Advertisement

Drug Safety

, Volume 42, Issue 2, pp 199–209 | Cite as

Safety and Tolerability of Anaplastic Lymphoma Kinase Inhibitors in Non-Small-Cell Lung Cancer

  • Danilo Rocco
  • Ciro Battiloro
  • Luigi Della Gravara
  • Cesare GridelliEmail author
Review Article

Abstract

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.

Notes

Compliance with Ethical Standards

Funding

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.

References

  1. 1.
    Dela Cruz CS, Tanoue LT, Matthay RA, et al. Lung cancer: epidemiology, etiology, and prevention. Clin Chest Med. 2011;32(4):605–44.  https://doi.org/10.1016/j.ccm.2011.09.001.CrossRefPubMedGoogle Scholar
  2. 2.
    Cardarella S, Johnson BE. The impact of genomic changes on treatment of lung cancer. Am J Respir Crit Care Med. 2013;188(7):770–5.  https://doi.org/10.1164/rccm.201305-0843PP.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 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.PubMedPubMedCentralGoogle Scholar
  4. 4.
    Torti D, Trusolino L. Oncogene addiction as a foundational rationale for targeted anti-cancer therapy: promises and perils. EMBO Mol Med. 2011;3(11):623–36.  https://doi.org/10.1002/emmm.201100176.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Morris SW, Kirstein MN, Valentine MB, et al. Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin’s lymphoma. Science. 1994;263(5151):1281–4.CrossRefPubMedGoogle Scholar
  6. 6.
    Orscheschek K, Merz H, Hella J, et al. Large-cell anaplastic lymphoma-specific translocation (t[2, 5] [p23;q35]) in Hodgkin’s disease: indication of a common pathogenesis? Lancet. 1995;345(8942):P87–90.  https://doi.org/10.1016/S0140-6736(95)90061-6.CrossRefGoogle Scholar
  7. 7.
    Soda M, Choi YL, Enomoto M, et al. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature. 2007;448(7153):561–6.CrossRefPubMedGoogle Scholar
  8. 8.
    Kris MG, Johnson BE, Berry LD, et al. Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs. JAMA. 2014;311(19):1998–2006.  https://doi.org/10.1001/jama.2014.3741.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 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.
  10. 10.
    Kwak EL, Bang YJ, Camidge DR, et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med. 2010;363:1693–703.  https://doi.org/10.1056/NEJMoa1006448.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Nix NM, Brown KS. Ceritinib for ALK-rearrangement-positive non-small cell lung cancer. J Adv Pract Oncol. 2015;6(2):156–60.PubMedPubMedCentralGoogle Scholar
  12. 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
  13. 13.
    Kinoshita K, Kobayashi T, Asoh K, et al. 9-Substituted 6, 6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazoles as highly selective and potent anaplastic lymphoma kinaseinhibitors. J Med Chem. 2011;54:6286–94.  https://doi.org/10.1021/jm200652u.CrossRefPubMedGoogle Scholar
  14. 14.
    Sakamoto H, Tsukaguchi T, Hiroshima S, et al. CH5424802, a selective ALK inhibitor capable of blocking the resistant gatekeeper mutant. Cancer Cell. 2011;19:679–90.  https://doi.org/10.1016/j.ccr.2011.04.004.CrossRefPubMedGoogle Scholar
  15. 15.
    Kodama T, Tsukaguchi T, Yoshida M, et al. Selective ALK inhibitor alectinib with potent antitumor activity in models of crizotinib resistance. Cancer Lett. 2014;351(2):215–21.  https://doi.org/10.1016/j.canlet.2014.05.020.CrossRefPubMedGoogle Scholar
  16. 16.
    Ou SH, Janne PA, Bartlett CH, et al. Clinical benefit of continuing ALK inhibition with crizotinib beyond initial disease progression in patients with advanced ALK-positive NSCLC. Ann Oncol. 2014;25(2):415–22.  https://doi.org/10.1093/annonc/mdt572.CrossRefPubMedGoogle Scholar
  17. 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. 18.
    Pfizer Canada. Xalkori. Crizotinib capsules: anaplastic lymphoma kinase (Alk) tyrosine kinase inhibitor [product monograph]. Kirkland (QC): Pfizer Canada; 2012.Google Scholar
  19. 19.
    Shaw AT, Kim DW, Mehra R, et al. Ceritinib in ALK-rearranged non-small-cell lung cancer. N Engl J Med. 2014;370(13):1189–97.  https://doi.org/10.1056/nejmoa1311107.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 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
  21. 21.
    Bedi S, Khan SA, AbuKhader MM, et al. A comprehensive review on brigatinib: a wonder drug for targeted cancer therapy in non-small cell lung cancer. Saudi Pharm J. 2018;26(6):755–63.  https://doi.org/10.1016/j.jsps.2018.04.010.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Shaw AT, Kim DW, Nakagawa K, et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med. 2013;368:2385–94.  https://doi.org/10.1056/NEJMoa1214886.CrossRefPubMedGoogle Scholar
