A first-in-human phase I study of a bivalent MET antibody, emibetuzumab (LY2875358), as monotherapy and in combination with erlotinib in advanced cancer

Lee S. Rosen, Jonathan W. Goldman, Alain P. Algazi, P. Kellie Turner, Brian Moser, Tianle Hu, Xuejing Aimee Wang, Jay Tuttle, Volker Wacheck, James E. Wooldridge, Michaela Banck

Research output: Contribution to journalArticle

27 Scopus citations

Abstract

Purpose: The MET/HGF pathway regulates cell proliferation and survival and is dysregulated in multiple tumors. Emibetuzumab (LY2875358) is a bivalent antibody that inhibits HGFdependent 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 0+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.

Original languageEnglish (US)
Pages (from-to)1910-1919
Number of pages10
JournalClinical Cancer Research
Volume23
Issue number8
DOIs
StatePublished - Apr 15 2017

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Rosen, L. S., Goldman, J. W., Algazi, A. P., Turner, P. K., Moser, B., Hu, T., Wang, X. A., Tuttle, J., Wacheck, V., Wooldridge, J. E., & Banck, M. (2017). A first-in-human phase I study of a bivalent MET antibody, emibetuzumab (LY2875358), as monotherapy and in combination with erlotinib in advanced cancer. Clinical Cancer Research, 23(8), 1910-1919. https://doi.org/10.1158/1078-0432.CCR-16-1418