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Alectinib: A Review in Advanced, ALK-Positive NSCLC

  • Julia Paik
  • Sohita Dhillon
Adis Drug Evaluation

Abstract

Alectinib (Alecensa®) is a potent and highly selective anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor. Oral alectinib monotherapy is approved in the EU as first-line treatment for adults with advanced ALK-positive non-small cell lung cancer (NSCLC) and for the treatment of adults with advanced ALK-positive NSCLC previously treated with crizotinib. In the USA, alectinib is indicated for the treatment of adults with ALK-positive metastatic NSCLC. The recommended dosage for alectinib in the EU and USA is 600 mg twice daily. Well-designed phase III studies in patients with ALK-positive NSCLC showed that during up to ≈ 19 months’ follow-up, progression-free survival (PFS) was significantly improved with alectinib relative to crizotinib as first-line therapy (ALEX study), and relative to chemotherapy in patients previously treated with crizotinib and platinum-doublet chemotherapy (ALUR study). Central nervous system (CNS)-related outcomes were significantly improved with alectinib in both these settings. Two phase II registrational studies (NP28673 and NP28761) in patients previously treated with crizotinib also demonstrated the efficacy of alectinib, as assessed by objective response rates (ORRs), during up to 21 months’ follow-up. Overall, alectinib had a manageable tolerability profile in these settings, with most adverse events (AEs) of mild or moderate severity. Current evidence indicates that alectinib is an important treatment option for patients with advanced ALK-positive NSCLC who are previously untreated or those previously treated with crizotinib. Given its efficacy and tolerability, current guidelines include alectinib as a treatment option in these settings, with the NCCN guidelines recommending it as a preferred option for first-line therapy.

Notes

Acknowledgements

During the peer review process, the manufacturer of alectinib was also offered an opportunity to review this article. Changes resulting from comments received were made on the basis of scientific and editorial merit.

Compliance with Ethical Standards

Funding

The preparation of this review was not supported by any external funding.

Conflict of interest

Julia Paik and Sohita Dhillon are salaried employees of Adis/Springer, are responsible for the article content and declare no relevant conflicts of interest.

