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Phase I study of TAS-121, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, in patients with non-small-cell lung cancer harboring EGFR mutations.

Abstract
Purpose We investigated the safety, tolerability, pharmacokinetics, and efficacy of TAS-121, a novel, potent, and highly selective third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) in Japanese patients with advanced EGFR mutation-positive non-small-cell lung cancer (NSCLC) previously treated with EGFR-TKI. Methods This was an open-label, non-randomized, multi-center, dose escalation, phase I study conducted in three phases (dose escalation, expansion, and extension phases). TAS-121 was administered orally once daily (QD) or twice daily (BID) under fasting conditions in a 21-day treatment cycle. The primary endpoint was dose-limiting toxicities (DLTs) during Cycle 1 of the dose escalation phase. Results In total, 134 patients received treatment. Five and three patients presented a DLT with the QD and BID regimens, respectively. The DLTs were drug-induced liver injury, platelet count decreased, urticaria, interstitial lung disease, and left ventricular failure. The maximum tolerated dose (MTD) was 10 mg/day QD and 8 mg/day BID in the dose escalation phase. The most common adverse drug reactions (ADRs) were dermatological toxicity (89.6%), platelet count decreased (67.2%), and pyrexia (44%) among all patients. Rate of discontinuations due to ADRs at the MTD level were 11.1% with TAS-121 10 mg/day QD and 7.9% with TAS-121 8 mg/day BID. Among 86 T790M-positive patients (confirmed by blood serum sampling in most patients), the objective response rate (ORR) was 28% and highest at 8 mg/day BID (39%). Among 16 T790M-negative patients, the ORR was 19%. Conclusions TAS-121 was well tolerated up to the MTD and demonstrated antitumor activity in Japanese T790M-positive NSCLC patients. Clinical trial registration: JapicCTI-142651.
AuthorsMakoto Nishio, Haruyasu Murakami, Yuichiro Ohe, Toyoaki Hida, Hiroshi Sakai, Kazuo Kasahara, Fumio Imamura, Tomohisa Baba, Kaoru Kubota, Yukio Hosomi, Tsuneo Shimokawa, Hidetoshi Hayashi, Kazutaka Miyadera, Tomohide Tamura
JournalInvestigational new drugs (Invest New Drugs) Vol. 37 Issue 6 Pg. 1207-1217 (12 2019) ISSN: 1573-0646 [Electronic] United States
PMID30790152 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)
Chemical References
  • Antineoplastic Agents
  • Protein Kinase Inhibitors
  • EGFR protein, human
  • ErbB Receptors
Topics
  • Administration, Oral
  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents (adverse effects, pharmacokinetics, therapeutic use)
  • Carcinoma, Non-Small-Cell Lung (drug therapy, genetics)
  • ErbB Receptors (antagonists & inhibitors, genetics)
  • Female
  • Humans
  • Lung Neoplasms (drug therapy, genetics)
  • Male
  • Maximum Tolerated Dose
  • Middle Aged
  • Mutation
  • Protein Kinase Inhibitors (adverse effects, pharmacokinetics, therapeutic use)
  • Treatment Outcome

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