Skip to main content

Advertisement

SpringerLink
Log in

Upcoming strategies for the treatment of metastatic melanoma

  • Review
  • Published:
Archives of Dermatological Research Aims and scope Submit manuscript

Abstract

Prognosis for advanced and metastatic melanoma is poor, with a 5-year survival of 78, 59 and 40% for patients with stage IIIA, IIIB and IIIC, respectively, and a 1-year survival of 62% for M1a, 53% for M1b and 33% for M1c. The unsatisfactory results of actual standard therapies for metastatic melanoma highlight the need for effective new therapeutic strategies. Several drugs, including BRAF, KIT and MEK inhibitors, are currently being evaluated after promising data from Phase I and Phase II studies; Vemurafenib, a BRAF-inhibitor agent, has been approved by the Food and Drug Administration (FDA) for the treatment of patients with unresectable or metastatic melanoma with the BRAF V600E mutation after a significant impact on both progression-free and overall survival was demonstrated compared with dacarbazine in a Phase III trial. Ipilimumab, an immunotherapeutic drug, has proven to be capable of inducing long-lasting responses and was approved for patients with advanced melanoma in first- and second-line treatment by the FDA and in second-line treatment by the European Medicines Agency. Furthermore, a significant survival benefit of the combination of ipilimumab with dacarbazine compared with dacarbazine alone for first-line treatment was reported. In the near future, patients with BRAF mutations could have the chance to benefit from treatment with BRAF inhibitors; patients harboring BRAF or NRAS mutations could be treated with MEK inhibitors; finally, the subgroup of patients with acral, mucosal or chronic sun-damaged melanoma harboring a KIT mutation could benefit from KIT inhibitors. Ipilimumab could become a standard treatment for metastatic melanoma, both as a single agent and in combination; its efficacy has been proven, and researchers should now address their efforts to understanding the predictive variables of response to treatment.

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

Similar content being viewed by others

References

  1. Aamdal S, Wolff I, Kaplan S, Paridaens R, Kerger J, Schachter J, Wanders J, Franklin HR, Verweij J (1994) Docetaxel (Taxotere) in advanced malignant melanoma: a phase II study of the EORTC early clinical trials group. Eur J Cancer 30A(8):1061–1064

    Article  PubMed  CAS  Google Scholar 

  2. Algazi AP, Soon CW, Daud AI (2010) Treatment of cutaneous melanoma: current approaches and future prospects. Cancer Manag Res 2:197–211

    PubMed  CAS  Google Scholar 

  3. Atallah E (2011) Nilotinib cardiac toxicity: should we still be concerned? Leuk Res 35(5):577–578

    Article  PubMed  Google Scholar 

  4. Atkins MB, Lotze MT, Dutcher JP, Fisher RI, Weiss G, Margolin K, Abrams J, Sznol M, Parkinson D, Hawkins M, Paradise C, Kunkel L, Rosenberg SA (1999) High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. J Clin Oncol 17(7):2105–2116

    PubMed  CAS  Google Scholar 

  5. Balch CM, Gershenwald JE, Soong SJ, Thompson JF, Atkins MB, Byrd DR, Buzaid AC et al (2009) Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol 27(36):6199–6206

    Article  PubMed  Google Scholar 

  6. Beadling C, Jacobson-Dunlop E, Hodi FS, Le C, Warrick A, Patterson J, Town A, Harlow A, Cruz F 3rd, Azar S, Rubin BP, Muller S, West R, Heinrich MC, Corless CL (2008) KIT gene mutations and copy number in melanoma subtypes. Clin Cancer Res 14(21):6821–6828

    Article  PubMed  CAS  Google Scholar 

  7. Bedikian AY, Weiss GR, Legha SS, Burris HA 3rd, Eckardt JR, Jenkins J, Eton O, Buzaid AC, Smetzer L, Von Hoff DD et al (1995) Phase II trial of docetaxel in patients with advanced cutaneous malignant melanoma previously untreated with chemotherapy. J Clin Oncol 13(12):2895–2899

    PubMed  CAS  Google Scholar 

  8. Beeram M, Patnaik A, Rowinsky EK (2005) Raf: a strategic target for therapeutic development against cancer. J Clin Oncol 23(27):6771–6790

