Skip to main content
SpringerLink
Log in
Book cover

Biologic and Systemic Agents in Dermatology pp 549–552Cite as

Update in Immunotherapies for Melanoma

  • Chapter
  • First Online:

  • 1471 Accesses

Abstract

In the setting of metastatic and advanced melanoma, systemic medications are often used. These new medications can be organized into those that target pathway alterations caused by gene mutations or those that augment the immune system to fight off the cancer. The key to targeted melanoma therapy primarily revolves around the mitogen-activated protein (MAP) kinase pathway. Vemurafenib and dabrafenib are inhibitors of mutated BRAF. They are used in combination with MEK inhibitors , such as trametinib and cobimetinib. Immunotherapy prompts the body’s immune system to recognize and eradicate the melanoma. Ipilimumab, a CTLA-4 monoclonal antibody, and pembrolizumab and nivolumab, PD-1 monoclonal antibodies, are mainstays of melanoma treatment.

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

References

  1. Beeram M, Patnaik A, Rowinsky EK. Raf: a strategic target for therapeutic development against cancer. J Clin Oncol. 2005;23:6771–90.

    Article  CAS  PubMed  Google Scholar 

  2. Curtin JA, Fridlyand J, Kageshita T, Patel HN, Busam KJ, Kutzner H, et al. Distinct sets of genetic alterations in melanoma. N Engl J Med. 2005;353:2135–47.

    Article  CAS  PubMed  Google Scholar 

  3. McArthur GA, Chapman PB, Robert C, Larkin J, Haanen JB, Dummer R, Ribas A, 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;15:323–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Flaherty L, Hamid O, Linette G, Schuchter L, Hallmeyer S, Gonzalez R, et al. A single-arm, open-label, expanded access study of vemurafenib in patients with metastatic melanoma in the United States. Cancer J. 2014;20:18–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Su F, Viros A, Milagre C, Trunzer K, Bollag G, Spleiss O, et al. RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors. N Engl J Med. 2012;366:207.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Poulikakos PI, Persaud Y, Janakiraman M, Kong X, Ng C, Moriceau G, et al. RAF inhibitor resistance is mediated by dimerization of aberrantly spliced BRAF(V600E). Nature. 2011;480:387–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Shi H, Moriceau G, Kong X, Lee MK, Lee H, Koya RC, et al. Melanoma whole-exome sequencing identifies (V600E)B-RAF amplification-mediated acquired B-RAF inhibitor resistance. Nat Commun. 2012;6:724.

    Article  Google Scholar 

  9. Shi H, Hugo W, Kong X, Hong A, Koya RC, Moriceau G, et al. Acquired resistance and clonal evolution in melanoma during BRAF inhibitor therapy. Cancer Discov. 2014;4:80–93.

    Article  CAS  PubMed  Google Scholar 

  10. Hugo W, Shi H, Sun L, Piva M, Song C, Kong X, et al. Non-genomic and immune evolution of melanoma acquiring MAPKi resistance. Cell. 2015;162(6):1271–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Flaherty KT, Robert C, Hersey P, Nathan P, Garbe C, Milhem M, et al. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med. 2012;367:107–14.

    Article  CAS  PubMed  Google Scholar 

  12. Ascierto PA, McArthur GA, Dréno B, Atkinson V, Liszkay G, Di Giacomo AM, 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;17:1248–60.

    Article  CAS  PubMed  Google Scholar 

  13. Long GV, Stroyakovskiy D, Gogas H, Levchenko E, de Braud F, Larkin J, Ascierto PA, McArthur GA, Dréno B, Atkinson V, Liszkay G, Di Giacomo AM, et al. Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. N Engl J Med. 2014;371:1877–88. https://doi.org/10.1056/NEJMoa1406037.

    Article  PubMed  Google Scholar 

  14. Robert C, Karaszewska B, Schachter J, Rutkowski P, Mackiewicz A, Stroiakovski D, et al. Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med. 2015;372:30.

    Article  PubMed  Google Scholar 

  15. Koller KM, Wang W, Schell TD, Cozza EM, Kokolus KM, Neves RI, et al. Malignant melanoma—the cradle of anti-neoplastic immunotherapy. Crit Rev Oncol Hematol. 2016;106:25–54. https://doi.org/10.1016/j.critrevonc.2016.04.010.

