467P - Phase I Study of U3-1287, A Human Monoclonal Antibody Targeting Her3, in Japanese Patients with Advanced Solid Tumors

Abstract

ABSTRACT Background HER3 is a key dimerization partner for HER-family members that activates oncogenic signaling pathways lead to cell survival and proliferation. Acquired-resistance to EGFR inhibitors may result from the activation of HER3 and/or HER2, which share overlapping the signaling pathways. U3-1287 is a fully human anti-HER3 monoclonal antibody that has demonstrated anticancer activity in preclinical models. In a preceding US phase I study, the tolerability of U3-1287 was evaluated up to the dose of 20 mg/kg without dose-limiting toxicities (DLTs). In this study, we evaluated the tolerability, pharmacokinetics (PK) and potential antitumor activities of U3-1287 in Japanese patients with solid tumors up to the dose of 18 mg/kg. Methods Patients received U3-1287 at a dose of 9 mg/kg or 18 mg/kg intravenously every 3 weeks (q3w). Tumor response, incidence of anti-U3-1287 antibodies (HAHA), and level of soluble HER3 (sHER3) were also evaluated. Results Nine patients, 3 at 9 mg/kg and 6 at 18 mg/kg, were enrolled. Five patients were male and median (range) age of 67 (50-69) years. Tumor types were lung (2), colorectal (2), esophageal (2), breast (1), cervical (1), and sarcoma (1). No DLTs were reported. U3-1287-related AEs were ALT increase (3 patients), thrombocytopenia, diarrhea, stomatitis, cheilitis, rash, and AST increase (2 each). Plasma disappearance was bi-phasic and terminal half-life at the dose of 18 mg/kg was approximately 9 days. PK profiles were similar to those in the US phase I study. Four patients had best responses of stable disease. All patients tested were negative for HAHA formation. Level of sHER3 unexpectedly increased about four times in all patients. Mean sHER3 concentrations at baseline and day 15 were 3.8 ng/mL and 16.5 ng/mL, respectively. These changes did not correlate with clinical response (at day15 in SD and PD patients; 16.7 ng/mL and 16.9 ng/ml, respectively). Conclusions U3-1287 was well tolerated up to 18 mg/kg in Japanese patients with solid tumors. These data support a dosing regimen of 18 mg/kg q3w in future studies. Disclosure All authors have declared no conflicts of interest.