Dacomitinib Has First-Line Activity in EGFR-Mutant NSCLC

First-generation noncovalent EGFR tyrosine kinase inhibitors such as erlotinib and gefitinib are the standard first-line therapy for patients with EGFR-mutant non–small cell lung cancer (NSCLC), but acquired resistance usually develops. Dacomitinib, a pan-HER inhibitor that covalently and irreversibly binds EGFR, HER2, and HER4, is active in patients with NSCLC previously treated with erlotinib or gefitinib, but it is unknown whether this second-generation EGFR inhibitor would be an effective first-line therapy. Jänne and colleagues report results of an open-label, multicenter, phase II study of dacomitinib as first-line treatment in treatment-naïve patients with advanced NSCLC. Patients were selected for those who had clinical or molecular characteristics associated with EGFR inhibitor response and received dacomitinib orally once daily. The primary endpoint was progression-free survival at 4 months, and secondary endpoints included overall response, progression-free and overall survival at data cutoff, safety, and tolerability. Treatment-related adverse events such as diarrhea and dermatitis acneiform occurred in most patients and led to dose reductions or temporary treatment interruption, but only 6% of patients withdrew due to treatment-related adverse events. The overall progression-free survival at 4 months was 76.8%, and among the 45 patients who harbored known activating exon 19 or 21 EGFR mutations, 76% experienced an objective response. The median overall survival was 40.2 months and the median progression-free survival among patients with activating EGFR mutations was 18.2 months, which was longer than the progression-free survival observed in similarly selected patients in the phase III trials of erlotinib or gefitinib as well as in a phase II trial of afatinib, another covalent EGFR inhibitor. Although direct comparison of dacomitinib to other first- and second-generation EGFR inhibitors in randomized clinical studies is necessary (a phase III trial comparing dacomitinib to gefitinib as first-line therapy in patients with EGFR-mutant NSCLC is ongoing), these results suggest that dacomitinib has promise as first-line treatment for EGFR-mutant NSCLC.

Jänne PA, Ou SH, Kim DW, Oxnard GR, Martins R, Kris MG, et al. Dacomitinib as first-line treatment in patients with clinically or molecularly selected advanced non-small-cell lung cancer: a multicentre, open-label, phase 2 trial. Lancet Oncol 2014 Nov 5 [Epub ahead of print].