Clinical Pharmacokinetic and Pharmacodynamic Considerations in the (Modern) Treatment of Melanoma

  • Hannah Yejin KimEmail author
  • Parth J. Upadhyay
  • Alia Fahmy
  • Xiaoman Liu
  • Janna K. Duong
  • Alan V. Boddy
Review Article


Targeted therapies, based on identification of common oncogenic mutations such as BRAF V600E/K and monoclonal antibody immunotherapies, have transformed the treatment of melanoma. Dual mitogen-activated protein kinase (MAPK) pathway inhibition of BRAF V600E/K and MEK 1/2 kinases with BRAF–MEK inhibitors using dabrafenib–trametinib, vemurafenib–cobimetinib and encorafenib–binimetinib is now the standard of care for BRAF V600E/K tumours. Monoclonal antibodies, such as pembrolizumab and nivolumab, against programmed cell death protein (PD-1) on T cells, as well as ipilimumab against cytotoxic T lymphocyte antigen-4 (CTLA-4), enable restoration of suppressed T-cell antitumour response, and have also shown improved clinical benefit compared with traditional chemotherapy. Exploration of different combination therapies, sequence of treatment, and dosing strategies is ongoing, and the understanding of the pharmacokinetics (PK) and pharmacodynamics (PD) of these new agents is fundamental in devising the optimal regimen. Preclinical and clinical studies, as well as population PK modelling, provide essential data in terms of PK parameters, metabolism, interpatient variability, drug interactions and PD effects at the target. This review gathers the current evidence and understanding of the clinical PK and PD of drugs used in the modern treatment of melanoma, and the factors determining drug disposition, exposure and clinical response, and also highlighting areas of further research.


Compliance with Ethical Standards

Conflict of interest

Hannah Yejin Kim, Parth J. Upadhyay, Alia Fahmy, Xiaoman Liu, Janna K. Duong, and Alan V. Boddy declare they have no conflicts of interest.


No sources of funding were used for this review.


  1. 1.
    Ferlay J, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136(5):E359–86.CrossRefPubMedGoogle Scholar
  2. 2.
    Schadendorf D, Hauschild A. Melanoma in 2013: melanoma—the run of success continues. Nat Rev Clin Oncol. 2014;11(2):75–6.CrossRefPubMedGoogle Scholar
  3. 3.
    Matthews NH, et al. Epidemiology of melanoma. In: Ward WH, Farma JM, editors. Cutaneous melanoma: etiology and therapy. Brisbane: Codon Publications; 2017.Google Scholar
  4. 4.
    Guy GP Jr, et al. Vital signs: melanoma incidence and mortality trends and projections—United States, 1982–2030. Morb Mortal Wkly Rep. 2015;64(21):591–6.Google Scholar
  5. 5.
    Luikart SD, Kennealey GT, Kirkwood JM. Randomized phase III trial of vinblastine, bleomycin, and cis-dichlorodiammine-platinum versus dacarbazine in malignant melanoma. J Clin Oncol. 1984;2(3):164–8.CrossRefPubMedGoogle Scholar
  6. 6.
    Chapman PB, et al. Phase III multicenter randomized trial of the Dartmouth regimen versus dacarbazine in patients with metastatic melanoma. J Clin Oncol. 1999;17(9):2745–51.CrossRefPubMedGoogle Scholar
  7. 7.
    Lui P, et al. Treatments for metastatic melanoma: synthesis of evidence from randomized trials. Cancer Treat Rev. 2007;33(8):665–80.CrossRefPubMedGoogle Scholar
  8. 8.
    Atkins MB, et al. High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. J Clin Oncol. 1999;17(7):2105–16.CrossRefPubMedGoogle Scholar
  9. 9.
    Atkins MB, et al. High-dose recombinant interleukin-2 therapy in patients with metastatic melanoma: long-term survival update. Cancer J Sci Am. 2000;6(Suppl 1):S11–4.PubMedGoogle Scholar
  10. 10.
    Creagan ET, et al. Phase II trials of recombinant leukocyte A interferon in disseminated malignant melanoma: results in 96 patients. Cancer Treat Rep. 1986;70(5):619–24.PubMedGoogle Scholar
  11. 11.
    Fecher LA, Amaravadi RK, Flaherty KT. The MAPK pathway in melanoma. Curr Opin Oncol. 2008;20(2):183–9.CrossRefPubMedGoogle Scholar
  12. 12.
    Ji Z, Flaherty KT, Tsao H. Molecular therapeutic approaches to melanoma. Mol Asp Med. 2010;31(2):194–204.CrossRefGoogle Scholar
  13. 13.
    Dhomen N, Marais R. BRAF signaling and targeted therapies in melanoma. Hematol Oncol Clin North Am. 2009;23(3):529–45, ix.Google Scholar
  14. 14.
    Wilson MA, Nathanson KL. Molecular testing in melanoma. Cancer J. 2012;18(2):117–23.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Houben R, et al. Constitutive activation of the Ras-Raf signaling pathway in metastatic melanoma is associated with poor prognosis. J Carcinog. 2004;3:6.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Chang DZ, et al. Clinical significance of BRAF mutations in metastatic melanoma. J Transl Med. 2004;2(1):46.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Ugurel S, et al. B-RAF and N-RAS mutations are preserved during short time in vitro propagation and differentially impact prognosis. PLoS One. 2007;2(2):e236.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Davies H, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417(6892):949–54.CrossRefPubMedGoogle Scholar
  19. 19.
