BACKGROUND:The present phase Ib study assessed the maximum tolerated dose (MTD), safety, pharmacokinetics, and antitumor activity of high-dose intermittent (HDI) afatinib monotherapy for patients with advanced solid tumors. The planned focus was patients with epidermal growth factor receptor (EGFR) T790M+ non-small-cell lung cancer (NSCLC). MATERIALS AND METHODS:Eligible patients had histologically confirmed advanced solid tumors that were unsuitable for, or unresponsive to, standard therapy. The study used a 3+3 design with a starting dose of 90 mg/d for 3 days every 14 days (28-day cycles) and incremental dose escalations to 200 mg/d. RESULTS:Thirty-five patients (18 with NSCLC) were treated (6 at 90 mg; 3 at 120 mg; 9 at 150 mg; 11 at 160 mg; and 6 at 200 mg). One patient in the 90-mg cohort (grade 3 rash) and 2 patients in the 200-mg cohort (grade 3 diarrhea; grade 3 mucositis) experienced a dose-limiting toxicity. The MTD was 160 mg. The most common treatment-related adverse events were diarrhea (total, 88.6%; grade 3, 14.3%), rash/acne (total, 62.9%; grade 3, 2.9%), and fatigue (total, 40.0; grade 3, 0%). The maximum afatinib plasma concentration at the MTD was 313 ng/mL, exceeding the in vitro IC50 (inhibitor concentration decreased by one half) range for T790M inhibition. The trough levels suggested no systematic change in afatinib plasma concentrations during long-term treatment at this dosing schedule. Of the 13 T790M+ NSCLC patients, 1 achieved an objective response (7.7%). CONCLUSION:HDI afatinib was feasible and tolerable and could potentially be further explored for NSCLC indications, including patients with central nervous system disease, rare EGFR mutations, or T790M+ NSCLC intolerant of third-generation EGFR tyrosine kinase inhibitors.