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

Eng-Huat Tan, Wan-Teck Lim, Myung-Ju Ahn, Quan-Sing Ng, Jin Seok Ahn, Daniel Shao-Weng Tan, Jong-Mu Sun, May Han, Francis C Payumo, Krista McKee, Wei Yin, Marc Credi, Shefali Agarwal, Jaroslaw Jac, Keunchil Park, Eng-Huat Tan, Wan-Teck Lim, Myung-Ju Ahn, Quan-Sing Ng, Jin Seok Ahn, Daniel Shao-Weng Tan, Jong-Mu Sun, May Han, Francis C Payumo, Krista McKee, Wei Yin, Marc Credi, Shefali Agarwal, Jaroslaw Jac, Keunchil Park

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 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 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.

Trial registration: ClinicalTrials.gov NCT01039948.

Keywords: NSCLC; ficlatuzumab; gefitinib; lung adenocarcinoma; non-small cell lung cancer.

© 2018, The Authors. Clinical Pharmacology in Drug Development published by Wiley Periodicals, Inc. on behalf of The American College of Clinical Pharmacology.

Figures

Figure 1
Figure 1
Mean ficlatuzumab concentrations (μg/mL) versus time by 10 and 20 mg/kg doses. Error bars reflect standard deviation. Solid vertical lines reflect separate treatment cycles, and dashed vertical lines reflect nominal ficlatuzumab dosing times.
Figure 2
Figure 2
Serum HGF levels (ng/mL) after ficlatuzumab and gefitinib treatment by patient number.

