TY - JOUR
T1 - A phase I, Dose escalation study of oral ASP8273 in patients with non–small cell lung cancers with epidermal growth factor receptor mutations
AU - Yu, Helena A.
AU - Spira, Alexander
AU - Horn, Leora
AU - Weiss, Jared
AU - West, Howard
AU - Giaccone, Giuseppe
AU - Evans, Tracey
AU - Kelly, Ronan J.
AU - Desai, Bhardwaj
AU - Krivoshik, Andrew
AU - Moran, Diarmuid
AU - Poondru, Srinivasu
AU - Jie, Fei
AU - Aoyama, Kouji
AU - Keating, Anne
AU - Oxnard, Geoffrey R.
N1 - Funding Information:
We would like to acknowledge all investigators, coordinators, and study site personnel, as well as patients and their families for their participation in this study. This research was sponsored by Astellas Pharma, Inc. Financial support for the development of this manuscript, including writing and editorial assistance under the authors' guidance, was provided by Regina Switzer, Ph.D., of SuccinctChoice and was funded by the study sponsor.
Funding Information:
H.A. Yu is a consultant/advisory board member for AstraZeneca. L. Horn is a consultant/advisory board member for Abbvie, AstraZeneca, Bayer, Bristol-Myers Squibb, Janssen, Lilly, Merck, Roche-Genentech, and Xcover. J. Weiss reports receiving commercial research grants from Astellas and AstraZeneca. H. West reports receiving speakers bureau honoraria from Genentech/Roche and is a consultant/advisory board member for Astellas, AstraZeneca, Boehringer-Ingelheim, and Genentech/Roche. R.J. Kelly is a consultant/advisory board member for Astellas. G.R. Oxnard is a consultant/advisory board member for AstraZeneca, Guardant, Inivata, Novartis, Sysmex, and Takeda. No potential conflicts of interest were disclosed by the other authors.
Publisher Copyright:
© 2017 American Association for Cancer Research.
PY - 2017
Y1 - 2017
N2 - 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 ¼ 36), response–expansion (n ¼ 36), RP2D (300 mg; n ¼ 19) and food–effect (n ¼ 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 ¼ 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.
AB - 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 ¼ 36), response–expansion (n ¼ 36), RP2D (300 mg; n ¼ 19) and food–effect (n ¼ 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 ¼ 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.
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U2 - 10.1158/1078-0432.CCR-17-1447
DO - 10.1158/1078-0432.CCR-17-1447
M3 - Article
C2 - 28954786
AN - SCOPUS:85038597450
SN - 1078-0432
VL - 23
SP - 7467
EP - 7473
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 24
ER -