Oncotarget

Clinical Research Papers:

Safety and pharmacokinetics of DS-6051b in Japanese patients with non-small cell lung cancer harboring ROS1 fusions: a phase I study

Yutaka Fujiwara _, Masayuki Takeda, Noboru Yamamoto, Kazuhiko Nakagawa, Kaname Nosaki, Ryo Toyozawa, Chihiro Abe, Ryota Shiga, Kenji Nakamaru and Takashi Seto

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Oncotarget. 2018; 9:23729-23737. https://doi.org/10.18632/oncotarget.25263

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Abstract

Yutaka Fujiwara1, Masayuki Takeda2, Noboru Yamamoto1, Kazuhiko Nakagawa2, Kaname Nosaki3, Ryo Toyozawa3, Chihiro Abe4, Ryota Shiga4, Kenji Nakamaru4 and Takashi Seto3

1Department of Experimental Therapeutics, National Cancer Center Hospital, Chuo-ku, Tokyo 104-0045, Japan

2Department of Medical Oncology, Kindai University Faculty of Medicine, Osaka-Sayama-shi, Osaka 589-8511, Japan

3Department of Thoracic Oncology, National Hospital Organization Kyushu Cancer Center, Minami-ku, Fukuoka-shi, Fukuoka 811-1395, Japan

4Daiichi Sankyo Co., Ltd., Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan

Correspondence to:

Yutaka Fujiwara, email: yutakafu@ncc.go.jp

Keywords: DS-6051b; non-small cell lung cancer; ROS1; pharmacokinetics; Japanese

Received: December 19, 2017     Accepted: April 06, 2018     Published: May 04, 2018

ABSTRACT

Oncogenic ROS1 and NTRK fusions were reported in solid tumors, including non-small cell lung cancer (NSCLC). DS-6051b is an oral, potent selective small molecule tyrosine kinase inhibitor. We report the safety, tolerability, efficacy, and pharmacokinetics of DS-6051b in 15 Japanese patients with NSCLC harboring ROS1 fusions. Patients received DS-6051b once daily (400 mg n = 6; 600 mg n = 6; or 800 mg n = 3) for cycles of 3 weeks. Safety, tolerability, maximum-tolerated dose, pharmacokinetics, and recommended dose for phase II were determined. Common treatment-related adverse events were increased: aspartate aminotransferase and alanine aminotransferase (80.0% each), diarrhea (53.3%), and nausea (46.7%). Dose-limiting toxicities (two grade-3 alanine aminotransferase increases) were seen in the 800 mg cohort. The maximum-tolerated dose and recommended phase II dose was 600 mg once daily. Plasma concentrations of free DS-6051b and DS-6051a increased with dose. Compared with a US phase I study, AUC0–24 h on day 15 was higher but narrowed after body weight correction. Objective response rate was 58.3% in patients with target lesions (n = 12) and 66.7% in crizotinib-naïve patients (n = 9). Disease control rate was 100%. DS-6051b is well tolerated and effective in Japanese patients with NSCLC harboring ROS1 fusions and might be a targeted therapy for advanced NSCLC.


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PII: 25263