, Volume 73, Issue 8, pp 767–777 | Cite as

Combination Molecularly Targeted Drug Therapy in Metastatic Melanoma: Progress to Date

  • Charlotte Lemech
  • Jeffrey Infante
  • Hendrik-Tobias Arkenau
Leading Article


Previously characterized by a median overall survival of between 6 and 12 months, metastatic melanoma now has a number of novel and effective treatment options. The ability to target the mitogen-activated protein kinase (MAPK) pathway with BRAF (v-raf murine sarcoma viral oncogene homolog B1) or MEK (mitogen-activated protein kinase kinase) inhibitors can result in rapid clinical benefit, but is too often associated with limited durability of response. Resistance inevitably develops either via reactivation of the MAPK pathway or via bypass signalling pathways, such as the PI3K (phosphoinositide 3-kinase) pathway. Combination strategies are thus appealing with an aim to overcome potential resistance mechanisms. Already, the combination of the BRAF inhibitor, dabrafenib, along with the MEK inhibitor, trametinib, has shown promising results clinically and with an improved toxicity profile. Other combination strategies with agents that target the PI3K pathway, angiogenesis, and the immune system are in development or already underway, although potential overlapping toxicities require close monitoring. The currently available molecularly targeted agents that target the MAPK pathway and development of combination therapies for treatment of metastatic melanoma are discussed in further detail.


