260 Multi-modality in vivo imaging of bone metabolism and tumor growth in a mouse model of bone metastasis

Abstract

Afatinib (Gilotrif, Giotrif, Boehringer) is an irreversible, 4-anilinoquinazoline second-generation tyrosine kinase inhibitor of EGFR (HER1; IC50 0.5 nM), HER2 (IC50 14 nM), and HER4 (IC50 1.0 nM); it also inhibits transphosphorylation of HER3 (this molecule is devoid of intrinsic kinase activity), thus blocking all members of the family. Importantly, afatinib inhibits some EGFR mutations in exons 19 and 21. In 2013, the Food and Drug Administration (FDA) approved its use as first-line treatment in patients with metastatic NSCLC harboring EGFR deletions in exon 19, or substitution mutations in exon 21 (L858R). In the same year, the European Medicines Agency (EMA) granted a restricted prescription for afatinib as monotherapy for the treatment of EGFR TKI-naïve adult patients with locally advanced, or metastatic NSCLC with activating EGFR mutations. The safety analysis of afatinib has been supported by various sets of data (SAF1-5), for a total of 3865 cancer patients, among whom approximately 2135 NCSLC patients received at least one dose of afatinib. The safety profile of afatinib is characterized by diarrhea, rash/dermatitis acneiform, stomatitis, paronychia, xerosis, decreased appetite, and pruritus. Other signs include fatigue, anorexia, cough/dyspnea, nausea/vomiting, and infection. Additional events of concern, although infrequent, include ILD, decreased LVEF/heart failure, keratitis, hepatic toxicity/failure, bullous and exfoliative skin lesions, and pancreatitis. Most of these events are also observed with other EGFR and/or HER2 inhibitors, either involving intracellular kinases in the catalytic domain area, such as erlotinib, gefitinib, and lapatinib, or targeting the extracellular receptors portion, such as the cetuximab or trastuzumab. Therefore, they are considered as typical AEs of this drug class.