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

Overview

abstract

  • Purpose: Acquired EGFR T790M mutations are the most frequently identified resistance mechanism to EGFR tyrosine kinase inhibitors (TKI) in patients with EGFR-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 EGFR T790M.Experimental Design: 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. EGFR 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.Results: A total of 110 patients were treated with ASP8273 across dose escalation (n = 36), response-expansion (n = 36), RP2D (300 mg; n = 19) and food-effect (n = 19) cohorts. The most common treatment-emergent adverse events included diarrhea, nausea, fatigue, constipation, vomiting, and hyponatremia. Across all doses, in patients with EGFR T790M, the response rate was 30.7% (n = 27/88; 95% CI, 19.5%-44.5%), and median progression-free survival was 6.8 months (95% CI, 5.5-10.1 months). EGFR mutations in cfDNA, both the activating mutation and EGFR T790M, became undetectable in most patients in the setting of clinical response and reemerged upon disease progression.Conclusions: ASP8273 was well tolerated and promoted antitumor activity in patients with EGFR-mutant lung cancer with disease progression on prior EGFR TKI therapy. Clin Cancer Res; 23(24); 7467-73. ©2017 AACR.

authors

  • Yu, Helena
  • Spira, Alexander
  • Horn, Leora
  • Weiss, Jared
  • West, Howard
  • Giaccone, Giuseppe
  • Evans, Tracey
  • Kelly, Ronan J
  • Desai, Bhardwaj
  • Krivoshik, Andrew
  • Moran, Diarmuid
  • Poondru, Srinivasu
  • Jie, Fei
  • Aoyama, Kouji
  • Keating, Anne
  • Oxnard, Geoffrey R

publication date

  • September 27, 2017

Research

keywords

  • Carcinoma, Non-Small-Cell Lung
  • Genes, erbB-1
  • Midazolam
  • Piperazines
  • Piperidines
  • Protein Kinase Inhibitors
  • Pyrazines
  • Pyrrolidines

Identity

Scopus Document Identifier

  • 85038597450

Digital Object Identifier (DOI)

  • 10.1158/1078-0432.CCR-17-1447

PubMed ID

  • 28954786

Additional Document Info

volume

  • 23

issue

  • 24