    Long GV, et al. Prognostic and clinicopathologic associations of oncogenic BRAF in metastatic melanoma. J Clin Oncol. 2011;29(10):1239–46.CrossRefPubMedGoogle Scholar
  20. 20.
    Willmore-Payne C, et al. Human malignant melanoma: detection of BRAF- and c-kit-activating mutations by high-resolution amplicon melting analysis. Hum Pathol. 2005;36(5):486–93.CrossRefPubMedGoogle Scholar
  21. 21.
    Long GV, et al. Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial. Lancet. 2015;386(9992):444–51.CrossRefPubMedGoogle Scholar
  22. 22.
    Long GV, et al. Dabrafenib plus trametinib versus dabrafenib monotherapy in patients with metastatic BRAF V600E/K-mutant melanoma: long-term survival and safety analysis of a phase 3 study. Ann Oncol. 2017;28(7):1631–9.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Dummer R, et al. Overall survival in patients with BRAF-mutant melanoma receiving encorafenib plus binimetinib versus vemurafenib or encorafenib (COLUMBUS): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2018;19(10):1315–27.CrossRefPubMedGoogle Scholar
  24. 24.
    Atkins MB, Larkin J. Immunotherapy combined or sequenced with targeted therapy in the treatment of solid tumors: current perspectives. J Natl Cancer Inst. 2016;108(6):djv414.CrossRefPubMedGoogle Scholar
  25. 25.
    Freeman GJ, et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med. 2000;192(7):1027–34.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Chen L. Co-inhibitory molecules of the B7-CD28 family in the control of T-cell immunity. Nat Rev Immunol. 2004;4(5):336–47.CrossRefPubMedGoogle Scholar
  27. 27.
    Ascierto PA, et al. Ipilimumab 10 mg/kg versus ipilimumab 3 mg/kg in patients with unresectable or metastatic melanoma: a randomised, double-blind, multicentre, phase 3 trial. Lancet Oncol. 2017;18(5):611–22.CrossRefPubMedGoogle Scholar
  28. 28.
    Schadendorf D, et al. Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in unresectable or metastatic melanoma. J Clin Oncol. 2015;33(17):1889–94.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Robert C, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015;372(4):320–30.CrossRefPubMedGoogle Scholar
  30. 30.
    Weber JS, et al. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2015;16(4):375–84.CrossRefPubMedGoogle Scholar
  31. 31.
    Schachter J, et al. Pembrolizumab versus ipilimumab for advanced melanoma: final overall survival results of a multicentre, randomised, open-label phase 3 study (KEYNOTE-006). Lancet. 2017;390(10105):1853–62.CrossRefPubMedGoogle Scholar
  32. 32.
    Larkin J, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015;373(1):23–34.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Wolchok JD, et al. Overall survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med. 2017;377(14):1345–56.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Sharma A, et al. Mutant V599EB-Raf regulates growth and vascular development of malignant melanoma tumors. Cancer Res. 2005;65(6):2412–21.CrossRefPubMedGoogle Scholar
  35. 35.
    Eisen T, et al. Sorafenib in advanced melanoma: a phase II randomised discontinuation trial analysis. Br J Cancer. 2006;95(5):581–6.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Hauschild A, et al. Results of a phase III, randomized, placebo-controlled study of sorafenib in combination with carboplatin and paclitaxel as second-line treatment in patients with unresectable stage III or stage IV melanoma. J Clin Oncol. 2009;27(17):2823–30.CrossRefPubMedGoogle Scholar
  37. 37.
    Bollag G, et al. Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma. Nature. 2010;467(7315):596–9.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Tsai J, et al. Discovery of a selective inhibitor of oncogenic B-Raf kinase with potent antimelanoma activity. Proc Natl Acad Sci USA. 2008;105(8):3041–6.CrossRefPubMedGoogle Scholar
  39. 39.
    Chapman PB, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364(26):2507–16.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Rizos H, et al. BRAF inhibitor resistance mechanisms in metastatic melanoma: spectrum and clinical impact. Clin Cancer Res. 2014;20(7):1965–77.CrossRefPubMedGoogle Scholar
  41. 41.
    Shi H, et al. Acquired resistance and clonal evolution in melanoma during BRAF inhibitor therapy. Cancer Discov. 2014;4(1):80–93.CrossRefPubMedGoogle Scholar
  42. 42.
    Van Allen EM, et al. The genetic landscape of clinical resistance to RAF inhibition in metastatic melanoma. Cancer Discov. 2014;4(1):94–109.CrossRefPubMedGoogle Scholar
  43. 43.
    Flaherty KT, et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med. 2012;367(18):1694–703.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Long GV, et al. Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. N Engl J Med. 2014;371(20):1877–88.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Robert C, et al. Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med. 2015;372(1):30–9.CrossRefPubMedGoogle Scholar
  46. 46.
