• Myung-Ju Ahn, Ji-Youn Han, Ki Hyeong Lee, Sang-We Kim, Dong-Wan Kim, Yun-Gyoo Lee, Eun Kyung Cho, Joo-Hang Kim, Gyeong-Won Lee, Jong-Seok Lee, Young Joo Min, Jin-Soo Kim, Sung Sook Lee, Hye Ryun Kim, Min Hee Hong, Jin Seok Ahn, Jong-Mu Sun, Heung Tae Kim, Dae Ho Lee, Sohee Kim, and Byoung Chul Cho.
• Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
• Lancet Oncol. 2019 Dec 1; 20 (12): 1681-1690.

BackgroundPatients with EGFR-mutated non-small-cell lung cancer (NSCLC) given EGFR tyrosine kinase inhibitors (TKIs) inevitably become resistant to first-generation or second-generation drugs. We assessed the safety, tolerability, pharmacokinetics, and activity of lazertinib-an irreversible, third-generation, mutant-selective, EGFR TKI-in patients with advanced NSCLC progressing after EGFR TKI therapy.MethodsThis first-in-human, open-label, multicentre, phase 1-2 study had three parts: dose escalation, dose expansion, and dose extension; here, we report results on dose escalation and dose expansion. The study was done in 14 hospitals in Korea. Eligible patients were aged 20 years or older and had advanced NSCLC harbouring an activating EGFR mutation and progressing after first-generation or second-generation EGFR TKI treatment, a defined tumour T790M mutation status, an Eastern Cooperative Oncology Group performance status of 0-1, at least one measurable extracranial lesion, defined according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, and adequate organ function. Patients were enrolled to seven dose-escalation cohorts according to a rolling six design; five cohorts were expanded. Patients were given oral lazertinib 20 mg, 40 mg, 80 mg, 120 mg, 160 mg, 240 mg, or 320 mg once daily continuously in 21-day cycles. Primary endpoints were safety and tolerability and secondary endpoints included objective response in evaluable patients. This study is registered with ClinicalTrials.gov, NCT03046992, and the phase 2 extension study is ongoing.FindingsBetween Feb 15, 2017, and May 28, 2018, 127 patients were enrolled into the dose escalation group (n=38) and dose expansion group (n=89). No dose-limiting toxicities occurred. There was no dose-dependent increase in adverse events. The most commonly reported adverse events were grade 1-2 rash or acne (in 38 [30%] of 127 patients) and pruritus (in 34 [27%]). Grade 3 or grade 4 adverse events occurred in 20 (16%) patients, with the most common being grade 3 pneumonia (four [3%]). Treatment-related grade 3 or 4 adverse events occurred in four (3%) patients; treatment-related serious adverse events were reported in six patients (5%). There were no adverse events with an outcome of death and no treatment-related deaths. The proportion of patients achieving an objective response by independent central review assessment was 69 (54%; 95% CI 46-63) of 127.InterpretationLazertinib had a tolerable safety profile and showed promosing clinical activity in patients with NSCLC progressing on or after EGFR TKI therapy. Our findings provide a rationale for further clinical investigations.FundingYuhan Corporation.Copyright © 2019 Elsevier Ltd. All rights reserved.

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