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Poster display session

1893 - Phase I study of TAS-121, a novel third-generation epidermal growth factor receptor (EGFR) inhibitor, in patients with EGFR mutation-positive non-small-cell lung cancer (NSCLC)

Date

09 Sep 2017

Session

Poster display session

Presenters

Haruyasu Murakami

Citation

Annals of Oncology (2017) 28 (suppl_5): v460-v496. 10.1093/annonc/mdx380

Authors

H. Murakami1, Y. Ohe2, T. Hida3, H. Sakai4, K. Kasahara5, F. Imamura6, T. Baba7, K. Kubota8, Y. Hosomi9, T. Shimokawa10, H. Hayashi11, K. Miyadera12, T. Tamura13, M. Nishio14

Author affiliations

  • 1 Division Of Thoracic Oncology, Shizuoka Cancer Center, 411-8777 - Shizuoka/JP
  • 2 Department Of Thoracic Oncology, National Cancer Center Hospital, 104-0045 - Tokyo/JP
  • 3 Department Of Thoracic Oncology, Aichi Cancer Center, 464-8681 - Nagoya/JP
  • 4 Department Of Thoracic Oncology, Saitama Cancer Center, 362-0806 - Saitama/JP
  • 5 Department Of Respiratory Medicine, Kanazawa University Graduate School of Medicine, 920-8641 - Kanazawa/JP
  • 6 Department Of Thoracic Oncology, Osaka International Cancer Institute, 541-8567 - Osaka/JP
  • 7 Department Of Respiratory Medicine, Kanagawa Cardiovascular and Respiratory Center, 236-0051 - Yokohama/JP
  • 8 Department Of Pulmonary Medicine And Oncology, Graduate School of Medicine, Nippon Medical School, 113-8603 - Tokyo/JP
  • 9 Department Of Thoracic Oncology And Respiratory Medicine, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, 113-0021 - Tokyo/JP
  • 10 Department Of Respiratory Medicine And Medical Oncology, Yokohama Municipal Citizen's Hospital, 240-8555 - Yokohama/JP
  • 11 Department Of Medical Oncology, Kindai University Faculty of Medicine, 589-8511 - Osaka/JP
  • 12 Gcmo Office, Taiho Pharmaceutical Co.,Ltd, 101-0047 - Tokyo/JP
  • 13 Thoracic Center, St. Luke's International Hospital, 104-8560 - Tokyo/JP
  • 14 Department Of Thoracic Medical Oncology, The Cancer Institute Hospital of JFCR, 135-8550 - Tokyo/JP
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Abstract 1893

Background

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.

Methods

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.

Results

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.

Conclusions

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

JapicCTI-142651

Legal entity responsible for the study

Taiho Pharmaceutical Co., Ltd

Funding

Taiho Pharmaceutical Co., Ltd

Disclosure

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.

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