    Ascierto PA, et al. Cobimetinib combined with vemurafenib in advanced BRAF(V600)-mutant melanoma (coBRIM): updated efficacy results from a randomised, double-blind, phase 3 trial. Lancet Oncol. 2016;17(9):1248–60.CrossRefPubMedGoogle Scholar
  47. 47.
    Dummer R, et al. Encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF-mutant melanoma (COLUMBUS): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2018;19(5):603–15.CrossRefPubMedGoogle Scholar
  48. 48.
    Zhang W, Heinzmann D, Grippo JF. Clinical pharmacokinetics of vemurafenib. Clin Pharmacokinet. 2017;56(9):1033–43.CrossRefPubMedGoogle Scholar
  49. 49.
    Grippo JF, et al. A phase I, randomized, open-label study of the multiple-dose pharmacokinetics of vemurafenib in patients with BRAF V600E mutation-positive metastatic melanoma. Cancer Chemother Pharmacol. 2014;73(1):103–11.CrossRefPubMedGoogle Scholar
  50. 50.
    Goldinger SM, et al. A single-dose mass balance and metabolite-profiling study of vemurafenib in patients with metastatic melanoma. Pharmacol Res Perspect. 2015;3(2):e00113.CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Roberts MS, et al. Enterohepatic circulation: physiological, pharmacokinetic and clinical implications. Clin Pharmacokinet. 2002;41(10):751–90.CrossRefPubMedGoogle Scholar
  52. 52.
    Kim G, et al. FDA approval summary: vemurafenib for treatment of unresectable or metastatic melanoma with the BRAFV600E mutation. Clin Cancer Res. 2014;20(19):4994–5000.CrossRefPubMedGoogle Scholar
  53. 53.
    ZELBORAF (vemurafenib) [prescribing information]. South San Francisco: Genentech, Inc.; 2011. Accessed Sept 2018.
  54. 54.
    Puszkiel A, et al. Plasma vemurafenib exposure and pre-treatment hepatocyte growth factor level are two factors contributing to the early peripheral lymphocytes depletion in BRAF-mutated melanoma patients. Pharmacol Res. 2016;113(Pt A):709–18.CrossRefPubMedGoogle Scholar
  55. 55.
    Wang Z-X, et al. Prediction of the likelihood of drug interactions with kinase inhibitors based on in vitro and computational studies. Fundam Clin Pharmacol. 2014;28(5):551–82.CrossRefPubMedGoogle Scholar
  56. 56.
    Zhang W, et al. Effect of vemurafenib on the pharmacokinetics of a single dose of digoxin in patients with BRAFV600 mutation-positive metastatic malignancy. J Clin Pharmacol. 2018;58(8):1067–73.CrossRefGoogle Scholar
  57. 57.
    Ribas A, et al. The effects of a high-fat meal on single-dose vemurafenib pharmacokinetics. J Clin Pharmacol. 2013;54(4):368–74.CrossRefGoogle Scholar
  58. 58.
    Flaherty KT, et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med. 2010;363(9):809–19.CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Trunzer K, et al. Pharmacodynamic effects and mechanisms of resistance to vemurafenib in patients with metastatic melanoma. J Clin Oncol. 2013;31(14):1767–74.CrossRefPubMedGoogle Scholar
  60. 60.
    Denton CL, et al. Concomitant oral and intravenous pharmacokinetics of dabrafenib, a BRAF inhibitor, in patients with BRAF V600 mutation-positive solid tumors. J Clin Pharmacol. 2013;53(9):955–61.CrossRefPubMedGoogle Scholar
  61. 61.
    Ouellet D, et al. Effects of particle size, food, and capsule shell composition on the oral bioavailability of dabrafenib, a BRAF inhibitor, in patients with BRAF mutation-positive tumors. J Pharm Sci. 2013;102(9):3100–9.CrossRefPubMedGoogle Scholar
  62. 62.
    Ouellet D, et al. Population pharmacokinetics of dabrafenib, a BRAF inhibitor: effect of dose, time, covariates, and relationship with its metabolites. J Clin Pharmacol. 2014;54(6):696–706.CrossRefPubMedGoogle Scholar
  63. 63.
    Falchook GS, et al. Dose selection, pharmacokinetics, and pharmacodynamics of BRAF inhibitor dabrafenib (GSK2118436). Clin Cancer Res. 2014;20(17):4449–58.CrossRefPubMedGoogle Scholar
  64. 64.
    Suttle AB, et al. Assessment of the drug interaction potential and single- and repeat-dose pharmacokinetics of the BRAF inhibitor dabrafenib. J Clin Pharmacol. 2015;55(4):392–400.CrossRefPubMedGoogle Scholar
  65. 65.
    Lawrence SK, et al. The metabolic drug–drug interaction profile of Dabrafenib: in vitro investigations and quantitative extrapolation of the P450-mediated DDI risk. Drug Metab Dispos. 2014;42(7):1180–90.CrossRefPubMedGoogle Scholar
  66. 66.
    Falchook GS, et al. Dabrafenib in patients with melanoma, untreated brain metastases, and other solid tumours: a phase 1 dose-escalation trial. Lancet. 2012;379(9829):1893–901.CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Bershas DA, et al. Metabolism and disposition of oral dabrafenib in cancer patients: proposed participation of aryl nitrogen in carbon–carbon bond cleavage via decarboxylation following enzymatic oxidation. Drug Metab Dispos. 2013;41(12):2215–24.CrossRefPubMedGoogle Scholar
  68. 68.
