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Phase 1b Trial of Ficlatuzumab, a Humanized Hepatocyte Growth Factor Inhibitory Monoclonal Antibody, in Combination With Gefitinib in Asian Patients With NSCLC.

ABSTRACT: Hepatocyte growth factor (HGF)/c-Met pathway dysregulation is a mechanism for epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). Ficlatuzumab (AV-299; SCH 900105), a humanized IgG1 ? HGF inhibitory monoclonal antibody, prevents HGF/c-Met pathway ligand-mediated activation. This phase 1b study assessed the safety/tolerability, pharmacokinetics/pharmacodynamics, and antitumor activity of ficlatuzumab plus gefitinib in Asian patients with previously treated advanced non-small cell lung cancer (NSCLC). Patients received intravenous ficlatuzumab either 10 mg/kg (cohort 1; n = 3) or 20 mg/kg (cohort 2; n = 12) every 2 weeks plus oral gefitinib 250 mg daily. Patients tolerated the drug combination well. Four treatment-related grade 3/4 adverse events were reported in 3 patients (cohort 2). Pharmacokinetic profiles for ficlatuzumab and gefitinib were consistent with prior single-agent trials. Partial responses were achieved in 5 patients (4 confirmed), all in cohort 2; objective response rate (ORR) was 33% (duration, 1.9-6.4 months). Responding patients had no prior EGFR TKI treatment, 2 without an EGFR mutation. Four additional patients had disease stabilization (cohort 2; duration, 2.7-9.1 months; 42% ORR). The recommended phase 2 dose for ficlatuzumab plus gefitinib 250 mg/day was 20 mg/kg every 2 weeks. This drug combination has shown preliminary dose-related antitumor activity in advanced NSCLC.

SUBMITTER: Tan EH

PROVIDER: S-EPMC6032914 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Phase 1b Trial of Ficlatuzumab, a Humanized Hepatocyte Growth Factor Inhibitory Monoclonal Antibody, in Combination With Gefitinib in Asian Patients With NSCLC.

Tan Eng-Huat EH Lim Wan-Teck WT Ahn Myung-Ju MJ Ng Quan-Sing QS Ahn Jin Seok JS Shao-Weng Tan Daniel D Sun Jong-Mu JM Han May M Payumo Francis C FC McKee Krista K Yin Wei W Credi Marc M Agarwal Shefali S Jac Jaroslaw J Park Keunchil K

Clinical pharmacology in drug development 20180118 5

Hepatocyte growth factor (HGF)/c-Met pathway dysregulation is a mechanism for epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). Ficlatuzumab (AV-299; SCH 900105), a humanized IgG<sub>1</sub> κ HGF inhibitory monoclonal antibody, prevents HGF/c-Met pathway ligand-mediated activation. This phase 1b study assessed the safety/tolerability, pharmacokinetics/pharmacodynamics, and antitumor activity of ficlatuzumab plus gefitinib in Asian patients with previously treated advanc ...[more]

PMID: 29346833

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Project description:IMPORTANCE:Ficlatuzumab can be used to treat head and neck squamous cell carcinoma (HNSCC) by inhibiting c-Met receptor-mediated cell proliferation, migration, and invasion. OBJECTIVE:To understand the effect of ficlatuzumab on HNSCC proliferation, migration, and invasion. DESIGN, SETTING, AND PARTICIPANTS:The effects of ficlatuzumab on HNSCC proliferation, invasion, and migration were tested. Mitigation of c-Met and downstream signaling was assessed by immunoblotting. The tumor microenvironment has emerged as an important factor in HNSCC tumor progression. The most abundant stromal cells in HNSCC tumor microenvironment are tumor-associated fibroblasts (TAFs). We previously reported that TAFs facilitate HNSCC growth and metastasis. Furthermore, activation of the c-Met tyrosine kinase receptor by TAF-secreted hepatocyte growth factor (HGF) facilitates tumor invasion. Ficlatuzumab is a humanized monoclonal antibody that sequesters HGF, preventing it from binding to and activating c-Met. We hypothesized that targeting the c-Met pathway with ficlatuzumab will mitigate TAF-mediated HNSCC proliferation, migration, and invasion. Representative HNSCC cell lines HN5, UM-SCC-1, and OSC-19 were used in these studies. EXPOSURES FOR OBSERVATIONAL STUDIES:The HNSCC cell lines were treated with ficlatuzumab, 0 to 100 µg/mL, for 24 to 72 hours. MAIN OUTCOMES AND MEASURES:Ficlatuzumab inhibited HNSCC progression through c-Met and mitogen-activated protein kinase (MAPK) signaling pathway. RESULTS:Ficlatuzumab significantly reduced TAF-facilitated HNSCC cell proliferation (HN5, P <?.001; UM-SCC-1, P <?.001), migration (HN5, P =?.002; UM-SCC-1, P =?.01; and OSC-19, P =?.04), and invasion (HN5, P =?.047; UM-SCC-1, P =?.03; and OSC-19, P =?.04) through a 3-dimensional peptide-based hydrogel (PGmatrix). In addition, ficlatuzumab also inhibited the phosphorylation of c-Met at Tyr1234/1235 and p44/42 MAPK in HNSCC cells exposed to recombinant HGF. CONCLUSIONS AND RELEVANCE:We demonstrate that neutralizing TAF-derived HGF with ficlatuzumab effectively mitigates c-Met signaling and decreases HNSCC proliferation, migration, and invasion. Thus, ficlatuzumab effectively mitigates stromal influences on HNSCC progression.

Dataset Information

Phase 1b Trial of Ficlatuzumab, a Humanized Hepatocyte Growth Factor Inhibitory Monoclonal Antibody, in Combination With Gefitinib in Asian Patients With NSCLC.

Publications

Phase 1b Trial of Ficlatuzumab, a Humanized Hepatocyte Growth Factor Inhibitory Monoclonal Antibody, in Combination With Gefitinib in Asian Patients With NSCLC.

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