References

  1. 1.
    Hu H, Qing Lin W, Zhu Q, et al. Is there a benefit of first- or second-line crizotinib in locally advanced or metastatic anaplastic lymphoma kinase-positive non-small cell lung cancer? A meta-analysis. Oncotarget. 2016;7(49):81090–8.PubMedPubMedCentralGoogle Scholar
  2. 2.
    Shaw AT, Yeap BY, Mino-Kenudson M, et al. Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK. J Clin Oncol. 2009;27(26):4247–53.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Webb TR, Slavish J, George RE, et al. Anaplastic lymphoma kinase: role in cancer pathogenesis and small-molecule inhibitor development for therapy. Expert Rev Anticancer Ther. 2009;9(3):331–56.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Sabir SR, Yeoh S, Jackson G, et al. EML4-ALK variants: biological and molecular properties, and the implications for patients. Cancers. 2017.  https://doi.org/10.3390/cancers9090118.PubMedPubMedCentralGoogle Scholar
  5. 5.
    Frampton JE. Crizotinib: a review of its use in the treatment of anaplastic lymphoma kinase-positive, advanced non-small cell lung cancer. Drugs. 2013;73(18):2031–51.CrossRefPubMedGoogle Scholar
  6. 6.
    Shaw AT, Kim DW, Nakagawa K, et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med. 2013;368(25):2385–94.CrossRefPubMedGoogle Scholar
  7. 7.
    Solomon BJ, Mok T, Kim DW, et al. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med. 2014;371(23):2167–77.CrossRefPubMedGoogle Scholar
  8. 8.
    Novello S, Barlesi F, Califano R, et al. Metastatic non-small-cell lung cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2016;27(S5):v1–27.CrossRefPubMedGoogle Scholar
  9. 9.
    National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: non-small cell lung cancer (version 3.2018). 2018. https://www.nccn.org/. Accessed 30 Apr 2018.
  10. 10.
    Katayama R, Lovly CM, Shaw AT. Therapeutic targeting of anaplastic lymphoma kinase in lung cancer: a paradigm for precision cancer medicine. Clin Can Res. 2015;21(10):2227–35.CrossRefGoogle Scholar
  11. 11.
    Shi W, Dicker AP. CNS metastases in patients with non-small-cell lung cancer and ALK gene rearrangement. J Clin Oncol. 2016;34(2):107–9.CrossRefPubMedGoogle Scholar
  12. 12.
    Betts K, Song J, Guo J, et al. Real-world treatment patterns and brain metastasis development in ALK-positive non-small cell lung cancer [abstract no. C10]. J Manag Care Spec Pharm. 2016;22(4):S30–1.Google Scholar
  13. 13.
    European Medicines Agency. Alecensa (alectinib): summary of product characteristics. 2018. http://www.ema.europa.eu. Accessed 2 Mar 2018.
  14. 14.
    Genentech Inc. Alecensa (alectinib): US prescribing information. 2017. https://www.accessdata.fda.gov/. Accessed 2 Mar 2018.
  15. 15.
    Sakamoto H, Tsukaguchi T, Hiroshima S, et al. CH5424802, a selective ALK inhibitor capable of blocking the resistant gatekeeper mutant. Cancer Cell. 2011;19(5):679–90.CrossRefPubMedGoogle Scholar
  16. 16.
    Kodama T, Tsukaguchi T, Satoh Y, et al. Alectinib shows potent antitumor activity against RET-rearranged non-small cell lung cancer. Mol Cancer Ther. 2014;13(12):2910–8.CrossRefPubMedGoogle Scholar
  17. 17.
    European Medicines Agency. Alecensa (alectinib): assessment report. 2016. http://www.ema.europa.eu/ema/. Accessed 2 Mar 2018.
  18. 18.
    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.CrossRefPubMedGoogle Scholar
  19. 19.
    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.CrossRefPubMedGoogle Scholar
  20. 20.
    Kodama T, Hasegawa M, Takanashi K, et al. Antitumor activity of the selective ALK inhibitor alectinib in models of intracranial metastases. Cancer Chemother Pharmacol. 2014;74(5):1023–8.CrossRefPubMedGoogle Scholar
  21. 21.
    Isozaki H, Ichihara E, Takigawa N, et al. Non-small cell lung cancer cells acquire resistance to the ALK inhibitor alectinib by activating alternative receptor tyrosine kinases. Cancer Res. 2016;76(6):1506–16.CrossRefPubMedGoogle Scholar
  22. 22.
    Tani T, Yasuda H, Hamamoto J, et al. Activation of EGFR bypass signaling by TGFalpha overexpression induces acquired resistance to alectinib in ALK-translocated lung cancer cells. Mol Cancer Ther. 2016;15(1):162–71.CrossRefPubMedGoogle Scholar
  23. 23.
    Puig O, Yang JCH, Ou SHI, et al. Pooled mutation analysis for the NP28673 and NP28761 studies of alectinib in ALK+ non-small-cell lung cancer (NSCLC) [abstract no. 9061]. J Clin Oncol. 2016;34(15 Suppl):9061.Google Scholar
  24. 24.
    Katayama R, Friboulet L, Koike S, et al. Two novel ALK mutations mediate acquired resistance to the next-generation ALK inhibitor alectinib. Clin Cancer Res. 2014;20(22):5686–96.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Kogita A, Togashi Y, Hayashi H, et al. Activated MET acts as a salvage signal after treatment with alectinib, a selective ALK inhibitor, in ALK-positive non-small cell lung cancer. Int J Oncol. 2015;46(3):1025–30.CrossRefPubMedGoogle Scholar
  26. 26.
    Gadgeel SM, Gandhi L, Riely GJ, et al. Safety and activity of alectinib against systemic disease and brain metastases in patients with crizotinib-resistant ALK-rearranged non-small-cell lung cancer (AF-002JG): results from the dose-finding portion of a phase 1/2 study. Lancet Oncol. 2014;15(10):1119–28.CrossRefPubMedGoogle Scholar
  27. 27.
    Hsu JC, Carnac R, Henschel V, et al. Population pharmacokinetics (popPK) and exposure-response (ER) analyses to confirm alectinib 600 mg BID dose selection in a crizotinib-progressed or intolerant population. J Clin Oncol. 2016;34(15 Suppl.):e20598.  https://doi.org/10.1200/JCO.2017.35.15_suppl.e20616.Google Scholar