    Menzies AM, et al. Characteristics of pyrexia in BRAFV600E/K metastatic melanoma patients treated with combined dabrafenib and trametinib in a phase I/II clinical trial. Ann Oncol. 2015;26(2):415–21.CrossRefPubMedGoogle Scholar
  69. 69.
    Rousset M, et al. Trough dabrafenib plasma concentrations can predict occurrence of adverse events requiring dose reduction in metastatic melanoma. Clin Chim Acta. 2017;472:26–9.CrossRefPubMedGoogle Scholar
  70. 70.
    TAFINLAR (dabrafenib) [prescribing information]. Zebulon: GlaxoSmithKline; 2014. Accessed Sept 2018.
  71. 71.
    Kulkarni DA, et al. Pharmacogenetic investigation of dabrafenib efficacy in a meta-analysis of three melanoma studies. J Clin Oncol. 2014;32(15 Suppl):e20018.CrossRefGoogle Scholar
  72. 72.
    Kulkarni D, et al. Pyrexia in dabrafenib-treated melanoma patients is not associated with common genetic variation or HLA polymorphisms. Pharmacogenomics. 2016;17(5):459–62.CrossRefPubMedGoogle Scholar
  73. 73.
    Cappellini MD, Fiorelli G. Glucose-6-phosphate dehydrogenase deficiency. Lancet. 2008;371(9606):64–74.CrossRefPubMedGoogle Scholar
  74. 74.
    Dean L. Dabrafenib therapy and BRAF and G6PD genotype. In: Pratt V, et al., editors. Medical genetics summaries. Bethesda: National Center for Biotechnology Information; 2012.Google Scholar
  75. 75.
    Delord JP, et al. Phase I dose-escalation and -expansion study of the BRAF inhibitor encorafenib (LGX818) in metastatic BRAF-mutant melanoma. Clin Cancer Res. 2017;23(18):5339–48.CrossRefPubMedGoogle Scholar
  76. 76.
    BRAFTOVI (encorafenib) [prescribing information]. Boulder: Array BioPharma Inc.; 2018. Accessed Sept 2018.
  77. 77.
    US Food and Drug Administration, Center for Drug Evaluation and Research. BRAFTOVI (encorafenib) multidisciplinary review. Application number 210496Orig1s000; 2017. Accessed Sept 2018.
  78. 78.
    Cho M, et al. A phase I clinical trial of binimetinib in combination with FOLFOX in patients with advanced metastatic colorectal cancer who failed prior standard therapy. Oncotarget. 2017;8(45):79750–60.PubMedPubMedCentralGoogle Scholar
  79. 79.
    O’Shea J, et al. A preclinical evaluation of the MEK inhibitor refametinib in HER2-positive breast cancer cell lines including those with acquired resistance to trastuzumab or lapatinib. Oncotarget. 2017;8(49):85120–35.CrossRefPubMedPubMedCentralGoogle Scholar
  80. 80.
    Finn RS, et al. Phase 1b investigation of the MEK inhibitor binimetinib in patients with advanced or metastatic biliary tract cancer. Investig New Drugs. 2018;36(6):1037–43.CrossRefGoogle Scholar
  81. 81.
    Ikeda M, et al. Efficacy and safety of trametinib in Japanese patients with advanced biliary tract cancers refractory to gemcitabine. Cancer Sci. 2018;109(1):215–24.CrossRefPubMedGoogle Scholar
  82. 82.
    Lim HY, et al. A phase II study of the efficacy and safety of the combination therapy of the MEK inhibitor refametinib (BAY 86-9766) plus sorafenib for Asian patients with unresectable hepatocellular carcinoma. Clin Cancer Res. 2014;20(23):5976–85.CrossRefPubMedGoogle Scholar
  83. 83.
    Grisham RN, et al. Phase Ib study of binimetinib with paclitaxel in patients with platinum-resistant ovarian cancer: final results, potential biomarkers, and extreme responders. Clin Cancer Res. 2018;24(22):5525–33.CrossRefPubMedGoogle Scholar
  84. 84.
    Gilmartin AG, et al. GSK1120212 (JTP-74057) is an inhibitor of MEK activity and activation with favorable pharmacokinetic properties for sustained in vivo pathway inhibition. Clin Cancer Res. 2011;17(5):989–1000.CrossRefPubMedGoogle Scholar
  85. 85.
    Wu PK, Park JI. MEK1/2 inhibitors: molecular activity and resistance mechanisms. Semin Oncol. 2015;42(6):849–62.CrossRefPubMedPubMedCentralGoogle Scholar
  86. 86.
    Wright CJ, McCormack PL. Trametinib: first global approval. Drugs. 2013;73(11):1245–54.CrossRefPubMedGoogle Scholar
  87. 87.
    Larkin J, et al. Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med. 2014;371(20):1867–76.CrossRefPubMedPubMedCentralGoogle Scholar
  88. 88.
