Chronic Plasma Exposure to Kinase Inhibitors in Patients with Oncogene-Addicted Non-Small Cell Lung Cancer

• Published in: Cancers Vol. 12; no. 12; p. 3758
• Main Authors: Geraud, Arthur, Mezquita, Laura, Auclin, Edouard, Combarel, David, Delahousse, Julia, Gougis, Paul, Massard, Christophe, Jovelet, Cécile, Caramella, Caroline, Adam, Julien, Naltet, Charles, Lavaud, Pernelle, Gazzah, Anas, Lacroix, Ludovic, Rouleau, Etienne, Vasseur, Damien, Mir, Olivier, Planchard, David, Paci, Angelo, Besse, Benjamin
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 14.12.2020; MDPI
• Subjects: Addictions; Cancer therapies; Chromatography; chronic plasmatic exposure; Drug dosages; Epidermal growth factor; Epidermal growth factor receptors; Gefitinib; kinase inhibitors; Kinases; Liquid chromatography; Lung cancer; Mass spectroscopy; Mutation; non-small cell lung cancer; Non-small cell lung carcinoma; oncogene addiction; Oncogenes; Patients; Pharmacokinetics; Plasma; Plasma levels; Population; Protein-tyrosine kinase; Raf protein; resistance mutation; Sarcoma; Small cell lung carcinoma; non-small cell lung cancer; chronic plasmatic exposure; oncogene addiction; kinase inhibitors; resistance mutation
• ISSN: 2072-6694; 2072-6694
• DOI: 10.3390/cancers12123758

Kinase inhibitors (KI) have dramatically improved the outcome of treatment in patients with non-small cell lung cancer (NSCLC), which harbors an oncogene addiction. This study assesses KI plasma levels and their clinical relevance in patients chronically exposed to KIs. Plasma samples were collected in NSCLC patients receiving erlotinib, gefitinib, osimertinib, crizotinib, or dabrafenib (with or without trametinib) for at least three months between November 2013 and February 2019 in a single institution. KI drug concentrations were measured by ultra-performance liquid chromatography coupled with tandem mass spectrometry and compared to published data defining optimal plasma concentration. The main outcome was the rate of samples with suboptimal KI plasma concentrations. Secondary outcomes included its impact on mutation emergence in patients receiving a first-generation epidermal growth factor receptor (EGFR) KI. Fifty-one samples were available from 41 patients with advanced NSCLC harboring driver genetic alterations, including , v-Raf murine sarcoma viral oncogene homolog B ( ), anaplastic lymphoma kinase ( ) or ROS proto-oncogene 1 ( ), and who had an available evaluation of chronic KI plasma exposure. Suboptimal plasma concentrations were observed in 51% (26/51) of cases. In -mutant cases failing first-generation KIs, exon 20 p.T790M mutation emergence was detected in 31% (4/13) of samples in optimal vs. none in suboptimal concentration (0/5). Suboptimal plasma concentrations of KIs are frequent in advanced NSCLC patients treated with a KI for at least three months and might contribute to treatment failure.