ROS1 or NTRK genetic abnormality is a key oncogenic driver, especially in non-small cell lung cancer (NSCLC). DS-6051b is an orally available and potent selective small molecule inhibitor of ROS1 and NTRK. Preclinical pharmacology studies exhibited antitumor activity of DS-6051b against several types of tumor with ROS1 or NTRK fusion gene.
This is an ongoing phase 1 study in Japanese patients with advanced solid tumors harboring either a ROS1 or NTRK fusion gene. Patients receive continuous once daily (QD) dosing of DS-6051b. Pharmacokinetics (PK) samples are collected from Day1 to Day22. If patients consented, liquid biopsy samples for circulating tumor DNA (ctDNA) analysis are collected at screening and study discontinuation. The primary objective is to evaluate the safety profile and secondary objectives are to determine the maximum tolerated dose (MTD), the recommended phase 2 dose (RP2D) and to assess the PK profile. Exploratory objectives are to assess the tumor responses to DS-6051b by means of Investigator evaluation per RECIST v.1.1 and to explore biomarkers. ClinicalTrials.gov identifier: NCT02675491.
As of Apr 10, 2017, 15 patients are enrolled. The median age is 51 (34-69) years, 46.7% are female, all 15 patients are ROS1 fusion positive NSCLC, and 4 had prior crizotinib (CRZ) treatment. Patients received DS-6051b at doses of 400mg QD (n = 6), 800mg QD (n = 3) and 600mg QD (n = 6). Common adverse events are AST increased, ALT increased, diarrhea and nausea. There are no DLTs in the 400mg and 600mg QD cohorts, and 2 out of 3 patients in the 800mg QD cohort experienced DLTs with grade 3 ALT increased. In 12 patients who had measurable target lesions, 7 demonstrated partial response (PR) and 5 demonstrated stable disease. In 9 CRZ-naïve patients, the overall response rate is 66.7% (6 PRs) and the disease control rate is 100%. Early clinical response was also shown in a subject with brain metastasis. The plasma drug concentration increased in a dose-dependent manner. Currently, ctDNA analyses obtained from pre/post DS-6051b treatment are ongoing.
DS-6051b is well tolerated in Japanese patients with NSCLC and effective especially in CRZ-naïve. The MTD/RP2D is identified as 600mg QD.
Clinical trial identification
Legal entity responsible for the study
Daiichi Sankyo Co., Ltd.
T. Seto: Consulting and advisory services, speaking or writing engagements, public presentations; 14 companies. Direct research support to the responsible project lead; 12 companies (including Daiichi Sankyo Co. Ltd.). Y. Fujiwara: Consulting and advisory services, speaking or writing engagements, public presentations; Bristol-Myers Squibb, Ono Pharmaceutical Co. Ltd., MSD, K.K. (€500-€20’000 p.a). N. Yamamoto: Consulting and advisory services, speaking or writing engagements, public presentations; Eisai Co., Ltd, Takeda Pharmaceutical Company, Ltd., OncoTherapy Science (€500 - €20’000 p.a). K. Nosaki: Consulting and advisory services, speaking or writing engagements, public presentations; 7 companies. Direct research support to the responsible project lead; 2 companies. C. Abe, R. Shiga, K. Nakamaru: Full-time employee of Daiichi Sankyo. Co., Ltd. K. Nakagawa: Consulting and advisory services, speaking or writing engagements, public presentations; Daiichi Sankyo Co,. Ltd., Pfizer Japan Inc. Direct research support to the responsible project lead; Daiichi Sankyo Co,. Ltd., Pfizer Japan Inc. All other authors have declared no conflicts of interest.