Skip to main content
SpringerLink
Log in

Clinical Pharmacokinetics and Pharmacodynamics of Selumetinib

  • Review Article
  • Published:
Clinical Pharmacokinetics Aims and scope Submit manuscript

Abstract

Selumetinib, a highly specific mitogen-activated protein kinase 1/2 inhibitor, is approved for children older than 2 years of age with neurofibromatosis 1 who have inoperable plexiform neurofibromas. By selectively binding to mitogen-activated protein kinase 1/2 proteins, selumetinib can arrest the mitogen-activated protein kinase/extracellular signal-regulated kinase signaling pathway that regulates critical cellular responses. Selumetinib has shown promising results as a single agent or in combination with conventional chemotherapy and other targeted therapies both preclinically and clinically, in multiple cancers including pediatric low-grade glioma, non-small cell lung cancer, and melanoma, among others. The pharmacokinetic profiles of selumetinib and its active metabolite N-desmethyl selumetinib have been well characterized in both adults and children. Both compounds exhibited rapid absorption and mean terminal elimination half-lives of about 7.5 h, with minimal accumulation at steady state. Three population pharmacokinetic models have been developed in adults and children, characterizing large inter- and intra-patient variabilities, and identifying significant covariates including food intake on selumetinib absorption, weight metrics, age, co-administration of cytochrome modulators, and Asian ethnicity on selumetinib apparent oral clearance. The most common side effects associated with selumetinib are dermatologic, gastrointestinal toxicities, and fatigue. Most toxicities are mild or moderate, generally tolerated and manageable. Cardiovascular and ocular toxicities remain less frequent but can be potentially more severe and require close monitoring. Overall, selumetinib exhibits a favorable safety profile and pharmacokinetic properties, with promising activity in multiple solid tumors, supporting current and further evaluation in combination with conventional chemotherapy and other targeted agents.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Chang L, Karin M. Mammalian MAP kinase signalling cascades. Nature. 2001;410(6824):37–40. https://doi.org/10.1038/35065000.

    Article  CAS  PubMed  Google Scholar 

  2. Burotto M, Chiou VL, Lee JM, Kohn EC. The MAPK pathway across different malignancies: a new perspective. Cancer. 2014;120(22):3446–56. https://doi.org/10.1002/cncr.28864.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Zhao Y, Adjei AA. The clinical development of MEK inhibitors. Nat Rev Clin Oncol. 2014;11(7):385–400. https://doi.org/10.1038/nrclinonc.2014.83.

    Article  CAS  PubMed  Google Scholar 

  4. Akinleye A, Furqan M, Mukhi N, Ravella P, Liu D. MEK and the inhibitors: from bench to bedside. J Hematol Oncol. 2013;6:27. https://doi.org/10.1186/1756-8722-6-27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Yeh TC, Marsh V, Bernat BA, Ballard J, Colwell H, Evans RJ, et al. Biological characterization of ARRY-142886 (AZD6244), a potent, highly selective mitogen-activated protein kinase kinase 1/2 inhibitor. Clin Cancer Res. 2007;13(5):1576–83. https://doi.org/10.1158/1078-0432.CCR-06-1150.

    Article  CAS  PubMed  Google Scholar 

  6. Davies BR, Logie A, McKay JS, Martin P, Steele S, Jenkins R, et al. AZD6244 (ARRY-142886), a potent inhibitor of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1/2 kinases: mechanism of action in vivo, pharmacokinetic/pharmacodynamic relationship, and potential for combination in preclinical models. Mol Cancer Ther. 2007;6(8):2209–19. https://doi.org/10.1158/1535-7163.MCT-07-0231.

    Article  CAS  PubMed  Google Scholar 

  7. Ludden LK, Strong JM, Kohn EC, Collins JM. Similarity of metabolism for CAI (NSC 609974) in human liver tissue in vitro and in humans in vivo. Clin Cancer Res. 1995;1:399–405.

    CAS  PubMed  Google Scholar 

  8. Leijen S, Soetekouw PM, Jeffry Evans TR, Nicolson M, Schellens JH, Learoyd M, et al. A phase I, open-label, randomized crossover study to assess the effect of dosing of the MEK 1/2 inhibitor selumetinib (AZD6244; ARRY-142866) in the presence and absence of food in patients with advanced solid tumors. Cancer Chemother Pharmacol. 2011;68(6):1619–28. https://doi.org/10.1007/s00280-011-1732-7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Mandal R, Becker S, Strebhardt K. Stamping out RAF and MEK1/2 to inhibit the ERK1/2 pathway: an emerging threat to anticancer therapy. Oncogene. 2016;35(20):2547–61. https://doi.org/10.1038/onc.2015.329.

