EGFR
tyrosine-kinase inhibitors (TKIs) have now been firmly established as the first-line treatment for
non-small-cell lung cancer (NSCLC) patients harboring activating EGFR mutations, based on seven prospective randomized Phase III trials. However, despite significantly improved overall response rate and improved median progression-free survival when compared to
platinum-doublet
chemotherapy, EGFR-mutant NSCLC patients treated with EGFR TKIs invariably progress due to the emergence of acquired resistances, with the gatekeeper T790M mutation accounting for up to 60% of the resistance mechanisms. Second-generation irreversible EGFR TKIs were developed in part to inhibit the T790M mutation, in addition to the common activating EGFR mutations.
Dacomitinib is one such second-generation EGFR TKI designed to inhibit both the wild-type (WT) EGFR and EGFR T790M.
Afatinib is another second-generation EGR TKI that has been now been approved for the first-line treatment of EGFR-mutant NSCLC patients, while
dacomitinib continues to undergo clinical evaluation. We will review the clinical development of
dacomitinib from Phase I to Phase III trials, including the two recently published negative large-scale randomized Phase III trials (ARCHER 1009, NCIC-BR-26). Results from another large-scale randomized trial (ARCHER 1050) comparing
dacomitinib to
gefitinib as first-line treatment of advanced treatment-naïve EGFR-mutant NSCLC patients will soon be available and will serve as the lynchpin trial for the potential approval of
dacomitinib in NSCLC. Meanwhile, third-generation EGFR TKIs (eg, CO-1686 [
rociletinib], AZ9291, HM61713,
EGF816, and
ASP8273) that preferentially and potently inhibit EGFR T790M but not WT EGFR are in full-scale clinical development, and some of these EGFR TKIs have received "breakthrough" designation by the US Food and Drug Administration and will likely be approved in late 2015. Given the rapid development of third-generation EGFR TKIs and the approval of
gefitinib,
erlotinib, and
afatinib as first-line treatment of EGFR-mutant NSCLC patients, the future role of
dacomitinib in the treatment of NSCLC seems to be limited.