Skip to main content

Advertisement

SpringerLink
Log in

Drug Combinations as the New Standard for Melanoma Treatment

  • Skin Cancer (BY Kwong, Section Editor)
  • Published:
Current Treatment Options in Oncology Aims and scope Submit manuscript

Opinion statement

Advanced melanoma is related to a very grim prognosis and fast progression. Until recently, there has been no indicated treatment that would affect the disease’s outcome. However, the progress in immunotherapy and molecular therapy has significantly changed the unfavourable prognosis of melanoma progression and its short survival rate. Both approaches have improved patients’ outcomes and provided renewed hope for successful treatment. Moreover, in order to further enhance patients’ outcomes and to avoid mechanisms of tumour resistance, investigators attempted a combined approach. Targeted therapy combinations allowed a better response rate and progression-free survival than monotherapy with one of the agents. Another promising combination, but with limiting toxicities, is a concurrent immuno- and molecular-targeted therapy. It is suspected that complimentary usage of these drugs may lead to synergism, providing robust and quick tumour responses as well as long-lasting effects. Results of currently ongoing clinical trials that investigate combination strategies in melanoma are expected to provide more mature data about the effectiveness and the safety profile of those therapies. Until more robust results of these studies occur, the best management of advanced and metastatic melanoma is immunotherapy with anti-PD1 drugs or targeted therapy with concomitant BRAF and MEK inhibitor. However, which of these two options should be used first is still under discussion.

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

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Cancer Statistics Review, 1975–2012, National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/csr/1975_2012/, based on November 2014 SEER data submission, posted to the SEER web site, April 2015. Accessed 2 Nov 2015.

  2. Cancer Research UK. 2015. http://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/skin-cancer/incidence. Accessed 2 Nov 2015.

  3. Whiteman D, Green A. Epidemiology of malignant melanoma. In: Dummer R, Pittelkow MR, Iwatsuki K, Green A, Elwan NM, editors. Skin cancer—a world-wide perspective. Berlin Heidelberg: Springer-Verlag; 2011. p. 13–26.

    Google Scholar 

  4. MacKie RM, Hauschild A, Eggermont AMM. Epidemiology of invasive cutaneous melanoma. Ann Oncol. 2009;20(Supplement 6):vi1–7.

    PubMed  PubMed Central  Google Scholar 

  5. Schmalbach CE. The management of head and neck melanoma. Curr Probl Surg. 2006;43(11):781–835.

    Article  PubMed  Google Scholar 

  6. Garbe C, Peris K, Hauschild A, et al. Diagnosis and treatment of melanoma: European consensus-based interdisciplinary guideline. Eur J Cancer. 2010;46(2):270–83.

    Article  PubMed  Google Scholar 

  7. Balch CM, Soong SJ, Gershenwald JE, et al. Prognostic factors analysis of 17, 600 melanoma patients: validation of the American joint committee on cancer melanoma staging system. J Clin Oncol. 2001;19:3622–34.

    CAS  PubMed  Google Scholar 

  8. Testori A, Rutkowski P, Marsden J, et al. Surgery and radiotherapy in the treatment of cutaneous melanoma. Ann Oncol. 2009;20(Supplement 6):vi22–9.

    PubMed  PubMed Central  Google Scholar 

  9. Fisher RA, Larkin J. Malignant melanoma (metastatic). BMJ Clin Evid. 2010;pii:1718.

  10. Lui P, Cashin R, Machado M, et al. Treatments for metastatic melanoma: synthesis of evidence from randomized trials. Cancer Treat Rev. 2007;33(8):665–80.

    Article  PubMed  Google Scholar 

  11. Davies H. Mutations of the BRAF gene in human cancer. Nature. 2002;417:949–54.

    Article  CAS  PubMed  Google Scholar 

  12. Bollag G, Hirth P, Tsai J, et al. Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma. Nature. 2010;467(7315):596–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364(26):2507–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. McArthur GA, Chapman PB, Robert C, et al. Safety and efficacy of vemurafenib in BRAF(V600E) and BRAF(V600K) mutation-positive melanoma (BRIM-3): extended follow-up of a phase 3, randomised, open-label study. Lancet Oncol. 2014;15(3):323–32 Long-term results of BRAF inhibitor treatment.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Hauschild A, Grob JJ, Demidov LV, et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2012;380(9839):358–65.

    Article  CAS  PubMed  Google Scholar 

  16. Hauschild A, Grob JJ, Demidov LV, et al. An update on BREAK-3, a phase III, randomized trial: Dabrafenib (DAB) versus dacarbazine (DTIC) in patients with BRAF V600E-positive mutation metastatic melanoma (MM). J Clin Oncol 31, 2013 (suppl; abstr 9013).

  17. EMA/CHMP/242419/2013/corr 1 CHMP assessment report. Tafinlar. International non-proprietary name: DABRAFENIB Procedure No EMEA/H/C/002604/0000. 27 June 2013.

