AMG 102, an HGF/SF antagonist, in combination with anti-angiogenesis targeted therapies in adult patients with advanced solid tumors

Abstract

3570 Background: AMG 102 is a novel, fully human monoclonal antibody that selectively targets hepatocyte growth factor/scatter factor (HGF/SF), the only ligand for the c-Met receptor, potentially inhibiting tumor cell proliferation, survival, and invasion. Bevacizumab and the small-molecule tyrosine kinase inhibitor motesanib diphosphate deter tumor angiogenesis by disrupting the VEGF pathway; in combination with AMG 102, they may have synergistic antitumor effects by targeting multiple signaling pathways. Methods: In an open-label Phase 1b study, 3 cohorts of 3–6 patients with advanced solid tumors received AMG 102 (3, 10, or 20 mg/kg) + bevacizumab 10 mg/kg every 2 weeks (Q2W); 2 patients received AMG 102 3 mg/kg IV Q2W + daily oral motesanib diphosphate 75 mg. Safety, tolerability, pharmacokinetics (PK), and tumor response (RECIST) were assessed. Results: Patient enrollment was complete in April 2007 with 14 patients (7 men, mean age 67). Prior treatment included radiotherapy (50%) and ≥ 3 lines of chemotherapy (71%). No dose-limiting toxicities were seen at any dosing levels. All patients reported treatment-related adverse events (AEs), most commonly nausea and fatigue. Serious treatment-related AEs included pulmonary embolism (PE) (n = 1) and hypotension (n = 1). Another case of PE was deemed not treatment-related. The PK profile of AMG 102 in combination with anti-angiogenic agents was similar to monotherapy. A decrease in the sum of tumor diameters and a best response of stable disease were seen in 8 of 10 evaluable patients. Stable disease persisted for > 12 months in a patient with carcinoid tumor (AMG 102 3 mg/kg + motesanib diphosphate) and > 9 months in a patient with endometrial cancer (AMG 102 10 mg/kg +bevacizumab). Levels of plasma HGF increased in all patients; the magnitude of increase appeared to be dose-dependent. Conclusions: AMG 102 in combination with anti-angiogenesis agents appeared to be well tolerated with an acceptable safety profile, and may inhibit tumor progression for some patients. Phase 2 evaluations of AMG 102 at 10–20 mg/kg are underway. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Amgen Inc. Amgen Inc. Amgen Inc. Amgen Inc.