A First-in-Human Phase I Study of a Bivalent MET Antibody, Emibetuzumab (LY2875358), as Monotherapy and in Combination with Erlotinib in Advanced Cancer.
Purpose:The MET/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 i.v. every 2 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 (PK), pharmacodynamics (PD), and antitumor activity.Results:Twenty-three patients with solid tumors received emibetuzumab monotherapy at 20, 70, 210, 700, 1,400, and 2,000 mg and 14 non-small cell lung cancer (NSCLC) patients at 700, 1,400, and 2,000 mg in combination with erlotinib 150 mg daily. No dose-limiting toxicities and related serious or ≥ 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 PK at doses >210 mg. Three durable partial responses were observed, one for emibetuzumab (700 mg) and two for emibetuzumab + erlotinib (700 mg and 2,000 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 to 2,000 mg i.v. Q2W.Clin Cancer Res; 23(8); 1910-9. ©2016 AACR.
Department of Medicine, University of California, Los Angeles, California. lrosen@mednet.ucla.edu.
Lee S
LS
Rosen
Department of Medicine, University of California, Los Angeles, California.
Jonathan W
JW
Goldman
Department of Medicine, University of California, San Francisco, California.
Alain P
AP
Algazi
Eli Lilly and Company, Indianapolis, Indiana.
P Kellie
PK
Turner
Eli Lilly and Company, Indianapolis, Indiana.
Brian
B
Moser
Eli Lilly and Company, Indianapolis, Indiana.
Tianle
T
Hu
Eli Lilly and Company, Indianapolis, Indiana.
Xuejing Aimee
XA
Wang
Eli Lilly and Company, Indianapolis, Indiana.
Jay
J
Tuttle
Eli Lilly Regional Operations GmbH, Vienna, Austria.
Volker
V
Wacheck
Eli Lilly and Company, Indianapolis, Indiana.
James E
JE
Wooldridge
Mayo Clinic Rochester, Rochester, Minnesota.
Michaela
M
Banck
D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D000069347:Erlotinib Hydrochloride / Q000008:administration & dosage*; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*
D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D000069347:Erlotinib Hydrochloride; C000599789:emibetuzumab