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

Makoto Nishio,Kaoru Kubota,Tomohisa Baba,Kazuo Kasahara,Yukio Hosomi,Hidetoshi Hayashi,Toyoaki Hida,Yuichiro Ohe,Kazutaka Miyadera,Tomohide Tamura,Tsuneo Shimokawa,Hiroshi Sakai,Haruyasu Murakami,Fumio Imamura

doi:10.1007/s10637-019-00732-4

Abstract

SummaryPurpose 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.

Highlights

The epidermal growth factor receptor (EGFR) is highly expressed in lung cancers [1]
Mutations in the EGFR tyrosine kinase (TK) domain are associated with lung tumorigenesis [2] and increased sensitivity to drugs that inhibit EGFR kinase activity [1, 3]
EGFR mutation-positive lung adenocarcinoma patients who were treated with gefitinib, a first-generation EGFR-TK inhibitor (EGFR-TKI), had better outcomes than those without EGFR mutations [4]

Summary

Introduction

The epidermal growth factor receptor (EGFR) is highly expressed in lung cancers [1]. In non-small-cell lung cancer (NSCLC) patients, the frequency of EGFR-TK domain mutations was found to be higher among Asian patients versus patients of other ethnicities (30% versus 8%, p < 0.001) [1]. EGFR mutation-positive lung adenocarcinoma patients who were treated with gefitinib, a first-generation EGFR-TK inhibitor (EGFR-TKI), had better outcomes than those without EGFR mutations [4]. Several EGFR-TKIs, such as gefitinib, erlotinib, and afatinib, were found to be superior to standard chemotherapy (carboplatin-paclitaxel, cisplatin-docetaxel, or platinum-pemetrexed) as an initial treatment for patients with EGFR mutation-positive advanced lung adenocarcinoma/ NSCLC in terms of progression-free survival (PFS) and quality of life [4,5,6,7]. EGFR-TKIs are currently the standard treatment for EGFR mutation-positive NSCLC

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Conclusion