    Cox DS, et al. Evaluation of the effects of food on the single-dose pharmacokinetics of trametinib, a first-in-class MEK inhibitor, in patients with cancer. J Clin Pharmacol. 2013;53(9):946–54.CrossRefPubMedGoogle Scholar
  89. 89.
    Infante JR, et al. Safety, pharmacokinetic, pharmacodynamic, and efficacy data for the oral MEK inhibitor trametinib: a phase 1 dose-escalation trial. Lancet Oncol. 2012;13(8):773–81.CrossRefPubMedGoogle Scholar
  90. 90.
    Yamazaki N, et al. Phase 1/2 study assessing the safety and efficacy of dabrafenib and trametinib combination therapy in Japanese patients with BRAF V600 mutation-positive advanced cutaneous melanoma. J Dermatol. 2018;45(4):397–407.CrossRefPubMedPubMedCentralGoogle Scholar
  91. 91.
    Ho MY, et al. Trametinib, a first-in-class oral MEK inhibitor mass balance study with limited enrollment of two male subjects with advanced cancers. Xenobiotica. 2014;44(4):352–68.CrossRefPubMedGoogle Scholar
  92. 92.
    Ouellet D, et al. Population pharmacokinetics and exposure-response of trametinib, a MEK inhibitor, in patients with BRAF V600 mutation-positive melanoma. Cancer Chemother Pharmacol. 2016;77(4):807–17.CrossRefPubMedGoogle Scholar
  93. 93.
    Filppula AM, Mustonen TM, Backman JT. In vitro screening of six protein kinase inhibitors for time-dependent inhibition of CYP2C8 and CYP3A4: possible implications with regard to drug–drug interactions. Basic Clin Pharmacol Toxicol. 2018;123(6):739–48.CrossRefPubMedGoogle Scholar
  94. 94.
    MEKINIST (trametinib) [prescribing information]. Zebulon: GlaxoSmithKline; 2013. Accessed Sept 2018.
  95. 95.
    Tolcher AW, et al. A phase IB trial of the oral MEK inhibitor trametinib (GSK1120212) in combination with everolimus in patients with advanced solid tumors. Ann Oncol. 2015;26(1):58–64.CrossRefPubMedGoogle Scholar
  96. 96.
    LoRusso PM, et al. Phase I pharmacokinetic and pharmacodynamic study of the oral MAPK/ERK kinase inhibitor PD-0325901 in patients with advanced cancers. Clin Cancer Res. 2010;16(6):1924–37.CrossRefPubMedGoogle Scholar
  97. 97.
    Musib L, et al. Absolute bioavailability and effect of formulation change, food, or elevated pH with rabeprazole on cobimetinib absorption in healthy subjects. Mol Pharm. 2013;10(11):4046–54.CrossRefPubMedGoogle Scholar
  98. 98.
    Rosen LS, et al. A first-in-human phase I study to evaluate the MEK1/2 inhibitor, cobimetinib, administered daily in patients with advanced solid tumors. Investig New Drugs. 2016;34(5):604–13.CrossRefGoogle Scholar
  99. 99.
    Takahashi RH, et al. Absorption, metabolism, excretion, and the contribution of intestinal metabolism to the oral disposition of [14C]cobimetinib, a MEK inhibitor, in humans. Drug Metab Dispos. 2016;44(1):28–39.CrossRefPubMedGoogle Scholar
  100. 100.
    Han K, et al. Population pharmacokinetics and dosing implications for cobimetinib in patients with solid tumors. Cancer Chemother Pharmacol. 2015;76(5):917–24.CrossRefPubMedGoogle Scholar
  101. 101.
    Choo EF, et al. Use of transgenic mouse models to understand the oral disposition and drug–drug interaction potential of cobimetinib, a MEK inhibitor. Drug Metab Dispos. 2015;43(6):864–9.CrossRefPubMedGoogle Scholar
  102. 102.
    Budha NR, et al. Evaluation of cytochrome P450 3A4-mediated drug–drug interaction potential for cobimetinib using physiologically based pharmacokinetic modeling and simulation. Clin Pharmacokinet. 2016;55(11):1435–45.CrossRefPubMedGoogle Scholar
  103. 103.
    COTELLIC (cobimetinib) [prescribing information]. South San Francisco: Genentech, Inc.; 2015 (updated Jan 2018). Accessed Oct 2018.
  104. 104.
    Jakob JA, et al. NRAS mutation status is an independent prognostic factor in metastatic melanoma. Cancer. 2012;118(16):4014–23.CrossRefPubMedGoogle Scholar
  105. 105.
    Dummer R, et al. Binimetinib versus dacarbazine in patients with advanced NRAS-mutant melanoma (NEMO): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2017;18(4):435–45.CrossRefPubMedGoogle Scholar
  106. 106.
    Bendell JC, et al. A phase 1 dose-escalation and expansion study of binimetinib (MEK162), a potent and selective oral MEK1/2 inhibitor. Br J Cancer. 2017;116(5):575–83.CrossRefPubMedPubMedCentralGoogle Scholar
  107. 107.
    MEKTOVI (binimetinib) [prescribing information]. Boulder: Array BioPharma Inc.; 2018. Accessed Sept 2018.
  108. 108.
    MEKTOVI (changed to BALIMEK) [binimetinib]. Assessment Report. London: European Medicines Agency (EMA); 2017. Accessed Sept 2018.
