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We hypothesized that high-dose intermittent (HDI) afatinib could increase efficacy compared with standard dosing but preserve tolerability. The present phase Ib study assessed HDI afatinib (3 days every 14 days) in 35 patients with advanced solid tumors. The maximum tolerated dose was 160 mg. HDI afatinib was feasible and tolerable and could provide benefit in a number of clinical settings.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).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.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%).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.