    Article  PubMed  Google Scholar 

  16. Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363:711.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Schadendorf D, Hodi FS, Robert C, Weber JS, Margolin K, Hamid O, 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Horvat TZ, Adel NG, Dang TO, Momtaz P, Postow MA, Callahan MK, et al. Immune related adverse events, need for systemic immunosuppression, and effects on survival and time to treatment failure in patients with melanoma treated with ipilimumab at Memorial Sloan Kettering Cancer Center. J Clin Oncol. 2015;33:3193–8. https://doi.org/10.1200/JCO.2015.60.8448.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Hamid O, Puzanov I, Dummer R, Schachter J, Daud A, Schadendorf D, et al. Final overall survival for KEYNOTE-002: pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma. Abstract 11070, presented at the 2016 European Society for Medical Oncology meeting.

    Google Scholar 

  20. Ribas A, Hamid O, Daud A, Hodi FS, Wolchok JD, Kefford R, et al. Association of pembrolizumab with tumor response and survival among patients with advanced melanoma. JAMA. 2016;315:1600.

    Article  CAS  PubMed  Google Scholar 

  21. Weber JS, D’Angelo SP, Minor D, Hodi FS, Gutzmer R, Neyns B, 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. https://doi.org/10.1016/S1470-2045(15)70076-8.

    Article  CAS  PubMed  Google Scholar 

  22. Robert C, Long GV, Brady B, Dutriaux C, Maio M, Mortier L, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015;372:320.

    Article  CAS  PubMed  Google Scholar 

  23. Weber JS, Hodi FS, Wolchok JD, Topalian SL, Schadendorf D, Larkin J, et al. Safety profile of nivolumab monotherapy: a pooled analysis of patients with advanced melanoma. J Clin Oncol. 2017;35:785–92. https://doi.org/10.1200/JCO.2015.66.1389.

    Article  PubMed  Google Scholar 

  24. Schacter J, Ribas A, Ling GV, Arance A, Grob JJ, Mortier L, et al. Pembrolizumab versus ipilimumab for advanced melanoma: Final overall survival analysis of KEYNOTE-006. Abstract 9504, American Society of Clinical Oncology 2016 annual meeting.

    Google Scholar 

  25. Wolchok JD, Chiarion-Sileni V, Gonzalez R, Piotr Rutkowski P, Grob JJ, Cowey CL, et al. Updated results from a phase III trial of nivolumab (NIVO) combined with ipilimumab (IPI) in treatment-naive patients (pts) with advanced melanoma (MEL) (CheckMate 067). Abstract 9505, American Society of Clinical Oncology 2016 annual meeting.

    Google Scholar 

  26. Hugo W, Zaretsky JM, Sun L, Song C, Moreno BH, Hu-Lieskovan S, et al. Genomic and transcriptomic features of response to anti-PD-1 therapy in metastatic melanoma. Cell. 2016;165:35–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Shin DS, Zaretsky JM, Escuin-Ordinas H, Garcia-Diaz A, Hu-Lieskovan S, Kalbasi A, et al. Primary resistance to PD-1 blockade mediated by JAK1/2 mutations. Cancer Discov. 2017;7:188–201.

    Article  CAS  PubMed  Google Scholar 

  28. Zaretsky JM, Garcia-Diaz A, Shin DS, Escuin-Ordinas H, Hugo W, Hu-Lieskovan S, et al. Mutations Associated with Acquired Resistance to PD-1 Blockade in Melanoma. N Engl J Med. 2016;375:819–29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Coit DG, Thompson JA, Algazi A, Andtbacka R, Bichakjian CK, Carson WE 3rd, et al. Melanoma, version 2.2016, NCCN clinical practice guidelines in oncology. J Natl Compr Cancer Netw. 2016;14:450–73.

    Article  Google Scholar 

  30. van Zeijl MC, van den Eertwegh AJ, Haanen JB, Wouters MW. (Neo)adjuvant systemic therapy for melanoma. Eur J Surg Oncol. 2017;43:534–43.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Dermatology, Department of Medicine, University of California, Los Angeles, 200 Med Plaza, Suite 450, Los Angeles, CA, 90095, USA

    Sabrina Martin MD, PhD & Roger Lo MD, PhD

Authors
  1. Sabrina Martin MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Roger Lo MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Roger Lo MD, PhD .

Editor information

Editors and Affiliations

  1. Division of Dermatology, David Geffen School of Medicine a UCLA, Los Angeles, California, USA

    Paul S. Yamauchi

Rights and permissions

Reprints and permissions

Copyright information

© 2018 Springer International Publishing AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Martin, S., Lo, R. (2018). Update in Immunotherapies for Melanoma. In: Yamauchi, P. (eds) Biologic and Systemic Agents in Dermatology. Springer, Cham. https://doi.org/10.1007/978-3-319-66884-0_48

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-66884-0_48

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-66883-3

  • Online ISBN: 978-3-319-66884-0

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation