title: Phase I study of the anti-MET antibody onartuzumab in patients with solid tumors and MET-positive lung cancer.
abstract: 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.
authors.affiliation: Department of Thoracic Medical Oncology, Cancer Institute Hospital of Japanese Foundation for Cancer Research, 3-10-6 Ariake, Koto-ku, Tokyo, 135-8550, Japan, mnishio@jfcr.or.jp.
authors.forename: Makoto
authors.initials: M
authors.lastname: Nishio
authors.forename: Atsushi
authors.initials: A
authors.lastname: Horiike
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nokihara
authors.forename: Hidehito
authors.initials: H
authors.lastname: Horinouchi
authors.forename: Shinji
authors.initials: S
authors.lastname: Nakamichi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Wakui
authors.forename: Fumiyoshi
authors.initials: F
authors.lastname: Ohyanagi
authors.forename: Keita
authors.initials: K
authors.lastname: Kudo
authors.forename: Noriko
authors.initials: N
authors.lastname: Yanagitani
authors.forename: Shunji
authors.initials: S
authors.lastname: Takahashi
authors.forename: Yasutoshi
authors.initials: Y
authors.lastname: Kuboki
authors.forename: Noboru
authors.initials: N
authors.lastname: Yamamoto
authors.forename: Yasuhide
authors.initials: Y
authors.lastname: Yamada
authors.forename: Masaichi
authors.initials: M
authors.lastname: Abe
authors.forename: Takashi
authors.initials: T
authors.lastname: Tahata
authors.forename: Tomohide
authors.initials: T
authors.lastname: Tamura
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D044466:Asian People; D004305:Dose-Response Relationship, Drug; D000069347:Erlotinib Hydrochloride / Q000627:therapeutic use; D005260:Female; D018628:Gene Dosage; D006801:Humans; D008175:Lung Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000097:blood / Q000235:genetics; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D000069347:Erlotinib Hydrochloride; D019859:Proto-Oncogene Proteins c-met; C584058:onartuzumab