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Combination Therapies for Melanoma: A New Standard of Care?

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Abstract

Recent data have demonstrated improved survival with targeted and immune therapies in patients with advanced melanoma, leading to much excitement amongst the oncology community and the widespread use of these drugs in combination regimens. However, the place of these combination therapies in the treatment of advanced melanoma remains to be fully determined. In this perspectives article, we critically review the available data and outline the rationale for these combinations being adopted as the standard of care for patients with advanced melanoma in the future.

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References

  1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015;65:5–29.

    Article  PubMed  Google Scholar 

  2. Korn EL, Liu PY, Lee SJ, et al. Meta-analysis of phase II cooperative group trials in metastatic stage IV melanoma: determining progression-free and overall survival benchmarks for future phase II trials. J Clin Oncol. 2008;26:527–34.

    Article  PubMed  Google Scholar 

  3. McArthur GA, Ribas AR. Targeting oncogenic drivers and the immune system in melanoma. J Clin Oncol. 2013;31:499–506.

    Article  CAS  PubMed  Google Scholar 

  4. Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;471:949–54.

    Article  Google Scholar 

  5. Tsai J, Lee JT, Wang W, Zhang J, et al. Discovery of a selective inhibitor of oncogenic B-Raf kinase with potent antimelanoma activity. Proc Natl Acad Sci USA. 2008;105:3041–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Flaherty KT, Puzanov I, Kim KB, et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med. 2010;363:809–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Gibney GT, Messina JL, Fedorenko IV, Sondak VK, Smalley KSM. Paradoxical oncogenesis: the long-term effects of BRAF inhibition in melanoma. Nat Rev Clin Oncol. 2013;10:390–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. 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.

    Article  CAS  PubMed  Google Scholar 

  9. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. 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;380:358–65.

    Article  CAS  PubMed  Google Scholar 

  11. Wagle N, Van Allen EM, Treacy DJ, et al. MAP kinase pathway alterations in BRAF-mutant melanoma patients with acquired resistance to combined RAF/MEK inhibition. Cancer Discov. 2014;4:61–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Long GV, Stroyakovskiy D, Gogas H, et al. Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. N Engl J Med. 2014;371:1877–88.

    Article  PubMed  Google Scholar 

  14. Robert C, Karaszewska B, Schachter J, et al. Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med. 2015;372:30–9.

    Article  PubMed  Google Scholar 

  15. Larkin J, Ascierto PA, Dreno B, et al. Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med. 2014;371:1867–76.

    Article  PubMed  Google Scholar 

  16. Sullivan RJ, Weber JS, Patel SP, et al. A phase Ib/II study of BRAF inhibitor (BRAFi) encorafenib (ENCO) plus MEK inhibitor (MEKi) binimetinib (BINI) in cutaneous melanoma patients naive to BRAFi treatment. J Clin Oncol 2015;33(Suppl):abstr 9007.

  17. Long GV, Stroyakovskiy D, Gogas H, 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;386:444–51.

    Article  CAS  PubMed  Google Scholar 

  18. Atkins MB, Lotze MT, Dutcher JP, 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;17:2105–16.

    CAS  PubMed  Google Scholar 

  19. Sznol M, Longo DL. Release the hounds! Activating the T-cell response to cancer. N Engl J Med. 2015;372:374–5.

    Article  CAS  PubMed  Google Scholar 

  20. Leach DR, Krummel MF, Allison JP. Enhancement of antitumor immunity by CTLA-4 blockade. Science. 1996;271:1734–6.

    Article  CAS  PubMed  Google Scholar 

  21. Hodi FS, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363:711–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. 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;33:1889–94.

    Article  CAS  PubMed  Google Scholar 

  23. Eroglu Z, Kim DW, Wang X, et al. Long term survival with cytotoxic T lymphocyte-associated antigen 4 blockade using tremelimumab. Eur J Cancer. 2015;51:2792–9.