    Article  PubMed  CAS  Google Scholar 

  9. Carvajal RD, Antonescu CR, Wolchok JD, Chapman PB, Roman RA, Teitcher J, Panageas KS, Busam KJ, Chmielowski B, Lutzky J, Pavlick AC, Fusco A, Cane L, Takebe N, Vemula S, Bouvier N, Bastian BC, Schwartz GK (2011) KIT as a therapeutic target in metastatic melanoma. JAMA 305(22):2327–2334

    Article  PubMed  CAS  Google Scholar 

  10. Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, Dummer R, Garbe C, Testori A, Maio M, Hogg D, Lorigan P, Lebbe C, Jouary T, Schadendorf D, Ribas A, O’Day SJ, Sosman JA, Kirkwood JM, Eggermont AM, Dreno B, Nolop K, Li J, Nelson B, Hou J, Lee RJ, Flaherty KT, McArthur GA (2011) Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 364(26):2507–2516

    Article  PubMed  CAS  Google Scholar 

  11. Comis RL (1976) DTIC (NSC-45388) in malignant melanoma: a perspective. Cancer Treat Rep 60(2):165–176

    PubMed  CAS  Google Scholar 

  12. Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W, Davis N, Dicks E, Ewing R, Floyd Y, Gray K, Hall S, Hawes R, Hughes J, Kosmidou V, Menzies A, Mould C, Parker A, Stevens C, Watt S, Hooper S, Wilson R, Jayatilake H, Gusterson BA, Cooper C, Shipley J, Hargrave D, Pritchard-Jones K, Maitland N, Chenevix-Trench G, Riggins GJ, Bigner DD, Palmieri G, Cossu A, Flanagan A, Nicholson A, Ho JW, Leung SY, Yuen ST, Weber BL, Seigler HF, Darrow TL, Paterson H, Marais R, Marshall CJ, Wooster R, Stratton MR, Futreal PA (2002) Mutations of the BRAF gene in human cancer. Nature 417(6892):949–954

    Article  PubMed  CAS  Google Scholar 

  13. Dienstmann R, Tabernero J (2011) BRAF as a target for cancer therapy. Anticancer Agents Med Chem 11(3):285–295

    PubMed  CAS  Google Scholar 

  14. Einzig AI, Hochster H, Wiernik PH, Trump DL, Dutcher JP, Garowski E, Sasloff J, Smith TJ (1991) A phase II study of taxol in patients with malignant melanoma. Invest New Drugs 9(1):59–64

    Article  PubMed  CAS  Google Scholar 

  15. Flaherty KT, Puzanov I, Kim KB, Ribas A, McArthur GA, Sosman JA, O’Dwyer PJ, Lee RJ, Grippo JF, Nolop K, Chapman PB (2010) Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med 363(9):809–819

    Article  PubMed  CAS  Google Scholar 

  16. Gilmartin AG, Bleam MR, Groy A, Moss KG, Minthorn EA, Kulkarni SG, Rominger CM, Erskine S, Fisher KE, Yang J, Zappacosta F, Annan R, Sutton D, Laquerre SG (2011) GSK1120212 (JTP-74057) is an inhibitor of MEK activity and activation with favorable pharmacokinetic properties for sustained in vivo pathway inhibition. Clin Cancer Res 17(5):989–1000

    Article  PubMed  CAS  Google Scholar 

  17. Guo J, Si L, Kong Y, Flaherty KT, Xu X, Zhu Y, Corless CL, Li L, Li H, Sheng X, Cui C, Chi Z, Li S, Han M, Mao L, Lin X, Du N, Zhang X, Li J, Wang B, Qin S (2011) Phase II, open-label, single-arm trial of imatinib mesylate in patients with metastatic melanoma harboring c-Kit mutation or amplification. J Clin Oncol 29(21):2904–2909

    Article  PubMed  CAS  Google Scholar 

  18. Hauschild A, Agarwala SS, Trefzer U, Hogg D, Robert C, Hersey P, Eggermont A, Grabbe S, Gonzalez R, Gille J, Peschel C, Schadendorf D, Garbe C, O’Day S, Daud A, White JM, Xia C, Patel K, Kirkwood JM, Keilholz U (2009) 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 27(17):2823–2830

    Article  PubMed  CAS  Google Scholar 

  19. Hodi FS, Friedlander P, Corless CL, Heinrich MC, Mac Rae S, Kruse A, Jagannathan J, Van den Abbeele AD, Velazquez EF, Demetri GD, Fisher DE (2008) Major response to imatinib mesylate in KIT-mutated melanoma. J Clin Oncol 26(12):2046–2051

    Article  PubMed  CAS  Google Scholar 

  20. Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC, Akerley W, van den Eertwegh AJ, Lutzky J, Lorigan P, Vaubel JM, Linette GP, Hogg D, Ottensmeier CH, Lebbé C, Peschel C, Quirt I, Clark JI, Wolchok JD, Weber JS, Tian J, Yellin MJ, Nichol GM, Hoos A, Urba WJ (2010) Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363(8):711–723

    Article  PubMed  CAS  Google Scholar 

  21. Hoos A, Eggermont AM, Janetzki S et al (2010) Improved endpoints for cancer immunotherapy trials. J Natl Cancer Inst 102(18):1388–1397

    Article  PubMed  CAS  Google Scholar 

  22. Kim KB, Eton O, Davis DW, Frazier ML, McConkey DJ, Diwan AH, Papadopoulos NE, Bedikian AY, Camacho LH, Ross MI, Cormier JN, Gershenwald JE, Lee JE, Mansfield PF, Billings LA, Ng CS, Charnsangavej C, Bar-Eli M, Johnson MM, Murgo AJ, Prieto VG (2008) Phase II trial of imatinib mesylate in patients with metastatic melanoma. Br J Cancer 99(5):734–740

    Article  PubMed  CAS  Google Scholar 

  23. Kong Y, Si L, Zhu Y, Xu X, Corless CL, Flaherty KT, Li L, Li H, Sheng X, Cui C, Chi Z, Li S, Han M, Mao L, Lu A, Guo J (2011) Large-scale analysis of KIT aberrations in Chinese patients with melanoma. Clin Cancer Res 17(7):1684–1691

    Article  PubMed  CAS  Google Scholar 

  24. Lasithiotakis KG, Sinnberg TW, Schittek B, Flaherty KT, Kulms D, Maczey E, Garbe C, Meier FE (2008) Combined inhibition of MAPK and mTOR signaling inhibits growth, induces cell death, and abrogates invasive growth of melanoma cells. J Invest Dermatol 128(8):2013–2023

    Article  PubMed  CAS  Google Scholar 

  25. Lutzky J, Bauer J, Bastian BC (2008) Dose-dependent, complete response to imatinib of a metastatic mucosal melanoma with a K642E KIT mutation. Pigment Cell Melanoma Res 21(4):492–493

    Article  PubMed  Google Scholar 

  26. Margolin KA, Di Giacomo AM, Maio M (2010) Brain metastasis in melanoma: clinical activity of CTLA-4 antibody therapy. Semin Oncol 37(5):468–472

    Article  PubMed  CAS  Google Scholar 

  27. McLaughlin CC, Wu XC, Jemal A, Martin HJ, Roche LM, Chen VW (2005) Incidence of noncutaneous melanomas in the US Cancer 103(5):1000–1007

    Article  PubMed  Google Scholar 

  28. Middleton MR, Grob JJ, Aaronson N, Fierlbeck G, Tilgen W, Seiter S, Gore M, Aamdal S, Cebon J, Coates A, Dreno B, Henz M, Schadendorf D, Kapp A, Weiss J, Fraass U, Statkevich P, Muller M, Thatcher N (2000) Randomized phase III study of temozolomide versus dacarbazine in the treatment of patients with advanced metastatic malignant melanoma. J Clin Oncol 18(1):158–166

    PubMed  CAS  Google Scholar 

  29. O’Day SJ, Maio M, Chiarion-Sileni V, Gajewski TF, Pehamberger H, Bondarenko IN, Queirolo P, Lundgren L, Mikhailov S, Roman L, Verschraegen C, Humphrey R, Ibrahim R, de Pril V, Hoos A, Wolchok JD (2010) Efficacy and safety of ipilimumab monotherapy in patients with pretreated advanced melanoma: a multicenter single-arm phase II study. Ann Oncol 21(8):1712–1717