    Article  CAS  PubMed  Google Scholar 

  10. Cargnello M, Roux PP. Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases. Microbiol Mol Biol Rev. 2011;75(1):50–83. https://doi.org/10.1128/MMBR.00031-10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Kidger AM, Sipthorp J, Cook SJ. ERK1/2 inhibitors: new weapons to inhibit the RAS-regulated RAF-MEK1/2-ERK1/2 pathway. Pharmacol Ther. 2018;187:45–60. https://doi.org/10.1016/j.pharmthera.2018.02.007.

    Article  CAS  PubMed  Google Scholar 

  12. Luke JJ, Ott PA, Shapiro GI. The biology and clinical development of MEK inhibitors for cancer. Drugs. 2014;74(18):2111–28. https://doi.org/10.1007/s40265-014-0315-4.

    Article  CAS  PubMed  Google Scholar 

  13. Ohren JF, Chen H, Pavlovsky A, Whitehead C, Zhang E, Kuffa P, et al. Structures of human MAP kinase kinase 1 (MEK1) and MEK2 describe novel noncompetitive kinase inhibition. Nat Struct Mol Biol. 2004;11(12):1192–7. https://doi.org/10.1038/nsmb859.

    Article  CAS  PubMed  Google Scholar 

  14. Roskoski R Jr. Allosteric MEK1/2 inhibitors including cobimetanib and trametinib in the treatment of cutaneous melanomas. Pharmacol Res. 2017;117:20–31. https://doi.org/10.1016/j.phrs.2016.12.009.

    Article  CAS  PubMed  Google Scholar 

  15. Wu PK, Park JI. MEK1/2 inhibitors: molecular activity and resistance mechanisms. Semin Oncol. 2015;42(6):849–62. https://doi.org/10.1053/j.seminoncol.2015.09.023.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Adjei AA, Cohen RB, Franklin W, Morris C, Wilson D, Molina JR, et al. Phase I pharmacokinetic and pharmacodynamic study of the oral, small-molecule mitogen-activated protein kinase kinase 1/2 inhibitor AZD6244 (ARRY-142886) in patients with advanced cancers. J Clin Oncol. 2008;26(13):2139–46. https://doi.org/10.1200/JCO.2007.14.4956.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. O’Neil BH, Goff LW, Kauh JS, Strosberg JR, Bekaii-Saab TS, Lee RM, et al. Phase II study of the mitogen-activated protein kinase 1/2 inhibitor selumetinib in patients with advanced hepatocellular carcinoma. J Clin Oncol. 2011;29(17):2350–6. https://doi.org/10.1200/JCO.2010.33.9432.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Bennouna J, Lang I, Valladares-Ayerbes M, Boer K, Adenis A, Escudero P, et al. A phase II, open-label, randomised study to assess the efficacy and safety of the MEK1/2 inhibitor AZD6244 (ARRY-142886) versus capecitabine monotherapy in patients with colorectal cancer who have failed one or two prior chemotherapeutic regimens. Invest New Drugs. 2011;29(5):1021–8. https://doi.org/10.1007/s10637-010-9392-8.

    Article  CAS  PubMed  Google Scholar 

  19. Banerji U, Camidge DR, Verheul HM, Agarwal R, Sarker D, Kaye SB, et al. The first-in-human study of the hydrogen sulfate (Hyd-sulfate) capsule of the MEK1/2 inhibitor AZD6244 (ARRY-142886): a phase I open-label multicenter trial in patients with advanced cancer. Clin Cancer Res. 2010;16(5):1613–23. https://doi.org/10.1158/1078-0432.CCR-09-2483.

    Article  CAS  PubMed  Google Scholar 

  20. Tomkinson H, McBride E, Martin P, Lisbon E, Dymond AW, Cantarini M, et al. Comparison of the pharmacokinetics of the phase II and phase III capsule formulations of selumetinib and the effects of food on exposure: results from two randomized crossover trials in healthy male subjects. Clin Ther. 2017;39(11):2260–75. https://doi.org/10.1016/j.clinthera.2017.08.022.

    Article  CAS  PubMed  Google Scholar 

  21. Patel P, Howgate E, Martin P, Carlile DJ, Aarons L, Zhou D. Population pharmacokinetics of the MEK inhibitor selumetinib and its active N-desmethyl metabolite: data from 10 phase I trials. Br J Clin Pharmacol. 2018;84(1):52–63. https://doi.org/10.1111/bcp.13404.

