OVERVIEW

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Selumetinib – Koselugo®

DRUG CLASS

Genetic Disorder Agents, Antineoplastic Agents

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

CHEMICAL FORMULA AND STRUCTURE

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DRUG	CAS REGISTRY NO.	MOLECULAR FORMULA	STRUCTURE
Selumetinib	606143-52-6	C17-H15-Br-Cl-F-N4-O3

ANNOTATED BIBLIOGRAPHY

References updated: January 21, 2021

• Zimmerman HJ. 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 protein kinase inhibitors such as selumetinib).
• 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 discusses several kinase inhibitors including imatinib, gefitinib, erlotinib and crizotinib, but not selumetinib).
• Wellstein A, Giaccone G, Atkins MB, Sausville EA. Pathway-targeted therapies: monoclonal antibodies, protein kinase inhibitors, and various small molecules. In, Brunton LL, Hilal-Dandan R, Knollman BC, eds. Goodman & Gilman's the pharmacological basis of therapeutics. 13th ed. New York: McGraw-Hill, 2018, pp. 1203-36.

  (Textbook of pharmacology and therapeutics; selumetinib is not discussed specifically).
• FDA. https://www​.accessdata​.fda.gov/drugsatfda_docs​/nda/2020/213756Orig1s000MultidisciplineR.pdf.

  (FDA website with medical review of efficacy and safety of selumetinib which formed the basis of its approval for use in neurofibromatosis, mentions that in registration trials in adults and children with neurofibromatosis there were no liver related serious adverse events, and although ALT elevations arose in 35% of children, none were associated with symptoms or jaundice).
• 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; selumetinib is not discussed).
• Spraggs CF, Xu CF, Hunt CM. Genetic characterization to improve interpretation and clinical management of hepatotoxicity caused by tyrosine kinase inhibitors. Pharmacogenomics. 2013;14:541–54. [PubMed: 23556451]

  (Review of genetic associations of serum ALT and bilirubin elevations during therapy with tyrosine kinase inhibitors focusing on lapatinib and pazopanib; selumetinib is not mentioned).
• Dombi E, Baldwin A, Marcus LJ, Fisher MJ, Weiss B, Kim A, Whitcomb P, et al. Activity of selumetinib in neurofibromatosis type 1-related plexiform neurofibromas. N Engl J Med. 2016;375:2550–60. [PMC free article: PMC5508592] [PubMed: 28029918]

  (Among 24 children with neurofibromatosis and symptomatic plexiform neurofibromas treated in 28 day cycles of 3 doses of selumetinib [20, 25 or 30 mg/m² twice daily] for a median of 30 cycles, tumor volume decreased in all subjects and dose limiting adverse events included CPK elevations, rash, cellulitis, mucositis and decline in ventricular ejection fraction; 11 episodes of ALT elevation arose but all were transient and mild [less than 3 times ULN]).
• Holkova B, Zingone A, Kmieciak M, Bose P, Badros AZ, Voorhees PM, Baz R, et al. A phase II trial of AZD6244 (selumetinib, ARRY-142886), an oral MEK1/2 inhibitor, in relapsed/refractory multiple myeloma. Clin Cancer Res. 2016;22:1067–75. [PMC free article: PMC4775365] [PubMed: 26446942]

  (Among 36 patients with refractory or relapsed multiple myeloma treated with selumetinib [75 mg twice daily in 28 day cycles], only 2 [6%] had an objective response and adverse events were common, mostly hematologic, 2 patients developing ALT elevations, one of which was above 20 times ULN).
• Alves Júnior SF, Zanetti G, Alves de Melo AS, Souza AS Jr, Souza LS, de Souza Portes Meirelles G, Irion KL, et al. Neurofibromatosis type 1: State-of-the-art review with emphasis on pulmonary involvement. Respir Med. 2019;149:9–15. [PubMed: 30885426]

  (Review of the pathogenesis, epidemiology, clinical features and natural history of neurofibromatosis type 1 [von Recklinghausen disease], an autosomal dominant condition affecting 1:3000 persons that typically presents in childhood with café au lait spots, multiple neurofibromas, pigmented hamartomas, in the iris, seizures, bone and eye disease and, in adulthood, diffuse lung disease).
• Fangusaro J, Onar-Thomas A, Young Poussaint T, Wu S, Ligon AH, Lindeman N, Banerjee A, et al. Selumetinib in paediatric patients with BRAF-aberrant or neurofibromatosis type 1-associated recurrent, refractory, or progressive low-grade glioma: a multicentre, phase 2 trial. Lancet Oncol. 2019;20:1011–22. [PMC free article: PMC6628202] [PubMed: 31151904]

  (Among 50 children with low grade gliomas treated with selumetinib [25 mg/m² twice daily], partial responses occurred in 35-40% and adverse events were frequent, ALT elevations arising in 21 [42%], but all but one was mild [less than 3 times ULN] and none were associated with symptoms or jaundice or required drug discontinuation).
• Gross AM, Wolters PL, Dombi E, Baldwin A, Whitcomb P, Fisher MJ, Weiss B, et al. Selumetinib in children with inoperable plexiform neurofibromas. N Engl J Med. 2020;382:1430–42. [PMC free article: PMC7305659] [PubMed: 32187457]

  (Among 50 children with neurofibromatosis and symptomatic plexiform neurofibromas treated with selumetinib in 28 day cycles, tumor volume decreased in 34 [68%] which was durable in 28 [56%] and accompanied by improvements in pain scores, quality of life and strength; adverse events were common and led to discontinuation in 10%; ALT elevations arose in 14 [28%], but only 1 [2%] was above 3 times ULN).
• Markham A, Keam SJ. Selumetinib: first approval. Drugs. 2020;80:931–7. [PubMed: 32504375]

  (Review of the history of development, pharmacology, mechanism of action, clinical efficacy and safety of selumetinib shortly after its initial approval as therapy of neurofibromatosis type 1 in the US; mentions occurrence of ALT elevations in 35% of subjects, but does not mention episodes of clinically apparent hepatotoxicity).
• Kenney C, Kunst T, Webb S, Christina D Jr, Arrowood C, Steinberg SM, Mettu NB, et al. Phase II study of selumetinib, an orally active inhibitor of MEK1 and MEK2 kinases, in KRAS-G12R-mutant pancreatic ductal adenocarcinoma. Invest New Drugs. 2021 Jan 6; Epub ahead of print. [PMC free article: PMC8068685] [PubMed: 33405090]

  (Among 8 patients with advanced pancreatic cancer and KRAS variants treated with selumetinib [75 mg twice daily], none had even a partial objective response and side effects were common, all 8 developed ALT elevations which were above 20 times ULN in 2 requiring dose discontinuation or reduction, one subject also developed jaundice; few details given).