Summary
Onartuzumab is a monovalent, humanized, monoclonal antibody that showed significant survival benefits in combination with erlotinib in MET-positive non-small-cell lung cancer (NSCLC) in pre-specified subgroup analyses of a randomized phase II study. We conducted a two-stage, open-label, multicenter, phase I study of onartuzumab in Japanese patients. Stage 1 investigated the safety, tolerability, pharmacokinetics (PK), and recommended dose of onartuzumab in patients with solid tumors, and Stage 2 determined the safety, tolerability, and PK of onartuzumab plus erlotinib in patients with MET-positive NSCLC. Nine patients received onartuzumab monotherapy (4, 15, or 30 mg/kg on Day 1 of each 21-day cycle) in Stage 1, and six patients received onartuzumab (15 mg/kg) plus erlotinib (150 mg/day) in Stage 2. There were no dose-limiting toxicities in either stage. Serious adverse events (AEs) occurred in one patient in Stage 1 (convulsion), and two patients in Stage 2 (once case each of diarrhea, vomiting, and pulmonary embolism), but there were no grade 4 AEs or AEs leading to death. Onartuzumab PKs were linear in the dose range of 4 to 30 mg/kg, and were not affected by co-administration with erlotinib. PK parameters of onartuzumab were similar to those reported in non-Japanese patients. A partial response was observed in a patient with MET immunohistochemistry 3+ NSCLC without MET gene amplification. Based on these results, the recommended dose of onartuzumab in Japanese patients with solid tumors is 15 mg/kg every 21 days. The combination of onartuzumab with erlotinib is feasible in Japanese patients with MET-positive lung cancer.
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References
Rosen EM, Goldberg ID (1997) Regulation of angiogenesis by scatter factor. EXS 79:193–208
Weimar IS, Voermans C, Bourhis JH, Miranda N, van den Berk PC, Nakamura T, de Gast GC, Gerritsen WR (1998) Hepatocyte growth factor/scatter factor (HGF/SF) affects proliferation and migration of myeloid leukemic cells. Leukemia 12:1195–1203
Schmidt NO, Westphal M, Hagel C, Ergün S, Stavrou D, Rosen EM, Lamszus K (1999) Levels of vascular endothelial growth factor, hepatocyte growth factor/scatter factor and basic fibroblast growth factor in human gliomas and their relation to angiogenesis. Int J Cancer 84:10–18
Fazekas K, Csuka O, Köves I, Rásó E, Tímár J (2000) Experimental and clinicopathologic studies on the function of the HGF receptor in human colon cancer metastasis. Clin Exp Metastasis 18:639–649
Derksen PW, de Gorter DJ, Meijer HP, Bende RJ, van Dijk M, Lokhorst HM, Bloem AC, Spaargaren M, Pals ST (2003) The hepatocyte growth factor/Met pathway controls proliferation and apoptosis in multiple myeloma. Leukemia 17:764–774
Lutterbach B, Zeng Q, Davis LJ, Hatch H, Hang G, Kohl E, Gibbs JB, Pan BS (2007) Lung cancer cell lines harboring MET gene amplification are dependent on Met for growth and survival. Cancer Res 67:2081–2088
Koeppen H, Rost S, Yauch RL (2014) Develo** biomarkers to predict benefit from HGF/MET pathway inhibitors. J Pathol 232:210–218
Ichimura E, Maeshima A, Nakajima T, Nakamura T (1996) Expression of c-met/HGF receptor in human non-small cell lung carcinomas in vitro and in vivo and its prognostic significance. Jpn J Cancer Res 87:1063–1069
Masuya D, Huang C, Liu D, Nakashima T, Kameyama K, Haba R, Ueno M, Yokomise H (2004) The tumour-stromal interaction between intratumoral c-Met and stromal hepatocyte growth factor associated with tumour growth and prognosis in non-small-cell lung cancer patients. Br J Cancer 90:1555–1562
Bean J, Brennan C, Shih JY, Riely G, Viale A, Wang L et al (2007) MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib. Proc Natl Acad Sci U S A 104:20932–20937
Merchant M, Ma X, Maun HR, Zheng Z, Peng J, Romero M et al (2013) Monovalent antibody design and mechanism of action of onartuzumab, a MET antagonist with anti-tumor activity as a therapeutic agent. Proc Natl Acad Sci U S A 110:E2987–E2996
Salgia R, Patel P, Bothos J, Yu W, Eppler S, Hegde P et al (2014) Phase I dose-escalation study of onartuzumab as a single agent and in combination with bevacizumab in patients with advanced solid malignancies. Clin Cancer Res 20:1666–1675
Spigel DR, Ervin TJ, Ramlau RA, Daniel DB, Goldschmidt JH Jr, Blumenschein GR Jr et al (2013) Randomized phase II trial of onartuzumab in combination with erlotinib in patients with advanced non-small-cell lung cancer. J Clin Oncol 31:4105–4114
Dziadziuszko R, Wynes MW, Singh S, Asuncion BR, Ranger-Moore J, Konopa K, Rzyman W, Szostakiewicz B, Jassem J, Hirsch FR (2012) Correlation between MET gene copy number by silver in situ hybridization and protein expression by immunohistochemistry in non-small cell lung cancer. J Thorac Oncol 7:340–347
Hidalgo M, Siu LL, Nemunaitis J, Rizzo J, Hammond LA, Takimoto C et al (2001) Phase I and pharmacologic study of OSI-774, an epidermal growth factor receptor tyrosine kinase inhibitor, in patients with advanced solid malignancies. J Clin Oncol 19:3267–3279
Yamamoto N, Horiike A, Fujisaka Y, Murakami H, Shimoyama T, Yamada Y, Tamura T (2008) Phase I dose-finding and pharmacokinetic study of the oral epidermal growth factor receptor tyrosine kinase inhibitor Ro50-8231 (erlotinib) in Japanese patients with solid tumors. Cancer Chemother Pharmacol 61:489–496
Kubota K, Nishiwaki Y, Tamura T, Nakagawa K, Matsui K, Watanabe K et al (2008) Efficacy and safety of erlotinib monotherapy for Japanese patients with advanced non-small cell lung cancer: a phase II study. J Thorac Oncol 3:1439–1445
Penuel E, Li C, Parab V, Burton L, Cowan KJ, Merchant M, Yauch RL, Patel P, Peterson A, Hampton GM, Lackner MR, Hegde PS (2013) HGF as a circulating biomarker of onartuzumab treatment in patients with advanced solid tumors. Mol Cancer Ther 12:1122–1130
Acknowledgments
We thank all of the participating patients and their families, as well as the investigators, study coordinators, operations staff, and the onartuzumab project team (Chugai Pharmaceutical Co., Ltd.). We especially acknowledge the help of Dr. Kawano, Dr. Kaburaki, and Dr. Saito from the Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan. Support for third-party writing assistance for this manuscript was provided by Chugai Pharmaceutical Co., Ltd.
Compliance with ethical standards
The protocol was approved by the institutional review board of the two participating medical centers. The study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines, and all patients provided written informed consent prior to any study-related procedures.
Conflicts of interest
Makoto Nishio has received honoraria from Chugai, Pfizer and Eli Lilly. Hiroshi Nokihara has received honoraria from Sanofi, Eli Lilly and Boehringer Ingelheim. Hidehito Horinouchi has received research support from National Cancer Center Research and Development Fund and honoraria from Johnson & Johnson, Taiho and Eli Lilly. Shunji Takahashi has received research support from Chugai, Taiho, Sanofi, Zenyaku and Novartis and honoraria from Astrazeneka, Novartis, Astellas and Daiichisankyo. Noboru Yamamoto has received support from a project sponsor Quintiles, Chugai, BMS, Astellas, Novartis and Taiho. Yasuhide Yamada has received honoraria from Taiho and Chugai. Masaichi Abe and Takashi Tahata are employees of Chugai, and Takashi Tahata holds stock in Chugai. Tomohide Tamura has received honoraria from Chugai, Eli Lilly, Kyowa Kirin, Pfizer and Exelixis.
Atsushi Horiike, Shinji Nakamichi, Hiroshi Wakui, Fumiyoshi Ohyanagi, Keita Kudo, Noriko Yanagitani, and Yasutoshi Kuboki declare that they have no conflicts of interest.
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Nishio, M., Horiike, A., Nokihara, H. et al. Phase I study of the anti-MET antibody onartuzumab in patients with solid tumors and MET-positive lung cancer. Invest New Drugs 33, 632–640 (2015). https://doi.org/10.1007/s10637-015-0227-5
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DOI: https://doi.org/10.1007/s10637-015-0227-5