Naquotinib(Naquotinib) - 药物靶点：EGFR T790M_专利_临床

概要

基本信息

药物类型

小分子化药

别名

Naquotinib (USAN/INN)、Naquotinib Mesylate、ASP-8273

+ [1]

靶点

EGFR T790M

作用方式

抑制剂

作用机制

EGFR T790M抑制剂(表皮生长因子受体T790M抑制剂)

治疗领域

肿瘤呼吸系统疾病消化系统疾病

在研适应症-

非在研适应症

转移性非小细胞肺癌非小细胞肺癌非小细胞肺癌IIIB期+ [1]

原研机构

Astellas Pharma, Inc.

在研机构-

非在研机构

Astellas Pharma Global Development, Inc.

Astellas Pharma, Inc.

安斯泰来制药（中国）有限公司

权益机构-

最高研发阶段终止临床3期

首次获批日期-

最高研发阶段(中国)终止

特殊审评-

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结构/序列

分子式C31H46N8O6S

InChIKeyALDUQYYVQWGTMR-GJFSDDNBSA-N

CAS号1448237-05-5

关联

8

项与 Naquotinib 相关的临床试验

NCT03082300

/ Terminated临床1期

A Phase 1, Randomized, 2-period Crossover Study to Assess Bioequivalence of a Tablet Formulation Versus a Capsule Formulation of ASP8273 in Subjects With Non-small Cell Lung Cancer Harboring Epidermal Growth Factor Receptor Mutations

The objective of this study is to evaluate the bioequivalence of a tablet formulation versus a capsule formulation of ASP8273 following a single dose under fasted condition in subjects with non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations. The study will also evaluate the safety and tolerability of a tablet formulation as a single dose and a capsule formulation as a single and multiple dose of ASP8273 in subjects with NSCLC harboring EGFR mutations.

开始日期2017-03-24

申办/合作机构

Astellas Pharma Global Development, Inc.

NCT03042013

/ Withdrawn临床2期

An Open-label, Multicenter, Rollover Study for Subjects Who Are Participating in an Astellas-sponsored ASP8273 Study

The purpose of the study is to evaluate long-term safety and tolerability of continuous treatment with ASP8273 in subjects who are participating in an Astellas-sponsored ASP8273 study which has completed, at a minimum, the primary analysis or have completed the individual study evaluation period and for whom the investigator feels the subject may have potential to continue to derive clinical benefit from treatment with ASP8273.

开始日期2017-02-28

申办/合作机构

Astellas Pharma Global Development, Inc.

NCT02674555

/ Withdrawn临床1期

A Phase 1 Study to Investigate the Absorption, Metabolism and Excretion of [14C]ASP8273 in Subjects With Solid Tumors Harboring Epidermal Growth Factor Receptor (EGFR) Mutations

This is a study to investigate the absorption, metabolism and excretion of [14C] labeled ASP8273 in subjects with solid tumors harboring EGFR mutations (per local testing). This study consists of two parts (A and B).

开始日期2016-11-15

申办/合作机构

Astellas Pharma Global Development, Inc.

100 项与 Naquotinib 相关的临床结果

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100 项与 Naquotinib 相关的转化医学

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100 项与 Naquotinib 相关的专利（医药）

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43

项与 Naquotinib 相关的文献（医药）

2025-01-01·Journal of Cancer

Third generation vs first generation EGFR-TKIs in the first line treatment for EGFR-mutated locally advanced or metastatic non-small cell lung cancer: a meta-analysis based on randomized controlled trials

Article

作者: Zhang, Wenxiong ; Lin, Xueying ; Chen, Yuan ; Feng, Tanggui ; Qin, Yi ; Hu, Wenjie ; Dong, Taoming

