HKI-272, an irreversible pan erbB receptor tyrosine kinase inhibitor: Preliminary phase 1 results in patients with solid tumors

3018 Background: HKI-272 is a potent, low molecular weight, orally active, irreversible pan erbB receptor tyrosine kinase inhibitor. It inhibits the growth of tumor cells that express erbB-1 (epidermal growth factor receptor, EGFR) and erbB-2 (HER-2) in culture and xenografts. HKI-272 also inhibits the growth of cultured cells that contain sensitizing and resistance-associated EGFR mutations (Kwak et al, Proc Natl Acad Sci USA 102:7665–70, 2005). We are conducting a phase 1 study in patients (pts) with advanced-stage tumors that express EGFR or HER-2 to assess HKI-272 for tolerability, safety, pharmacokinetics, and preliminary antitumor activity. Methods: Pts (3–6/cohort) received 40, 80, 120, 180, 240, 320, or 400 mg HKI-272 orally once on day 1 and then once daily beginning on day 8. Timed blood samples were collected on days 1 and 21 for pharmacokinetic analysis. Results: Enrollment of 73 pts is complete. Preliminary data for 51 pts as of 28 Nov 2005 are presented. Patients were a median 60 years and 26% men. The most frequently occurring tumor types at primary diagnosis were breast (23 pts), non-small cell lung (9), and colorectal, ovarian, and renal (3 pts each). Dose escalation ended when 2 pts who received 400 mg HKI-272/day had drug-related dose-limiting toxicity of grade 3 diarrhea. Thus, the maximum tolerated dose (MTD) was 320 mg HKI-272/day. HKI-272-related adverse events (AEs), any grade, that occurred in ≥10% of pts were diarrhea (84%), nausea (55%), asthenia (45%), anorexia (31%), vomiting (29%), chills (12%), and rash (10%). Grade 3 related AEs that occurred in >1 pt were diarrhea (11) and asthenia (4). HKI-272 C max and AUC increased in a dose-dependent manner. At steady state at the MTD, mean values were C max : 112±58 ng/mL, AUC: 1618±930 ng.h/mL, t 1/2 : 15±2.5 h. Day 1 and 21 AUC values were comparable. Tumor assessments (modified RECIST criteria) were made at baseline and at the end of alternate cycles (28 days/cycle). Two breast cancer pts had confirmed partial responses (PRs) and 2 had unconfirmed PRs. Conclusions: When HKI-272 was administered on a continuous, once-daily, oral treatment schedule, the MTD was 320 mg/day, with diarrhea as the most frequently occurring related AE. HKI-272 has antitumor activity in HER-2-positive breast cancer. [Table: see text]