    Article  CAS  PubMed  Google Scholar 

  22. Dymond AW, Howes C, Pattison C, So K, Mariani G, Savage M, et al. Metabolism, excretion, and pharmacokinetics of selumetinib, an MEK1/2 inhibitor, in healthy adult male subjects. Clin Ther. 2016;38(11):2447–58. https://doi.org/10.1016/j.clinthera.2016.09.002.

    Article  CAS  PubMed  Google Scholar 

  23. Tong X, Xu H, Carlile DJ, Tomkinson H, Al-Huniti N, Zhou D. Population pharmacokinetic and exposure-response analysis of selumetinib and its N-desmethyl metabolite in patients with non-small cell lung cancer. J Clin Pharmacol. 2019;59(1):112–22. https://doi.org/10.1002/jcph.1295.

    Article  CAS  PubMed  Google Scholar 

  24. Deming DA, Cavalcante LL, Lubner SJ, Mulkerin DL, LoConte NK, Eickhoff JC, et al. A phase I study of selumetinib (AZD6244/ARRY-142866), a MEK1/2 inhibitor, in combination with cetuximab in refractory solid tumors and KRAS mutant colorectal cancer. Invest New Drugs. 2016;34(2):168–75. https://doi.org/10.1007/s10637-015-0314-7.

    Article  CAS  PubMed  Google Scholar 

  25. Zhou D, So K, Dymond AW, Vik T, Al-Huniti N, Mariani G, et al. Evaluation of the effect of selumetinib on cardiac repolarization: a randomized, placebo- and positive-controlled crossover QT/QTc study in healthy subjects. Clin Ther. 2016;38(12):2555–66. https://doi.org/10.1016/j.clinthera.2016.10.004.

    Article  CAS  PubMed  Google Scholar 

  26. Denton CL, Gustafson DL. Pharmacokinetics and pharmacodynamics of AZD6244 (ARRY-142886) in tumor-bearing nude mice. Cancer Chemother Pharmacol. 2011;67(2):349–60. https://doi.org/10.1007/s00280-010-1323-z.

    Article  CAS  PubMed  Google Scholar 

  27. Dymond AW, Martin P, So K, Huang Y, Severin P, Holmes V, et al. Pharmacokinetics of a single oral dose of the MEK1/2 inhibitor selumetinib in subjects with end-stage renal disease or varying degrees of hepatic impairment compared with healthy subjects. J Clin Pharmacol. 2017;57(5):592–605. https://doi.org/10.1002/jcph.848.

    Article  CAS  PubMed  Google Scholar 

  28. Koselugo [package insert]. Wilmington (DE): AstraZeneca Pharmaceuticals LP. 2020. https://www.azpicentral.com/koselugo/koselugo.pdf#page=1. Accessed 22 Aug 2020.

  29. de Gooijer MC, Zhang P, Weijer R, Buil LCM, Beijnen JH, van Tellingen O. The impact of P-glycoprotein and breast cancer resistance protein on the brain pharmacokinetics and pharmacodynamics of a panel of MEK inhibitors. Int J Cancer. 2018;142(2):381–91. https://doi.org/10.1002/ijc.31052.

    Article  CAS  PubMed  Google Scholar 

  30. Dymond AW, Elks C, Martin P, Carlile DJ, Mariani G, Lovick S, et al. Pharmacokinetics and pharmacogenetics of the MEK1/2 inhibitor, selumetinib, in Asian and Western healthy subjects: a pooled analysis. Eur J Clin Pharmacol. 2017;73(6):717–26. https://doi.org/10.1007/s00228-017-2217-3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Dymond AW, So K, Martin P, Huang Y, Severin P, Mathews D, et al. Effects of cytochrome P450 (CYP3A4 and CYP2C19) inhibition and induction on the exposure of selumetinib, a MEK1/2 inhibitor, in healthy subjects: results from two clinical trials. Eur J Clin Pharmacol. 2017;73(2):175–84. https://doi.org/10.1007/s00228-016-2153-7.

    Article  CAS  PubMed  Google Scholar 

  32. Infante JR, Cohen RB, Kim KB, Burris HA 3rd, Curt G, Emeribe U, et al. A phase I dose-escalation study of selumetinib in combination with erlotinib or temsirolimus in patients with advanced solid tumors. Invest New Drugs. 2017;35(5):576–88. https://doi.org/10.1007/s10637-017-0459-7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. LoRusso PM, Infante JR, Kim KB, Burris HA 3rd, Curt G, Emeribe U, et al. A phase I dose-escalation study of selumetinib in combination with docetaxel or dacarbazine in patients with advanced solid tumors. BMC Cancer. 2017;17(1):173. https://doi.org/10.1186/s12885-017-3143-6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Seto T, Hirai F, Saka H, Kogure Y, Yoh K, Niho S, et al. Safety and tolerability of selumetinib as a monotherapy, or in combination with docetaxel as second-line therapy, in Japanese patients with advanced solid malignancies or non-small cell lung cancer. Jpn J Clin Oncol. 2018;48(1):31–42. https://doi.org/10.1093/jjco/hyx144.

