Background: S-222611 is a novel oral, potent, reversible tyrosine kinase inhibitor with antiproliferative activity in human tumor cell lines expressing EGFR and/or HER2 in vitro and in mouse xenograft models. We conducted the first study in patients (pts) with solid tumors expressing EGFR or HER2. Methods: Daily oral doses of S-222611 were escalated in successive cohorts from 100 mg to a maximum 1600 mg, using a 3 + 3 design. Full plasma pharmacokinetic (PK) profiles were obtained in all pts for 7 days after a single dose on Day 1 and for 24 h following 21 days of once daily dosing (Cycle 1). Trough PK samples were drawn weekly during the first 3 weeks of daily dosing. A CT scan was performed at baseline and every 8 weeks post-dose to assess response (RECIST). Results: Of 23 treated pts (16 male) aged 24-77y, 19 completed Cycle 1. One dose-limiting toxicity (DLT) has been seen to date, a rash at 1200 mg, which resolved on interruption and dose reduction. Other adverse events related to drug, diarrhea, rash, and nausea, were mild (grade 1 or 2) but more frequent at higher doses. Tumor responses have been seen over a wide range of doses. One complete clinical response was observed at 1200 mg in a pt with HER2 positive breast carcinoma previously treated with lapatinib and trastuzumab. Two pts showed confirmed partial responses (one with EGFR positive renal cell carcinoma at 200 mg daily and one with EGFR and HER2 positive esophageal carcinoma at 400 mg daily); 2 pts showed unconfirmed partial responses and 3 pts (with vaginal, gastric and pancreatic adenoCa) showed stable disease for >6 months (mo); 2 pts have been treated for >12 mo. Plasma C_max, AUC and steady state concentrations increased with dose up to 1200 mg, exceeding those eliciting maximal responses in mice. The plasma t_½ is >24 h. Conclusions: S-222611 was generally tolerated well in doses up to 1200 mg, with only one DLT; rash, diarrhea and nausea have been readily manageable. PK data support once daily dosing to achieve highly effective concentrations. A substantial proportion of patients with HER2 or EGFR expressing tumors have shown partial responses or stable disease (>6 mo) and one patient has shown a complete clinical response.