Abstract A47: Clinical profile of ASP8273, a mutant-selective EGFR inhibitor, in subjects with EGFR-mutation positive non-small cell lung cancer: interim results from an ongoing, phase 1, open-label, dose-escalation study
Authors: Yu Helena , Oxnard Geoffrey R. , Spira Alexander , Horn Leora , Weiss Jared , Feng Yan , West Howard , Giaccone Giuseppe , Evans Tracey , Kelly Ronan , Fleege Tanya , Poondru Srinivasu , Jie Fei , Aoyama Kouji , Whitcomb Debbie , Keating Anne , Krivoshik Andrew 
Published: May 2016

Abstract
Introduction: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) have demonstrated antitumor effects in patients with EGFR-mutant lung cancers; however, within a year, patients typically become resistant to TKI treatment. ASP8273 is a third-generation, once daily, orally administered, irreversible EGFR TKI that selectively inhibits EGFR mutations (e.g., exon 19 deletions, L858R, exon 20 insertion) as well as a secondary mutation associated with TKI resistance (T790M).
Methods: ASP8273 is under evaluation in an ongoing, Phase 1 dose-escalation study conducted in the United States. Subjects diagnosed with EGFR mutation-positive non-small cell lung cancer (NSCLC) previously treated with an EGFR TKI were enrolled into the dose escalation cohort (25-500 mg) and response expansion (100-400 mg) cohorts. Response expansion cohorts enrolled subjects with EGFR T790M mutation and required submission of tissue samples for central confirmatory testing. Primary endpoint was tolerability assessed via adverse events (AEs) monitoring; secondary endpoints were pharmacokinetic (PK) parameters and antitumor activity based on RECIST 1.1 criteria.
Results: As of June 18, 2015, 69 subjects (19 M/50 F) with a median age of 64 years (range: 38-85 years) had been enrolled into the dose escalation (n = 34) and response expansion (n = 35) cohorts. All patients had EGFR mutation(s); exon 19 deletions, L858R, and exon 20 insertions were identified in 54%, 17%, and 3% of subjects, respectively. EGFR T790M mutation was confirmed in 51% of subjects. Diarrhea, nausea, and fatigue (all Grades) were the most common treatment-emergent and treatment-related AEs. Hyponatremia (n = 8), anemia (n = 2), diarrhea (n = 2), nausea (n = 2), and progressive disease (n = 2) were the only Grade ≥3 treatment-emergent AEs reported in ≥2 subjects; serious AEs reported in ≥2 subjects were hyponatremia (n = 2), nausea (n = 2), and progressive disease (n = 2). ASP8273 exposure appeared dose proportional with peak concentration occurring approximately 1-4 h after administration with a half-life of 6-14 h. Of the 45 subjects treated with ASP8273 100-500 mg with evaluable data, partial response (PR) has been achieved by 42% (19/45) subjects. PR was reached by 12 of the 25 (48%) T790M-positive subjects, 3 of the 6 (50%) T790M-negative subjects, 4 of the 14 (29%) of subjects with unknown T790M status, and 1 of the 2 (50%) subjects with a confirmed exon 20 insertion.
Conclusions: ASP8273, at doses &lt;400 mg/day, was generally well tolerated with dose-proportional PK. At doses of ≥100 mg, ASP8273 demonstrated antitumor activity in subjects with EGFR mutation-positive NSCLC, including subjects with and without EGFR T790M and patients with EGFR exon 20 insertions.
Citation Format: Helena Yu, Geoffrey R. Oxnard, Alexander Spira, Leora Horn, Jared Weiss, Yan Feng, Howard West, Giuseppe Giaccone, Tracey Evans, Ronan Kelly, Tanya Fleege, Srinivasu Poondru, Fei Jie, Kouji Aoyama, Debbie Whitcomb, Anne Keating, Andrew Krivoshik. Clinical profile of ASP8273, a mutant-selective EGFR inhibitor, in subjects with EGFR-mutation positive non-small cell lung cancer: interim results from an ongoing, phase 1, open-label, dose-escalation study. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A47.