  1. 1.
    Cancer Research UK. Skin Cancer—UK Incidence Statistics 2010. http://info.cancerresearchuk.org/cancerstats/types/skin/incidence/ (Accessed 29 Nov 2011).
  2. 2.
    Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363(8):711–23.PubMedCrossRefGoogle Scholar
  3. 3.
    Robert C, Thomas L, Bondarendo I, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011;364(26):2517–26.PubMedCrossRefGoogle Scholar
  4. 4.
    Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364:2507–16.PubMedCrossRefGoogle Scholar
  5. 5.
    Flaherty KT, Infante JR, Daud A, et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med. 2012;367:1694–703. doi:10.1056/NEJMoa1210093.Google Scholar
  6. 6.
    Platz A, Egyhazi S, Ringborg U, Hansson J. Human cutaneous melanoma; a review of NRAS and BRAF mutation frequencies in relation to histogenic subclass and body site. Mol Oncol. 2008;1:395–405.PubMedCrossRefGoogle Scholar
  7. 7.
    Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417:949–54.PubMedCrossRefGoogle Scholar
  8. 8.
    Lemech C, Infante JR, Arkenau H-T. The potential for BRAF V600 inhibitors in advanced cutaneous melanoma: rationale and latest evidence. Ther Adv Med Oncol. 2012;4(2):61–73.PubMedCrossRefGoogle Scholar
  9. 9.
    Long GV, Menzies AM, Nagrial AM, et al. Prognostic and clinicopathologic associations of oncogenic BRAF in metastatic melanoma. J Clin Oncol. 2011;29(10):1239–46.PubMedCrossRefGoogle Scholar
  10. 10.
    Cheng S, Chu P, Hinshaw M, et al. Frequency of mutations associated with targeted therapy in malignant melanoma patients. J Clin Oncol. 2011;29(suppl):abstract 8597.Google Scholar
  11. 11.
    Rubinstein JC, Sznol M, Pavlick AC, et al. Incidence of the V600K mutation among melanoma patients with BRAF mutations, and potential therapeutic response to the specific BRAF inhibitor PLX4032. J Transl Med. 2010;6:67.CrossRefGoogle Scholar
  12. 12.
    Smalley KSM, Xiao M, Villanueva J, Nguyen TK, Flaherty KT, Letrero R, Van Belle P, Elder DE, Wang Y, Nathanson KL, Herlyn M. CRAF inhibition induces apoptosis in melanoma cells with non-V600E BRAF mutations. Oncogene. 2009;28:85–94.PubMedCrossRefGoogle Scholar
  13. 13.
    Wan PTC, Garnett MJ, Roe M, Lee S, Niculescu-Duvaz D, Good VM, Jones M, Marshall CJ, Springer CJ, Barford D, Marais R. Mechanism of activation of the RAF-ERK signalling pathway by oncogenic mutations of BRAF. Cell. 2004;116:855–67.PubMedCrossRefGoogle Scholar
  14. 14.
    Nazarian R, Shi H, Wang Q, Kong X, Koya RC, Lee H, Chen Z, Lee M-K, Atar N, Sazegar H, Chodon T, Nelson SF, McArthur F, Sosman JA, Ribas A, Lo RS. Melanomas acquire resistance to B-RAF (V600E) inhibition by RTK or N-RAS upregulation. Nature. 2010;468:973–7.PubMedCrossRefGoogle Scholar
  15. 15.
    Wagle N, Emery C, Berger MF, Davis MJ, Sawyer A, Pochanard P, Kehoe SM, Johannessen CM, MacConaill LE, Hahn WC, Meyerson M, Garraway LA. Dissecting therapeutic resistance to RAF inhibition in melanoma by tumour genomic profiling. J Clin Oncol. 2011;29:3085–96.PubMedCrossRefGoogle Scholar
  16. 16.
    Flaherty KT, Puzanov I, Kim KB, et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med. 2010;363(9):809–19.PubMedCrossRefGoogle Scholar
  17. 17.
    Ribas A, Kim KB, Schuchter LM, et al. BRIM-2: an open-label, multicenter phase II study of vemurafenib in previously treated patients with BRAFV600E mutation-positive metastatic melanoma. J Clin Oncol. 2011;29(suppl):8509.Google Scholar
  18. 18.
    Chapman PB, Hauschild A, Robert C, et al. Updated overall survival (OS) results for BRIM-3, a phase III randomized, open-label, multicenter trial comparing BRAF inhibitor vemurafeni (vem) with dacarbazine (DTIC) in previously untreated patients with BRAF V600E-mutated melanoma. J Clin Oncol 2012;30(abst 8502).Google Scholar
  19. 19.
    Kim KB, Flaherty KT, Chapman PB, et al. Pattern and outcome of disease progression in phase I study of vemurafenib in patients with metastatic melanoma. J Clin Oncol. 2011;29(suppl):8519.Google Scholar
  20. 20.
    Kefford R, Arkenau H, Brown MP, et al. Phase I/II study of GSK2118436, a selective inhibitor of oncogenic mutant BRAF kinase, in patients with metastatic melanoma and other solid tumours. J Clin Oncol. 2010;28(15s):abstr 8503.Google Scholar
  21. 21.
