Osimertinib as first-line treatment of EGFR mutant advanced non-small-cell lung cancer

Liam, Chong Kin

doi:10.21037/tlcr.2017.10.10

Cited by 10 publications

(4 citation statements)

References 16 publications

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“…Osimertinib crosses the blood-brain barrier and inhibits the growth of CNS metastases in animal models [ 4 ]. Osimertinib may potentially delay the emergence of resistance, as observed in an in vitro study in which the emergence of resistance in PC9 cells with the EGFR ex19del mutation was delayed with osimertinib compared with other EGFR TKIs [ 7 , 8 ].…”

Section: How Does Osimertinib Work?mentioning

confidence: 99%

Osimertinib as first-line therapy in advanced NSCLC: a profile of its use

Scott

2018

Drugs Ther Perspect

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Osimertinib (Tagrisso®) is an oral, CNS-active, third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that selectively inhibits EGFR TKI-activating mutations over wild-type EGFR in patients with advanced non-small cell lung cancer (NSCLC), including the T790M mutation that often underlies acquired resistance to earlier generation EGFR TKIs. Relative to standard of care first-generation EGFR TKIs (erlotinib or gefitinib) as first-line treatment of EGFR activating mutation-positive advanced NSCLC, osimertinib significantly prolongs median progression-free survival (PFS), with separation of the Kaplan-Meier PFS survival curves evident by the first assessment timepoint of 6 weeks. Osimertinib prolongs PFS relative to standard EGFR TKI therapy in all prespecified groups, irrespective of the EGFR mutation present at study entry and presence of CNS metastases at study entry. Overall survival data are not yet mature. Osimertinib has a generally manageable tolerability profile.

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Section: How Does Osimertinib Work?mentioning

confidence: 99%

Osimertinib as first-line therapy in advanced NSCLC: a profile of its use

Scott

2018

Drugs Ther Perspect

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“…Additionally, the toxicological predictions have established in the case of the T790M/L858R mutation, that DB03878 would be a promising compound for pharmacological therapy since of the analysed analogues, it presented a class 4 toxicity with a value of LD50 of 1206 mg/Kg orally, a value that is well above that obtained with the reference drug which was 368,2 mg/Kg orally. dose-related toxicities up to 240 mg daily have been detected in clinical trials with osimertinib and there is little experience regarding accidental overdoses (25). Finally, dacomitinib has an asymptomatic maximum dose in rats of 50 mg/Kg has been established; Doselimiting and overdose toxicities include stomatitis, rash, palmar-plantar erythrodystesia syndrome, dehydration, paronychia, and diarrhea.…”

Section: Discussionmentioning

confidence: 99%

Virtual screening of Osimertinib and Dacomitinib Analogues with potential activity on EGFR (T790M and l858R Mutations) for non-small cell lung cancer treatment

2021

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Introduction: Tyrosine kinase inhibitors (TKIs) drugs act on epidermal growth factor (EGFR) receptors to treat Non-small cell lung cancer (NSCLC). However, mutations on EGFR receptors T790M and L858R allow just a global response rate (GRR) of 80% with Osimertinib, while Erlotinib and Gefitinib only 10%. Objective: To identify promising molecules analogues to tyrosine kinase inhibitor (TKIs) drugs with the potential capacity to bind the native and mutated EGFR receptor (T790M and L858R) to avoid mutational resistance in NSCLC. Methods: Virtual screening by molecular docking between analogues of Osimertinib (DB09330) and Dacomitinib (DB11963) drugs retrieved of DRUGBANK database and receptors of native EGFR and mutated on L585R and T790M obtained of Protein Data Bank was performed, using PyRx software. Finally, toxicological prediction was made using GUSAR. Results: Analogues studied, DB03878, DB04739, DB07280 and DB06876 achieved significant affinity (-9,1 y -8,3 Kcal/mol) on mutated T790M EGFR compared with osimertinib (-7,6 Kcal/mol). Similarly, DB08091, DB08730, DB07220 and DB06920 achieved significant affinity (between 9.4 and -8.9 Kcal/mol) on L858R EGFR mutated compared with dacomitinib (-7.0 Kcal/mol). Overall, there were predominance of Van der Waals forces and links π-alkyl. Also, two analogues were safe with category IV according to predictions, DB08730 and DB03878. Conclusions: Eight TKI analogues showed superior binding energy over EGFR compared to reference drugs. According to toxicological predictions only 2 analogues were selected as promising TKI-type safe candidates for the treatment of resistant NSCLC.