  109. 109.
    Lee PA, et al. Abstract 2515: preclinical development of ARRY-162, a potent and selective MEK 1/2 inhibitor. Cancer Res. 2010;70(8 Suppl):2515.CrossRefGoogle Scholar
  110. 110.
    Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–74.CrossRefGoogle Scholar
  111. 111.
    Curiel TJ, et al. Blockade of B7-H1 improves myeloid dendritic cell-mediated antitumor immunity. Nat Med. 2003;9(5):562–7.CrossRefPubMedGoogle Scholar
  112. 112.
    Hino R, et al. Tumor cell expression of programmed cell death-1 ligand 1 is a prognostic factor for malignant melanoma. Cancer. 2010;116(7):1757–66.CrossRefPubMedGoogle Scholar
  113. 113.
    Wang C, et al. In vitro characterization of the anti-PD-1 antibody nivolumab, BMS-936558, and in vivo toxicology in non-human primates. Cancer Immunol Res. 2014;2(9):846–56.CrossRefPubMedGoogle Scholar
  114. 114.
    Brahmer JR, et al. Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol. 2010;28(19):3167–75.CrossRefPubMedPubMedCentralGoogle Scholar
  115. 115.
    Topalian SL, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366(26):2443–54.CrossRefPubMedPubMedCentralGoogle Scholar
  116. 116.
    Patnaik A, et al. Phase I study of pembrolizumab (MK-3475; anti-PD-1 monoclonal antibody) in patients with advanced solid tumors. Clin Cancer Res. 2015;21(19):4286–93.CrossRefPubMedGoogle Scholar
  117. 117.
    Ribas A, et al. Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet Oncol. 2015;16(8):908–18.CrossRefPubMedGoogle Scholar
  118. 118.
    KEYTRUDA (pembrolizumab) [prescribing information]. Carlow: Merck Sharp & Dohme Corp.; 2014. Accessed Oct 2018.
  119. 119.
    Longoria TC, Tewari KS. Evaluation of the pharmacokinetics and metabolism of pembrolizumab in the treatment of melanoma. Expert Opin Drug Metab Toxicol. 2016;12(10):1247–53.CrossRefPubMedPubMedCentralGoogle Scholar
  120. 120.
    Ahamadi M, et al. Model-based characterization of the pharmacokinetics of pembrolizumab: a humanized anti-PD-1 monoclonal antibody in advanced solid tumors. CPT Pharmacomet Syst Pharmacol. 2017;6(1):49–57.CrossRefGoogle Scholar
  121. 121.
    Freshwater T, et al. Evaluation of dosing strategy for pembrolizumab for oncology indications. J Immunother Cancer. 2017;5:43.CrossRefPubMedPubMedCentralGoogle Scholar
  122. 122.
    Robert C, et al. Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. Lancet. 2014;384(9948):1109–17.CrossRefPubMedGoogle Scholar
  123. 123.
    Robert C, et al. Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med. 2015;372(26):2521–32.CrossRefPubMedGoogle Scholar
  124. 124.
    Eggermont AMM, et al. Adjuvant pembrolizumab versus placebo in resected stage III melanoma. N Engl J Med. 2018;378(19):1789–801.CrossRefPubMedGoogle Scholar
  125. 125.
    Daud AI, et al. Programmed death-ligand 1 expression and response to the anti-programmed death 1 antibody pembrolizumab in melanoma. J Clin Oncol. 2016;34(34):4102–9.CrossRefPubMedPubMedCentralGoogle Scholar
  126. 126.
    OPDIVO (nivolumab) [prescribing information]. Princeton: Bristol-Myers Squibb; 2014 (updated 2018). Accessed Oct 2018.
  127. 127.
    Bajaj G, et al. Model-based population pharmacokinetic analysis of nivolumab in patients with solid tumors. CPT Pharmacomet Syst Pharmacol. 2017;6(1):58–66.CrossRefGoogle Scholar
  128. 128.
    Long GV, et al. Assessment of nivolumab exposure and clinical safety of 480 mg every 4 weeks flat-dosing schedule in patients with cancer. Ann Oncol. 2018;29(11):2208–13.PubMedPubMedCentralGoogle Scholar
  129. 129.
    Zhao X, et al. Assessment of nivolumab benefit-risk profile of a 240-mg flat dose relative to a 3-mg/kg dosing regimen in patients with advanced tumors. Ann Oncol. 2017;28(8):2002–8.CrossRefPubMedPubMedCentralGoogle Scholar
  130. 130.
    OPDIVO (nivolumab) [product information]. European Public Assessment Report (EPAR). London: European Medicines Agency. 2015 (updated 2018). Accessed Oct 2018.
  131. 131.
    Liu C, et al. Association of time-varying clearance of nivolumab with disease dynamics and its implications on exposure response analysis. Clin Pharmacol Ther. 2017;101(5):657–66.CrossRefPubMedGoogle Scholar
  132. 132.
    Agrawal S, et al. Nivolumab dose selection: challenges, opportunities, and lessons learned for cancer immunotherapy. J Immunother Cancer. 2016;4:72.CrossRefPubMedPubMedCentralGoogle Scholar
  133. 133.
