Delving into the Latest Updates on Naquotinib with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

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

+ [1]

Target

EGFR T790M

Action

inhibitors

Mechanism

EGFR T790M inhibitors(EGFR T790M inhibitors)

Therapeutic Areas

NeoplasmsRespiratory DiseasesDigestive System Disorders

Active Indication-

Inactive Indication

Non-Small Cell Lung CancerNon-small cell lung cancer stage IIIBStomach Cancer

Originator Organization

Astellas Pharma, Inc.

Active Organization-

Inactive Organization

Astellas Pharma Global Development, Inc.

Astellas Pharma, Inc.

Astellas Pharma China, Inc.

Drug Highest PhaseDiscontinuedPhase 3

First Approval Date-

Regulation-

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Structure/Sequence

Molecular FormulaC31H46N8O6S

InChIKeyALDUQYYVQWGTMR-GJFSDDNBSA-N

CAS Registry1448237-05-5

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.

Start Date24 Mar 2017

Sponsor / Collaborator

Astellas Pharma Global Development, Inc.

NCT03042013

/ WithdrawnPhase 2

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.

Start Date28 Feb 2017

Sponsor / Collaborator

Astellas Pharma Global Development, Inc.

NCT02674555

/ WithdrawnPhase 1

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).

Start Date15 Nov 2016

Sponsor / Collaborator

Astellas Pharma Global Development, Inc.

100 Clinical Results associated with Naquotinib

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100 Translational Medicine associated with Naquotinib

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100 Patents (Medical) associated with Naquotinib

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42

Literatures (Medical) associated with Naquotinib

01 Jan 2025·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

Author: Zhang, Wenxiong ; Chen, Yuan ; Lin, Xueying ; 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.

05 Nov 2024·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

Author: 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.

01 Feb 2024·Molecular pharmacology

A Constitutive EGFR Kinase Dimer to Study Inhibitor Pharmacology

Article

Author: 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 Deals associated with Naquotinib

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External Link

KEGG	Wiki	ATC	Drug Bank
D10958	-	-	DB12036

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Non-small cell lung cancer stage IIIB	Phase 3	United States	Astellas Pharma Global Development, Inc.	11 Feb 2016
Non-small cell lung cancer stage IIIB	Phase 3	Japan	Astellas Pharma Global Development, Inc.	11 Feb 2016
Non-small cell lung cancer stage IIIB	Phase 3	Australia	Astellas Pharma Global Development, Inc.	11 Feb 2016
Non-small cell lung cancer stage IIIB	Phase 3	Belgium	Astellas Pharma Global Development, Inc.	11 Feb 2016
Non-small cell lung cancer stage IIIB	Phase 3	Canada	Astellas Pharma Global Development, Inc.	11 Feb 2016
Non-small cell lung cancer stage IIIB	Phase 3	Chile	Astellas Pharma Global Development, Inc.	11 Feb 2016
Non-small cell lung cancer stage IIIB	Phase 3	France	Astellas Pharma Global Development, Inc.	11 Feb 2016
Non-small cell lung cancer stage IIIB	Phase 3	Germany	Astellas Pharma Global Development, Inc.	11 Feb 2016
Non-small cell lung cancer stage IIIB	Phase 3	Hungary	Astellas Pharma Global Development, Inc.	11 Feb 2016
Non-small cell lung cancer stage IIIB	Phase 3	Italy	Astellas Pharma Global Development, Inc.	11 Feb 2016

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT02588261 (Pubmed) Manual	Phase 3	EGFR-mutated non-small Cell Lung Cancer First line EGFR Mutation	530	ASP8273	xijvemlrnu(hsqfhplngm) = mmlweviwur lulgtdrxwf (xtaunbkosb, 5.6 - 11.1) View more	Negative	01 Jul 2019
NCT02588261 (Pubmed) Manual	Phase 3		530	gefitinib+erlotinib	xijvemlrnu(hsqfhplngm) = jhmiqezzyl lulgtdrxwf (xtaunbkosb, 8.8 - NE) View more	Negative	01 Jul 2019
NCT02588261 (SOLAR, CTgov)	Phase 3	Non-small cell lung cancer stage IIIB	530	naquotinib mesilate (ASP8273)	rbyvujvfxe(atqfskxjfl) = semtbspudk obnkqgayjo (knrytxnafe, uwulzxgvav - qrwtjaimmn) View more	-	12 Feb 2019
NCT02588261 (SOLAR, CTgov)	Phase 3	Non-small cell lung cancer stage IIIB	530	Erlotinib+Gefitinib (Erlotinib or Gefitinib)	rbyvujvfxe(atqfskxjfl) = juvhzpnheh obnkqgayjo (knrytxnafe, roxyjplpfn - kqvpujskfd) View more	-	12 Feb 2019
NCT02192697 (Pubmed \| Cancer Sci) Manual	Phase 1/2	EGFR T790M Mutation Positive Non-Small Cell Lung Carcinoma EGFR Activation \| EGFR T790M Mutation	121	ASP8273	extjcyllru(pytdbwkoik) = ijhlglgvyd hucvfdiawo (bwybaneoxu, 30.9 - 54.0) View more	Positive	01 Sep 2018
NCT02500927 (Pubmed \| Cancer Sci) Manual	Phase 2	EGFR positive non-small cell lung cancer EGFR Mutation	31	ASP8273	wvahuelnbw(fvdinsrkkn) = diarrhea 77% ajmpvmqdbh (tirrasmsar )	Positive	01 Aug 2018
NCT02113813 (Pubmed) Manual	Phase 1	EGFR-mutated non-small Cell Lung Cancer EGFR Mutation	110	ASP8273	tchoqydpxn(usppxmcasq) = diarrhea, nausea, fatigue, constipation, vomiting, and hyponatremia cuerlzeonk (psbhfoylam )	Positive	15 Dec 2017
NCT02192697 (WCLC2017)	Phase 1/2	EGFR T790M Mutation Positive Non-Small Cell Lung Carcinoma	123	ASP8273	lcnzzcsonh(tdsolipjct) = decreased appetite (n=26/76) dulujasput (bnqgdewour ) View more	-	16 Oct 2017
NCT02500927 (ASCO2017)	Phase 2	Non-Small Cell Lung Cancer	31	ASP8273 300 mg	ybafnflzul(zgpdxrvzta) = cniggdfsbe xblbfjmgzq (lwezclbzim ) View more	-	30 May 2017
NCT02113813 (ASCO2016)	Phase 1	EGFR positive non-small cell lung cancer	60	ASP8273 300 mg	ldcsseambs(ypfsixkmgo) = eqnjgiffge sdxbaggflj (qlzjomffgy ) View more	Positive	20 May 2016
NCT02192697 \| NCT02113813 (AACR2015)	Phase 1/2	EGFR mutation Glioblastoma	-	ASP8273	gfrlbebqpm(mbyprpumea) = mkodnorahq grcwmfguud (fyeohretuj )	-	01 Aug 2015