First-Line Dacomitinib (PF-00299804), an Irreversible Pan-Her Tyrosine Kinase Inhibitor, for Patients with EGFR-Mutant Lung Cancers

ABSTRACT Background Dacomitinib irreversibly inhibits EGFR, HER2 and HER4, and showed superior activity versus reversible EGFR tyrosine kinase inhibitors in EGFR-mutant lung cancer models, including resistant forms. This open-label phase II study evaluates dacomitinib as first-line treatment (tx) for patients with lung cancers. Patients with sensitizing EGFR deletions/mutations in exons 19 or 21 are reported here. Methods Patients had stage IIIB/IV adenocarcinoma, no prior systemic tx, had smoked Results Ninety-two patients enrolled; 47 had EGFR mutation in exons 19 (n = 25) or 21 (n = 22), 33 were female and 27 Asian. Of the 46 evaluable patients with EGFR exon 19 or 21 mutations, 34 had a PR (PR rate = 74%; 95% CI: 59–86; exon 19 = 72%; exon 21 = 76%). PR rates and preliminary PFS were not significantly different for exons 19 and 21. Preliminary PFS at 4M was 96% (95% CI: 84–99), preliminary PFS rate at 1 year was 77% (95% CI: 61–87) and preliminary median PFS was 17 months (95% CI: 13–24). The median tx duration was 13.1 months. For patients with EGFR wild-type lung cancers, PR and PFS at 4M rates were 7% (n = 14; 95% CI: 0–34) and 33% (n = 14; 95% CI: 11–58), respectively, and for patients with EGFR unknown lung cancers, 46% (n = 22; 95% CI: 24–68) and 68% (n = 24; 95% CI: 45–83), respectively. Seven patients had lung cancers with non-sensitizing EGFR mutations; 2 had a PR and 3 SD. For all 92 patients, common side-effects included dermatitis acneiform (grade 3/4 = 16.9%/0) and diarrhea (13.5%/0). Of the 46 patients with EGFR exon 19 or 21 mutations, 3 discontinued tx due to drug-related toxicity. Conclusions Sevnty-four percent of patients in this cohort with EGFR exon 19 or 21 mutant lung cancers experienced PRs with first-line dacomitinib; the preliminary PFS rate was 77% at 1 year; preliminary median PFS was 17 months; further research is planned in this patient population. As dacomitinib is well tolerated, with preclinical activity against HER2, a cohort of patients with HER2 mutant lung cancers is recruiting.