Background: The prevailing belief is that third-generation tyrosine kinase inhibitors (TKIs) targeting the epidermal growth factor receptor (EGFR) (TGET) outperform first-generation EGFR-TKIs (FGET) in managing advanced-stage EGFR-mutated non-small cell lung cancer (NSCLC). However, this standpoint lacks substantiation in evidence-based medicine. Therefore, this meta-analysis was conducted to compare the efficacy and adverse effects (AEs) of these two categories. Methods: We searched seven databases for relevant randomized controlled trials (RCTs), focusing on primary endpoints such as progression-free survival (PFS), overall survival (OS), and central nervous system PFS (CNS-PFS). Additional factors considered included treatment responses and AEs. Results: We analyzed 15 studies from 6 RCTs on six third-generation TKIs: Osimertinib, Lazertinib, Furmonertinib, Aumolertinib, Naquotinib, and Befotertinib. TGET showed better efficacy in PFS (hazard ratio [HR]: 0.55 [0.41, 0.75]), CNS-PFS (HR: 0.48 [0.35, 0.66]), CNS-objective response rate (CNS-ORR, risk ratio [RR]: 1.40 [1.19, 1.65]), and duration of response (DOR, HR: 0.52 [0.38, 0.72]). Most subgroups confirmed the PFS advantage. With longer survival time, the superiority in PFS, OS, and CNS-PFS of TGETs became more evident. Both groups had similar OS (HR: 0.86), ORR, CNS-DOR, total AEs, and grade 3-5 AEs. However, TGETs had more severe AEs (RR: 1.17 [1.02, 1.35]). Additionally, there were more grade 3-4 cases of diarrhea, decreased platelet count, pulmonary embolism, fatigue, decreased neutrophil count, and rash, and fewer grade 3-4 increases in alanine transaminase (ALT) and aspartate transaminase (AST) in the TGET group. The top 5 AEs in the TGET group were diarrhea (36.32%), rash (30.24%), decreased platelet count (29.15%), elevated serum creatinine (23.63%), and decreased white blood cell count (22.02%). Conclusions: Except for Naquotinib, TGETs demonstrate superiority over FGETs in treating EGFR-mutated locally advanced or metastatic NSCLC, showing improved survival and responses. However, the increased incidence of AEs necessitates careful consideration.

2024-11-05·PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

Biochemical analysis of EGFR exon20 insertion variants insASV and insSVD and their inhibitor sensitivity

Article

作者: Eck, Michael J. ; Beyett, Tyler S. ; Rana, Jaimin K. ; Schaeffner, Ilse K. ; Zhao, Hanchen ; Jiang, Jie ; Santana, Jhasmer ; Jänne, Pasi A.

Somatic mutations in the epidermal growth factor receptor (EGFR) are a major cause of non–small cell lung cancer. Among these structurally diverse alterations, exon 20 insertions represent a unique subset that rarely respond to EGFR tyrosine kinase inhibitors (TKIs). Therefore, there is a significant need to develop inhibitors that are active against this class of activating mutations. Here, we conducted biochemical analysis of the two most frequent exon 20 insertion variants, V769_D770insASV (insASV) and D770_N771insSVD (insSVD) to better understand their drug sensitivity and resistance. From kinetic studies, we found that EGFR insASV and insSVD are similarly active, but have lower K m, ATP values compared to the L858R variant, which contributes to their lack of sensitivity to 1st-3rd generation EGFR TKIs. Biochemical, structural, and cellular studies of a diverse panel of EGFR inhibitors revealed that the more recently developed compounds BAY-568, TAS6417, and TAK-788 inhibit EGFR insASV and insSVD in a mutant-selective manner, with BAY-568 being the most potent and selective versus wild-type (WT) EGFR. Cocrystal structures with WT EGFR reveal the binding modes of each of these inhibitors and of poziotinib, a potent but not mutantselective inhibitor, and together they define interactions shared by the mutant-selective agents. Collectively, our results show that these exon20 insertion variants are not inherently inhibitor resistant, rather they differ in their drug sensitivity from WT EGFR. However, they are similar to each other, indicating that a single inhibitor should be effective for several of the diverse exon 20 insertion variants.