    Article  PubMed  Google Scholar 

  35. Oxnard GR, Yang JC, Yu H, Kim SW, Saka H, Horn L, et al. TATTON: a multi-arm, phase Ib trial of osimertinib combined with selumetinib, savolitinib, or durvalumab in EGFR-mutant lung cancer. Ann Oncol. 2020;31(4):507–16. https://doi.org/10.1016/j.annonc.2020.01.013.

    Article  CAS  PubMed  Google Scholar 

  36. Patel YT, Daryani VM, Patel P, Zhou D, Fangusaro J, Carlile DJ, et al. Population pharmacokinetics of selumetinib and its metabolite N-desmethyl-selumetinib in adult patients with advanced solid tumors and children with low-grade gliomas. CPT Pharmacometrics Syst Pharmacol. 2017;6(5):305–14. https://doi.org/10.1002/psp4.12175.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Banerjee A, Jakacki RI, Onar-Thomas A, Wu S, Nicolaides T, Young Poussaint T, et al. A phase I trial of the MEK inhibitor selumetinib (AZD6244) in pediatric patients with recurrent or refractory low-grade glioma: a Pediatric Brain Tumor Consortium (PBTC) study. Neuro Oncol. 2017;19(8):1135–44. https://doi.org/10.1093/neuonc/now282.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Fangusaro J, Onar-Thomas A, Young Poussaint T, Wu S, Ligon AH, Lindeman N, 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(7):1011–22. https://doi.org/10.1016/S1470-2045(19)30277-3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Gross AM, Frone M, Gripp KW, Gelb BD, Schoyer L, Schill L, et al. Advancing RAS/RASopathy therapies: an NCI-sponsored intramural and extramural collaboration for the study of RASopathies. Am J Med Genet A. 2020;182(4):866–76. https://doi.org/10.1002/ajmg.a.61485.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Dombi E, Baldwin A, Marcus LJ, Fisher MJ, Weiss B, Kim A, et al. Activity of selumetinib in neurofibromatosis type 1-related plexiform neurofibromas. N Engl J Med. 2016;375(26):2550–60. https://doi.org/10.1056/NEJMoa1605943.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Krishnamurthy A, Dasari A, Noonan AM, Mehnert JM, Lockhart AC, Leong S, et al. Phase Ib results of the rational combination of selumetinib and cyclosporin A in advanced solid tumors with an expansion cohort in metastatic colorectal cancer. Cancer Res. 2018;78(18):5398–407. https://doi.org/10.1158/0008-5472.CAN-18-0316.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Greystoke A, Steele N, Arkenau HT, Blackhall F, Md Haris N, Lindsay CR, et al. SELECT-3: a phase I study of selumetinib in combination with platinum-doublet chemotherapy for advanced NSCLC in the first-line setting. Br J Cancer. 2017;117(7):938–46. https://doi.org/10.1038/bjc.2017.271.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Bridgewater J, Lopes A, Beare S, Duggan M, Lee D, Ricamara M, et al. A phase 1b study of selumetinib in combination with cisplatin and gemcitabine in advanced or metastatic biliary tract cancer: the ABC-04 study. BMC Cancer. 2016;16:153. https://doi.org/10.1186/s12885-016-2174-8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Tai WM, Yong WP, Lim C, Low LS, Tham CK, Koh TS, et al. A phase Ib study of selumetinib (AZD6244, ARRY-142886) in combination with sorafenib in advanced hepatocellular carcinoma (HCC). Ann Oncol. 2016;27(12):2210–5. https://doi.org/10.1093/annonc/mdw415.

    Article  CAS  PubMed  Google Scholar 

  45. Wilky BA, Rudek MA, Ahmed S, Laheru DA, Cosgrove D, Donehower RC, et al. A phase I trial of vertical inhibition of IGF signalling using cixutumumab, an anti-IGF-1R antibody, and selumetinib, an MEK 1/2 inhibitor, in advanced solid tumours. Br J Cancer. 2015;112(1):24–31. https://doi.org/10.1038/bjc.2014.515.

