Abstract
The third-generation tyrosine kinase inhibitor (TKI), osimertinib, has revolutionized the treatment of patients with non-small cell lung carcinoma with epidermal growth factor receptor (EGFR)-activating mutation, and resistant to first- and second-generation TKIs. Osimertinib is now also proposed as a first-line therapy, thus extending the scope of applications in lung oncology. Personalized medicine approaches are still necessary to monitor if patients are exposed to adequate concentrations of osimertinib during their treatment. It would also help to understand the appearance of new resistances in patients after several months of dosing with osimertinib. Liquid chromatography–tandem mass spectrometry (LC–MS/MS) is currently the gold standard for the quantification of drugs in plasma enabling pharmacokinetic analyses and patient monitoring. In the present study, we propose an alternative to LC–MS/MS methods for the rapid and sensitive quantification of osimertinib in plasma using matrix-assisted laser desorption/ionization (MALDI) –MS. The presented assay requires only 3 min per sample for their preparation, analysis, and data extraction, and less than 3 h for quantification. A lower limit of quantification (LLOQ) of 5 ng/mL in plasma was retrieved. The method was fully validated, following the guidelines of the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for bioanalytical method validation. The present developments prove the importance to consider alternative MS assays for time-efficient quantification of small molecule inhibitors in plasma in the context of personalized medicine for targeted therapies.
Highlights
Small molecular inhibitors and, in particular tyrosine kinase inhibitors (TKIs), are gaining increasing importance among oncological therapies
The goal of the study was to establish a rapid method for the quantification of osimertinib in plasma from patients treated for non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutation using matrix-assisted laser desorption/ionization (MALDI)–ion mobility (IM)–Mass spectrometry (MS)/MS and to validate it according to the guidelines of the Food and Drug Administration (FDA) and European Medicines Agency (EMA) for bioanalytical method validation
We aimed to provide an alternative to liquid chromatography (LC)–MS/MS for faster sample preparation and analysis turnaround that is sensitive enough to measure therapeutic concentrations in plasma
Summary
In particular tyrosine kinase inhibitors (TKIs), are gaining increasing importance among oncological therapies. In non-small cell lung cancer (NSCLC), progresses are being made to circumvent the mechanism of resistance to other TKIs such as gefitinib, erlotinib, afatinib, Cancers 2020, 12, 1897; doi:10.3390/cancers12071897 www.mdpi.com/journal/cancers. In 2017, the third-generation TKI, osimertinib, was approved by the US Food and Drug Administration (FDA) for the treatment of NSCLC patients with the EGFR-activating mutation T790M. Improved median progression-free survival, median duration of response, and survival rates at 18 months of osimertinib over standard EGFR-TKIs for EGFR mutation-positive advanced NSCLC were recently reported in the FLAURA study [1]. Osimertinib is currently recommended as first-line therapy for metastatic NSCLC with EGFR mutation [2]. Despite the great performance of osimertinib, lower efficacy is observed with patients with poor Eastern Cooperative Oncology Group performance status [3]
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