TAS-121 is an orally available, potent, novel epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) selectively targeting EGFR activating and T790M resistance mutations. This first-in-human phase I study evaluated the maximum tolerated dose (MTD), safety, tolerability, pharmacokinetics (PK), and antitumor activity of TAS-121.
The study was conducted in Japan and consisted of three phases: dose escalation phase (DEP), expansion phase first stage (EP1), and second stage (EP2). Patients were eligible for inclusion in the study if they had advanced EGFR mutation-positive non-small-cell lung cancer (NSCLC) and were previously treated with a first or second-generation EGFR-TKI, or both. The central confirmation of EGFR T790M mutation in plasma circulating cell-free DNA or tumor tissue or both was required for enrollment in the EP2 phase.
As of January 31, 2017, 127 patients had received 4–16 mg TAS-121 dose once daily (QD) or 8–12 mg daily in two divided doses (BID). The most common adverse drug reactions (ADRs) were platelet count decreased (66.9%), pyrexia (44.9%), and rash (37.8%). Other notable ADRs were interstitial lung disease (ILD) (7.9%) and pulmonary embolism (7.1%). All ILD incidences were manageable, and no treatment-related deaths occurred during the study. Dose-limiting toxicities (DLTs) were observed in five and three patients treated QD (drug-induced liver injury, platelet count decreased, urticaria, and ILD) and BID (ILD, platelet count decreased, and left ventricular failure), respectively. The MTD was determined as 10 mg QD and 8 mg BID. PK analyses showed that the area under the curve (AUC) of TAS-121 even at the lowest dose was significantly higher than that of the effective dose in preclinical tumor xenografts model. Furthermore, in the EP2 group, confirmed objective responses according to the independent central review were observed in 25.0 and 44.4% of patients (4/16 and 8/18) administered 8 mg QD and BID, respectively.
TAS-121 was well tolerated up to the MTD and demonstrated antitumor activity in this preliminary phase I study in patients with EGFR T790M mutation-positive NSCLC.
Clinical trial identification
Legal entity responsible for the study
Taiho Pharmaceutical Co., Ltd
Taiho Pharmaceutical Co., Ltd
H. Murakami: Honorarium; Taiho Pharmaceutical, Astrazeneca, Chugai pharma, Novartis, Boehringer Ingelheim, Phizer, Lilly Japan, Ono Pharmaceutical, Bristol-Myers Squibb Japan, Teijin Pharma. Y. Ohe: Honorarium/Consultant/Expert Testimony/Research Funding (Institution); AstraZeneca, Chugai, Lilly, ONO, BMS, Daiichi-Sankyo, Nipponkayaku, Boehringer, Bayer, Pfizer, MSD, Taiho, Clovis, Sanofi, Novartis, Kyorin, Dainippon-Sumitomo, Merck. T. Hida: Honorarium/Research funding (Institution); MSD, Chugai, Pfizer, Novartis, Eli Lilly, Ono, Taiho, AstraZeneca, Nippon Boehringer, BMS, Clovis, Eisai, Takeda Bio, Dainippon Sumitomo, Abbvie, Merck Serono, Kyowa Hakko Kirin, Daiichi Sankyo, Astellas. H. Sakai: Honorarium; Chugai, Ono, Bristol-Meyers Squibb, Eli Lilly, Taiho, MSD, Research Funding (Institution); Chugai, Ono, Bristol-Meyers Squibb, Eli Lilly, Taiho, AstraZeneca, MSD, Merck Serono. K. Kasahara: Honorarium; AstraZeneca, Chugai, Lily Japan. F. Imamura: Speakers’ Bureau; Taiho pharmaceutical, Pfizer, AstraZeneca, Novartis Pharma, Kyowa Hakko Kirin, Boehinger Ingelheim, Ono Pharmaceutical, Eli Lilly Japan, Chugai Pharceutical, Bristol-Myers Squibb. T. Baba: Honorarium; Ono Pharmaceutical, AstraZeneca, Speakers’ Bureau; Ono Pharmaceutical, AstraZeneca. K. Kubota: Speakers’ Bureau; Chugai-Pharma, Japan Eli Lilly, Boehringer–ingelheim, Taiho PharmaceuticaL, MSD, AstraZeneca, Novartis Pharma, Bristol-Myers Squibb, Amgen, Research Funding; Novartis Pharma, Daiichi Sankyo, Boehringer-ingelheim. Y. Hosomi: Personal Fees; AstraZeneca, Eli Lilly Japan, Taiho Pharmaceutical, Chugai Pharmaceutical, Ono Pharmaceutical, Bristol-Myers Squibb, Boehringer-ingelheim. T. Shimokawa: Research Funding (Institution); Taiho Pharmaceutical, Takeda, Ono Pharmaceutical, Bristol-Myers Squibb, MSD, AstraZeneca, Chugai Pharma, Lilly Japan, Merck Serono, Astellas Pharma. H. Hayashi: Advisory boards; AstraZeneca, Eli Lilly Japan, Boehinger, Speakers’ Bureau; Ono Pharmaceutical, Bristol-Myers Squibb, AstraZeneca, Eli Lilly Japan, MSD, Taiho Pharmaceutical, Chugai Pharmaceutical, Boehinger, Research Funding; Ono Pharmaceutical. K. Miyadera: Employment; Taiho Pharmaceutical, Stock; Otsuka Holdings. T. Tamura: Honorarium; Taiho, Chugai, Boehringer Ingelheim, Eli Lilly, Eisai, Yakult, Bristol-Myers Squibb, Ono, Kyowa-Krin. M. Nishio: Research funding; Novartis, ONO, Chugai, Bristol-Myers Squibb, Taiho, Eli Lilly, Pfizer, Astellas Pharma, AstraZeneca, Honorarium; Pfizer, Bristol-Myers Squibb, ONO, Chugai, Eli Lilly, TAIHO, AstraZeneca.