2024-02-01·Molecular pharmacology

A Constitutive EGFR Kinase Dimer to Study Inhibitor Pharmacology

Article

作者: Eck, Michael J ; Beyett, Tyler S ; Kim, Justin J ; Heppner, David E ; Jänne, Pasi A ; Schaeffner, Ilse K ; To, Ciric

Lung cancer is commonly caused by activating mutations in the epidermal growth factor receptor (EGFR). Allosteric kinase inhibitors are unaffected by common ATP-site resistance mutations and represent a promising therapeutic strategy for targeting drug-resistant EGFR variants. However, allosteric inhibitors are antagonized by kinase dimerization, and understanding this phenomenon has been limited to cellular experiments. To facilitate the study of allosteric inhibitor pharmacology, we designed and purified a constitutive EGFR kinase dimer harboring the clinically relevant L858R/T790M mutations. Kinetic characterization revealed that the EGFR kinase dimer is more active than monomeric EGFR(L858R/T790M) kinase and has the same K_m,ATP Biochemical profiling of a large panel of ATP-competitive and allosteric EGFR inhibitors showed that allosteric inhibitor potency decreased by >500-fold in the kinase dimer compared with monomer, yielding IC₅₀ values that correlate well with Ba/F3 cellular potencies. Thus, this readily purifiable constitutive asymmetric EGFR kinase dimer represents an attractive tool for biochemical evaluation of EGFR inhibitor pharmacology, in particular for allosteric inhibitors. SIGNIFICANCE STATEMENT: Drugs targeting epidermal growth factor receptor (EGFR) kinase are commonly used to treat lung cancers but are affected by receptor dimerization. Here, we describe a locked kinase dimer that can be used to study EGFR inhibitor pharmacology.

100 项与 Naquotinib 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D10958	-	-	DB12036

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
非小细胞肺癌IIIB期	临床3期	美国	Astellas Pharma Global Development, Inc.	2016-02-11
非小细胞肺癌IIIB期	临床3期	日本	Astellas Pharma Global Development, Inc.	2016-02-11
非小细胞肺癌IIIB期	临床3期	澳大利亚	Astellas Pharma Global Development, Inc.	2016-02-11
非小细胞肺癌IIIB期	临床3期	比利时	Astellas Pharma Global Development, Inc.	2016-02-11
非小细胞肺癌IIIB期	临床3期	加拿大	Astellas Pharma Global Development, Inc.	2016-02-11
非小细胞肺癌IIIB期	临床3期	智利	Astellas Pharma Global Development, Inc.	2016-02-11
非小细胞肺癌IIIB期	临床3期	法国	Astellas Pharma Global Development, Inc.	2016-02-11
非小细胞肺癌IIIB期	临床3期	德国	Astellas Pharma Global Development, Inc.	2016-02-11
非小细胞肺癌IIIB期	临床3期	匈牙利	Astellas Pharma Global Development, Inc.	2016-02-11
非小细胞肺癌IIIB期	临床3期	意大利	Astellas Pharma Global Development, Inc.	2016-02-11

