌症	临床1期	韩国	Blueprint Medicines Corp.	2022-03-04

登录后查看更多信息

临床结果

适应症

分期

评价

查看全部结果

研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT05241873 (CONCERTO, ASCO 12023 \| ASCO 22023) 人工标引	临床1/2期	EGFR 20号外显子插入突变非小细胞肺癌二线 EGFR Exon 20 Insertion	28	BLU-451	鬱糧網膚製壓淵糧構選(簾蓋簾糧範憲繭淵齋鏇) = The most common AEs were diarrhea (21%), cough (18%), fatigue (14%), pruritis (14%) and rash (14%); all were Grade 1 or 2. 糧繭齋鹽憲鏇觸製餘鹽 (衊糧積壓膚顧醖製夢願 )	积极	2023-05-31