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Immunotherapy of advanced melanoma with immune checkpoint inhibition

Jeffrey A Sosman, MD
Section Editor
Michael B Atkins, MD
Deputy Editor
Michael E Ross, MD


Although the incidence of malignant melanoma is increasing, most cases are diagnosed at an early stage. In that setting, surgical excision is curative in most cases, and patients at high-risk of developing metastatic disease may benefit from adjuvant immunotherapy. (See "Initial surgical management of melanoma of the skin and unusual sites" and "Adjuvant immunotherapy for melanoma".)

The management of patients with disseminated disease is a difficult problem, although recent advances have led to important improvements in patient outcomes. These approaches include immunotherapy (particularly with checkpoint inhibition) and targeted therapy that inhibits the MAP kinase pathway.

This topic reviews the efficacy and role of immune checkpoint inhibitors in the treatment of advanced melanoma (algorithm 1). The toxicity associated with these agents is discussed separately, as is an overview of the management of advanced melanoma is presented separately. (See "Toxicities associated with checkpoint inhibitor immunotherapy" and "Overview of the management of advanced cutaneous melanoma".)


Activation of cellular immunity begins when T cells recognize peptide fragments of intracellular proteins that are expressed on the surface of antigen presenting cells (APCs) bound to specific mixed histocompatibility complex (MHC) molecules. This interaction requires the presence of a costimulatory molecule (B7) and this activation results in upregulation of cytotoxic T-lymphocyte antigen 4 (CTLA-4). The CTLA-4 receptor on T lymphocytes is a negative regulator of T cell activation that outcompetes CD28 for binding to B7 on antigen presenting cells. CTLA-4 thereby serves as a physiologic "brake" on the activated immune system. (See "Principles of cancer immunotherapy".)

A second co-inhibitory pathway uses the programmed cell death 1 receptor (PD-1), which is another inhibitory receptor present on activated T cells. When PD-1 binds to its ligand (PD-L1) (often present on tumor cells), the ability of the activated T cell to produce an effective immune response is down-modulated. Antibodies directed against PD-1 (nivolumab, pembrolizumab) or the PD-1 ligand thus may restore or augment an antitumor immune response and produce tumor responses in patients with advanced melanoma. (See 'Programmed death 1 protein' below.)