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“…Overexpression of the epidermal growth factor receptor (EGFR) and its family members has been found to be an increasingly common trait in patients with advanced non-small cell lung cancer (NSCLC), which makes EGFR become an attractive target for research into the treatment of advanced NSCLC. [1,2] Representative EGFR-targeting small molecule inhibitors, such as Gefitinib, [3] Erlotinib, [4] Afatinib [5] and Osimertinib, [6] are now widely used in clinical treatment, and these agents have also been shown to be effective in relieving symptoms of patients with NSCLC, with significant benefits in terms of disease stability and quality of life. Nonetheless, a substantial proportion of patients invariably develop acquired resistance within the temporal window of 6 to 12 months subsequent to the initiation of therapeutic intervention.…”

Section: Introductionmentioning

confidence: 99%

Insights into the Overcoming EGFR^{Del19/T790M/C797S} Mutation: A Perspective on the 2‐Aryl‐4‐aminothienopyrimidine Backbone

Zhang,

He,

et al. 2024

ChemMedChem

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The epithelial growth factor receptor signaling pathway has been proposed to benefit non‐small cell lung cancer treatment. In this manuscript, we investigated the modification of 2‐aryl‐4‐aminoquinazoline, the classical backbone of the fourth‐generation EGFR inhibitors, in addition to obtaining a series of novel 2‐aryl‐4‐aminothienopyrimidine derivatives (A1~A45), we also gained further understanding of the modification of this framework. The bioactivity of these compounds was evaluated and it’s suggested that compound A9 could effectively inhibit the proliferation of A549 and H1975 cells, with an IC50 of 0.77 ± 0.08 and 6.90 ± 0.83 μM, respectively. At concentration of 10 μM, A9 can be employed as the fourth‐generation of EGFR inhibitors with the ability to overcome the C797S drug resistance since it can suppress EGFRDel19/T790M/C797S cells and kinase by 98.90% and 85.88%, respectively. Moreover, the tumor‐bearing nude mice experiment further shows that A9 can significantly inhibit the growth of tumor in vivo, with the tumor inhibition rate (TIR) of 55.92%, which was equivalent to the positive group. After that, from the result of HE staining experiment and blood biochemical analysis experiment, A9 show low toxicity and good safety, which is worthy of further research and development.

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Osimertinib as first-line treatment of EGFR mutant advanced non-small-cell lung cancer

Cited by 10 publications

References 16 publications

Osimertinib as first-line therapy in advanced NSCLC: a profile of its use

Osimertinib as first-line therapy in advanced NSCLC: a profile of its use

Virtual screening of Osimertinib and Dacomitinib Analogues with potential activity on EGFR (T790M and l858R Mutations) for non-small cell lung cancer treatment

Insights into the Overcoming EGFR^{Del19/T790M/C797S} Mutation: A Perspective on the 2‐Aryl‐4‐aminothienopyrimidine Backbone

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Osimertinib as first-line treatment of EGFR mutant advanced non-small-cell lung cancer

Cited by 10 publications

References 16 publications

Osimertinib as first-line therapy in advanced NSCLC: a profile of its use

Osimertinib as first-line therapy in advanced NSCLC: a profile of its use

Virtual screening of Osimertinib and Dacomitinib Analogues with potential activity on EGFR (T790M and l858R Mutations) for non-small cell lung cancer treatment

Insights into the Overcoming EGFRDel19/T790M/C797S Mutation: A Perspective on the 2‐Aryl‐4‐aminothienopyrimidine Backbone

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Insights into the Overcoming EGFR^{Del19/T790M/C797S} Mutation: A Perspective on the 2‐Aryl‐4‐aminothienopyrimidine Backbone