  18. Latimer NR, Abrams KR, Amonkar MM, et al. Adjusting for the confounding effects of treatment switching-the BREAK-3 trial: dabrafenib versus dacarbazine. Oncologist. 2015;20(7):798–805.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Hodi S, 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011;364(26):2517–26.

    Article  CAS  PubMed  Google Scholar 

  21. Prieto PA, Yang JC, Sherry RM, et al. CTLA-4 blockade with Ipilimumab: long-term follow-up of 177 patients with metastatic melanoma. Clin Cancer Res. 2012;18(7):2039–47 Long-term results of anti-CTLA-4 treatment.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Maio M, Grob JJ, Aamdal S, 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 Long-term results of anti-CTLA-4 + DTIC treatment.

    Article  CAS  PubMed  Google Scholar 

  23. Schadendorf D, Hodi FS, Robert C, 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 Long-term results of anti-CTLA-4 treatment.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12(4):252–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Robert C, Schachter J, Long GV, et al. Pembrolizumab versus Ipilimumab in Advanced Melanoma. N Engl J Med. 2015;372(26):2521–32.

    Article  CAS  PubMed  Google Scholar 

  26. Robert C, Long GV, Brady B, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015;372(4):320–30.

    Article  CAS  PubMed  Google Scholar 

  27. EMA/444458/2015 Procedure No. EMEA/H/C/003820/0000 Keytruda. International non-proprietary name: pembrolizumab. Committee for Medicinal Products for Human Use (CHMP) Assessment report 21 May 2015.

  28. EMA/CHMP/557664/2011 Procedure No.: EMEA/H/C/002213 Assessment Report For Yervoy (ipilimumab). Committee for Medicinal Products for Human Use (CHMP). 19 May 2011.

  29. Sosman JA, Kim KB, Schuchter L, et al. Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. N Engl J Med. 2012;366(8):707–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Flaherty KT, Robert C, Hersey P, et al. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med. 2012;367(2):107–14.

    Article  CAS  PubMed  Google Scholar 

  31. EMA/CHMP/258608/2014. Procedure No.: EMEA/H/C/002643/0000. Mekinist. International non-proprietary name: trametinib. CHMP assessment report. 25 April 2014.

  32. Ribas A, Puzanov I, Dummer R, 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.

    Article  CAS  PubMed  Google Scholar 

  33. Topolian S, Sznol M, McDermott DF, et al. Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab. J Clin Oncol. 2014;32(10):1020–30.

    Article  Google Scholar 

  34. Weber JS, D'Angelo SP, Minor D, 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.

    Article  CAS  PubMed  Google Scholar 

  35. EMA/CHMP/76688/2015 Procedure No. EMEA/H/C/003985/0000.OPDIVO International non-proprietary name: nivolumab. Committee for Medicinal Products for Human Use (CHMP). Assessment report 23 April 2015.

  36. Solit DB, Rosen N. Resistance to BRAF inhibition in melanomas. N Engl J Med. 2011;364(8):772–4.

    Article  CAS  PubMed  Google Scholar 

  37. 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.

    Article  PubMed  Google Scholar 

  38. Chang DZ, Panageas KS, Osman I, et al. Clinical significance of BRAF mutations in metastatic melanoma. J Transl Med. 2004;2(1):46.

    Article  PubMed  PubMed Central  Google Scholar 

  39. 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.

    Article  CAS  PubMed  Google Scholar 

  40. Anforth R, Menzies A, Byth K, et al. Factors influencing the development of cutaneous squamous cell carcinoma in patients on BRAF inhibitor therapy. J Am Acad Dermatol. 2015;72(5):809–15.

    Article  CAS  PubMed  Google Scholar 

  41. Nazarian R, Shi H, Wang Q, et al. Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation. Nature. 2010;468(7326):973–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Poulikakos PI, Persaud Y, Janakiraman M, et al. RAF inhibitor resistance is mediated by dimerization of aberrantly spliced BRAF(V600E). Nature. 2011;480(7377):387–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Rizos H, Menzies AM, Pupo GM, et al. BRAF inhibitor resistance mechanisms in metastatic melanoma: spectrum and clinical impact. Clin Cancer Res. 2014;20(7):1965–77.

    Article  CAS  PubMed  Google Scholar 

  44. Shi H, Hong A, Kong X, et al. A novel AKT1 mutant amplifies an adaptive melanoma response to BRAF inhibition. Cancer Discov. 2014;4(1):69–79.

    Article  CAS  PubMed  Google Scholar 

  45. Schadendorf D, Fisher DE, Garbe C, et al. Melanoma. Nature Rev Dis Primers. 2015;1:1–20.

    Google Scholar 

  46. Larkin J, Ascierto PA, Dréno B, et al. Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med. 2014;371(20):1867–76 Large randomised trial testing mono- vs combined therapy with BRAF and MEK inhibitors (VEM+COBI vs VEM).

    Article  PubMed  Google Scholar 

  47. Robert C, Karaszewska B, Schachter J, et al. Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med. 2015;372(1):30–9 Large randomised trial testing mono- vs combined therapy with BRAF and MEK inhibitors (DAB+TRAM vs VEM).

