Selective oral epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 is generally well-tolerated and has activity in non-small-cell lung cancer and other solid tumors: Results of a phase I trial

Purpose: To investigate safety, tolerability, close-related pharmacologic properties, and pharmacodynamics of ZD1839 (gefinitib, Iressa; AstraZeneca Pharmacueticals, Wilmington, DE), an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, in patients with solid tumor types known to express or highly express EGFR. Methods: This was an open-label, phase 1, dose escalation safety/tolerability trial of oral ZD1839 (150 to 1,000 mg/d), administered once daily for 28-continuous-day cycles until disease progression or undue toxicity. Results: Of 71 (69 assessable for safety, 58 for efficacy) patients at seven dose levels, most had non-small-cell lung (n = 39) or head and neck (n = 18) cancer, and 68 of 71 patients received prior cancer therapy (two or more regimens in 54 patients [78%]). Diarrhea and rash, the primary dose-limiting toxicities (DLTs), occurred at 800 mg. Frequent treatment-related grade 1/2 adverse events were diarrhea (55%), asthenia (44%), and acne-like follicular rash (46%). At doses greater than or equal to800 mg, 45% of patients required dose reductions. No increased or cumulative toxicity was observed over 250 patient-months of exposure. Pharmacokinetic analysis showed that steady-state occurred by day 7, interpatient exposure was more variable than intrapatient exposure, and variability of exposure did not change with dose. One patient experienced a partial response, but antitumor activity manifested mainly as prolonged stable disease (45% of patients greater than or equal to3 months, 22% greater than or equal to6 months, and 7.2% greater than or equal to1 year). No relationship between dose, response, or duration on study was observed. Conclusion: Rash and diarrhea, generally mild and tolerable at doses greater than or equal to 600 mg/d, were DLTs at 800 mg/d (maximum-tolerated dose). Antitumor activity was observed at all doses. Pharmacokinetic analyses confirmed suitability of once-daily oral dosing. (C) 2002 by American Society of Clinical Oncology.