A Phase I, Dose Escalation Study of Oral ASP8273 in Patients with Non-small Cell Lung Cancers with Epidermal Growth Factor Receptor Mutations.

Abstract

<b>Purpose:</b> Acquired <i>EGFR</i> T790M mutations are the most frequently identified resistance mechanism to EGFR tyrosine kinase inhibitors (TKI) in patients with <i>EGFR</i>-mutant lung cancers. ASP8273 is a third-generation EGFR TKI with antitumor activity in preclinical models of EGFR-mutant lung cancer that targets mutant EGFR, including <i>EGFR</i> T790M.<b>Experimental Design:</b> In this multicohort, phase I study (NCT02113813), escalating doses of ASP8273 (25-500 mg) were administered once daily to non-small cell lung cancer (NSCLC) patients with disease progression after prior treatment with an EGFR TKI. <i>EGFR</i> T790M was required for all cohorts, except the dose escalation cohort. Primary endpoints were safety/tolerability; secondary endpoints were determination of the RP2D, pharmacokinetic profile, and preliminary antitumor activity of ASP8273. Evaluation of the use of EGFR mutations in circulating free DNA (cfDNA) as a biomarker of ASP8273 treatment effects was an exploratory endpoint.<b>Results:</b> A total of 110 patients were treated with ASP8273 across dose escalation (<i>n</i> = 36), response-expansion (<i>n</i> = 36), RP2D (300 mg; <i>n</i> = 19) and food-effect (<i>n</i> = 19) cohorts. The most common treatment-emergent adverse events included diarrhea, nausea, fatigue, constipation, vomiting, and hyponatremia. Across all doses, in patients with <i>EGFR</i> T790M, the response rate was 30.7% (<i>n</i> = 27/88; 95% CI, 19.5%-44.5%), and median progression-free survival was 6.8 months (95% CI, 5.5-10.1 months). <i>EGFR</i> mutations in cfDNA, both the activating mutation and <i>EGFR</i> T790M, became undetectable in most patients in the setting of clinical response and reemerged upon disease progression.<b>Conclusions:</b> ASP8273 was well tolerated and promoted antitumor activity in patients with <i>EGFR</i>-mutant lung cancer with disease progression on prior EGFR TKI therapy. <i>Clin Cancer Res; 23(24); 7467-73. ©2017 AACR</i>.