New generation kinase inhibitors in NSCLC: afatinib

Summary First-generation, reversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), erlotinib and gefitinib, represented an important addition to the treatment 30 armamentarium for non-small cell lung cancer (NSCLC) patients with activating EGFR mutations. However, all patients inevitably develop acquired resistance to these agents. It was hypothesized that development of second generation TKIs with broader inhibitory profiles could confer longer lasting clinical activity and overcome acquired resistance to first-generation inhibitors. Afatinib - an irreversible ErbB family blocker that potently inhibits signaling of all homodimers and heterodimers formed by EGFR, human epidermal growth factor receptor (HER- 2), HER-2 and HER-4 receptor. Afatinib has demonstrated clinical activity in NSCLC patients who had progressed on erlotinib|gefitinib, particularly when combined with cetuximab and offers treatment beyond progression benefit when combined with paclitaxel versus chemotherapy alone. The activity of Afatinib in both first-line and relapse/refractory settings may reflect its ability to irreversibly inhibit all ErbB family members. Afatinib has an acceptable toxicity profile; frequent adverse events are gastrointestinal and skin toxicities.