    Article  CAS  PubMed  Google Scholar 

  46. Tolcher AW, Khan K, Ong M, Banerji U, Papadimitrakopoulou V, Gandara DR, et al. Antitumor activity in RAS-driven tumors by blocking AKT and MEK. Clin Cancer Res. 2015;21(4):739–48. https://doi.org/10.1158/1078-0432.CCR-14-1901.

    Article  CAS  PubMed  Google Scholar 

  47. Lauchle JO, Kim D, Le DT, Akagi K, Crone M, Krisman K, et al. Response and resistance to MEK inhibition in leukaemias initiated by hyperactive Ras. Nature. 2009;461(7262):411–4. https://doi.org/10.1038/nature08279.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Jessen WJ, Miller SJ, Jousma E, Wu J, Rizvi TA, Brundage ME, et al. MEK inhibition exhibits efficacy in human and mouse neurofibromatosis tumors. J Clin Invest. 2013;123(1):340–7. https://doi.org/10.1172/JCI60578.

    Article  CAS  PubMed  Google Scholar 

  49. Gross AM, Wolters PL, Dombi E, Baldwin A, Whitcomb P, Fisher MJ, et al. Selumetinib in children with inoperable plexiform neurofibromas. N Engl J Med. 2020;382(15):1430–42. https://doi.org/10.1056/NEJMoa1912735.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Bouffet E, Jakacki R, Goldman S, Hargrave D, Hawkins C, Shroff M, et al. Phase II study of weekly vinblastine in recurrent or refractory pediatric low-grade glioma. J Clin Oncol. 2012;30(12):1358–63. https://doi.org/10.1200/JCO.2011.34.5843.

    Article  CAS  PubMed  Google Scholar 

  51. Ater JL, Zhou T, Holmes E, Mazewski CM, Booth TN, Freyer DR, et al. Randomized study of two chemotherapy regimens for treatment of low-grade glioma in young children: a report from the Children’s Oncology Group. J Clin Oncol. 2012;30(21):2641–7. https://doi.org/10.1200/JCO.2011.36.6054.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Ostrom QT, Cioffi G, Gittleman H, Patil N, Waite K, Kruchko C, et al. CBTRUS statistical report: primary brain and other central nervous system tumors diagnosed in the United States in 2012–2016. Neuro Oncol. 2019;21(Suppl. 5):v1-100. https://doi.org/10.1093/neuonc/noz150.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Ryall S, Zapotocky M, Fukuoka K, Nobre L, Guerreiro Stucklin A, Bennett J, et al. Integrated molecular and clinical analysis of 1000 pediatric low-grade gliomas. Cancer Cell. 2020;37(4):569–83. https://doi.org/10.1016/j.ccell.2020.03.011.

    Article  CAS  PubMed  Google Scholar 

  54. Kolb EA, Gorlick R, Houghton PJ, Morton CL, Neale G, Keir ST, et al. Initial testing (stage 1) of AZD6244 (ARRY-142886) by the Pediatric Preclinical Testing Program. Pediatr Blood Cancer. 2010;55(4):668–77. https://doi.org/10.1002/pbc.22576.

    Article  PubMed  PubMed Central  Google Scholar 

  55. Kirkwood JM, Bastholt L, Robert C, Sosman J, Larkin J, Hersey P, et al. Phase II, open-label, randomized trial of the MEK1/2 inhibitor selumetinib as monotherapy versus temozolomide in patients with advanced melanoma. Clin Cancer Res. 2012;18(2):555–67. https://doi.org/10.1158/1078-0432.CCR-11-1491.

    Article  CAS  PubMed  Google Scholar 

  56. Catalanotti F, Solit DB, Pulitzer MP, Berger MF, Scott SN, Iyriboz T, et al. Phase II trial of MEK inhibitor selumetinib (AZD6244, ARRY-142886) in patients with BRAFV600E/K-mutated melanoma. Clin Cancer Res. 2013;19(8):2257–64. https://doi.org/10.1158/1078-0432.CCR-12-3476.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Haass NK, Sproesser K, Nguyen TK, Contractor R, Medina CA, Nathanson KL, et al. The mitogen-activated protein/extracellular signal-regulated kinase kinase inhibitor AZD6244 (ARRY-142886) induces growth arrest in melanoma cells and tumor regression when combined with docetaxel. Clin Cancer Res. 2008;14(1):230–9. https://doi.org/10.1158/1078-0432.CCR-07-1440.

