Irreversible EGFR-TKIs: dreaming perfection

In the last few year, the treatment of Non-Small-Cell Lung Cancer (NSCLC) has dramatically changed. Presence of activating mutations in the Epidermal Growth Factor Receptor (EGFR) identified a particular group of NSCLC patients with different clinical characteristics and outcome. For EGFR mutant patients first-generation EGFR tyrosine-kinase inhibitors (TKIs), such as gefitinib and erlotinib, represent the best therapeutic option in first, second and maintenance setting. Unfortunately, all patients develop acquired resistance and despite an initial benefit, virtually all patients progress due to the development of resistance. Several molecular mechanisms are responsible for acquired resistance and the two prominent are the up-regulation of the downstream signal by mesenchymal-epidermal transition (MET) amplification and the emergence of T790M EGFR gatekeeper mutation. Preclinical and early clinical trials suggested a potential efficacy of a new class of panHER inhibitor, also called irreversible or covalent inhibitor, in overcome acquired resistance related to T790M. Afatinib, dacomitinib and neratinib, are currently in development in different setting and results from these trials are awaited in order to establish the role of these new compounds in the treatment of NSCLC.