References

    1. NCCN Clinical Practice Guidelines in Oncology . Non‐small cell lung cancer. V7.2017. 2017. . Accessed July 13, 2017.
    1. Amann J, Kalyankrishna S, Massion PP, et al. Aberrant epidermal growth factor receptor signaling and enhanced sensitivity to EGFR inhibitors in lung cancer. Cancer Res. 2005;65:226–235.
    1. Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non‐small‐cell lung cancer to gefitinib. N Engl J Med. 2004;350:2129–2139.
    1. Sequist LV, Martins RG, Spigel D, et al. First‐line gefitinib in patients with advanced non‐small‐cell lung cancer harboring somatic EGFR mutations. J Clin Oncol. 2008;26:2442–2449.
    1. Miller VA, Riely GJ, Zakowski MF, et al. Molecular characteristics of bronchioloalveolar carcinoma and adenocarcinoma, bronchioloalveolar carcinoma subtype, predict response to erlotinib. J Clin Oncol. 2008;26:1472–1478.
    1. Eberhard DA, Johnson BE, Amler LC, et al. Mutations in the epidermal growth factor receptor and in KRAS are predictive and prognostic indicators in patients with non‐small‐cell lung cancer treated with chemotherapy alone and in combination with erlotinib. J Clin Oncol. 2005;23:5900–5909.
    1. Mok TS, Wu Y‐L, Thongprasert S, et al. Gefitinib or carboplatin‐paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361:947–957.
    1. Riely GJ, Pao W, Pham D, et al. Clinical course of patients with non‐small cell lung cancer and epidermal growth factor receptor exon 19 and exon 21 mutations treated with gefitinib or erlotinib. Clin Cancer Res. 2006;12:839–844.
    1. Kobayashi S, Boggon TJ, Dayaram T, et al. EGFR mutation and resistance of non‐small‐cell lung cancer to gefitinib. N Engl J Med. 2005; 352:786–792.
    1. Pao W, Miller VA, Politi KA, et al. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med. 2005;2:e73.
    1. Engelman JA, Jänne PA. Mechanisms of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non‐small cell lung cancer. Clin Cancer Res. 2008;14:2895–2899.
    1. Yano S, Wang W, Li Q, et al. Hepatocyte growth factor induces gefitinib resistance of lung adenocarcinoma with epidermal growth factor receptor‐activating mutations. Cancer Res. 2008;68:9479–9487.
    1. Yano S, Yamada T, Takeuchi S, et al. Hepatocyte growth factor expression in EGFR mutant lung cancer with intrinsic and acquired resistance to tyrosine kinase inhibitors in a Japanese cohort. J Thorac Oncol. 2011;6:2011–2017.
    1. Birchmeier C, Birchmeier W, Gherardi E, Vande Woude GF. Met, metastasis, motility and more. Nat Rev Mol Cell Biol. 2003;4:915–925.
    1. Trusolino L, Comoglio PM. Scatter‐factor and semaphorin receptors: cell signalling for invasive growth. Nat Rev Cancer. 2002;2:289–300.
    1. Weidner KM, Sachs M, Birchmeier W. The Met receptor tyrosine kinase transduces motility, proliferation, and morphogenic signals of scatter factor/hepatocyte growth factor in epithelial cells. J Cell Biol. 1993;121:145–154.
    1. Siegfried JM, Weissfeld LA, Luketich JD, Weyant RJ, Gubish CT, Landreneau RJ. The clinical significance of hepatocyte growth factor for non‐small cell lung cancer. Ann Thorac Surg. 1998;66:1915–1918.
    1. Masago K, Togashi Y, Fujita S, et al. Clinical significance of serum hepatocyte growth factor and epidermal growth factor gene somatic mutations in patients with non‐squamous non‐small cell lung cancer receiving gefitinib or erlotinib. Med Oncol. 2012;29:1614–1621.
    1. Han JY, Kim JY, Lee SH, Yoo NJ, Choi BG. Association between plasma hepatocyte growth factor and gefitinib resistance in patients with advanced non‐small cell lung cancer. Lung Cancer. 2011;74:293–299.
    1. Turke AB, Zejnullahu K, Wu YL, et al. Preexistence and clonal selection of MET amplification in EGFR mutant NSCLC. Cancer Cell. 2010;17:77–88.
    1. Zhang YW, Staal B, Essenburg C, et al. MET kinase inhibitor SGX523 synergizes with epidermal growth factor receptor inhibitor erlotinib in a hepatocyte growth factor‐dependent fashion to suppress carcinoma growth. Cancer Res. 2010;70:6880–6890.
    1. Meetze KA, Boudrow A, Connolly K, Huang R, Rideout W, Gyuris J. Anti‐tumor activity of SCH 900105 (AV299), an anti‐HGF antibody, in non‐small cell lung cancer models [AACR abstract C173]. Mol Cancer Ther. 2009;8(suppl 1).
    1. Meetze KA, Connolly K, Boudrow A, et al. Preclinical efficacy and pharmacodynamics of SCH 900105 (AV‐299) an anti‐HGF antibody in an intracranial glioblastoma model [AACR abstract C181]. Mol Cancer Ther. 2009;8(suppl 1).
    1. Sano Y, Hashimoto E, Nakatani N, et al. Combining onartuzumab with erlotinib inhibits growth of non‐small cell lung cancer with activating EGFR mutations and HGF overexpression. Mol Cancer Ther. 2015;14(2):533–541.
    1. Stabile LP, Rothstein ME, Keohavong P, et al. Targeting of both the c‐Met and EGFR pathways results in additive inhibition of lung tumorigenesis in transgenic mice. Cancers (Basel). 2010;2:2153–2170.
    1. Wang W, Li Q, Takeuchi S, Yamada T, et al. Met kinase inhibitor E7050 reverses three different mechanisms of hepatocyte growth factor‐induced tyrosine kinase inhibitor resistance in EGFR mutant lung cancer. Clin Cancer Res. 2012;18:1663–1671.
    1. Okamoto W, Okamoto I, Tanaka K, et al. TAK‐701, a humanized monoclonal antibody to hepatocyte growth factor, reverses gefitinib resistance induced by tumor‐derived HGF in non‐small cell lung cancer with an EGFR mutation. Mol Cancer Ther. 2010;9:2785–2792.
    1. Tan E, Park K, Lim WT, et al. Phase Ib study of ficlatuzumab (formerly AV‐299), an anti‐hepatocyte growth factor (HGF) monoclonal antibody (MAb) in combination with gefitinib (G) in Asian patients (pts) with NSCLC [ASCO abstract 7571]. J Clin Oncol. 2011;29(suppl).
    1. Han M, Breault L, Wright K, et al. In vivo genetic screens designed to complement loss of HER2 or kRas functions identify c‐Met/HGF pathway as potent driver of growth/survival in solid tumor models [AACR abstract 4887]. Cancer Res. 2007;67(suppl 9).
    1. Meetze KA, Connolly K, Zi T, Heyer J, Gyuris J, Han M. Antitumor activity of ficlatuzumab in combination with cetuximab on squamous cell carcinomas of the head and neck. Eur J Cancer. 2012;48(suppl 6):92.
    1. Patnaik A, Weiss GJ, Papadopoulos K, et al. Phase I ficlatuzumab monotherapy or with erlotinib for refractory advanced solid tumors and multiple myeloma. Br J Cancer. 2014;111:272–280.
    1. Mok TS, Geater SL, Su WC, et al. A randomized phase 2 study comparing the combination of ficlatuzumab and gefitinib with gefitinib alone in Asian patients with advanced stage pulmonary adenocarcinoma. J Thorac Oncol. 2016;11(10):1736–1744.
    1. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228–247.
    1. Spigel DR, Edelman MJ, Mok T, et al. The MetLUNG study: A randomized, double‐blind, phase III study of onartuzumab (MetMAb) plus erlotinib in patients with advanced, MET‐positive non‐small cell lung cancer (NSCLC) [ASCO abstract TPS7616]. J Clin Oncol. 2012:30(suppl).
    1. Feng Y, Thiagarajan PS, Ma PC. MET signaling: novel targeted inhibition and its clinical development in lung cancer. J Thorac Oncol. 2012:7;459–467.
    1. Gozdzik‐Spychalska J, Szyszka‐Barth K, Spychalski L, et al. c‐MET inhibitors in the treatment of lung cancer. Curr Treat Options Oncol. 2014;15:670–682.
    1. Scagliotti GV, Novello S, von Pawel J. The emerging role of MET/HGF inhibitors in oncology. Cancer Treat Rev. 2013;39:793–801.
    1. Tabernero J, Elez ME, Herranz M, et al. A pharmacodynamic/pharmacokinetic study of ficlatuzumab in patients with advanced solid tumors and liver metastases. Clin Cancer Res. 2014;20:2793–2804.
    1. Gordon MS, Sweeney CS, Mendelson DS, et al. Safety, pharmacokinetics, and pharmacodynamics of AMG 102, a fully human hepatocyte growth factor–neutralizing monoclonal antibody, in a first‐in‐human study of patients with advanced solid tumors. Clin Cancer Res. 2010;16;699–710.

Source: PubMed

Szponzorok és közreműködők

Egészségi állapot

Kábítószer-beavatkozások

3
Iratkozz fel