PMID- 34647107
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20220427
IS  - 2666-3643 (Electronic)
IS  - 2666-3643 (Linking)
VI  - 2
IP  - 10
DP  - 2021 Oct
TI  - Cardiac Safety Assessment of Lazertinib: Findings From Patients With EGFR 
      Mutation-Positive Advanced NSCLC and Preclinical Studies.
PG  - 100224
LID - 10.1016/j.jtocrr.2021.100224 [doi]
LID - 100224
AB  - INTRODUCTION: Lazertinib is a potent, irreversible, brain-penetrant, 
      mutant-selective, and wild-type-sparing third-generation EGFR tyrosine kinase 
      inhibitor (TKI), creating a wide therapeutic index. Cardiovascular adverse events 
      (AEs), including QT prolongation, decreased left ventricular ejection fraction 
      (LVEF), and heart failure, have emerged as potential AEs with certain EGFR TKI 
      therapies. METHODS: Cardiac safety of lazertinib was evaluated in TKI-tolerant 
      adults with EGFR mutation-positive locally advanced or metastatic NSCLC receiving 
      lazertinib (20-320 mg/d). QT intervals corrected with Fridericia's formula (QTcF) 
      prolongation, time-matched concentration-QTcF relationship, change of LVEF, and 
      cardiac failure-associated AEs were evaluated. The clinical findings were 
      supplemented by the following three preclinical studies: an in vitro hERG 
      inhibition assay, an ex vivo isolated perfused rabbit heart study, and an in vivo 
      telemetry-instrumented beagle dog study. RESULTS: Preclinical evaluation revealed 
      little to no physiological effect on the basis of electrocardiogram, 
      electrophysiological, proarrhythmic, and hemodynamic parameters. Clinical 
      evaluation of 181 patients revealed no clinically relevant QTcF prolongation by 
      centralized electrocardiogram in any patient and at any dose level. The predicted 
      magnitude of QTcF value increase at maximum steady-state plasma concentration for 
      the therapeutic dose of lazertinib (240 mg/d) was 2.2 msec (upper bound of the 
      two-sided 90% confidence interval: 3.6 msec). No patient had clinically relevant 
      LVEF decrease (i.e., minimum postbaseline LVEF value of <50% and a maximum 
      decrease in LVEF value from baseline of >/=10 percentage points). Cardiac 
      failure-associated AE occurred in one patient (grade 2 decreased LVEF) and 
      resolved without any dose modifications. CONCLUSIONS: Our first-in-human study, 
      together with preclinical data, indicates that lazertinib is not associated with 
      increased cardiac risk.
CI  - (c) 2021 THE AUTHORS.
FAU - Jang, Seong Bok
AU  - Jang SB
AD  - Clinical Development Department, Yuhan Corporation, Seoul, Republic of Korea.
FAU - Kim, Kyeong Bae
AU  - Kim KB
AD  - Yuhan R&D Institute, Yuhan Corporation, Yongin, Republic of Korea.
FAU - Sim, Sujin
AU  - Sim S
AD  - Clinical Development Department, Yuhan Corporation, Seoul, Republic of Korea.
FAU - Cho, Byoung Chul
AU  - Cho BC
AD  - Division of Medical Oncology, Yonsei Cancer Center, Yonsei University College of 
      Medicine, Seoul, Republic of Korea.
FAU - Ahn, Myung-Ju
AU  - Ahn MJ
AD  - Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, 
      Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
FAU - Han, Ji-Youn
AU  - Han JY
AD  - Center for Lung Cancer, Research Institute and Hospital, National Cancer Center, 
      Goyang, Republic of Korea.
FAU - Kim, Sang-We
AU  - Kim SW
AD  - Department of Oncology, Asan Medical Center, University of Ulsan College of 
      Medicine, Seoul, Republic of Korea.
FAU - Lee, Ki Hyeong
AU  - Lee KH
AD  - Division of Medical Oncology, Department of Medicine, Chungbuk National 
      University Hospital, Chungbuk National University College of Medicine, Cheongju, 
      Republic of Korea.
FAU - Cho, Eun Kyung
AU  - Cho EK
AD  - Gil Medical Center, Gachon University College of Medicine, Incheon, Republic of 
      Korea.
FAU - Haddish-Berhane, Nahor
AU  - Haddish-Berhane N
AD  - Janssen R&D, Spring House, Pennsylvania.
FAU - Mehta, Jaydeep
AU  - Mehta J
AD  - Janssen R&D, Spring House, Pennsylvania.
FAU - Oh, Se-Woong
AU  - Oh SW
AD  - Yuhan R&D Institute, Yuhan Corporation, Yongin, Republic of Korea.
LA  - eng
PT  - Journal Article
DEP - 20210908
PL  - United States
TA  - JTO Clin Res Rep
JT  - JTO clinical and research reports
JID - 101769967
CIN - JTO Clin Res Rep. 2021 Oct 13;2(10):100233. PMID: 34704082
PMC - PMC8501499
OTO - NOTNLM
OT  - Cardiac toxicity
OT  - Lazertinib
OT  - Non-small cell lung cancer
OT  - Tyrosine kinase inhibitor
EDAT- 2021/10/15 06:00
MHDA- 2021/10/15 06:01
PMCR- 2021/09/08
CRDT- 2021/10/14 06:43
PHST- 2021/06/01 00:00 [received]
PHST- 2021/08/26 00:00 [revised]
PHST- 2021/08/29 00:00 [accepted]
PHST- 2021/10/14 06:43 [entrez]
PHST- 2021/10/15 06:00 [pubmed]
PHST- 2021/10/15 06:01 [medline]
PHST- 2021/09/08 00:00 [pmc-release]
AID - S2666-3643(21)00083-7 [pii]
AID - 100224 [pii]
AID - 10.1016/j.jtocrr.2021.100224 [doi]
PST - epublish
SO  - JTO Clin Res Rep. 2021 Sep 8;2(10):100224. doi: 10.1016/j.jtocrr.2021.100224. 
      eCollection 2021 Oct.