OVERVIEW

PRODUCT INFORMATION

CHEMICAL FORMULA AND STRUCTURE

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DRUG	CAS REGISTRY NO.	MOLECULAR FORMULA	STRUCTURE
Alectinib	1256580-46-7	C30-H34-N4-O2

ANNOTATED BIBLIOGRAPHY

References updated: 30 May 2017

Abbreviations: ALK, anaplastic lymphoma kinase; NCSLC, non-small cell lung cancer; ULN, upper limit of normal.

• 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. Kinase inhibitors. Cancer chemotherapy. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013, pp. 556-7.

  (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).
• Seto T, Kiura K, Nishio M, Nakagawa K, Maemondo M, Inoue A, Hida T, et al. CH5424802 (RO5424802) for patients with ALK-rearranged advanced non-small-cell lung cancer (AF-001JP study): a single-arm, open-label, phase 1-2 study. Lancet Oncol 2013; 14: 590-8. [PubMed: 23639470]

  (Among 46 patients with ALK-positive NSCLC treated with alectinib [up to 300 mg twice daily], 93% had an objective response, and side effects included ALT elevations in 10 patients [22%] which were above 5 times ULN in one [2%] and bilirubin elevations in 28%, but most changes resolved without symptoms or residual injury, although one patient has reported to have developed sclerosing cholangitis).
• Gadgeel SM, Gandhi L, Riely GJ, Chiappori AA, West HL, Azada MC, Morcos PN, 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: 1119-28. [PubMed: 25153538]

  (Among 47 patients with ALK-positive NCSLC resistant to crizotinib therapy who were treated with alectinib [300-900 mg twice daily], 54% had an objective response, and side effects included fatigue [30%], myalgia [17%], edema [17%], and ALT elevations [13%], but none were above 5 times ULN).
• McKeage K. Alectinib: a review of its use in advanced ALK-rearranged non-small cell lung cancer. Drugs 2015; 75: 75-82. [PubMed: 25428710]

  (Review of the development of alectinib, its structure, pharmacology, efficacy and safety; mentions a case of sclerosing cholangitis arising during therapy [Seto 2013], but does not discuss ALT elevations or hepatotoxicity).
• Larkins E, Blumenthal GM, Chen H, He K, Agarwal R, Gieser G, Stephens O, 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. [PubMed: 27413075]

  (Review of clinical trial results that supported the FDA-accelerated approval of alectinib for crizotinib-refractory, ALK-positive NCSLC which included safety data on 253 patients in whom common side effects were fatigue [41%], constipation [34%], edema [30%], myalgia [29%] and increased ALT [34%], bilirubin [39%] and alkaline phosphatase levels [47%]; 4 patients had ALT elevations above 5 times ULN, and 2 were diagnosed with drug induced liver injury).
• Ou SH, Ahn JS, De Petris L, Govindan R, Yang JC, Hughes B, Lena H, et al. Alectinib in crizotinib-refractory ALK-rearranged non-small-cell lung cancer: a phase II global study. J Clin Oncol 2016; 34: 661-8. [PubMed: 26598747]

  (Abstract: Among 138 patients with crizotinib- refractory, ALK-positive NSCLC treated with alectinib, the objective response rate was 79% and common side effects were constipation, fatigue and peripheral edema).
• Shaw AT, Gandhi L, Gadgeel S, Riely GJ, Cetnar J, West H, Camidge DR, et al.; study investigators. Alectinib in ALK-positive, crizotinib-resistant, non-small-cell lung cancer: a single-group, multicentre, phase 2 trial. Lancet Oncol 2016; 17: 234-42. [PMC free article: PMC4752892] [PubMed: 26708155]

  (Among 87 patients with ALK-positive, crizotinib-resistant NSCLC treated with alectinib [600 mg twice daily], the objective response rate was 48%, and side effects included constipation [36%], fatigue [33%], myalgia [24%], peripheral edema [23%] and ALT elevations [26%], which were above 5 times ULN in 5%, with two patients discontinuing therapy early because of "serious liver injury" although no specific details provided).
• Jassem J. Alectinib in crizotinib-resistant, ALK-positive NSCLC. Lancet Oncol 2016; 1: 134-5. [PubMed: 26708154]

  (Editorial accompanying publication by Shaw [2016] discussing the promises and challenges of the second-generation ALK inhibitors such as alectinib and ceritinib).
• Hida T, Nokihara H, Kondo M, Kim YH, Azuma K, Seto T, Takiguchi Y, 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. [PubMed: 28501140]

  (Among 207 Japanese patients with ALK-positive NSCLC treated with alectinib or crizotinib for an average of 12 months, progressionc free survival was greater with alectinib while adverse events were less including ALT elevations [9% vs 32%] which were above 5 times ULN in 1% vs 13%).
• Gainor JF, Shaw AT. J-ALEX: alectinib versus crizotinib in ALK-positive lung cancer. Lancet 2017; 390 (10089): 3-4. [PubMed: 28501139]

  (Editorial in response to Hida [2017] mentions the greater potency against ALK and better brain penetration of alectinib compared to crizotinib).
• Tamura T, Kiura K, Seto T, Nakagawa K, Maemondo M, Inoue A, Hida T, et al. Three-year follow-up of an alectinib phase I/II study in ALK-positive non-small-cell lung cancer: AF-001JP. J Clin Oncol 2017; 35: 1515-21. [PMC free article: PMC5455704] [PubMed: 28296581]

  (Further follow up of 46 patients with ALK-positive NSCLC treated with alectinib, identified 25 patients still on therapy after 3 years and adverse events included AST elevations in 33% and 6 patients who discontinued therapy because of side effects including one for sclerosing cholangitis and one for ALT elevations above 5 times ULN).