    Article  PubMed  Google Scholar 

  24. Van Allen EM, Miao D, Schilling B, et al. Genomic correlates of response to CTLA-4 blockade in metastatic melanoma. Science. 2015;350:207–11.

    Article  PubMed  Google Scholar 

  25. Synder A, Makarov V, Merghoub T, et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med. 2014;371:2189–99.

    Article  Google Scholar 

  26. Vétizou M, Pitt JM, Daillère R, et al. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science. 2015;350:1079–84.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Sivan A, Corrales L, Hubert N, et al. Commensural Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science. 2015;350:1084–9.

    Article  CAS  PubMed  Google Scholar 

  28. Sznol M, Chen L. Antagonist antibodies to PD-1 and B7-H1 (PD-L1) in the treatment of advanced human cancer. Clin Cancer Res. 2013;19:1021–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366:2443–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Hamid O, Robert C, Daud A, et al. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med. 2013;369:134–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. 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;16:375–84.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  33. 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;16:908–18.

    Article  CAS  PubMed  Google Scholar 

  34. 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 

  35. Antonia SJ, Larkin J, Ascierto PA. Immuno-oncology combinations: a review of clinical experience and future prospects. Clin Cancer Res. 2014;20:6258–68.

    Article  CAS  PubMed  Google Scholar 

  36. Postow MA, Chesney J, Pavlick AC, et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med. 2015;372:2006–17.

    Article  PubMed  Google Scholar 

  37. 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.

    Article  CAS  PubMed  Google Scholar 

  38. Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015;372:supplemental data (available online).

  39. Hodi FS, Lee S, McDermott DF, et al. Ipilimumab plus sargramostim vs ipilimumab alone for treatment of metastatic melanoma: a randomized clinical trial. JAMA. 2014;312:1744–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Grob JJ, Long GV, Schadendorf D, Flaherty K. Disease kinetics for decision-making in advanced melanoma: a call for scenario-driven strategy trials. Lancet Oncol. 2015;16:e522–6.

    Article  PubMed  Google Scholar 

  41. Frederick DT, Piris A, Cogdill AP, 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;19:1225–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Wilmott JS, Long GV, Howle JR, et al. Selective BRAF inhibitors induce marked T-cell infiltration into human metastatic melanoma. Clin Cancer Res. 2012;18:1386–94.

    Article  CAS  PubMed  Google Scholar 

  43. 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;28:611–2.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Ribas A, Butler M, Lutzky J, et al. Phase I study combining anti-PD-L1 (MEDI4736) with BRAF (dabrafenib) and/or MEK (trametinib) inhibitors in advanced melanoma. J Clin Oncol. 2015;33(Suppl):3003.

    Google Scholar 

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Author information

Authors and Affiliations

  1. The Department of Cutaneous Oncology, Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL, USA

    Keiran S. M. Smalley, Zeynep Eroglu & Vernon K. Sondak

  2. The Department of Tumor Biology, Moffitt Cancer Center and Research Institute, Tampa, FL, USA

    Keiran S. M. Smalley

Authors
  1. Keiran S. M. Smalley
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  2. Zeynep Eroglu
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  3. Vernon K. Sondak
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Corresponding author

Correspondence to Keiran S. M. Smalley.

Ethics declarations

This work was supported by R01 CA161107-01, R21 CA198550, and SPORE grant CA168536 from the National Institutes of Health. Vernon K Sondak has served as a consultant to BMS, GSK, Merck, Novartis, OncoSec, Genentech/Roche, Navidea, Amgen, and Provectus. Keiran SM Smalley and Zeynep Eroglu declare no conflicts of interest.

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Smalley, K.S.M., Eroglu, Z. & Sondak, V.K. Combination Therapies for Melanoma: A New Standard of Care?. Am J Clin Dermatol 17, 99–105 (2016). https://doi.org/10.1007/s40257-016-0174-8

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  • DOI: https://doi.org/10.1007/s40257-016-0174-8

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