Protein Kinase Inhibitors Indicated for Lung Cancer: Pharmacodynamics, Pharmacokinetics, Adverse Drug Reactions, and Evaluation in Clinical Trials

WhatIs Known and Objective. Anti-EGFR (epidermal growth factor receptor) drugs are indicated for non-small-cell lung cancer (NSCLC). This review summarises the information available to date on the first anti-EGFRs granted market authorisation: erlotinib TARCEVA (R), gefitinib IRESSA (R), afatinib GIOTRIF (R), dacomitinib VIZIMPRO (R), and osimertinib TAGRISSO (R). Methods. A literature search was conducted in the PubMed database including studies published in English using the terms gefitinib, erlotinib, afatinib, dacomitinib, and osimertinib. Furthermore, bibliographies of selected references were also studied for relevant articles. Clinical trial (CT) data were extracted from clinicaltrials.gov (ongoing trials and adverse events (AEs)). Assessment of AEs for these drugs was conducted using global pharmacovigilance data from VigiBase (R). Results and Discussion. Erlotinib and gefitinib are first-generation anti-EGFR drugs, able to bind competitively and reversibly to the ATP- (adenosine triphosphate-) binding site of the EGFR exon 19 and exon 21 mutations. Afatinib and dacomitinib are second-generation anti-EGFRs able to bind covalently and irreversibly to the ATP site and inhibit EGFR and HER (human epidermal growth factor receptor) such as HER2 and HER4 enzyme activity. Osimertinib is a third-generation PKI and overcomes the EGFR T790M gatekeeper mutation through covalent binding at the ATP site. Medical interactions with these drugs are reported, notably with cytochrome P450 inducers or inhibitors. The most reported AEs in CTs are cutaneous reactions and gastrointestinal disorders. The occurrence of cutaneous reactions is less reported with third generation than with first- and second-generation anti-EGFR drugs. These results are consistent with the results from the VigiBase (R) global pharmacovigilance database. What Is New and Conclusion. This review summarises current knowledge regarding five anti-EGFRs in the literature. The third-generation anti-EGFR appears to be more effective than the first and second generations and is indicated as first-line therapy. This trial is registered with NCT01523587, NCT01466660, NCT01774721, NCT01360554, and NCT02296125.