Clinical activity of ASP8273 in Asian patients with non-small-cell lung cancer with EGFR activating and T790M mutations
Journal
Cancer Science
Journal Volume
109
Journal Issue
9
Pages
2852-2862
Date Issued
2018
Author(s)
Murakami H
Nokihara H
Hayashi H
Seto T
Park K
Azuma K
Tsai C.-M
Nishio M
Kim S.-W
Kiura K
Inoue A
Takeda K
Kang J.-H
Nakagawa T
Takeda K
Akazawa R
Kaneko Y
Shimazaki M
Morita S
Fukuoka M
Nakagawa K.
Abstract
Epidermal growth factor receptor (EGFR)-activating mutations confer sensitivity to tyrosine kinase inhibitor (TKI) treatment for non-small-cell lung cancer (NSCLC). ASP8273 is a highly specific, irreversible, once-daily, oral, EGFR TKI that inhibits both activating and resistance mutations. This ASP8273 dose-escalation/dose-expansion study (NCT02192697) was undertaken in two phases. In phase I, Japanese patients (aged ?20?years) with NSCLC previously treated with ?1 EGFR TKI received escalating ASP8273 doses (25-600?mg) to assess safety/tolerability and to determine the maximum tolerated dose (MTD) and/or the recommended phase II dose (RP2D) by the Bayesian Continual Reassessment Method. In phase II, adult patients with T790M-positive NSCLC in Japan, Korea, and Taiwan received ASP8273 at RP2D to further assess safety/tolerability and determine antitumor activity, which was evaluated according to Simon's two-stage design (threshold response?=?30%, expected response?=?50%, α?=?0.05, β?=?0.1). Overall, 121 (n?=?45 [33W/12M] phase I, n?=?76 [48W/28M]) phase 2) patients received ?1 dose of ASP8273. In phase I, RP2D and MTD were established as 300 and 400?mg, respectively. As 27 of the 63 patients treated with ASP8273 300?mg achieved a clinical response, ASP8273 was determined to have antitumor activity. The overall response rate at week 24 in all patients was 42% (n?=?32/76; 95% confidence interval, 30.9-54.0). Median duration of progression-free survival was 8.1?months (95% confidence interval, 5.6, upper bound not reached). The most commonly reported treatment-related adverse event in phase II was diarrhea (57%, n?=?43/76). ASP8273 300?mg was generally well tolerated and showed antitumor activity in Asian patients with both EGFR-activating and T790M mutations. ? 2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.
Subjects
clinical trial; epidermal growth factor receptor; non-small-cell carcinoma; signal transduction inhibitors/kinase inhibitor; tyrosine kinase inhibitor
SDGs
Other Subjects
alanine aminotransferase; aspartate aminotransferase; epidermal growth factor receptor; naquotinib; antineoplastic agent; EGFR protein, human; epidermal growth factor receptor; naquotinib; piperazine derivative; piperidine derivative; protein kinase inhibitor; pyrazine derivative; pyrrolidine derivative; adult; aged; anemia; antineoplastic activity; area under the curve; Article; Asian; bleeding; cohort analysis; colitis; confidence interval; constipation; creatinine blood level; decreased appetite; dehydration; diarrhea; drug activity; drug blood level; drug dose escalation; drug dose increase; drug safety; drug tolerability; dry skin; dysgeusia; electrolyte disturbance; febrile neutropenia; female; gene; gene mutation; hematologic disease; human; hypoalbuminemia; hyponatremia; interstitial lung disease; Japanese (people); Korea; major clinical study; malaise; male; maximum tolerated dose; nausea and vomiting; neutropenia; non small cell lung cancer; peripheral neuropathy; phase 1 clinical trial; phase 2 clinical trial; platelet count; priority journal; progression free survival; QT prolongation; rash; recommended drug dose; sensory neuropathy; side effect; t790m gene; Taiwan; thrombocyte transfusion; thrombocytopenia; treatment response; antagonists and inhibitors; clinical trial; genetics; lung tumor; middle aged; mortality; mutation; non small cell lung cancer; Adult; Aged; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Female; Humans; Lung Neoplasms; Male; Middle Aged; Mutation; Piperazines; Piperidines; Protein Kinase Inhibitors; Pyrazines; Pyrrolidines; Receptor, Epidermal Growth Factor
Publisher
Blackwell Publishing Ltd
Type
journal article