    Article  CAS  PubMed  Google Scholar 

  58. Engelman JA, Chen L, Tan X, Crosby K, Guimaraes AR, Upadhyay R, et al. Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers. Nat Med. 2008;14(12):1351–6. https://doi.org/10.1038/nm.1890.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Hainsworth JD, Cebotaru CL, Kanarev V, Ciuleanu TE, Damyanov D, Stella P, et al. A phase II, open-label, randomized study to assess the efficacy and safety of AZD6244 (ARRY-142886) versus pemetrexed in patients with non-small cell lung cancer who have failed one or two prior chemotherapeutic regimens. J Thorac Oncol. 2010;5(10):1630–6. https://doi.org/10.1097/JTO.0b013e3181e8b3a3.

    Article  PubMed  Google Scholar 

  60. Melosky B, Bradbury P, Tu D, Florescu M, Reiman A, Nicholas G, et al. Selumetinib in patients receiving standard pemetrexed and platinum-based chemotherapy for advanced or metastatic KRAS wildtype or unknown non-squamous non-small cell lung cancer: a randomized, multicenter, phase II study. Canadian Cancer Trials Group (CCTG) IND.219. Lung Cancer. 2019;133:48–55. https://doi.org/10.1016/j.lungcan.2019.04.027.

    Article  PubMed  Google Scholar 

  61. Janne PA, Shaw AT, Pereira JR, Jeannin G, Vansteenkiste J, Barrios C, et al. Selumetinib plus docetaxel for KRAS-mutant advanced non-small-cell lung cancer: a randomised, multicentre, placebo-controlled, phase 2 study. Lancet Oncol. 2013;14(1):38–47. https://doi.org/10.1016/S1470-2045(12)70489-8.

    Article  CAS  PubMed  Google Scholar 

  62. Janne PA, van den Heuvel MM, Barlesi F, Cobo M, Mazieres J, Crino L, et al. Selumetinib plus docetaxel compared with docetaxel alone and progression-free survival in patients with KRAS-mutant advanced non-small cell lung cancer: the SELECT-1 randomized clinical trial. JAMA. 2017;317(18):1844–53. https://doi.org/10.1001/jama.2017.3438.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Janne PA, Smith I, McWalter G, Mann H, Dougherty B, Walker J, et al. Impact of KRAS codon subtypes from a randomised phase II trial of selumetinib plus docetaxel in KRAS mutant advanced non-small-cell lung cancer. Br J Cancer. 2015;113(2):199–203. https://doi.org/10.1038/bjc.2015.215.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Gopal YN, Deng W, Woodman SE, Komurov K, Ram P, Smith PD, et al. Basal and treatment-induced activation of AKT mediates resistance to cell death by AZD6244 (ARRY-142886) in Braf-mutant human cutaneous melanoma cells. Cancer Res. 2010;70(21):8736–47. https://doi.org/10.1158/0008-5472.CAN-10-0902.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Patel SP, Lazar AJ, Papadopoulos NE, Liu P, Infante JR, Glass MR, et al. Clinical responses to selumetinib (AZD6244; ARRY-142886)-based combination therapy stratified by gene mutations in patients with metastatic melanoma. Cancer. 2013;119(4):799–805. https://doi.org/10.1002/cncr.27790.

    Article  CAS  PubMed  Google Scholar 

  66. Gupta A, Love S, Schuh A, Shanyinde M, Larkin JM, Plummer R, et al. DOC-MEK: a double-blind randomized phase II trial of docetaxel with or without selumetinib in wild-type BRAF advanced melanoma. Ann Oncol. 2014;25(5):968–74. https://doi.org/10.1093/annonc/mdu054.

    Article  CAS  PubMed  Google Scholar 

  67. Robert C, Dummer R, Gutzmer R, Lorigan P, Kim KB, Nyakas M, et al. Selumetinib plus dacarbazine versus placebo plus dacarbazine as first-line treatment for BRAF-mutant metastatic melanoma: a phase 2 double-blind randomised study. Lancet Oncol. 2013;14(8):733–40. https://doi.org/10.1016/S1470-2045(13)70237-7.

    Article  CAS  PubMed  Google Scholar 

  68. Carvajal RD, Sosman JA, Quevedo JF, Milhem MM, Joshua AM, Kudchadkar RR, et al. Effect of selumetinib vs chemotherapy on progression-free survival in uveal melanoma: a randomized clinical trial. JAMA. 2014;311(23):2397–405. https://doi.org/10.1001/jama.2014.6096.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Carvajal RD, Piperno-Neumann S, Kapiteijn E, Chapman PB, Frank S, Joshua AM, et al. Selumetinib in combination with dacarbazine in patients with metastatic uveal melanoma: a phase III, multicenter, randomized trial (SUMIT). J Clin Oncol. 2018;36(12):1232–9. https://doi.org/10.1200/JCO.2017.74.1090.