  23. 23.
    Solomon BJ, Mok T, Kim D-W, et al. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med. 2014;371:2167–77.  https://doi.org/10.1056/NEJMoa1408440.CrossRefPubMedGoogle Scholar
  24. 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.Google Scholar
  25. 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. 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. 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
  28. 28.
    Peters S, Camidge DR, Shaw AT, et al. Alectinib versus crizotinib in untreated ALK-positive non-small-cell lung cancer. N Engl J Med. 2017;31(377):829–38.  https://doi.org/10.1056/NEJMoa1704795.CrossRefGoogle Scholar
  29. 29.
    Toyoaki H, Nokihara H, Kondo M, et al. Alectinib versus crizotinib in patients with ALK-positive non-small-cell lung cancer (J-ALEX): an open-label, randomised phase 3 trial. Lancet. 2017;390(10089):29–39.  https://doi.org/10.1016/S0140-6736(17)30565-2.CrossRefGoogle Scholar
  30. 30.
    Kim DW, Tiseo M, Ahn MJ, et al. Brigatinib in patients with crizotinib-refractory anaplastic lymphoma kinase-positive non-small-cell lung cancer: a randomized, multicenter phase II trial. J Clin Oncol. 2017;35:2490–8.  https://doi.org/10.1200/JCO.2016.71.5904.CrossRefPubMedGoogle Scholar
  31. 31.
    Zhu Q, Hu H, Weng DS, et al. Pooled safety analyses of ALK-TKI inhibitor in ALK-positive NSCLC. BMC Cancer. 2017;17:412.  https://doi.org/10.1186/s12885-017-3405-3.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Liu B, Yuan M, Sun Y, et al. Incidence and risk of hepatic toxicities associated with anaplastic lymphoma kinase inhibitors in the treatment of non-small-cell lung cancer: a systematic review and meta-analysis. Oncotarget. 2017;9(10):9480–8.PubMedPubMedCentralGoogle Scholar
  33. 33.
    Gainor JF, Dardaei L, Yoda S, et al. Molecular mechanisms of resistance to first- and second-generation ALK inhibitors in ALK-rearranged lung cancer. Cancer Discov. 2016;6:1118–33.  https://doi.org/10.1158/2159-8290.CD-16-0596.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Zou HY, Friboulet L, Kodack DP, et al. PF-06463922, an ALK/ROS1 inhibitor, overcomes resistance to first and second generation ALK inhibitors in preclinical models. Cancer Cell. 2015;28(1):70–81.  https://doi.org/10.1016/j.ccell.2015.05.010.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 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
  36. 36.
    Chao MV. Neurotrophins and their receptors: a convergence point for many signalling pathways. Nat Rev Neurosci. 2003;4(4):299–309.CrossRefPubMedGoogle Scholar
  37. 37.
    Amatu A, Sartore-Bianchi A, Siena S. NTRK gene fusions as novel targets of cancer therapy across multiple tumour types. ESMO Open. 2016;1(2):e000023.  https://doi.org/10.1136/esmoopen-2015-000023.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 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.Google Scholar
  39. 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.Google Scholar
  40. 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
  41. 41.
    Horn L, Infante JR, Reckamp KL, et al. Ensartinib (X-396) in ALK-positive non-small cell lung cancer: results from a first-in-human phase I/II, multicenter study. Clin Cancer Res. 2018;24(12):2771–9.  https://doi.org/10.1158/1078-0432.CCR-17-2398.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 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. 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
  44. 44.
    Khozin S, Blumenthal GM, Zhang L, et al. FDA approval: ceritinib for the treatment of metastatic anaplastic lymphoma kinase-positive non-small cell lung cancer. Clin Cancer Res. 2015;21(11):2436–9.  https://doi.org/10.1158/1078-0432.CCR-14-3157.CrossRefPubMedGoogle Scholar
  45. 45.
    Larkins E, Blumenthal GM, Chen H, et al. FDA approval: alectinib for the treatment of metastatic, ALK-positive non-small cell lung cancer following crizotinib. Clin Cancer Res. 2016;22(21):5171–6.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Danilo Rocco
    • 1
  • Ciro Battiloro
    • 1
  • Luigi Della Gravara
    • 2
  • Cesare Gridelli
    • 3
    Email author
  1. 1.Division of Pulmonary OncologyAzienda Ospedaliera Dei Colli MonaldiNaplesItaly
  2. 2.“Luigi Vanvitelli” UniversityCasertaItaly
  3. 3.Division of Medical Oncology“S.G. Moscati” HospitalAvellinoItaly

Personalised recommendations