    Falchook GS, Long GV, Kurzrock R, et al. Dabrafenib in patients with melanoma, untreated brain metastases and other solid tumours: a phase I dose-escalation trial. Lancet. 2012;379(9829):1893–901.PubMedCrossRefGoogle Scholar
  22. 22.
    Trefzer U, Minor D, Ribas A, et al. BREAK-2: a phase IIa trial of the selective BRAF kinase inhibitor GSK2118436 in patients with BRAF (V600E/K) mutation positive metastatic melanoma. Pigment Cell Mel Res. 2011;24(5):Abst LBA1-1.Google Scholar
  23. 23.
    Hauschild A, Grob JJ, Demidov LV, et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomized controlled trial. Lancet. 2012;380(9839):358–65.PubMedCrossRefGoogle Scholar
  24. 24.
    Kirkwood JM, Long GV, Trefzer U, et al. BREAK-MB: a phase II study assessing overall intracranial response rate (OIRR) to dabrafenib (GSK2118436) in patients (pts) with BRAF V600E/K mutation-positive melanoma with brain metastases (mets). J Clin Oncol 2012;30(suppl):abstr 8501.Google Scholar
  25. 25.
    Su F, Viros A, Milagre C, et al. RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors. N Engl J Med. 2012;366(3):207–15.PubMedCrossRefGoogle Scholar
  26. 26.
    Poulikakos PI, Zhang C, Bollag G, Shokat KM, Rosen N. RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF. Nature. 2010;464:427–30.PubMedCrossRefGoogle Scholar
  27. 27.
    Infante JR, Fecher LA, Falchook GS, 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.PubMedCrossRefGoogle Scholar
  28. 28.
    Falchook G, Infante JR, Fecher LA, et al. The oral MEK 1/2 inhibitor GSK1120212 demonstrates early efficacy signals. Ann Oncol. 2010;21(suppl 8):abstract 4950.Google Scholar
  29. 29.
    Flaherty KT, Robert C, Hersey P, et al. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med. 2012;367:107–14.PubMedCrossRefGoogle Scholar
  30. 30.
    Sosman JA, Kim KB, Schuchter L, et al. Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. N Engl J Med. 2012;366:707–14.PubMedCrossRefGoogle Scholar
  31. 31.
    Flaherty KT. BRAF inhibitors and melanoma. Cancer J. 2011;17:505–11.PubMedCrossRefGoogle Scholar
  32. 32.
    Nathanson KL, Martin A, Letrero R, et al. Tumour genetic analyses of patients with metastatic melanoma treated with the BRAF inhibitor GSK2118436 (GSK436). J Clin Oncol. 2011;29(suppl):abstract 8501.Google Scholar
  33. 33.
    Deng W, Gopal YNV, Scott A, et al. Role and therapeutic potential of PI3K-mTOR signalling in de novo resistance to BRAF inhibition. Pigment Cell Melanoma Res. 2011;25:248–58.CrossRefGoogle Scholar
  34. 34.
    Smalley KSM, Lioni M, Palma MD, et al. Increased cyclin D1 expression can mediate BRAF inhibitor resistance in BRAF V600E-mutated melanoma. Mol Cancer Ther. 2008;7(9):2876–83.PubMedCrossRefGoogle Scholar
  35. 35.
    Johannessen CM, Boehm JS, Kim SY, et al. COT drives resistance to RAF inhibition through MAP kinase pathway reactivation. Nature. 2010;468:968–72.PubMedCrossRefGoogle Scholar
  36. 36.
    McArthur G, Ribas A, Chapman PB, et al. Molecular analyses from a Phase 1 trial of vemurafenib to study mechanism of action and resistance in repeated biopsies from BRAF mutation positive metastatic melanoma patients. J Clin Oncol. 2011;29(suppl):abstr 8502.Google Scholar
  37. 37.
    Corcoran RB, Settleman J, Engelman JA. Potential therapeutic strategies to overcome acquired resistance to BRAF or MEK inhibitors in BRAF mutant cancers. Oncotarget. 2011;2:336–46.PubMedGoogle Scholar
  38. 38.
    Adjei AA, Cohen RB, Franklin W, 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;26:2139–46.PubMedCrossRefGoogle Scholar
  39. 39.
    Emery CM, Vijayendram KG, Zipser MC, et al. MEK1 mutations confer resistance to MEK and BRAF inhibition. Proc Natl Acad Sci USA. 2009;106(48):20411–6.PubMedCrossRefGoogle Scholar
  40. 40.
    Shi H, Moriceau G, Kong X, et al. Melanoma whole-exome sequencing identifies V600E BRAF amplification-mediated acquired BRAF inhibitor resistance. Nat Commun. 2012;3:724. doi:10.1038/ncomms1727.
  41. 41.
    Poulikakos PI, Persaud Y, Janakiraman M, et al. RAF inhibitor resistance is mediated by dimerization of aberrantly spliced BRAF (V600E). Nature. 2011;480:387–90.PubMedCrossRefGoogle Scholar
  42. 42.
    Montagut C, Sharma SV, Shioda T, et al. Elevated CRAF as a potential mechanism of acquired resistance to BRAF inhibition in melanoma. Cancer Res. 2008;68:4853–61.PubMedCrossRefGoogle Scholar
