Abstract 570P
Background
Up-regulation of AXL tyrosine kinase expression is observed various tumor types including EGFR-mutant (EGFRm) NSCLC with progressive disease on EGFR tyrosine kinase inhibitors (TKIs), especially in a T790M negative population. Xenograft studies have demonstrated that combined inhibition of AXL and EGFR can overcome and delay the onset of resistance. DS-1205c is a novel, orally administered, highly selective small molecule inhibitor of AXL, and it’s first-in-human clinical study is described here.
Methods
An ongoing first-in-human, multicenter, open-label, dose escalation Phase 1 study of DS-1205c in combination with gefitinib in metastatic or unresectable EGFRm NSCLC is being conducted. Eligible subjects must have evidence of radiological disease progression during treatment with an EGFR TKI without the T790M resistance mutation. Subjects initially receive DS-1205c monotherapy twice daily (BID) during a run-in period of one week, followed by combination treatment with gefitinib 250 mg once daily. Escalation of DS-1205c dosing is guided by the modified Continuous Reassessment Method using a Bayesian logistic regression model following the escalation with overdose control principle. Primary and secondary endpoints include safety, pharmacokinetics, and preliminary efficacy. Exploratory biomarker analyses include assessment of tumor AXL expression through immunohistochemistry and circulating biomarkers.
Results
Dose Escalation in Cohort 1 (200 mg BID; n=5), Cohort 2 (400 mg BID; n=4), Cohort 3 (800 mg BID; n=6), Cohort 4 (1,000 mg BID; n=1), and Cohort 5 (1,200 mg BID; n=4) has been completed as of Apr 8, 2020. One subject in Cohort 3 and 1 subjects in Cohort 5 experienced dose limiting toxicity, and recommended dose for expansion (RDE) was determined as 800 mg BID. There have been no serious adverse events directly related to DS-1205c. Preliminary analysis of efficacy data reveals that one patient had prolonged stable disease beyond 100 days (RECIST v.1.1).
Conclusions
Dose Escalation has been completed with the result that RDE is 800 mg BID, and updated clinical and biomarker data will be presented.
Clinical trial identification
NCT03599518.
Editorial acknowledgement
Legal entity responsible for the study
Daiichi Sankyo.
Funding
Daiichi Sankyo.
Disclosure
M. Nishio: Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Pfizer; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Chugai Pharmaceutical; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Eli Lilly; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Taiho Pharmaceutical; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): AstraZeneca; Advisory/Consultancy, Speaker Bureau/Expert testimony: Boehringer-Ingelheim; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): MSD; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Novartis; Advisory/Consultancy, Speaker Bureau/Expert testimony: Merck Biopharma; Advisory/Consultancy, Speaker Bureau/Expert testimony: Daiichi Sankyo; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Takeda Pharmaceutical Company Limited; Advisory/Consultancy, Speaker Bureau/Expert testimony: Teijin Pharma Limited.; Advisory/Consultancy, Speaker Bureau/Expert testimony: AbbVie. I. Okamoto: Honoraria (self), Research grant/Funding (institution): AstraZeneca; Honoraria (self), Research grant/Funding (institution): Taiho Pharmaceutical; Honoraria (self), Research grant/Funding (institution): Ono Pharmaceutical; Honoraria (self), Research grant/Funding (institution): MSD Oncology; Honoraria (self), Research grant/Funding (institution): Lilly; Honoraria (self), Research grant/Funding (institution): Astellas Pharma; Honoraria (self), Research grant/Funding (institution): Bristol-Myers Squibb; Honoraria (self), Research grant/Funding (institution): Chugai Pharma; Honoraria (self), Research grant/Funding (institution): AbbVie. H. Murakami: Honoraria (self), Research grant/Funding (institution): AstraZeneca; Honoraria (self), Research grant/Funding (institution): Chugai pharma; Honoraria (self), Research grant/Funding (institution): Lilly Japan; Honoraria (self), Research grant/Funding (institution): Taiho Pharmaceutical; Honoraria (self), Research grant/Funding (institution): Takeda; Honoraria (self): Ono Pharmaceutical; Honoraria (self): Bristol-Myers Squibb Japan; Honoraria (self): MSD; Research grant/Funding (institution): Daiichi Sankyo; Research grant/Funding (institution): AbbVie; Research grant/Funding (institution): IQvia. H. Horinouchi: Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Lilly; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): AstraZeneca; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): MSD; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Chugai; Honoraria (self), Research grant/Funding (institution): Kyowa-Kirin; Honoraria (self), Research grant/Funding (institution): BMS; Honoraria (self), Research grant/Funding (institution): Ono; Research grant/Funding (institution): Merck Biophama; Research grant/Funding (institution): Novartis; Research grant/Funding (institution): Daiichi-Sankyo; Research grant/Funding (institution): Jansen; Research grant/Funding (institution): Boehringer; Research grant/Funding (institution): Genomic Health. R. Toyozawa: Honoraria (self): Kyowa Hakko Kirin; Honoraria (self): Nippon Kayaku; Honoraria (self): Novartis Pharma; Research grant/Funding (institution): AbbVie; Research grant/Funding (institution): Daiichi Sankyo; Research grant/Funding (institution): Pfizer Japan ; Research grant/Funding (institution): Takeda Pharmaceutical. M. Takeda: Honoraria (self), Research grant/Funding (institution): Boehringer Ingelheim; Honoraria (self), Research grant/Funding (institution): Chugai Pharmaceutical; Honoraria (self), Research grant/Funding (institution): AstraZeneca; Honoraria (self), Research grant/Funding (institution): Ono Pharmaceutical; Honoraria (self): Novartis; Research grant/Funding (institution): Daiichi Sankyo; Research grant/Funding (institution): Eisai; Research grant/Funding (institution): Taiho Pharmaceutical; Research grant/Funding (institution): MSD; Research grant/Funding (institution): Takeda; Research grant/Funding (institution): Pfizer; Research grant/Funding (institution): Merck; Research grant/Funding (institution): Bristol-Myers Squibb. M. Uno: Full/Part-time employment: Daiichi Sankyo. N. Crawford: Full/Part-time employment: Daiichi Sankyo; Shareholder/Stockholder/Stock options, Full/Part-time employment: Sanofi. T. Jimbo: Shareholder/Stockholder/Stock options, Full/Part-time employment: Daiichi Sankyo. M. Ishigami: Shareholder/Stockholder/Stock options, Full/Part-time employment: Daiichi-Sankyo Co., Ltd.. G. Takayama: Full/Part-time employment: Daiichi Sankyo. S. Nakayama: Full/Part-time employment: Daiichi Sankyo. S. Ohwada: Full/Part-time employment: Daiichi Sankyo. E. Slosberg: Shareholder/Stockholder/Stock options, Full/Part-time employment: Daiichi Sankyo. K. Goto: Honoraria (self), Research grant/Funding (self), Research grant/Funding (institution): Daiichi Sankyo Co., Ltd..