Pharmacokinetic drug evaluation of osimertinib for the treatment of non-small cell lung cancer

Abstract

First- and second-generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib, erlotinib, icotinib, and afatinib are the standard-of-care for first-line therapy of non-small-cell lung cancer (NSCLC) harboring activating EGFR mutations. Unfortunately, after initial activity of an average 9-13 months, disease progression has been reported in the majority of patients. In about 50% of cases the progression is due to the onset of the T790M mutation in exon 20 of the EGFR gene. Third-generation EGFR-TKIs targeting this mutation were investigated, with osimertinib the only reaching clinical practice. Areas covered: A structured search of bibliographic databases for peer-reviewed research literature and of main meetings using a focused review question addressing osimertinib, was undertaken. Expert opinion: Osimertinib is the standard-of-care for EGFR-mutated patients progressing to first-line EGFR-TKIs due to the acquired EGFR T790M mutation. Results from the head-to-head first-line trial comparing osimertinib versus gefitinib or erlotinib in activating EGFR mutations might change the front-line approach. Osimertinib in combination regimens, such as immunotherapy, and in adjuvant setting are ongoing. Thus, the strategic approach for the management of EGFR-mutated NSCLC patients will change further in the next few years.

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

“…Pharmacokinetic studies of osimertinib have shown that it is slowly absorbed with an absolute bioavailability of 70% [57]. Osimertinib is orally dispensed at a dose of 80 mg once daily [54] and is quite widely distributed.…”

Pharmacokinetics and Bioequivalence Evaluation of Erlotinib Hydrochloride Tablets: Randomized, Open‐Label, 2‐Period Crossover Study in Healthy Chinese Subjects

“…Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase that plays a significant role in epithelial tissue maintenance and growth 6 . EGFR is prevalent in NSCLC cells, and a mutation in EGFR is frequently observed in patients with lung cancer, 7 especially in Asia‐Pacific NSCLC patients 8 . Erlotinib, a first‐generation reversible tyrosine kinase inhibitor that targets the EGFR, has been approved for the first‐line treatment of patients with EGFR mutation‐positive NSCLC.…”

“…Previous studies have shown that erlotinib is metabolized primarily by cytochrome P450 (CYP)‐dependent enzymes. This is mediated predominantly by hepatic and intestinal CYP3A4 and CYP3A5 and to a lesser extent by CYP1A2, and by extrahepatic isoforms CYP1A1 and CYP1B1 8,13,15,19–21 . Erlotinib and its metabolites are primarily excreted in the feces (83%) and to a lesser extent in the urine (8%) 22 .…”

“…6 EGFR is prevalent in NSCLC cells, and a mutation in EGFR is frequently observed in patients with lung cancer, 7 especially in Asia-Pacific NSCLC patients. 8 Erlotinib, a first-generation reversible tyrosine kinase inhibitor that targets the EGFR, has been approved for the first-line treatment of patients with EGFR mutationpositive NSCLC. Erlotinib demonstrates significant antitumor activity and survival benefits for patients with NSCLC.…”

“…This is mediated predominantly by hepatic and intestinal CYP3A4 and CYP3A5 and to a lesser extent by CYP1A2, and by extrahepatic isoforms CYP1A1 and CYP1B1. 8,13,15,[19][20][21] Erlotinib and its metabolites are primarily excreted in the feces (83%) and to a lesser extent in the urine (8%). 22 In drug-drug interaction studies, because of the involvement of CYP enzymes in erlotinib metabolism, concomitant administration of an inhibitor or an inducer of CYP enzymes increases or decreases exposure to erlotinib, respectively.…”