A First-in-Human Phase I Study of a Bivalent MET Antibody, Emibetuzumab (LY2875358), as Monotherapy and in Combination with Erlotinib in Advanced Cancer

Abstract

Purpose: The MET/hepatocyte growth factor (HGF) pathway regulates cell proliferation and survival and is dysregulated in multiple tumors. Emibetuzumab (LY2875358) is a bivalent antibody that inhibits HGF-dependent and HGF-independent MET signaling. Here we report dose escalation results from the first-in-human phase I trial of emibetuzumab. Experimental Design: The study comprised a 3+3 dose escalation for emibetuzumab monotherapy (Part A) and in combination with erlotinib (Part A2). Emibetuzumab was administered IV every two weeks (Q2W) using a flat dosing scheme. The primary objective was to determine a recommended Phase II dose (RPTD) range; secondary endpoints included tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity. Results: Twenty-three patients with solid tumors received emibetuzumab monotherapy at 20, 70, 210, 700, 1400, and 2000 mg and fourteen NSCLC patients at 700, 1400, and 2000mg in combination with erlotinib 150mg daily. No dose-limiting toxicities, related serious or {greater than or equal to} grade 3 adverse events were observed. The most common emibetuzumab-related adverse events included mild diarrhea, nausea, and vomiting, and mild to moderate fatigue, anorexia, and hypocalcemia in combination with erlotinib. Emibetuzumab showed linear pharmacokinetics at doses >210mg. Three durable partial responses were observed, one for emibetuzumab (700 mg) and two for emibetuzumab + erlotinib (700 mg and 2000 mg). Both of the responders to emibetuzumab + erlotinib had progressed to prior erlotinib and were positive for MET protein tumor expression. Conclusions: Based on tolerability, PK/PD analysis, and preliminary clinical activity, the RPTD range for emibetuzumab single agent and in combination with erlotinib is 700-2000 mg IV Q2W.