Moser, Brian A.

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 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.

Abstract Background: Activation of the hepatocyte growth factor (HGF)/mesenchymal-epithelial transition factor receptor (MET) pathway promotes tumor growth, invasion and dissemination. Emibetuzumab is a humanized IgG4 monoclonal antibody that binds to and inhibits ligand-dependent and ligand-independent activation of MET. In the first-in-human dose escalation study NCT0128756, emibetuzumab demonstrated favorable tolerability when administered up to 2000mg Q2W IV in unselected patients. The study was expanded to evaluate emibetuzumab in expansion cohorts for patients with tumors positive for MET expression. Methods: Patients with locally advanced or metastatic castration-resistant prostate cancer (CRPC) with bone metastasis, renal cell carcinoma (RCC), non-small cell lung cancer (NSCLC), and hepatocellular carcinoma (HCC) received 2000 mg emibetuzumab Q2W IV on a 28-day cycle. RCC, NSCLC, and HCC patients were required to have measurable disease as defined by RECIST v1.1 and have MET positive tumors (≥50% of cells to be ≥2+ for MET expression) as determined by a MET IHC assay (Ventana). The objectives were to evaluate the safety and activity of emibetuzumab in patients with MET positive tumors. Additional objectives included pharmacokinetics (PK) and pharmacodynamics (PD). Results: A total of 62 patients received emibetuzumab across the 4 cohorts: CRPC n = 15, RCC n = 19, NSCLC n = 19,and HCC n = 9, with a median of prior systemic oncology therapies of 6, 3, 5, and 3, respectively. Common possibly related treatment-emergent adverse events included fatigue (29% all grades, 3% Gr3/4), nausea (13% all grades, no Gr3/4), edema of limbs (8% all grades, 2% Gr3/4), and anorexia (8%, no Gr3/4) and were similar among cohorts. No evidence of clinical activity was observed in CRPC patients. For RCC, NSCLC, and HCC patients with MET positive tumors, an overall disease control rate (DCR = partial response [PR] + stable disease [SD]) of 32% (15/47) was observed. In the individual cohorts, DCR was 26% (5/19) in RCC, 26% (5/19) in NSCLC, and 56% (5/9) in HCC. The median duration of disease stabilization in the 3 cohorts was: 4.2 months (range 1.6-24.6) in RCC, 3.9 months (range 2.5-6.4) in NSCLC, and 3.7 months (range 1.2-6.6) in HCC. One PR was observed in an HCC patient with MET amplification. After a single dose of 2000 mg emibetuzumab, PK parameters were similar among these cohorts and also comparable to patients treated at this dose during dose escalation. Conclusions: In cohorts enriched for tumor MET expression, limited single-agent activity of emibetuzumab was observed indicating that MET positivity by IHC (Ventana assay) at the cut-point employed here might not be a sufficient predictive biomarker to select patients receiving benefit from emibetuzumab monotherapy for the tumor types studied. Further evaluation of biomarkers/assays to identify patients who may benefit from treatment with emibetuzumab may be warranted. Citation Format: Michaela S. Banck, Rashmi Chugh, Ronald B. Natale, Alain Algazi, Bradley C. Carthon, Lee S. Rosen, Michael E. Menefee, Andrew Xiuxuan Zhu, Takami Sato, Brian Moser, P. Kellie Turner, Jay Tuttle, Xuejing Aimee Wang, Volker Wacheck, Frederick E. Millard. Phase 1 results of emibetuzumab (LY2875358), a bivalent MET antibody, in patients with advanced castration-resistant prostate cancer, and MET positive renal cell carcinoma, non-small cell lung cancer, and hepatocellular carcinoma. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A55.