    Buchbinder EI, Desai A. CTLA-4 and PD-1 pathways: similarities, differences, and implications of their inhibition. Am J Clin Oncol. 2016;39(1):98–106.CrossRefPubMedPubMedCentralGoogle Scholar
  134. 134.
    Krummel MF, Allison JP. CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation. J Exp Med. 1995;182(2):459–65.CrossRefPubMedGoogle Scholar
  135. 135.
    Parry RV, et al. CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol Cell Biol. 2005;25(21):9543–53.CrossRefPubMedPubMedCentralGoogle Scholar
  136. 136.
    Hodi FS, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363(8):711–23.CrossRefPubMedPubMedCentralGoogle Scholar
  137. 137.
    Robert C, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011;364(26):2517–26.CrossRefPubMedGoogle Scholar
  138. 138.
    Maio M, et al. Five-year survival rates for treatment-naive patients with advanced melanoma who received ipilimumab plus dacarbazine in a phase III trial. J Clin Oncol. 2015;33(10):1191–6.CrossRefPubMedPubMedCentralGoogle Scholar
  139. 139.
    Weber JS, et al. Phase I/II study of ipilimumab for patients with metastatic melanoma. J Clin Oncol. 2008;26(36):5950–6.CrossRefPubMedGoogle Scholar
  140. 140.
    Wolchok JD, et al. Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study. Lancet Oncol. 2010;11(2):155–64.CrossRefPubMedGoogle Scholar
  141. 141.
    YERVOY (ipilimumab) [product information]. European Public Assessment Report (EPAR). London: European Medicines Agency (EMA). 2011 (updated Oct 2018). Accessed Oct 2018.
  142. 142.
    Merchant MS, et al. Phase I clinical trial of ipilimumab in pediatric patients with advanced solid tumors. Clin Cancer Res. 2016;22(6):1364–70.CrossRefPubMedGoogle Scholar
  143. 143.
    Feng Y, et al. Model-based clinical pharmacology profiling of ipilimumab in patients with advanced melanoma. Br J Clin Pharmacol. 2014;78(1):106–17.CrossRefPubMedPubMedCentralGoogle Scholar
  144. 144.
    Postow MA, et al. Pharmacodynamic effect of ipilimumab on absolute lymphocyte count (ALC) and association with overall survival in patients with advanced melanoma. J Clin Oncol. 2013;31(15 Suppl):9052.Google Scholar
  145. 145.
    Delyon J, et al. Experience in daily practice with ipilimumab for the treatment of patients with metastatic melanoma: an early increase in lymphocyte and eosinophil counts is associated with improved survival. Ann Oncol. 2013;24(6):1697–703.CrossRefPubMedGoogle Scholar
  146. 146.
    Simeone E, et al. Immunological and biological changes during ipilimumab treatment and their potential correlation with clinical response and survival in patients with advanced melanoma. Cancer Immunol Immunother. 2014;63(7):675–83.CrossRefPubMedGoogle Scholar
  147. 147.
    Martens A, et al. Increases in absolute lymphocytes and circulating CD4+ and CD8+ T cells are associated with positive clinical outcome of melanoma patients treated with ipilimumab. Clin Cancer Res. 2016;22(19):4848–58.CrossRefPubMedPubMedCentralGoogle Scholar
  148. 148.
    Tang DN, et al. Increased frequency of ICOS+ CD4 T cells as a pharmacodynamic biomarker for anti-CTLA-4 therapy. Cancer Immunol Res. 2013;1(4):229–34.CrossRefPubMedCentralGoogle Scholar
  149. 149.
    Feng Y, et al. Exposure-response relationships of the efficacy and safety of ipilimumab in patients with advanced melanoma. Clin Cancer Res. 2013;19(14):3977–86.CrossRefPubMedGoogle Scholar
  150. 150.
    Queirolo P, et al. Association of CTLA-4 gene variants with response to therapy and long-term survival in metastatic melanoma patients treated with ipilimumab: an Italian melanoma intergroup study. Front Immunol. 2017;8:386.CrossRefPubMedPubMedCentralGoogle Scholar
  151. 151.
    Breunis WB, et al. Influence of cytotoxic T lymphocyte-associated antigen 4 (CTLA4) common polymorphisms on outcome in treatment of melanoma patients with CTLA-4 blockade. J Immunother. 2008;31(6):586–90.CrossRefPubMedPubMedCentralGoogle Scholar
  152. 152.
    Romano E, et al. Ipilimumab-dependent cell-mediated cytotoxicity of regulatory T cells ex vivo by nonclassical monocytes in melanoma patients. Proc Natl Acad Sci USA. 2015;112(19):6140–5.CrossRefPubMedGoogle Scholar
  153. 153.
    Arce Vargas F, et al. Fc effector function contributes to the activity of human anti-CTLA-4 antibodies. Cancer Cell. 2018;33(4):649–663e4.CrossRefPubMedPubMedCentralGoogle Scholar
  154. 154.
    Liu C, et al. BRAF inhibition increases tumor infiltration by T cells and enhances the antitumor activity of adoptive immunotherapy in mice. Clin Cancer Res. 2013;19(2):393–403.CrossRefPubMedGoogle Scholar
  155. 155.
