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Spotlight on Lorlatinib and Its Potential in the Treatment of NSCLC: the Evidence to Date

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Spotlight on Lorlatinib and Its Potential in the Treatment of NSCLC: the Evidence to Date Journal name: OncoTargets and Therapy Article Designation: Review Year: 2018 Volume: 11 OncoTargets and Therapy Dovepress Running head verso: Akamine et al Running head recto: Spotlight on lorlatinib in the treatment of NSCLC open access to scientific and medical research DOI: 165511 Open Access Full Text Article REVIEW Spotlight on lorlatinib and its potential in the treatment of NSCLC: the evidence to date Takaki Akamine1 Abstract: The identification of anaplastic lymphoma kinase (ALK), an oncogenetic driver Gouji Toyokawa1 mutation, in lung cancer has paved the way for a new era in the treatment of non-small cell Tetsuzo Tagawa1 lung cancer (NSCLC). Targeting ALK using tyrosine kinase inhibitors (TKI) has dramatically Takashi Seto2 improved the prognosis of patients with ALK-rearranged NSCLC. However, most patients relapse on ALK-TKI therapy within a few years because of acquired resistance. One mechanism 1Department of Surgery and Science, Graduate School of Medical Sciences, of acquiring resistance is a second mutation on the ALK gene, and the representative mutation Kyushu University, Higashi-ku, is L1996M in the gatekeeper residue. In particular, the solvent-front ALK G1202R mutation is 2 Fukuoka, Japan; Department of the common cause of resistance against first- and second-generation ALK-TKIs. Another major Thoracic Oncology, National Kyushu Cancer Center, Minami-ku, Fukuoka, concern regarding ALK-TKI is metastasis to the central nervous system, commonly observed Japan in patients relapsing after ALK-TKI therapy. The next-generation ALK inhibitor lorlatinib (PF-06463922) has therefore been developed to inhibit resistant ALK mutations, including ALK For personal use only. G1202R, and to penetrate the blood–brain barrier. In a Phase I/II trial, the safety and efficacy of lorlatinib were demonstrated in patients with advanced ALK-positive NSCLC, most of whom had central nervous system metastases and had previous ALK-TKI treatment. In this review, we discuss the structure, pharmacodynamics, and pharmacokinetics of lorlatinib and compare its characteristics with those of other ALK inhibitors. Furthermore, clinical trials for lorlatinib are summarized, and future perspectives in the management of patients with ALK-rearranged NSCLC are discussed. Keywords: non-small cell lung cancer, anaplastic lymphoma kinase, ALK inhibitor, lorlatinib Introduction The identification of oncogenetic driver mutations in lung cancer has heralded a new OncoTargets and Therapy downloaded from https://www.dovepress.com/ by 54.70.40.11 on 27-Oct-2019 era in the treatment of non-small cell lung cancer (NSCLC). In particular, oncogenic driver mutations in EGFR, anaplastic lymphoma kinase (ALK), ret proto-oncogene (RET), c-ros oncogene 1, and receptor tyrosine kinase (ROS1) have recently been iden- tified in basic and clinical studies.1,2 These oncogenetic mutation profiles subclassify NSCLC, especially lung adenocarcinomas, and patients with these oncogenes can be successfully treated with specific kinase inhibitors. The ALK rearrangement is a potent oncogene and was first identified in NSCLC by Soda et al in 2007.3 There are several partners that fuse with ALK, including echino- Correspondence: Gouji Toyokawa derm microtubule-associated protein-like 4 (EML4), Huntingtin interacting protein 1 Department of Surgery and Science, (HIP1), and Translocated Promoter Region (TPR), resulting in a potent transforming Graduate School of Medical Sciences, activity in NSCLC.3–5 For instance, the EML4–ALK fusion gene was first identified by Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan Soda et al, and it is constitutively oligomerized via the coiled coil domain within the Tel +81 92 642 5466 EML4 region, leading to the activation of downstream signaling via the Ras/MAPK, Fax +81 92 642 5482 Email [email protected] PI3K/AKT, and JAK/STAT pathways, among others.3,6 submit your manuscript | www.dovepress.com OncoTargets and Therapy 2018:11 5093–5101 5093 Dovepress © 2018 Akamine et al. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you http://dx.doi.org/10.2147/OTT.S165511 hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). Powered by TCPDF (www.tcpdf.org) 1 / 1 Akamine et al Dovepress Approximately 5% of patients with NSCLC harbor Administration (FDA) in April 2017. According to data the ALK fusion gene, and the characteristics of this patient presented at the 18th World Conference on Lung Cancer cohort are as follows: younger age, ever or never smoker, (WCLC) in October 2017, the systemic and intracranial adenocarcinoma histology, no definite racial differences in overall response rates (ORR) were as high as 62.4% and frequency of ALK rearrangement, and mutual exclusion of 54.9%, respectively, in ALK-positive patients who had other driver oncogenes.7–9 previously received ALK inhibitors.30 Thus, lorlatinib has Importantly, ALK inhibition showed remarkable anti- attracted much attention because of its antitumor efficacy tumor efficacy in mouse xenograft models transduced against both systemic and intracranial lesions. with NIH3T3 cells expressing the EML4–ALK fusion In this review, we discuss the structure, pharmacody- gene. In clinical settings, targeting of ALK using tyrosine namics, and pharmacokinetics of lorlatinib, and compare kinase inhibitors (TKI), such as crizotinib, alectinib, and its characteristics with those of other ALK inhibitors. ceritinib, demonstrated remarkable antitumor efficacy and Furthermore, clinical trials for lorlatinib are summarized improvement of prognosis in patients with ALK-rearranged and future perspectives in the management of patients with NSCLC.10–15 Unfortunately, despite these promising results, ALK-rearranged NSCLC are discussed. most patients relapsed on TKI therapy within a few years because of acquired resistance.13,15–18 There are two main Structural characteristics of lorlatinib resistance mechanisms to ALK inhibitors: ALK dominant or Lorlatinib (product name PF-06463922) is a small-molecule 18,19 ALK nondominant. ALK dominant resistance mechanisms macrocyclic ALK-TKI with the molecular formula C21H19 include secondary mutations and copy number gain in the FN6O2 and chemical structure (10R)–7-Amino-12-fluoro-2, ALK gene, while ALK nondominant resistance mechanisms 10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4- include the activation of bypass downstream signaling via, (metheno) pyrazolo[4,3-hour][2,5,11]-benzoxadiazacyclotet- for example, EGFR, Kirsten rat sarcoma viral oncogene radecine-3-carbonitrile (Figure 1).31 It is an ATP-competitive homolog (KRAS), v-kit Hardy–Zuckerman 4 feline sarcoma inhibitor of recombinant ALK and ROS1 kinases, resulting For personal use only. viral oncogene homolog (KIT), met proto-oncogene (MET), in the deactivation of ALK tyrosine kinase in the cytoplasm. and insulin-like growth factor 1 receptor. With respect to the The macrocycle of lorlatinib (Figure 1) is its main structural former type of mechanism, the solvent-front mutation ALK difference from other ALK inhibitors. Lorlatinib was devel- G1202R is established as the common cause of resistance oped from crizotinib using a structure-based drug design against first- and second-generation ALK-TKI therapy.20 approach to overcome ALK mutant resistance and high Another major concern is metastasis to the central P-gp efflux (Figure 1).31,32 During the development process, nervous system (CNS), considered a sanctuary site owing the macrocyclic structure was associated with improved to the blood–brain barrier (BBB).21 A limitation of the first- metabolic stability and low propensity for P-gp efflux than generation ALK inhibitor crizotinib was that relapse in the the acyclic analog. 21,22 OncoTargets and Therapy downloaded from https://www.dovepress.com/ by 54.70.40.11 on 27-Oct-2019 brain after treatment was commonly reported. Although second-generation ALK inhibitors ceritinib and alectinib Pharmacodynamic properties have demonstrated effectiveness against brain metastasis in In biochemical assays, lorlatinib showed a mean Ki crizotinib-relapsed patients, these patients frequently relapse of ,0.07 nM against wild-type ALK. In addition, mean Ki 21 with CNS progression. In a Phase I/II trial of alectinib values of lorlatinib against crizotinib-resistant mutants such 23 (AF-002JG), the CNS response rate was 52%. This effect as L1196M, G1269A, 1151Tins, and F1174L were as low may partly be associated with poor BBB permeability, which as ,0.1–0.9 nM.29 is attributed to the expression of p-glycoprotein (P-gp) at the luminal side of the BBB endothelium.24–27 Therefore, next-generation ALK inhibitors, such as &UL]RWLQLE /RUODWLQLE ) brigatinib (AP26113) and lorlatinib (PF-06463922), were 2 + 1 1 1+ 1 designed to inhibit resistant ALK mutants and to penetrate the 1 28,29 &, 2 1 1 BBB. Lorlatinib, was developed by Pfizer to specifically ) 2 1 inhibit TKI-resistant ALK mutants with optimal brain pen- + &, 1 1 etration.29 A novel oral ATP-competitive macrocyclic TKI, + 1 targeting ALK as well
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