  28. 28.
    Morcos PN, Dall GC, Parrott NJ, et al. Effect of food and the proton pump inhibitor (PPI) esomeprazole on the pharmacokinetics (PK) of alectinib, a highly selective ALK inhibitor, in healthy subjects [abstract no. PI-120]. Clin Pharmacol Ther. 2016;99(Suppl 1):S62–3.Google Scholar
  29. 29.
    Nakagawa T, Fowler S, Takanashi K, et al. In vitro metabolism of alectinib, a novel potent ALK inhibitor, in human: contribution of CYP3A enzymes. Xenobiot Fate Foreign Compd Biol Syst. 2018;48(6):546–54.CrossRefGoogle Scholar
  30. 30.
    Hida T, 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.CrossRefPubMedGoogle Scholar
  31. 31.
    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;377:829–38.CrossRefPubMedGoogle Scholar
  32. 32.
    Camidge DR, Peters S, Mok T, et al. Updated efficacy and safety data from the global phase III ALEX study of alectinib (AL) versus crizotinib (CZ) in untreated advanced ALK+ NSCLC. J Clin Oncol. 2018;36(15 Suppl):9043.  https://doi.org/10.1200/JCO.2018.36.15_suppl.9043.Google Scholar
  33. 33.
    European Medicines Agency. Alecensa (alectinib): assessment report. 2017. http://www.ema.europa.eu/ema/. Accessed 2 Mar 2018.
  34. 34.
    Ou SH, Ahn JS, De Petris L, et al. Alectinib in crizotinib-refractory ALK-rearranged non-small-cell lung cancer: a phase II global study. J Clin Oncol. 2016;34(7):661–8.CrossRefPubMedGoogle Scholar
  35. 35.
    Shaw AT, Gandhi L, Gadgeel S, et al. Alectinib in ALK-positive, crizotinib-resistant, non-small-cell lung cancer: a single-group, multicentre, phase 2 trial. Lancet Oncol. 2016;17(2):234–42.CrossRefPubMedGoogle Scholar
  36. 36.
    Barlesi F, Dingemans AMC, Yang JCH, et al. Updated efficacy and safety from the global phase II NP28673 study of alectinib in patients (pts) with previously treated ALK+ non-small-cell lung cancer (NSCLC) [abstract no. 1263P]. Ann Oncol. 2016;27(Suppl 6):1263P.Google Scholar
  37. 37.
    Camidge DR, Gadgeel S, Ou S-H, et al. Updated efficacy and safety data from the phase 2 NP28761 study of alectinib in ALK-positive non-small-cell lung cancer [abstract no. MA07.02]. J Thorac Oncol. 2017;12(Suppl 1):S378.CrossRefGoogle Scholar
  38. 38.
    Ou S-HI, Gandhi L, Shaw A, et al. Updated pooled analysis of CNS endpoints in two phase II studies of alectinib in ALK+ NSCLC [abstract no. MA07.01]. J Thorac Oncol. 2017;12(Suppl 1):377.Google Scholar
  39. 39.
    Novello S, Mazieres J, Oh IJ, et al. Alectinib versus chemotherapy in crizotinib-pretreated anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer: results from the phase III ALUR study. Ann Oncol. 2018.  https://doi.org/10.1093/annonc/mdy121.PubMedCentralGoogle Scholar
  40. 40.
    Gerber DE, Minna JD. ALK inhibition for non-small cell lung cancer: from discovery to therapy in record time. Cancer Cell. 2010;18(6):548–51.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Ou SH. Crizotinib: a novel and first-in-class multitargeted tyrosine kinase inhibitor for the treatment of anaplastic lymphoma kinase rearranged non-small cell lung cancer and beyond. Drug Des Dev Ther. 2011;5:471–85.CrossRefGoogle Scholar
  42. 42.
    Dagogo-Jack I, Shaw AT. Crizotinib resistance: implications for therapeutic strategies. Ann Oncol. 2016;27(Suppl 3):iii42–50.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Song Z, Wang M, Zhang A. Alectinib: a novel second generation anaplastic lymphoma kinase (ALK) inhibitor for overcoming clinically-acquired resistance. Acta Pharm Sin B. 2015;5(1):34–7.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    National Institute for Health and Care Excellence. Alectinib for untreated ALK-positive advanced non-small-cell lung cancer. 2018. https://www.nice.org.uk/. Accessed 29 Jun 2018.
  45. 45.
    European Medicines Agency. Zykadia (ceritinib): summary of product characteristics. 2015. http://www.ema.europa.eu/ema/. Accessed 2 Mar 2018.
  46. 46.
    Novartis. Prescribing information for Zykadia® (ceritinib). 2017. https://www.accessdata.fda.gov/. Accessed 2 Mar 2018.
  47. 47.
    Sullivan I, Planchard D. ALK inhibitors in non-small cell lung cancer: the latest evidence and developments. Ther Adv Med Oncol. 2016;8(1):32–47.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Luo P, Fan J, Zou Z. Efficacy of ALK inhibitors in the treatment of ALK-rearranged non-small cell lung cancer and brain metastases: a meta-analysis [abstract no. PUB025]. J Thorac Oncol. 2017;12(Suppl 2):S2373.CrossRefGoogle Scholar
  49. 49.
    Peters GJ, Muller IB, Giovannetti E. Should alectinib or ceritinib be given as first line therapy for ALK positive non-small cell lung cancer patients instead of crizotinib? Transl Cancer Res. 2017;6(Suppl 6):S1010–3.CrossRefGoogle Scholar
  50. 50.
    Gridelli C, Casaluce F, Sgambato A, et al. J-ALEX trial will crown alectinib as the standard choice for anaplastic lymphoma kinase positive untreated non-small cell lung cancer patients? J Thorac Dis. 2018;10(1):106–8.CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Soria JC, Tan DS, 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.CrossRefPubMedGoogle Scholar
  52. 52.
    Shaw AT, Kim TM, Crino 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.CrossRefPubMedGoogle Scholar
  53. 53.
    Carlson JJ, Canestaro W, Ravelo A, et al. The cost-effectiveness of alectinib in anaplastic lymphoma kinase-positive (ALK+) advanced NSCLC previously treated with crizotinib. J Med Econ. 2017;20(7):671–7.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  1. 1.SpringerAucklandNew Zealand

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