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临床结果

适应症

分期

评价

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT02588261 (Pubmed) 人工标引	临床3期	EGFR突变的非小细胞肺癌一线 EGFR Mutation	530	ASP8273	網遞鹹鑰艱蓋淵憲糧夢(夢獵廠衊淵積醖鬱憲餘) = 鑰餘壓製遞壓鹹願網鬱淵鏇醖壓選鑰觸製網構 (鹽壓顧鏇構製選糧願積, 5.6 ~ 11.1) 更多	不佳	2019-07-01
NCT02588261 (Pubmed) 人工标引	临床3期	EGFR突变的非小细胞肺癌一线 EGFR Mutation	530	gefitinib+erlotinib	網遞鹹鑰艱蓋淵憲糧夢(夢獵廠衊淵積醖鬱憲餘) = 範廠繭構憲構願壓膚積淵鏇醖壓選鑰觸製網構 (鹽壓顧鏇構製選糧願積, 8.8 ~ NE) 更多	不佳	2019-07-01
NCT02588261 (SOLAR, CTgov)	临床3期	非小细胞肺癌IIIB期	530	naquotinib mesilate (ASP8273)	範獵壓願齋齋製艱繭鏇(餘廠膚淵糧顧淵鏇鹽廠) = 襯鏇窪餘觸鏇願願積範製鹹遞顧膚選膚壓願遞 (製廠廠構齋壓淵壓網簾, 鏇觸膚醖顧衊糧築淵願 ~ 顧鏇範積窪憲鏇窪觸鹽) 更多	-	2019-02-12
NCT02588261 (SOLAR, CTgov)	临床3期	非小细胞肺癌IIIB期	530	Erlotinib+Gefitinib (Erlotinib or Gefitinib)	範獵壓願齋齋製艱繭鏇(餘廠膚淵糧顧淵鏇鹽廠) = 網餘構範構夢窪鏇鹽積製鹹遞顧膚選膚壓願遞 (製廠廠構齋壓淵壓網簾, 鹽淵窪齋製鹽艱範齋鬱 ~ 遞構憲艱壓壓憲獵醖蓋) 更多	-	2019-02-12
NCT02192697 (Pubmed \| Cancer Sci) 人工标引	临床1/2期	EGFR-T790M 突变非小细胞肺癌 EGFR Activation \| EGFR T790M Mutation	121	ASP8273	壓壓簾鹹鬱艱憲獵艱鬱(鬱願網獵衊網膚鬱網獵) = 鏇願窪廠淵膚繭衊鑰鬱願鑰膚壓獵鑰獵鹽願範 (壓鏇鬱窪壓壓衊鑰觸襯, 30.9 ~ 54.0) 更多	积极	2018-09-01
NCT02500927 (Pubmed \| Cancer Sci) 人工标引	临床2期	EGFR阳性非小细胞肺癌 EGFR Mutation	31	ASP8273	窪艱膚鑰獵鏇壓衊齋襯(糧構鏇範積觸顧餘廠構) = diarrhea 77% 艱淵鑰夢築膚鬱鑰網觸 (觸鏇壓網夢鹽窪獵築築 )	积极	2018-08-01
NCT02113813 (Pubmed) 人工标引	临床1期	EGFR突变的非小细胞肺癌 EGFR Mutation	110	ASP8273	網願夢選鹽觸壓餘壓衊(製網鏇廠網夢鹽鹹鏇醖) = diarrhea, nausea, fatigue, constipation, vomiting, and hyponatremia 醖醖衊獵繭壓遞糧鹹淵 (範衊膚獵積鹽願鑰窪遞 )	积极	2017-12-15
NCT02192697 (WCLC2017)	临床1/2期	EGFR-T790M 突变非小细胞肺癌	123	ASP8273	願艱簾鹹觸積願繭網鹹(觸夢築蓋廠積艱繭積遞) = decreased appetite (n=26/76) 鏇憲艱齋構鑰餘範選壓 (範網願壓鏇淵觸鹹齋簾 ) 更多	-	2017-10-16
NCT02500927 (ASCO2017)	临床2期	非小细胞肺癌	31	ASP8273 300 mg	鑰選壓願選簾構齋範夢(廠遞積糧鬱繭製衊構憲) = 蓋夢遞鬱顧餘網範窪遞築積築構鹹廠構製窪鹹 (選範膚鹽鬱襯製醖選構 ) 更多	-	2017-05-30
NCT02113813 (ASCO2016)	临床1期	EGFR阳性非小细胞肺癌	60	ASP8273 300 mg	簾繭淵簾網構糧簾範觸(餘鏇窪築餘壓艱願鹹窪) = 廠顧鬱夢窪餘鑰鬱築衊膚壓鬱鹽餘積選築願選 (鏇壓選鏇鑰構膚襯餘艱 ) 更多	积极	2016-05-20
NCT02192697 \| NCT02113813 (AACR2015)	临床1/2期	EGFR突变胶质母细胞瘤	-	ASP8273	鏇獵膚遞鬱膚鹹鹹襯襯(鑰積憲構繭製鬱衊範築) = 範觸膚築窪夢積範窪憲遞淵鬱憲窪顧鏇遞鹽構 (糧壓製襯蓋壓築遞蓋壓 )	-	2015-08-01