Safety and Tolerability of Anaplastic Lymphoma Kinase Inhibitors in Non-Small-Cell Lung Cancer
The chimeric protein echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase, resulting from the rearrangement of the homonym genes, is one of the currently targetable oncogenic drivers in anaplastic lymphoma kinase-positive non-small-cell lung cancer. In fact, four first- and second-generation anaplastic lymphoma kinase tyrosine kinase inhibitors, crizotinib (PF-02341066), ceritinib (LDK378), alectinib (CH5424802), and brigatinib (AP26113), are presently approved for clinical practice; however, these agents are not devoid of complications and thus should be administered meaningfully. Furthermore, third-generation inhibitors are currently under development to overcome acquired resistance mechanisms inevitably resulting from treatment with first- and second-generation tyrosine kinase inhibitors. Therefore, this article aims to provide a comprehensive state-of-the-art review about the pharmacodynamics, pharmacokinetics, safety, and tolerability profiles of currently available and promising under-development anaplastic lymphoma kinase tyrosine kinase inhibitors.
Compliance with Ethical Standards
No sources of funding were received for the preparation of this article.
Conflict of interest
Cesare Gridelli received honoraria as a speaker bureau and advisory board member and a consultant for Pfizer, Novartis, and Roche. Danilo Rocco, Ciro Battiloro, and Luigi Della Gravara have no conflicts of interest that are directly relevant to the contents of this article.
- 3.Chan BA, Hughes BG. Targeted therapy for non-small cell lung cancer: current standards and the promise of the future. Transl Lung Cancer Res. 2015;4(1):36–54. https://doi.org/10.3978/j.issn.2218-6751.2014.05.01.CrossRefPubMedPubMedCentralGoogle Scholar
- 9.National Comprehensive Cancer Network. NCCN guidelines for NSCLC. Version 6. 2018. Available from: https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf. Accessed Aug 2018.
- 12.Marsilje TH, Pei W, Chen B, et al. Synthesis, structure-activity relationships, and in vivo efficacy of the novel potent and selective anaplastic lymphoma kinase (ALK) inhibitor 5-chloro-N2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine (LDK378) currently in phase 1 and phase 2 clinical trials. J Med Chem. 2013;56(14):5675–90. https://doi.org/10.1021/jm400402q.CrossRefPubMedGoogle Scholar
- 17.Zhang S, Anjum R, Squillace R, et al. The potent ALK inhibitor brigatinib (AP26,113) overcomes mechanisms of resistance to first- and second-generation ALK inhibitors in preclinical models. Clin Cancer Res. 2016;22(22):5527–38. https://doi.org/10.1158/1078-0432.CCR-16-0569.CrossRefPubMedGoogle Scholar
- 18.Pfizer Canada. Xalkori. Crizotinib capsules: anaplastic lymphoma kinase (Alk) tyrosine kinase inhibitor [product monograph]. Kirkland (QC): Pfizer Canada; 2012.Google Scholar
- 20.Morcos PN, Yu L, Bogman K, et al. Absorption, distribution, metabolism and excretion (ADME) of the ALK inhibitor alectinib: results from an absolute bioavailability and mass balance study in healthy subjects. Xenobiotica. 2017;47(3):217–29. https://doi.org/10.1080/00498254.2016.1179821.CrossRefPubMedGoogle Scholar
- 24.Felip E, Orlov S, Park K, et al. ASCEND-3: a single-arm, open-label, multicenter phase II study of ceritinib in ALKi-naïve adult patients (pts) with ALK-rearranged (ALK+) non-small cell lung cancer (NSCLC). J Clin Oncol. 2015;33(15_Suppl.):8060. https://doi.org/10.1200/jco.2015.33.15_suppl.CrossRefGoogle Scholar
- 25.Soria JC, Tan DSW, Chiari R, et al. First-line ceritinib versus platinum-based chemotherapy in advanced ALK-rearranged non-small-cell lung cancer (ASCEND-4): a randomised, open-label, phase 3 study. Lancet. 2017;389(10072):917–29. https://doi.org/10.1016/S0140-6736(17)30123-X.CrossRefPubMedGoogle Scholar
- 26.Shaw AT, Kim TM, Crinò L, et al. Ceritinib versus chemotherapy in patients with ALK-rearranged non-small-cell lung cancer previously given chemotherapy and crizotinib (ASCEND-5): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2017;18(7):874–86. https://doi.org/10.1016/s1470-2045(17)30339-x.CrossRefPubMedGoogle Scholar
- 27.Cho BC, Kim DW, Bearz A, et al. ASCEND-8: a randomized phase 1 study of ceritinib, 450 mg or 600 mg, taken with a low-fat meal versus 750 mg in fasted state in patients with anaplastic lymphoma kinase (ALK)-rearranged metastatic non-small cell lung cancer (NSCLC). J Thorac Oncol. 2017;12(9):1357–67. https://doi.org/10.1016/j.jtho.2017.07.005.CrossRefPubMedGoogle Scholar
- 35.Shaw AT, Felip E, Bauer TM, et al. Lorlatinib in non-small-cell lung cancer with ALK or ROS1 rearrangement: an international, multicentre, open-label, single-arm first-in-man phase 1 trial. Lancet Oncol. 2017;18(12):1590–9. https://doi.org/10.1016/S1470-2045(17)30680-0.CrossRefPubMedPubMedCentralGoogle Scholar
- 38.De Braud FG, Niger M, Damian S, et al. Alka-372-001: first-in-human, phase I study of entrectinib, an oral pan-trk, ROS1, and ALK inhibitor, in patients with advanced solid tumors with relevant molecular alterations. J Clin Oncol. 2015;33(15_Suppl.):2517. https://doi.org/10.1200/jco.2015.33.15_suppl.2517.CrossRefGoogle Scholar
- 39.Patel MR, Bauer TM, Liu SV, et al. STARTRK-1: phase 1/2a study of entrectinib, an oral Pan-Trk, ROS1, and ALK inhibitor, in patients with advanced solid tumors with relevant molecular alterations. J Clin Oncol. 2015;33(15_Suppl.):2596. https://doi.org/10.1200/jco.2015.33.15_suppl.2596.CrossRefGoogle Scholar
- 40.Drilon A, Siena S, Ou SI, et al. Safety and antitumor activity of the multi-targeted Pan-TRK, ROS1, and ALK inhibitor entrectinib (RXDX-101): combined results from two phase 1 trials (ALKA-372-001 and STARTRK-1). Cancer Discov. 2017;7(4):400–9. https://doi.org/10.1158/2159-8290.CD-16-1237.CrossRefPubMedPubMedCentralGoogle Scholar
- 42.Horn L, Wu YL, Reck M, et al. eXalt3: a phase III study of ensartinib (X-396) in anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC). J Clin Oncol. 35(15 Suppl.). https://doi.org/10.1200/jco.2017.35.15_suppl.tps8578.
- 43.Kazandjian D, Blumenthal GM, Chen HY, et al. FDA approval summary: crizotinib for the treatment of metastatic non-small cell lung cancer with anaplastic lymphoma kinase rearrangements. Oncologist. 2014;19(10):e5–11. https://doi.org/10.1634/theoncologist.2014-0241.CrossRefPubMedPubMedCentralGoogle Scholar