LY2875358), As Monotherapy and in Combination with Erlotinib in Advanced Cancer Lee S

Published OnlineFirst October 10, 2016; DOI: 10.1158/1078-0432.CCR-16-1418 Cancer Therapy: Clinical Clinical Cancer Research 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. Rosen1, Jonathan W. Goldman1, Alain P. Algazi2, P. Kellie Turner3, Brian Moser3, Tianle Hu3, Xuejing Aimee Wang3, Jay Tuttle3, Volker Wacheck4, James E. Wooldridge3, and Michaela Banck5 Abstract Purpose: The MET/HGF pathway regulates cell proliferation mg and 14 non–small cell lung cancer (NSCLC) patients at 700, and survival and is dysregulated in multiple tumors. Emibetuzu- 1,400, and 2,000 mg in combination with erlotinib 150 mg daily. mab (LY2875358) is a bivalent antibody that inhibits HGF- No dose-limiting toxicities and related serious or grade 3 dependent and HGF-independent MET signaling. Here, we report adverse events were observed. The most common emibetuzu- dose escalation results from the first-in-human phase I trial of mab-related adverse events included mild diarrhea, nausea, and emibetuzumab. vomiting, and mild to moderate fatigue, anorexia, and hypocal- Experimental Design: The study comprised a 3þ3dose cemia in combination with erlotinib. Emibetuzumab showed escalation for emibetuzumab monotherapy (Part A) and in linear PK at doses >210 mg. Three durable partial responses were combination with erlotinib (Part A2). Emibetuzumab was observed, one for emibetuzumab (700 mg) and two for emibe- administered i.v. every 2 weeks (Q2W) using a flat dosing tuzumab þ erlotinib (700 mg and 2,000 mg). Both of the scheme. The primary objective was to determine a recom- responders to emibetuzumab þ erlotinib had progressed to prior mended phase II dose (RPTD) range; secondary endpoints erlotinib and were positive for MET protein tumor expression. included tolerability, pharmacokinetics (PK), pharmacody- Conclusions: Based on tolerability, PK/PD analysis, and pre- namics (PD), and antitumor activity. liminary clinical activity, the RPTD range for emibetuzumab Results: Twenty-three patients with solid tumors received emi- single agent and in combination with erlotinib is 700 to 2,000 betuzumab monotherapy at 20, 70, 210, 700, 1,400, and 2,000 mg i.v. Q2W. Clin Cancer Res; 1–10. Ó2016 AACR. Introduction induced by ligand-independent mechanisms such as MET gene amplification, mutation, or receptor heterodimerization (4). The MET/HGF signaling pathway is involved in formation of Increased expression of MET protein has been reported in metastasis and an invasive tumor phenotype through increased various types of human cancers, including gastric, colorectal, cell proliferation, motility, invasion, angiogenesis, and sup- breast, pancreatic, lung, and hepatocellular carcinoma (1, 5). In pression of apoptotic cell death (1–3). The MET proto-onco- these tumors, high MET expression is correlated with poor gene is encoding a cell surface tyrosine kinase receptor com- prognosis (1, 2). MET and HGF upregulation has collectively posed of extracellular and intracellular domains. Upon binding been identified as a mechanism of acquired resistance to of HGF as its only known ligand, MET forms a homodimer that tyrosine kinase inhibitors of the EGFR, including erlotinib and triggers the activation of its intracellular kinase domain. Besides gefitinib (6–8). Clinical studies with MET/HGF pathway inhi- this ligand-dependent activation, MET signaling can also be bitors in combination with erlotinib have demonstrated clinical efficacy in phase II trials (9, 10). Emibetuzumab is a humanized IgG4 bivalent mAb that binds 1Department of Medicine, University of California, Los Angeles, California. to the extracellular domain of MET, preventing HGF from binding 2 3 Department of Medicine, University of California, San Francisco, California. Eli to MET and thereby inhibiting ligand-dependent activation of 4 Lilly and Company, Indianapolis, Indiana. Eli Lilly Regional Operations GmbH, MET. Moreover, emibetuzumab triggers MET receptor internali- Vienna, Austria. 5Mayo Clinic Rochester, Rochester, Minnesota. zation and downregulation of total membrane MET expression, Note: Supplementary data for this article are available at Clinical Cancer leading to inhibition of ligand-independent activation of MET Research Online (http://clincancerres.aacrjournals.org/). signaling, as well (11). Corresponding Author: Lee S. Rosen, UCLA Santa Monica Hematology-Oncol- In preclinical models, emibetuzumab inhibited growth of ogy, 2020 Santa Monica Blvd., Suite 600, Santa Monica, CA 90404. Phone: 310- tumors that are dependent on MET, including tumors that 633-8400; Fax: 310-633-8419; E-mail: [email protected] exhibit HGF-dependent and HGF-independent biology. doi: 10.1158/1078-0432.CCR-16-1418 Administration of a single