Weekly high-dose erlotinib in patients with non-small cell lung cancer (NSCLC): A phase I/II study

Abstract

7085 Background: In preclinical studies, higher concentrations of the oral epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) erlotinib (Tarceva™) effectively inhibit MAPK and Akt, downstream components of the EGFR signaling pathway that may confer resistance to this agent. In BT-20 and MDA468 cells, the dose response curves for the inhibition of these kinases are steep (Akita et al. Semin. Oncol. 2003; 30: 15–24.). Notably, a prior Phase I study suggested these erlotinib concentrations can be attained clinically on a weekly schedule at doses less than 2000 mg (Karp et al. Proc ASCO 1999;40:#1499). We undertook this phase I/II study to explore high doses of erlotinib given once weekly. Methods: Patients with previously treated advanced NSCLC were enrolled in 3-patient cohorts, with no intrapatient escalation, at dose levels of 1200, 1600, and 2000 mg weekly. Six patients were planned for study at the 2000 mg dose level. Results: 11 patients have been enrolled to date. The first 2 dose levels (n=6) are completed. Pt characteristics: Female: 3; Karnofsky Performance Status median 80% (70–90%); age median 68 (54–76); prior chemotherapy median 2 (1–3). Toxicity (≥ Grade 2) by dose level 1200 mg: G2 rash (n=1), G2 diarrhea (n=1); 1600 mg : G2 diarrhea (n=1), G2 emesis (n=1). To date, all Grade 2 toxicities have resolved within one week of onset. Five additional patients have been enrolled at the 2000 mg dose level and are in their first month of treatment; none have experienced DLT to date. Conclusions: Weekly erlotinib at a dose of 1600 mg is tolerable for patients with advanced NSCLC refractory to initial chemotherapy. MTD has not yet been defined. The Phase II portion of the trial will commence after the MTD is identified. Supported, in part, by Genentech. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech, Inc. AstraZeneca; Genentech, Inc. Genentech, Inc. AstraZeneca Genentech, Inc.