  43. 43.
    Greger JG, Eastman SD, Zhang V, Bleam MR, Hughes AM, Smitheman KN, Dickerson SH, Laquerre SG, Liu L, Gilmer TM. Combinations of BRAF, MEK, and PI3K/mTOR inhibitors overcome acquired resistance to the BRAF inhibitor GSK2118436 dabrafenib, mediated by NRAS or MEK mutations. Mol Cancer Ther. 2012. doi:10.1158/1535-7163.MCT-11-0989.
  44. 44.
    Villanueva J, Vultur A, Lee JT, et al. Acquired resistance to BRAF inhibitors mediated by a RAF kinase switch in melanoma can be overcome by targeting MEK and IGF-1R/PI3K. Cancer Cell. 2010;18:683–95.PubMedCrossRefGoogle Scholar
  45. 45.
    Paraiso KHT, Xiang Y, Rebecca VW, et al. PTEN loss confers BRAF inhibitor resistance to melanoma cells through the suppression of BIM expression. Cancer Res. 2011;71(7):2750–60.PubMedCrossRefGoogle Scholar
  46. 46.
    Heidorn SJ, Milagre C, Whittaker S, et al. Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF. Cell. 2010;140(2):209–21.PubMedCrossRefGoogle Scholar
  47. 47.
    Hatzivassiliou G, Song K, Yen I, et al. RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth. Nature. 2010;464(7287):431–5.PubMedCrossRefGoogle Scholar
  48. 48.
    Gonzalez R, Ribas A, Daud A, et al. Phase IB study of vemurafenib in combination with the MEK inhibitor, GDC-0973, in patients (pts) with unresectable or metastatic BRAFV600 mutated melanoma (BRIM7). Ann Oncol. 2012;23(suppl 9):e1-ixe30 (abstr LBA28).Google Scholar
  49. 49.
    Kim KB, Kefford R, Pavlick AC, et al. Phase II study of the MEK1/MEK2 inhibitor trametinib in patients with metastatic BRAF-mutant cutaneous melanoma previously treated with or without a BRAF inhibitor. J Clin Oncol. 2012;31(4):482–9.PubMedCrossRefGoogle Scholar
  50. 50.
    Stuart DD, Li N, Poon DJ, et al. Abstract 3790: Preclinical profile of LGX818: a potent and selective RAF kinase inhibitor. In: Proceedings of the 103rd annual meeting of the American Association for Cancer Research; 2012 Mar 31–Apr 4; Chicago, IL. Philadelphia (PA): AACR; ZA. Cancer Res 2012;72(8 Suppl):Abstract nr 3790. doi:10.1158/1538-7445.AM2012-3790.
  51. 51.
    ClinicalTrials.gov (2012). http://www.clinicaltrials.gov (ClinicalTrials.gov Identifier NCT01436656).
  52. 52.
    Smalley KS, Haass NK, Brafford PA, et al. Multiple signalling pathways must be targeted to overcome drug resistance in cell lines derived from melanoma metastases. Mol Cancer Ther. 2006;5:1136–44.PubMedCrossRefGoogle Scholar
  53. 53.
    Cheung M, Sharma A, Madhunapantula SV, Robertson GP. Akt3 and mutant V600E BRAF cooperated to promote early melanoma development. Cancer Res. 2008;68:3429–39.PubMedCrossRefGoogle Scholar
  54. 54.
    ClinicalTrials.gov (2012). http://www.clinicaltrials.gov (ClinicalTrials.gov Identifier NCT0512251, NCT01616199, NCT01596140, NCT01510444, NCT01166126, NCT01390818) (Accessed 18 Oct 2012).
  55. 55.
    Infante JR, Patnaik A, Jones SF, et al. A phase IB study of the MEK inhibitor GSK1120212 combined with everolimus in patients with solid tumours: interim results. Mol Cancer Ther. 2011;10(11):suppl 1 (abstr B128).Google Scholar
  56. 56.
    Shapiro G, LoRusso P, Kwak EL, et al. Clinical combination of the MEK inhibitor GDC-0973 and the PI3K inhibitor GDC-0941: a first-in-human phase Ib study testing daily and intermittent dosing schedules in patients with advanced solid tumours. J Clin Oncol. 2011;29:suppl (abstr 3005).Google Scholar
  57. 57.
    Graells J, Vinyals A, Figueras A, et al. Overproduction of VEGF concomitantly expressed with its receptors promotes growth and survival of melanoma cells through MAPK and PI3K signalling. J Invest Dermatol. 2004;123(6):1151–61.PubMedCrossRefGoogle Scholar
  58. 58.
    ClinicalTrials.gov (2012). http://www.clinicaltrials.gov (ClinicalTrials.gov Identifier NCT01495988, NCT 01364051) (Accessed 18 Oct 2012).
  59. 59.
    Whitesell L, Lindquist SL. HSP90 and the chaperoning of cancer. Nat Rev Cancer. 2005;5:761–72.PubMedCrossRefGoogle Scholar
  60. 60.
    Paraiso KHT, Haarberg HE, Wood E, et al. The HSP90 inhibitor XL888 overcomes BRAF inhibitor resistance mediated through diverse mechanisms. Clin Cancer Res. 2012;18(9):2502–14.PubMedCrossRefGoogle Scholar
  61. 61.
    ClinicalTrials.gov (2012). http://www.clinicaltrials.gov (ClinicalTrials.gov Identifier NCT01657591) (Accessed 18 Oct 2012).
