FDA- and EMA-Approved Tyrosine Kinase Inhibitors in Advanced EGFR-Mutated Non-Small Cell Lung Cancer: Safety, Tolerability, Plasma Concentration Monitoring, and Management

Abstract

Non-small-cell lung cancer (NSCLC) is the most common form of primary lung cancer. The discovery of several oncogenic driver mutations in patients with NSCLC has allowed the development of personalized treatments based on these specific molecular alterations, in particular in the tyrosine kinase (TK) domain of the epidermal growth factor receptor (EGFR) gene. Gefitinib, erlotinib, afatinib, and osimertinib are TK inhibitors (TKIs) that specifically target EGFR and are currently approved by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) as first line treatment for sensitive EGFR-mutant patients. However, these four drugs are associated with severe adverse events (AEs) that can significantly impact patient health-related quality of life and patient monitoring. EGFR-TKIs are commonly used together with other types of medication that can substantially interact. Here, we review approaches used for the management of TKI-AEs in patients with advanced NSCLC to promote the benefits of treatments and minimize the risk of TKI treatment discontinuation. We also consider potential TKI–drug interactions and discuss the usefulness of plasma concentration monitoring TKIs based on chromatographic and mass spectrometry approaches to guide clinical decision-making. Adjusting the most appropriate therapeutic strategies and drug doses may improve the performance therapy and prognosis of patients with advanced EGFR-mutated NSCLC.

Phase I Trial to Evaluate the Tolerance, Pharmacokinetics and Efficacy of the Broad-Spectrum ErbB Family Inhibitor Larotinib Mesylate in Patients with Advanced Solid Tumors

“…The acquired missense mutation in exon 20 of EGFR (T790M) has been identi ed as the most common causative factor in more than half of patients [15]. The third-generation EGFR-TKI osimertinib has been developed to overcome the acquired T790M mutation and has been approved as a rst-line drug for treating advanced EGFR-mutated NSCLC, but tumoral clone resistance often occurs after 6-17 months treatment [16][17][18][19].…”

“…1) is a novel, potent broad-spectrum TKI with EGFR as the main target with a 50% inhibitory concentration (IC 50 ) of 0.6 nM (data not published). It has shown distinct mechanisms of action from other rst-generation and second-generation EGFR inhibitors on the market in that multiple EGFR subtypes were found to be potently inhibited in a larotinib mesylate in vitro study, including wild-type EGFR (IC 50 = 0.611 nM, 3-fold and 37-fold greater inhibitory activity than erlotinib and ge tinib, respectively), EGFR with the L858R mutation (IC 50 = 0.563 nM), EGFR with the L861Q mutation (IC 50 = 0.423 nM), and EGFR with a deletion in the exon 19. With respect to the most common resistance mechanism against rst-generation agents, the acquired missense mutation in exon 20 of EGFR (T790M), larotinib mesylate also exhibits moderate inhibitory activity (IC50 = 45.2 nM).…”

The Role of Micro-RNAs and Circulating Tumor Markers as Predictors of Response to Neoadjuvant Therapy in Locally Advanced Rectal Cancer

“…Their clinical relevance in human diseases as diagnostic, prognostic, and therapeutic biomarkers is also evidenced by the number of clinical trials that at present have been completed ( ). However, only a few potential biomarkers are currently used in the clinical practice [ 124 , 125 , 126 , 127 , 128 ]. To date, the European medicines agency (EMA) and FDA approved the detection of mutations of the EGFR gene from ctDNA in order to select patients affected by non-small cell lung cancer who are eligible for treatment with erlotinib (FDA), afatinib (FDA), gefitinib (EMA), or osimertinib (EMA and FDA), thus avoiding biopsies for some patients [ 124 , 125 , 126 ].…”

Transcription and Translation Inhibitors in Cancer Treatment

“…Both of these oncogenes were previously thought to be undruggable but nevertheless, a few inhibitors for both of them have been published in the last few years. The readers interested in the drugs designed for oncogenic kinases or other oncogenic pathways are referred to other reviews (Bhullar et al, 2018;Solassol et al, 2019;Tang and Zhao, 2019;Wang et al, 2019;Zhang et al, 2019b).…”