    Article  PubMed  Google Scholar 

  30. Puzanov I, Flaherty KT (2010) Targeted molecular therapy in melanoma. Semin Cutan Med Surg 29(3):196–201

    Article  PubMed  CAS  Google Scholar 

  31. Rigel DS (2010) Epidemiology of melanoma. Semin Cutan Med Surg 29(4):204–209

    Article  PubMed  CAS  Google Scholar 

  32. Robert C, Thomas L, Bondarenko I, O’Day S, MD JW, Garbe C, Lebbe C, Baurain JF, Testori A, Grob JJ, Davidson N, Richards J, Maio M, Hauschild A, Miller WH Jr, Gascon P, Lotem M, Harmankaya K, Ibrahim R, Francis S, Chen TT, Humphrey R, Hoos A, Wolchok JD (2011) Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 364(26):2517–2526

    Article  PubMed  CAS  Google Scholar 

  33. Smalley KS, Haass NK, Brafford PA, Lioni M, Flaherty KT, Herlyn M (2006) Multiple signaling pathways must be targeted to overcome drug resistance in cell lines derived from melanoma metastases. Mol Cancer Ther 5(5):1136–1144

    Article  PubMed  CAS  Google Scholar 

  34. Spofford LS, Abel EV, Boisvert-Adamo K, Aplin AE (2006) Cyclin D3 expression in melanoma cells is regulated by adhesion-dependent phosphatidylinositol 3-kinase signaling and contributes to G1-S progression. J Biol Chem 281(35):25644–25651

    Article  PubMed  CAS  Google Scholar 

  35. Thumar JR, Kluger HM (2010) Ipilimumab: a promising immunotherapy for melanoma. Oncology (Williston Park) 24(14):1280–1288

    Google Scholar 

  36. Tseng JR, Stuart D, Aardalen K, Kaplan A, Aziz N, Hughes NP, Gambhir SS (2011) Use of DNA microarray and small animal positron emission tomography in preclinical drug evaluation of RAF265, a novel B-Raf/VEGFR-2 inhibitor. Neoplasia 13(3):266–275

    PubMed  CAS  Google Scholar 

  37. Ugurel S, Hildenbrand R, Zimpfer A, La Rosée P, Paschka P, Sucker A, Keikavoussi P, Becker JC, Rittgen W, Hochhaus A, Schadendorf D (2005) Lack of clinical efficacy of imatinib in metastatic melanoma. Br J Cancer 92(8):1398–1405

    Article  PubMed  CAS  Google Scholar 

  38. Villanueva J, Vultur A, Lee JT, Somasundaram R, Fukunaga-Kalabis M, Cipolla AK, Wubbenhorst B, Xu X, Gimotty PA, Kee D, Santiago-Walker AE, Letrero R, D’Andrea K, Pushparajan A, Hayden JE, Brown KD, Laquerre S, McArthur GA, Sosman JA, Nathanson KL, Herlyn M (2010) Acquired resistance to BRAF inhibitors mediated by a RAF kinase switch in melanoma can be overcome by cotargeting MEK and IGF-1R/PI3K. Cancer Cell 18(6):683–695

    Article  PubMed  CAS  Google Scholar 

  39. Wyman K, Atkins MB, Prieto V, Eton O, McDermott DF, Hubbard F, Byrnes C, Sanders K, Sosman JA (2006) Multicenter phase II trial of high-dose imatinib mesylate in metastatic melanoma: significant toxicity with no clinical efficacy. Cancer 106(9):2005–2011

    Article  PubMed  CAS  Google Scholar 

Download references

Conflict of interest

Francesco Spagnolo, M.D. has no financial interest in any of the products, devices or drugs mentioned in this article. Paola Queirolo, M.D. received lecture fees from Bristol-Myers Squibb and Roche and served on advisory boards for Bristol-Myers Squibb, Roche and Schering-Plough.

Author information

Authors and Affiliations

  1. Plastic and Reconstructive Surgery, IRCCS Azienda Ospedaliera Universitaria San Martino – IST Istituto Nazionale per la Ricerca sul Cancro, L.go R. Benzi, 10, 16132, Genoa, Italy

    Francesco Spagnolo

  2. Medical Oncology, IRCCS Azienda Ospedaliera Universitaria San Martino – IST Istituto Nazionale per la Ricerca sul Cancro, L.go R. Benzi, 10, 16132, Genoa, Italy

    Paola Queirolo

Authors
  1. Francesco Spagnolo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Paola Queirolo
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Francesco Spagnolo.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Spagnolo, F., Queirolo, P. Upcoming strategies for the treatment of metastatic melanoma. Arch Dermatol Res 304, 177–184 (2012). https://doi.org/10.1007/s00403-012-1223-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00403-012-1223-7

Keywords

Search

Navigation