  62. 62.
    McArthur GA, Ribas A. Targeting oncogenic drivers and the immune system in melanoma. J Clin Oncol. 2013;31(4):499–506.PubMedCrossRefGoogle Scholar
  63. 63.
    Vanneman M, Dranoff G. Combining immunotherapy and targeted therapies in cancer treatment. Nat Rev Cancer. 2012;12:237–51.PubMedCrossRefGoogle Scholar
  64. 64.
    Rakhra K, Bachireddy P, Zabuawala T, et al. CD4+ T cells contribute to the remodelling of the microenvironment required for sustained tumour regression upon oncogene inactivation. Cancer Cell. 2010;18:485–98.PubMedCrossRefGoogle Scholar
  65. 65.
    Boni A, Cogdill AP, Dang P, et al. Selective BRAF V600E inhibition enhances T-cell recognition of melanoma without affecting lymphocyte function. Cancer Res. 2010;70(13):5213–9.PubMedCrossRefGoogle Scholar
  66. 66.
    Comin-Anduix B, Chodon T, Sazegar H, 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;70:5213–9.Google Scholar
  67. 67.
    Long GV, Wilmott JS, Howle JR, et al. Morphologic and immunohistochemical (IHC) changes in metastatic melanoma (MM) tissue and associations with clinical outcome in patients on BRAF inhibitors (BRAFi). J Clin Oncol. 2011;29(suppl):abstr 8542.Google Scholar
  68. 68.
    Weber J. Ipilimumab: controversies in its development, utility and autoimmune adverse events. Cancer Immunol Immunother. 2009;58:823–30.PubMedCrossRefGoogle Scholar
  69. 69.
    ClinicalTrials.gov (2012) http://www.clinicaltrials.gov (ClinicalTrials.gov Identifier NCT01400451, NCT01673854) (Accessed 18 Oct 2012).
  70. 70.
    Lemech C, Arkenau HT. Novel treatments for metastatic cutaneous melanoma and the management of emergent toxicities. Clin Med Insights Oncol. 2012;6:53–66.PubMedGoogle Scholar
  71. 71.
    Topalian SL, Hodi S, Brahmer JR, et al. Safety, activity and immune correlates of anti-PD-1 antibody in cancer. New Engl J Med. 2012;366:2443–54.PubMedCrossRefGoogle Scholar
  72. 72.
    Brahmer JR, Tykodi SS, Chow LQM, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366:2455–65.PubMedCrossRefGoogle Scholar
  73. 73.
    ClinicalTrials.gov; 2012. http://www.clinicaltrials.gov (ClinicalTrials.gov Identifier NCT01656642, NCT01611675, NCT01585415, NCT01683188, NCT01603212, NCT01659151) (Accessed 18 Oct 2012).
  74. 74.
    Curtin JA, Busam K, Pinkel A, et al. Somatic activation of KIT in distinct subtypes of melanoma. J Clin Oncol. 2006;24:4340–6.PubMedCrossRefGoogle Scholar
  75. 75.
    Carvajal RD, Antonescu CR, Wolchok JD, et al. KIT as a therapeutic target in metastatic melanoma. JAMA. 2011;305:2327–34.PubMedCrossRefGoogle Scholar
  76. 76.
    Ascierto PA, Schadendorf D, Berking C, et al. MEK162 for patients with advanced melanoma harbouring NRAS or Val600 BRAF mutations: a non-randomised, open-label phase 2 study. Lancet Oncol. 2013;14:249–56.PubMedCrossRefGoogle Scholar
  77. 77.
    Curtin JA, Fridlyand J, Kageshita T, et al. Distinct sets of genetic alterations in melanoma. N Engl J Med. 2005;353:2135–47.PubMedCrossRefGoogle Scholar
  78. 78.
    Gast A, Scherer D, Chen B, et al. Somatic alterations in the melanoma genome: a high-resolution array-based comparative genomic hybridization study. Genes Chromosomes Cancer. 2010;49:733–45.PubMedCrossRefGoogle Scholar
  79. 79.
    Gembarska A, Luciani F, Fedele C, et al. MDM4 is a key therapeutic target in cutaneous melanoma. Nat Med. 2012;18:1239–47.CrossRefGoogle Scholar
  80. 80.
    ClinicalTrials.gov; 2013. http://www.clinicaltrials.gov (ClinicalTrials.gov Identifier NCT01024231) (Accessed 18 March 2013).
  81. 81.
    Postow MA, Callahan MK, Barker CA, et al. Immunologic correlates of the abscopal effect in a patient with melanoma. N Engl J Med. 2012;366:925–31.PubMedCrossRefGoogle Scholar
  82. 82.
    ClinicalTrials.gov; 2012. http://www.clinicaltrials.gov (ClinicalTrials.gov Identifier NCT01707037, NCT01682083, NCT01682213) (Accessed 18 Oct 2012).

Copyright information

© Springer International Publishing Switzerland 2013

Authors and Affiliations

  • Charlotte Lemech
    • 1
    • 2
  • Jeffrey Infante
    • 3
  • Hendrik-Tobias Arkenau
    • 1
    • 2
  1. 1.Sarah Cannon Research UKLondonUK
  2. 2.University College LondonLondonUK
  3. 3.Sarah Cannon Research InstituteNashvilleUSA

Personalised recommendations