OVERVIEW

PRODUCT INFORMATION

CHEMICAL FORMULA AND STRUCTURE

View in own window

DRUG	CAS REGISTRY NO.	MOLECULAR FORMULA	STRUCTURE
Ceritinib	1032900-25-6	Not available

ANNOTATED BIBLIOGRAPHY

References updated: 01 June 2017

Abbreviations used: ALK, anaplastic lymphoma kinase; NSCLC, non-small cell lung cancer;

• Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999.

  (Review of hepatotoxicity published in 1999 before the availability of tyrosine kinase receptor inhibitors).
• DeLeve LD. Erlotinib. Cancer chemotherapy. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013, pp. 556.

  (Review of hepatotoxicity of cancer chemotherapeutic agents published in 2013; discusses the hepatotoxicity of crizotinib, but not alectinib or ceritinib).
• Chabner BA, Barnes J, Neal J, Olson E, Mujagic H, Sequist L, Wilson W, et al. Targeted therapies: tyrosine kinase inhibitors, monoclonal antibodies, and cytokines. In, Brunton LL, Chabner BA, Knollman BC, eds. Goodman & Gilman's the pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill, 2011, pp. 1731-54.

  (Textbook of pharmacology and therapeutics).
• Shaw AT, Engelman JA. ALK in lung cancer: past, present, and future. J Clin Oncol 2013; 31: 1105-11. [PMC free article: PMC4209068] [PubMed: 23401436]

  (Review of the history of discovery of ALK mutations and development of crizotinib as therapy of NSCLC patients with this mutation as well as next-generation ALK inhibitors in development; no discussion of hepatotoxicity or ALT elevations).
• Shah RR, Morganroth J, Shah DR. Hepatotoxicity of tyrosine kinase inhibitors: clinical and regulatory perspectives. Drug Saf 2013; 36: 491-503. [PubMed: 23620168]

  (Review of the hepatotoxicity of 18 tyrosine kinase inhibitors approved for use in cancer in the US as of 2013; crizotinib is listed as causing liver enzyme elevations in up to 57% of patients [ ≥5 times ULN in 6%] and to having been linked cases of hepatitis and fatal hepatic failure; no mention of alectinib or ceritinib).
• Shaw AT, Kim DW, Mehra R, Tan DS, Felip E, Chow LQ, Camidge DR, et al. Ceritinib in ALK-rearranged non-small-cell lung cancer. N Engl J Med 2014; 370: 1189-97. [PMC free article: PMC4079055] [PubMed: 24670165]

  (Among 59 patients with ALK-rearranged NSCLC enrolled in dose escalation studies and 71 patients treated in open label studies at the optimal dose of ceritinib, overall objective response rates were 58% at the higher doses and adverse events included ALT elevations in 35%, which were above 5 times the ULN in 21%, both rates being greater with higher doses).
• Ceritinib (Zykadia) for non-small cell lung cancer. Med Lett Drugs Ther 2014; 56 (1447): 62-3. [PubMed: 25046419]

  (Concise review of the mechanism of action, clinical efficacy, safety and costs of ceritinib, the second oral tyrosine kinase inhibitor with activity against ALK-positive metastatic NCSLC; mentions that ALT elevations are common during therapy and hepatotoxicity has been reported).
• Chabner BA. Approval after phase I: ceritinib runs the three-minute mile. Oncologist 2014; 19: 577-8. [PMC free article: PMC4041677] [PubMed: 24789171]

  (Editorial in response to the accelerated approval of ceritinib for ALK-positive metastatic NSCLC mentioning its rapid, 3 year development and approval based upon limited, open label, phase 1 and 2 studies only and, as a consequence, the incomplete knowledge about side effects).
• Gainor JF, Tan DS, De Pas T, Solomon BJ, Ahmad A, Lazzari C, de Marinis F, et al. Progression free and overall survival in ALK-positive NSCLC patients treated with sequential crizotinib and ceritinib. Clin Cancer Res 2015; 21: 2745-52. [PMC free article: PMC4470734] [PubMed: 25724526]

  (In a retrospective analysis of 73 patients with ALK-positive NSCLC who were treated sequentially with crizotinib and then ceritinib, median overall survival was 49 months; no discussion of adverse event rates).
• Cooper MR, Chim H, Chan H, Durand C. Ceritinib: a new tyrosine kinase inhibitor for non-small-cell lung cancer. Ann Pharmacother 2015; 49: 107-12. [PubMed: 25258420]

  (Systematic review of the literature on ceritinib therapy of NSCLC identified only one article and two abstracts; listing, but no discussion of ALT elevations and hepatotoxicity).
• Crinò L, Ahn MJ, De Marinis F, Groen HJ, Wakelee H, Hida T, Mok T, 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. [PubMed: 27432917]

  (Among 140 patients with crizotinib resistant, ALK-positive NSCLC treated with ceritinib [750 mg daily], the overall objective response rate was 39% and all patients reported adverse events that were "grade 3 or 4" in 71% with ALT elevations in 44% of patients that were above 5 times ULN in 17%; no mention of clinically apparent liver injury or hepatic failure).
• Sassier M, Mennecier B, Gschwend A, Rein M, Coquerel A, Humbert X, Alexandre J, et al. Successful treatment with ceritinib after crizotinib induced hepatitis. Lung Cancer 2016; 95: 15-6. [PubMed: 27040846]

  (Two patients with ALK-positive NSCLC who developed ALT elevations while on crizotinib [ALT 1825 U/L after 10 days and ALT 531 U/L after 1 month] both had recurrent ALT elevations within days of restarting crizotinib at a lower dose, yet both later tolerated ceritinib [for 7 months or more] without recurrence of ALT abnormalities).
• Kim DW, Mehra R, Tan DS, Felip E, Chow LQ, Camidge DR, Vansteenkiste J, et al. Activity and safety of ceritinib in patients with ALK-rearranged non-small-cell lung cancer (ASCEND-1): updated results from the multicentre, open-label, phase 1 trial. Lancet Oncol 2016; 17: 452-63. [PMC free article: PMC5063047] [PubMed: 26973324]

  (Among 255 patients with NSCLC treated with ceritinib in an extension of phase 1 studies [median follow up 11 months], the overall objective response rate was 67% and side effects included ALT elevations above 5 times ULN in 30%, with 3 patients discontinuing drug due to liver test abnormalities and one due to "cholestatic hepatitis").
• Soria JC, Tan DS, Chiari R, Wu YL, Paz-Ares L, Wolf J, Geater SL, 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. [PubMed: 28126333]

  (Among 376 previously untreated patients with ALK-positive NSCLC treated with ceritinib or platinum based chemotherapy, progression free survival rates were greater with ceritinib [16.6 vs 8.1 months] while overall adverse event rates were similar, although ALT elevations were more frequent with ceritinib [60% vs 22%] as were ALT elevations above 5 times ULN [31% vs 3%], although there were no instances of clinically apparent liver injury in either group).