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Literature review current through: Jul 2017. | This topic last updated: Jul 05, 2017.
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  1. Snyder 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.
  2. Wolchok JD, Hoos A, O'Day S, et al. Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res 2009; 15:7412.
  3. Hodi FS, Hwu WJ, Kefford R, et al. Evaluation of Immune-Related Response Criteria and RECIST v1.1 in Patients With Advanced Melanoma Treated With Pembrolizumab. J Clin Oncol 2016; 34:1510.
  4. 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.
  5. Brahmer JR, Tykodi SS, Chow LQ, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 2012; 366:2455.
  6. Ribas A, Hamid O, Daud A, et al.. Association of Pembrolizumab With Tumor Response and Survival Among Patients With Advanced Melanoma. JAMA 2016; 315:1600.
  7. Robert C, Ribas A, Hamid O, et al. Three-year overall survival for patients with advanced melanoma treated with pembrolizumab in KEYNOTE-001. Abstract 9503, American Society of Clinical Oncology 2016 annual meeting
  8. Daud AI, Wolchok JD, Robert C, et al. Programmed death-ligand 1 expression in response to the anti-programmed death 1 antibody pembrolizumab in melanoma. J Clin Oncol 2016.
  9. 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.
  10. Hamid O, Puzanov I, Dummer R, 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.
  11. Robert C, Schachter J, Long GV, et al. Pembrolizumab versus Ipilimumab in Advanced Melanoma. N Engl J Med 2015; 372:2521.
  12. Topalian SL, 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; 32:1020.
  13. Hodi FS, Sznol M, Kluger HM, et al. Long-term survival of ipilimumab-naive patients (pts) with advanced melanoma (MEL) treated with nivolumab (anti-PD-1, BMS-936558, ONO-4538) in a phase I trial (abstract 9002). 2014 American Society of Clinical Oncology (ASCO) meeting.
  14. Hodi FS, Kluger HM, Sznol M, et al. Long-term Survival of Ipilimumab-naïve Patients with Advanced Melanoma Treated with Nivolumab in A Phase 1 Trial. Presented at the 2014 Society for Melanoma Research Congress.
  15. Hodi FS, Kluger H, Sznol M, et al. Durable, longterm survival in previously treated patients with advanced melanoma (MEL) whoreceived nivolumab (NIVO) monotherapy in a phase I trial (abstract CT001). 2016 American Association for Cancer Research meeting.
  16. Robert C, Long GV, Brady B, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med 2015; 372:320.
  17. Long GV, Atkinson V, Ascierto PA, et al. Effect of nivolumab on health-related quality of life in patients with treatment-naïve advanced melanoma: results from the phase III CheckMate 066 study. Ann Oncol 2016; 27:1940.
  18. 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.
  19. Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. N Engl J Med 2015; 373:23.
  20. Larkin J, Lao CD, Urba WJ, et al. Efficacy and Safety of Nivolumab in Patients With BRAF V600 Mutant and BRAF Wild-Type Advanced Melanoma: A Pooled Analysis of 4 Clinical Trials. JAMA Oncol 2015; 1:433.
  21. FDA label http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/125554s017s018lbl.pdf?et_cid=38363328&et_rid=931310737&linkid=http%3a%2f%2fwww.accessdata.fda.gov%2fdrugsatfda_docs%2flabel%2f2016%2f125554s017s018lbl.pdf (Accessed on September 15, 2016).
  22. Hamid O, et al. Clinical activity, safety, and biomarkers of MPDL3280A, an engineered PD-L1 antibody in patients with locally advanced or metastatic melanoma (abstract #9010). American Society of Clinical Oncology 2013 meeting.
  23. Hodi FS, O'Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010; 363:711.
  24. Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 2011; 364:2517.
  25. 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; 33:1191.
  26. 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.
  27. Wolchok JD, Neyns B, Linette G, et al. Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study. Lancet Oncol 2010; 11:155.
  28. Ascierto PA, Del Vecchio M, Robert C, et al. Ipilimumab 10 mg/kg versus ipilimumab 3 mg/kg in patients with unresectable or metastatic melanoma: a randomised, double-blind, multicentre, phase 3 trial. Lancet Oncol 2017.
  29. Robert C, Long GV, Schachter J, et al. Long-term outcomes in patients with ipilimumab-naïve advanced melanoma in the phase 3 KEYNOTE–006 study who completed pembrolizumab treatment (abstract 9504). 2017 American Society of Clinical Oncology annual meeting.
  30. Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med 2013; 369:122.
  31. Sznol M, Kluger HM, Callahan MK, et al. Survival, response duration, and activity by BRAF mutation (MT) status of nivolumab (NIVO, anti-PD-1, BMS-936558, ONO-4538) and ipilimumab (IPI) concurrent therapy in advanced melanoma (MEL) (abstract LBA9003). 2014 American Society of Clinical Oncology (ASCO) meeting.
  32. Postow MA, Chesney J, Pavlick AC, et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med 2015; 372:2006.
  33. Hodi FS, Chesney J, Pavlick AC, et al. Combined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, phase 2 trial. Lancet Oncol 2016; 17:1558.
  34. Wolchok JD, Chiarion-Sileni V, Gonzalez R, e 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.
  35. Long GV, Atkinson V, Cebon JS,et al. Pembrolizumab (pembro) plus ipilimumab (ipi) for advanced melanoma: Results of the KEYNOTE-029 expansion cohort. Abstract 9506, American Society of Clinical Oncology 2016 annual meeting.
  36. Weber JS, Gibney G, Sullivan RJ, et al. Sequential administration of nivolumab and ipilimumab with a planned switch in patients with advanced melanoma (CheckMate 064): an open-label, randomised, phase 2 trial. Lancet Oncol 2016; 17:943.
  37. 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.
  38. Munhoz RR, Shoushtari AN, Kuk D, et al. Clinical activity of anti-programmed death-1 (PD-1) agents in acral and mucosal melanoma. J Clin Oncol 34, 2016 (suppl; abstr 9516)
  39. Sznol M, Hodi FS, Margolin K, et al. Phase I study of BMS-663513, a fully human anti-CD137 agonist monoclonal antibody, in patients with advanced cancer (abstract #3007). J Clin Oncol 2008.
  40. Curti B, Weinberg A, Morris N, et al. A phase I trial of monoclonal antibody to OX40 in patients with advanced cancer (abstract). International Society for Biological Therapy of Cancer Annual Meeting, 2007.