    Koya RC, et al. BRAF inhibitor vemurafenib improves the antitumor activity of adoptive cell immunotherapy. Cancer Res. 2012;72(16):3928–37.CrossRefPubMedPubMedCentralGoogle Scholar
  156. 156.
    Comin-Anduix B, et al. The oncogenic BRAF kinase inhibitor PLX4032/RG7204 does not affect the viability or function of human lymphocytes across a wide range of concentrations. Clin Cancer Res. 2010;16(24):6040–8.CrossRefPubMedPubMedCentralGoogle Scholar
  157. 157.
    Boni A, et al. Selective BRAFV600E inhibition enhances T-cell recognition of melanoma without affecting lymphocyte function. Cancer Res. 2010;70(13):5213–9.CrossRefPubMedGoogle Scholar
  158. 158.
    Hu-Lieskovan S, et al. Improved antitumor activity of immunotherapy with BRAF and MEK inhibitors in BRAF(V600E) melanoma. Sci Transl Med. 2015;7(279):279ra41.CrossRefPubMedPubMedCentralGoogle Scholar
  159. 159.
    Frederick DT, et al. BRAF inhibition is associated with enhanced melanoma antigen expression and a more favorable tumor microenvironment in patients with metastatic melanoma. Clin Cancer Res. 2013;19(5):1225–31.CrossRefPubMedPubMedCentralGoogle Scholar
  160. 160.
    Liu L, et al. The BRAF and MEK inhibitors dabrafenib and trametinib: effects on immune function and in combination with immunomodulatory antibodies targeting PD-1, PD-L1, and CTLA-4. Clin Cancer Res. 2015;21(7):1639–51.CrossRefPubMedGoogle Scholar
  161. 161.
    Wyluda EJ, et al. Durable complete responses off all treatment in patients with metastatic malignant melanoma after sequential immunotherapy followed by a finite course of BRAF inhibitor therapy. Cancer Biol Ther. 2015;16(5):662–70.CrossRefPubMedPubMedCentralGoogle Scholar
  162. 162.
    Ascierto PA, et al. Sequential treatment with ipilimumab and BRAF inhibitors in patients with metastatic melanoma: data from the Italian cohort of the ipilimumab expanded access program. Cancer Investig. 2014;32(4):144–9.CrossRefGoogle Scholar
  163. 163.
    Ackerman A, et al. Outcomes of patients with metastatic melanoma treated with immunotherapy prior to or after BRAF inhibitors. Cancer. 2014;120(11):1695–701.CrossRefPubMedGoogle Scholar
  164. 164.
    Gonzalez-Cao M, et al. Fatal gastrointestinal toxicity with ipilimumab after BRAF/MEK inhibitor combination in a melanoma patient achieving pathological complete response. Oncotarget. 2016;7(35):56619–27.CrossRefPubMedPubMedCentralGoogle Scholar
  165. 165.
    Ribas A, et al. Hepatotoxicity with combination of vemurafenib and ipilimumab. N Engl J Med. 2013;368(14):1365–6.CrossRefPubMedGoogle Scholar
  166. 166., National Library of Medicine (US). A study of the safety and efficacy of pembrolizumab (MK-3475) in combination with trametinib and dabrafenib in participants with advanced melanoma (MK-3475-022/KEYNOTE-022) [ identifier: NCT02130466]. 29 Feb 2000. Accessed 9 Feb 2019.
  167. 167.
    Dummer R, et al. The anti-PD-1 antibody spartalizumab (PDR001) in combination with dabrafenib and trametinib in previously untreated patients with advanced BRAF V600-mutant melanoma: first efficacy, safety, and biomarker findings from the part 2 biomarker cohort of COMBi-i. Cancer Res. 2018;78(13 Suppl):abstract no. CT182.Google Scholar
  168. 168., National Library of Medicine (US). A prospective randomized and phase 2 trial for metastatic melanoma using adoptive cell therapy with tumor infiltrating lymphocytes plus IL-2 either alone or following the administration of pembrolizumab [ identifier: NCT02621021]. Accessed 9 Feb 2019.
  169. 169., National Library of Medicine (US). The ACTIVATE (Adoptive Cell Therapy InVigorated to Augment Tumor Eradication) Trial (ACTIVATE) [ identifer: NCT03158935]. 29 Feb 2000. Accessed 9 Feb 2019.
  170. 170., National Library of Medicine (US). Combined therapy of nivolumab and adoptive T cell therapy in metastatic melanoma patients (Nivo-TIL) [ identifier: NCT03374839]. 29 Feb 2000. Accessed 9 Feb 2019.

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Hannah Yejin Kim
    • 1
    Email author
  • Parth J. Upadhyay
    • 1
  • Alia Fahmy
    • 1
  • Xiaoman Liu
    • 1
  • Janna K. Duong
    • 1
  • Alan V. Boddy
    • 2
    • 3
  1. 1.School of Pharmacy, Faculty of Medicine and HealthThe University of SydneySydneyAustralia
  2. 2.School of Pharmacy and Medical SciencesUniversity of South AustraliaAdelaideAustralia
  3. 3.UniSA Cancer Research InstituteUniversity of South AustraliaAdelaideAustralia

Personalised recommendations