Purpose: The dose-limiting toxicities, maximum tolerated dose, pharmacokinetic profile, and preliminary antitumor activity of neratinib (HKI-272), an irreversible pan ErbB inhibitor, were determined in patients with advanced solid tumors. Experimental Design: Neratinib was administered orally as a single dose, followed by a 1-week observation period, and then once daily continuously. Planned dose escalation was 40, 80,120, 180, 240, 320, 400, and 500 mg. For pharmacokinetic analysis, timed blood samples were collected after administration of the single dose and after the first 14 days of continuous daily administration. Results: Dose-limiting toxicity was grade 3 diarrhea, which occurred in one patient treated with 180 mg and in four patients treated with 400 mg neratinib; hence, the maximum tolerated dose was determined to be 320 mg. Other common neratinib-related toxicities included nausea, vomiting, fatigue, and anorexia. Exposure to neratinib was dose dependent, and the pharmacokinetic profile of neratinib supports a once-a-daydosing regimen. Partial response was observed for 8 (32%) of the 25 evaluable patients with breast cancer. Stable disease ≥24 weeks was observed in one evaluable breast cancer patient and 6 (43%) of the 14 evaluable non - small cell lung cancer patients. Conclusion :The maximum tolerated dose of once-dailyoral neratinib is 320 mg.The most common neratinib-related toxicity was diarrhea. Antitumor activity was observed in patients with breast cancer who had previous treatment with trastuzumab, anthracyclines, and taxanes, and tumors with a baseline ErbB-2 immunohistochemical staining intensityof 2+ or 3+. The antitumor activity, tolerable toxicityprofile, and pharmacokinetic properties of neratinib warrant its further evaluation.