dose of emibetuzumab resulted in Ó2016 American Association for Cancer Research. continuous reduction of MET protein expression for 14 days in www.aacrjournals.org OF1 Downloaded from clincancerres.aacrjournals.org on September 25, 2021. © 2016 American Association for Cancer Research. Published OnlineFirst October 10, 2016; DOI: 10.1158/1078-0432.CCR-16-1418 Rosen et al. Patient population Translational Relevance Eligible patients were 18 years of age with advanced and/or The MET/HGF pathway is involved in oncogenic processes, metastatic cancer after failure of standard-of-care therapy(s), or such as cell proliferation, survival, invasion, motility, and for whom there was no standard therapy. Additional key eligi- metastasis, and its activation is associated with poor patient bility criteria included adequate hematologic, renal and hepatic outcomes. This first-in-human dose phase I study demon- function, and an Eastern Cooperative Oncology Group perfor- strates a favorable safety profile for emibetuzumab—a human- mance status of 2. For patients receiving combination therapy of ized, bivalent monoclonal antibody. Emibetuzumab blocks LY2875358 and erlotinib, a confirmed diagnosis of squamous or HGF-dependent signaling by binding to MET, and also blocks nonsquamous non–small cell lung cancer (NSCLC; Stage IIIB independent signaling of the MET receptor by subsequent with malignant pleural effusion or Stage IV per American Joint internalization and degradation. Pharmacokinetic/pharmaco- Committee on Cancer Staging Criteria, 6th Edition) and measur- dynamic modeling and simulation suggest that emibetuzu- able disease as defined by Response Evaluation Criteria in Solid mab exposures achieved by 700 mg every 2 weeks (Q2W) or Tumors (RECIST v1.1) were required (12). higher are expected to prevent MET signaling, reduce expres- Patients were excluded if they had received any cancer therapy sion of MET, and inhibit MET-driven growth of tumors based within 21 days or 5 half-lives prior to study enrollment (which- on preclinical studies (11). Three patients treated in the ever was shorter), had not recovered from the acute effects of biologically efficacious dose range of 700 to 2,000 mg emi- treatment-related toxicities, had liver cirrhosis with a Child–Pugh betuzumab 700 mg Q2W or greater demonstrated partial Stage of B or C, or had a second primary malignancy that may response according to Response Evaluation Criteria in Solid affect the interpretation of results. Patients were excluded from Tumors. An additional 9 patients achieved stable disease. Part A2 if they had a symptomatic central nervous system malig- Based on these data, further clinical evaluation of emibetu- nancy or metastasis, prior MET targeting therapy, or if they had zumab is warranted. been previously intolerant of erlotinib therapy. Study treatments Patients in Part A received emibetuzumab at doses of 20, 70, 210, 700, 1,400, or 2,000 mg using a flat dosing scheme every 14 mouse xenografts. Emibetuzumab demonstrated dose-depen- days (Q2W). The starting dose and the dose range were selected dent, single-agent activity in various MET-expressing tumor based on toxicology results and modeling of PK and PD data from models, and additive effects were observed in combination nonclinical studies (11). Emibetuzumab was administered intra- with erlotinib for reducing tumor volume in lung cancer mouse venously over 90 minutes at the 20- to 700-mg dose levels and xenograft models (11). over 150 minutes at the 1,400- and 2,000-mg dose levels. No fi Herein, we report results from the rst-in-human dose intrapatient dose escalations were allowed. In Part A2, patients (FHD) phase I dose-escalation trial of emibetuzumab as mono- with advanced NSCLC were treated with emibetuzumab at esca- therapy (Part A) or combination with erlotinib (Part A2) in lating flat doses of 700, 1,400, and 2,000 mg in combination with patients with advanced or metastatic cancer. The primary erlotinib administered at the dose of 150 mg QD. Part A2 was objectiveofthisstudywastoidentify a recommended phase initiated at a dose level of 700-mg emibetuzumab after the 1,400- 2 dose range for emibetuzumab, when administered as mono- mg emibetuzumab monotherapy dose in Part A was judged to be therapy or in combination with erlotinib to patients with safe and tolerable. advanced cancer. Safety Patients and Methods Safety and tolerability were assessed through clinical and Study design laboratory evaluations at weekly intervals for the first two cycles This study was a multicenter, nonrandomized, open-label, and Q2W thereafter. Adverse events (AE) were graded according to FHD phase I, dose-escalation study of emibetuzumab given as the Common Terminology Criteria for Adverse

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