    Article  CAS  PubMed  Google Scholar 

  70. Hochster HS, Uboha N, Messersmith W, Gold PJ, BH ON, Cohen D, et al. Phase II study of selumetinib (AZD6244, ARRY-142886) plus irinotecan as second-line therapy in patients with K-RAS mutated colorectal cancer. Cancer Chemother Pharmacol. 2015;75(1):17–23. https://doi.org/10.1007/s00280-014-2609-3.

  71. Bodoky G, Timcheva C, Spigel DR, La Stella PJ, Ciuleanu TE, Pover G, et al. A phase II open-label randomized study to assess the efficacy and safety of selumetinib (AZD6244 [ARRY-142886]) versus capecitabine in patients with advanced or metastatic pancreatic cancer who have failed first-line gemcitabine therapy. Invest New Drugs. 2012;30(3):1216–23. https://doi.org/10.1007/s10637-011-9687-4.

    Article  CAS  PubMed  Google Scholar 

  72. Chung V, McDonough S, Philip PA, Cardin D, Wang-Gillam A, Hui L, et al. Effect of selumetinib and MK-2206 vs oxaliplatin and fluorouracil in patients with metastatic pancreatic cancer after prior therapy: SWOG S1115 Study randomized clinical trial. JAMA Oncol. 2017;3(4):516–22. https://doi.org/10.1001/jamaoncol.2016.5383.

    Article  PubMed  PubMed Central  Google Scholar 

  73. Zaman K, Winterhalder R, Mamot C, Hasler-Strub U, Rochlitz C, Mueller A, et al. Fulvestrant with or without selumetinib, a MEK 1/2 inhibitor, in breast cancer progressing after aromatase inhibitor therapy: a multicentre randomised placebo-controlled double-blind phase II trial, SAKK 21/08. Eur J Cancer. 2015;51(10):1212–20. https://doi.org/10.1016/j.ejca.2015.03.016.

    Article  CAS  PubMed  Google Scholar 

  74. Eroglu Z, Tawbi HA, Hu J, Guan M, Frankel PH, Ruel NH, et al. A randomised phase II trial of selumetinib vs selumetinib plus temsirolimus for soft-tissue sarcomas. Br J Cancer. 2015;112(10):1644–51. https://doi.org/10.1038/bjc.2015.126.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Hayes DN, Lucas AS, Tanvetyanon T, Krzyzanowska MK, Chung CH, Murphy BA, et al. Phase II efficacy and pharmacogenomic study of Selumetinib (AZD6244; ARRY-142886) in iodine-131 refractory papillary thyroid carcinoma with or without follicular elements. Clin Cancer Res. 2012;18(7):2056–65. https://doi.org/10.1158/1078-0432.CCR-11-0563.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Galanina N, Smith SM, Liao C, Petrich A, Libao B, Gartenhaus R, et al. University of Chicago phase II consortium trial of selumetinib (MEKi) demonstrates low tolerability and efficacy in relapsed DLBCL. Br J Haematol. 2018;181(2):264–7. https://doi.org/10.1111/bjh.14544.

    Article  PubMed  Google Scholar 

  77. Jain N, Curran E, Iyengar NM, Diaz-Flores E, Kunnavakkam R, Popplewell L, et al. Phase II study of the oral MEK inhibitor selumetinib in advanced acute myelogenous leukemia: a University of Chicago phase II consortium trial. Clin Cancer Res. 2014;20(2):490–8. https://doi.org/10.1158/1078-0432.CCR-13-1311.

    Article  CAS  PubMed  Google Scholar 

  78. Farley J, Brady WE, Vathipadiekal V, Lankes HA, Coleman R, Morgan MA, et al. Selumetinib in women with recurrent low-grade serous carcinoma of the ovary or peritoneum: an open-label, single-arm, phase 2 study. Lancet Oncol. 2013;14(2):134–40. https://doi.org/10.1016/S1470-2045(12)70572-7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Bekaii-Saab T, Phelps MA, Li X, Saji M, Goff L, Kauh JS, et al. Multi-institutional phase II study of selumetinib in patients with metastatic biliary cancers. J Clin Oncol. 2011;29(17):2357–63. https://doi.org/10.1200/JCO.2010.33.9473.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Endo M, Yamamoto H, Setsu N, Kohashi K, Takahashi Y, Ishii T, et al. Prognostic significance of AKT/mTOR and MAPK pathways and antitumor effect of mTOR inhibitor in NF1-related and sporadic malignant peripheral nerve sheath tumors. Clin Cancer Res. 2013;19(2):450–61. https://doi.org/10.1158/1078-0432.CCR-12-1067.

