Recurrent hyperglycemic hyperosmolar state after re-administration of dose-reduced ceritinib, an anaplastic lymphoma kinase inhibitor

Abstract

Ceritinib is a second-generation anaplastic lymphoma kinase (ALK) inhibitor with clinical activity in crizotinib-resistant ALK-positive non-small cell lung cancer and in treatment-naïve ALK-positive disease. Hyperglycemia is a known adverse event, but the mechanism by which ceritinib causes hyperglycemia is unknown, and whether ceritinib causes hyperglycemic emergencies is unclear. Here, we report the case of a patient with a hyperglycemic hyperosmolar state (HHS) recurrence after the re-administration of dose-reduced ceritinib. A 78-year-old man with type 2 diabetes diagnosed as having advanced lung adenocarcinoma had been treated with alogliptin (25 mg/day) for the diabetes and with ceritinib for the lung cancer. After 28 days of ceritinib administration, he was admitted to our hospital due to HHS. His blood glucose level improved with insulin therapy after discontinuation of the ceritinib. He then received re-administration with a decreased ceritinib dose while maintaining the insulin treatment to control his blood glucose, but his HHS recurred. We discontinued the ceritinib for other side effects and noticed the HHS disappeared. Our findings suggest that ceritinib can cause HHS and that HHS may recur even after dose reductions.

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References

  1. 1.

    Goldman JW, Mendenhall MA, Rettinger SR. Hyperglycemia associated with targeted oncologic treatment: mechanisms and management. Oncologist. 2016;21:1326–36.

    CAS  Article  Google Scholar 

  2. 2.

    Shaw AT, Kim D-W, Mehra R, et al. Ceritinib in ALK-rearranged non-small-cell lung cancer. N Engl J Med. 2014;370:1189–97.

    CAS  Article  Google Scholar 

  3. 3.

    Camidge DR, Kim HR, Ahn M-J. Brigatinib versus crizotinib in ALK-positive non-small-cell lung cancer. N Engl J Med. 2018;379:2027–39.

    CAS  Article  Google Scholar 

  4. 4.

    Novartis Pharmaceuticals Zykadia (ceritinib): US prescribing information; 2019. https://www.pharma.us.novartis.com/sites/www.pharma.us.novartis.com/files/zykadia.pdf. Accessed 31 May 2020.

  5. 5.

    Raedler LA. Zykadia (Ceritinib) approved for patients with crizotinib-resistant ALK-positive non-small-cell lung cancer. Am Health Drug Benefits. 2015;8:163–6.

    PubMed  PubMed Central  Google Scholar 

  6. 6.

    Busaidy NL, Farooki A, Dowlati A, et al. Management of metabolic effects associated with anticancer agents targeting the PI3K-Akt-mTOR pathway. J Clin Oncol. 2012;30:2919–28.

    CAS  Article  Google Scholar 

  7. 7.

    Lovly CM, McDonald NT, Chen H, et al. Rationale for co-targeting IGF-1R and ALK in ALK fusion-positive lung cancer. Nat Med. 2014;20:1027–34.

    CAS  Article  Google Scholar 

  8. 8.

    Dhillon S, Clark M. Ceritinib: first global approval. Drugs. 2014;74:1285–91.

    CAS  Article  Google Scholar 

  9. 9.

    Mok T, Spigel D, Felip E, et al. ASCEND-2: a single-arm, open-label, multicenter phase II study of ceritinib in adult patients (pts) with ALK-rearranged (ALK+) non-small cell lung cancer (NSCLC) previously treated with chemotherapy and crizotinib (CRZ). J Clin Oncol. 2015;33:8059.

    Article  Google Scholar 

  10. 10.

    Crouthamel M-C, Kahana JA, Korenchuk S, et al. Mechanism and management of AKT inhibitor-induced hyperglycemia. Clin Cancer Res. 2009;15:217–25.

    CAS  Article  Google Scholar 

  11. 11.

    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;56:5675–90.

    CAS  Article  Google Scholar 

  12. 12.

    Crino L, Ahn MJ, De Marinis F, et al. Multicenter phase II study of whole-body and intracranial activity with ceritinib in patients with ALK-rearranged non-small-cell lung cancer previously treated with chemotherapy and crizotinib: results from ASCEND-2. J Clin Oncol. 2016;34:2866–73.

    CAS  Article  Google Scholar 

  13. 13.

    Jean-Charles S, Daniel SWT, Rita C, et al. First-line ceritinib versus platinum-based chemotherapy in advanced ALK-rearranged non-small-cell lung cancer (ASCEND-4): a randomized, open-label, phase 3 study. Lancet. 2017;389:917–29.

    Article  Google Scholar 

  14. 14.

    Fujita H, Murakami T, Tomoike F, et al. Ceritinib-associated hyperglycemia in the Japanese Adverse Drug Event Report database. J Diabetes Investig. 2020;11:726–30.

    CAS  Article  Google Scholar 

  15. 15.

    Sakuma I, Nagano H, Yoshino I, et al. Ceritinib aggravates glycemic control in insulin-treated patients with diabetes and metastatic ALK-positive lung cancer. Intern Med. 2019;58:817–20.

    CAS  Article  Google Scholar 

  16. 16.

    Scheen AJ. Dipeptidylpeptidase-4 inhibitors (gliptins): focus on drug-drug interactions. Clin Pharmacokinet. 2010;49:573–88.

    CAS  Article  Google Scholar 

  17. 17.

    Miyoshi Y, Ogawa O, Oyama Y. Nivolumab, an anti-programmed cell death-1 antibody, induces fulminant type 1 diabetes. Tohoku J Exp Med. 2016;239:155–8.

    CAS  Article  Google Scholar 

  18. 18.

    Sakurai K, Niitsuma S, Sato R, Takahashi K, Arihara Z. Painless thyroiditis and fulminant type 1 diabetes mellitus in a patient treated with an immune checkpoint inhibitor, nivolumab. Tohoku J Exp Med. 2018;244:33–40.

    Article  Google Scholar 

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Acknowledgements

We would like to acknowledge every nurse and resident doctor who took care of the patient.

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Correspondence to Osamu Ogawa.

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Yuka Miyoshi, Osamu Ogawa, Ai Nishida, and Masahiro Masuzawa declare having no conflict of interest.

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We obtained an informed consent or a substitute for it from the patient for being included in the study. We also obtained an additional informed consent from the patient for any identifying information included in this article.

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Miyoshi, Y., Ogawa, O., Nishida, A. et al. Recurrent hyperglycemic hyperosmolar state after re-administration of dose-reduced ceritinib, an anaplastic lymphoma kinase inhibitor. Diabetol Int (2020). https://doi.org/10.1007/s13340-020-00442-w

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Keywords

  • Hyperglycemic hyperosmolar state
  • Ceritinib
  • ALK inhibitor
  • IGF-1 receptor