    Article  PubMed  Google Scholar 

  48. Long GV, Stroyakovskiy D, Gogas H, et al. Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. N Engl J Med. 2014;371(20):1877–88 Large randomised trial testing mono- vs combined therapy with BRAF and MEK inhibitors (DAB+TRAM vs DAB).

    Article  PubMed  Google Scholar 

  49. Johnson DB, Flaherty KT, Weber JS, et al. Combined BRAF (dabrafenib) and MEK inhibition (trametinib) in patients with BRAFV600-mutant melanoma experiencing progression with single-agent BRAF inhibitor. J Clin Oncol. 2014;32(33):3697–704 Trial showing limited effectives of combined therapy after failure of BRAF inhibitor monotherapy.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. 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. 2013;31(4):482–9.

    Article  CAS  PubMed  Google Scholar 

  51. Gowrishankar K, Snoyman S, Pupo GM, et al. Acquired resistance to BRAF inhibition can confer cross-resistance to combined BRAF/MEK inhibition. J Invest Dermatol. 2012;132(7):1850–9.

    Article  CAS  PubMed  Google Scholar 

  52. Sánchez-Hernández I, Baquero P, Calleros L, et al. Dual inhibition of (V600E) BRAF and the PI3K/AKT/mTOR pathway cooperates to induce apoptosis in melanoma cells through a MEK-independent mechanism. Cancer Lett. 2012;314(2):244–55.

    Article  PubMed  Google Scholar 

  53. Bozic I, Reiter JG, Allen B, et al. Evolutionary dynamics of cancer in response to targeted combination therapy. Elife. 2013;2:e00747.

    Article  PubMed  PubMed Central  Google Scholar 

  54. 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 cotargeting MEK and IGF-1R/PI3K. Cancer Cell. 2010;18(6):683–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Frederick DT, Salas Fragomeni RA, et al. Clinical profiling of BCL-2 family members in the setting of BRAF inhibition offers a rationale for targeting de novo resistance using BH3 mimetics. PLoS One. 2014;9(7):e101286.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Shi H, Kong X, Ribas A, et al. Combinatorial treatments that overcome PDGFRβ-driven resistance of melanoma cells to V600EB-RAF inhibition. Cancer Res. 2011;71(15):5067–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Shimizu T, Tolcher AW, Papadopoulos KP, et al. The clinical effect of the dual-targeting strategy involving PI3K/AKT/mTOR and RAS/MEK/ERK pathways in patients with advanced cancer. Clin Cancer Res. 2012;18(8):2316–25.

    Article  CAS  PubMed  Google Scholar 

  58. Tolcher AW, Patnaik A, Papadopoulos KP, et al. Phase I study of the MEK inhibitor trametinib in combination with the AKT inhibitor afuresertib in patients with solid tumors and multiple myeloma. Cancer Chemother Pharmacol. 2015;75(1):183–9 First trial testing MEK and AKT inhibitor combination in two malignant melanoma patients.

    Article  CAS  PubMed  Google Scholar 

  59. Postow MA, Chesney J, Pavlick AC, et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med. 2015;372(21):2006–17 Randomised trial testing combination of immunotherapies.

    Article  PubMed  Google Scholar 

  60. Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015;373(1):23–34 Large randomised trial testing combination of immunotherapies.

    Article  PubMed  Google Scholar 

  61. Robert L, Ribas A, Hu-Lieskovan S. Combining targeted therapy with immunotherapy. Can 1+1 equal more than 2? Semin Immunol. 2016;pii: S1044–5323(16)00002–6

  62. Ribas A, Hodi FS, Callahan M, et al. Hepatotoxicity with combination of vemurafenib and ipilimumab. N Engl J Med. 2013;368(14):1365–6.

    Article  CAS  PubMed  Google Scholar 

  63. Minor DR, Puzanov I, Callahan MK, et al. Severe gastrointestinal toxicity with administration of trametinib in combination with dabrafenib and ipilimumab. Pigment Cell Melanoma Res. 2015;28(5):611–2 Two cases of patients treated with triple therapy of BRAF+MEK+anti-CTLA-4.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Clinical Pharmacy and Pharmaceutical Care, Faculty of Pharmacy, Medical University of Warsaw, Banacha st. 1, 02-097, Warsaw, Poland

    Marta Polkowska M. Pharm, Edyta Czepielewska PhD & Małgorzata Kozłowska-Wojciechowska MD, PhD, Prof

Authors
  1. Marta Polkowska M. Pharm
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Edyta Czepielewska PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Małgorzata Kozłowska-Wojciechowska MD, PhD, Prof
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Marta Polkowska M. Pharm.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

This article is part of the Topical Collection on Skin Cancer

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Polkowska, M., Czepielewska, E. & Kozłowska-Wojciechowska, M. Drug Combinations as the New Standard for Melanoma Treatment. Curr. Treat. Options in Oncol. 17, 61 (2016). https://doi.org/10.1007/s11864-016-0436-y

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11864-016-0436-y

Keywords

Search

Navigation