    Article  CAS  PubMed  Google Scholar 

  81. Watson AL, Anderson LK, Greeley AD, Keng VW, Rahrmann EP, Halfond AL, et al. Co-targeting the MAPK and PI3K/AKT/mTOR pathways in two genetically engineered mouse models of schwann cell tumors reduces tumor grade and multiplicity. Oncotarget. 2014;5(6):1502–14. https://doi.org/10.18632/oncotarget.1609.

    Article  PubMed  PubMed Central  Google Scholar 

  82. Matheson EC, Thomas H, Case M, Blair H, Jackson RK, Masic D, et al. Glucocorticoids and selumetinib are highly synergistic in RAS pathway-mutated childhood acute lymphoblastic leukemia through upregulation of BIM. Haematologica. 2019;104(9):1804–11. https://doi.org/10.3324/haematol.2017.185975.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Balagula Y, Barth Huston K, Busam KJ, Lacouture ME, Chapman PB, Myskowski PL. Dermatologic side effects associated with the MEK 1/2 inhibitor selumetinib (AZD6244, ARRY-142886). Invest New Drugs. 2011;29(5):1114–21. https://doi.org/10.1007/s10637-010-9567-3.

    Article  CAS  PubMed  Google Scholar 

  84. Klesse LJ, Jordan JT, Radtke HB, Rosser T, Schorry E, Ullrich N, et al. The use of MEK inhibitors in neurofibromatosis type 1-associated tumors and management of toxicities. Oncologist. 2020;25(7):e1109–16. https://doi.org/10.1634/theoncologist.2020-0069.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Dy GK, Adjei AA. Understanding, recognizing, and managing toxicities of targeted anticancer therapies. CA Cancer J Clin. 2013;63(4):249–79. https://doi.org/10.3322/caac.21184.

    Article  PubMed  Google Scholar 

  86. Abdel-Rahman O, ElHalawani H, Ahmed H. Risk of selected cardiovascular toxicities in patients with cancer treated with MEK inhibitors: a comparative systematic review and meta-analysis. J Glob Oncol. 2015;1(2):73–82. https://doi.org/10.1200/JGO.2015.000802.

    Article  PubMed  PubMed Central  Google Scholar 

  87. Totzeck M, Schuler M, Stuschke M, Heusch G, Rassaf T. Cardio-oncology: strategies for management of cancer-therapy related cardiovascular disease. Int J Cardiol. 2019;280:163–75. https://doi.org/10.1016/j.ijcard.2019.01.038.

    Article  PubMed  Google Scholar 

  88. Stjepanovic N, Velazquez-Martin JP, Bedard PL. Ocular toxicities of MEK inhibitors and other targeted therapies. Ann Oncol. 2016;27(6):998–1005. https://doi.org/10.1093/annonc/mdw100.

    Article  CAS  PubMed  Google Scholar 

  89. Avery RA, Trimboli-Heidler C, Kilburn LB. Separation of outer retinal layers secondary to selumetinib. J AAPOS. 2016;20(3):268–71. https://doi.org/10.1016/j.jaapos.2016.01.012.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors acknowledge the support of the National Cancer Institute (Grant number CS21765) and the American Lebanese Syrian Associated Charities (ALSAC) at St. Jude Children’s Research Hospital.

Author information

Authors and Affiliations

  1. Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105-2794, USA

    Olivia Campagne & Clinton F. Stewart

  2. Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, Boston, MA, USA

    Kee Kiat Yeo

  3. Department of Hematology, Oncology, and Stem Cell Transplantation, Children’s Healthcare of Atlanta and Emory University, Atlanta, GA, USA

    Jason Fangusaro

Authors
  1. Olivia Campagne
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kee Kiat Yeo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jason Fangusaro
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Clinton F. Stewart
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Clinton F. Stewart.

Ethics declarations

Funding

No funding was received for the preparation of this article.

Conflicts of Interest

Olivia Campagne, Kee Kiat Yeo, Jason Fangusaro, and Clinton F. Stewart have no conflicts of interest that are directly relevant to the content of this article.

Ethics Approval

Not applicable.

Consent to Participate

Not applicable.

Consent for Publication

Not applicable.

Availability of Data and Material

Not applicable.

Code availability

Not applicable.

Authors’ Contributions

OC, KKY, JF, and CFS conducted the literature search and wrote and revised the manuscript.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Campagne, O., Yeo, K.K., Fangusaro, J. et al. Clinical Pharmacokinetics and Pharmacodynamics of Selumetinib. Clin Pharmacokinet 60, 283–303 (2021). https://doi.org/10.1007/s40262-020-00967-y

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40262-020-00967-y

Search

Navigation