Review Article | Published:

Targeted agents and immunotherapies: optimizing outcomes in melanoma

Nature Reviews Clinical Oncology volume 14, pages 463482 (2017) | Download Citation


Treatment options for patients with metastatic melanoma, and especially BRAF-mutant melanoma, have changed dramatically in the past 5 years, with the FDA approval of eight new therapeutic agents. During this period, the treatment paradigm for BRAF-mutant disease has evolved rapidly: the standard-of-care BRAF-targeted approach has shifted from single-agent BRAF inhibition to combination therapy with a BRAF and a MEK inhibitor. Concurrently, immunotherapy has transitioned from cytokine-based treatment to antibody-mediated blockade of the cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) and, now, the programmed cell-death protein 1 (PD-1) immune checkpoints. These changes in the treatment landscape have dramatically improved patient outcomes, with the median overall survival of patients with advanced-stage melanoma increasing from approximately 9 months before 2011 to at least 2 years — and probably longer for those with BRAF-V600-mutant disease. Herein, we review the clinical trial data that established the standard-of-care treatment approaches for advanced-stage melanoma. Mechanisms of resistance and biomarkers of response to BRAF-targeted treatments and immunotherapies are discussed, and the contrasting clinical benefits and limitations of these therapies are explored. We summarize the state of the field and outline a rational approach to frontline-treatment selection for each individual patient with BRAF-mutant melanoma.

Key points

  • Clinical therapeutics for advanced-stage melanoma have improved dramatically with the development of BRAF and MEK inhibitors, cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed cell-death protein 1 (PD-1) blocking antibodies, and a modified oncolytic herpes virus that is delivered intratumourally

  • The overall survival of patients with advanced-stage melanoma has improved from 9 months before 2011 to an as yet undefined timeframe, with a subset of patients having ongoing long-term tumour control

  • Melanoma, particularly cutaneous melanoma, is amendable to immunotherapy for various reasons, including extensive tumour infiltration by T cells, a high mutational load, and crosstalk between oncogenic signalling pathways and immunobiology

  • Resistance mechanisms to BRAF-targeted treatments and immunotherapies are being elucidated; reactivation of the MAPK pathway is common after BRAF inhibition, whereas the effectiveness of both approaches might be limited by loss of tumour antigen presentation and T-cell trafficking

  • To move the field of clinical therapeutics forward, a greater focus on specific patient populations (based on serum lactose dehydrogenase levels, ECOG performance status, and number of metastases), as well as on landmark progression-free and overall survival measures, will be required in clinical trials

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  1. 1.

    & Chemotherapy in the management of advanced cutaneous malignant melanoma. Clin. Dermatol. 31, 290–297 (2013).

  2. 2.

    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. 17, 2105–2116 (1999).

  3. 3.

    et al. Mutations of the BRAF gene in human cancer. Nature 417, 949–954 (2002).

  4. 4.

    , & Enhancement of antitumor immunity by CTLA-4 blockade. Science 271, 1734–1736 (1996).

  5. 5.

    Cancer Genome Atlas Network. Genomic classification of cutaneous melanoma. Cell 161, 1681–1696 (2015).

  6. 6.

    et al. Cancer genome landscapes. Science 339, 1546–1558 (2013).

  7. 7.

    et al. Efficacy and safety of programmed death receptor-1 (PD-1) blockade in metastatic uveal melanoma (UM). J. Clin. Oncol. 34 (Suppl.), abstr. 9507 (2016).

  8. 8.

    et al. Clinical activity of ipilimumab for metastatic uveal melanoma: a retrospective review of the Dana-Farber Cancer Institute, Massachusetts General Hospital, Memorial Sloan-Kettering Cancer Center, and University Hospital of Lausanne experience. Cancer 119, 3687–3695 (2013).

  9. 9.

    et al. Distinct sets of genetic alterations in melanoma. N. Engl. J. Med. 353, 2135–2147 (2005).

  10. 10.

    et al. A cell cycle regulator potentially involved in genesis of many tumor types. Science 264, 436–440 (1994).

  11. 11.

    , , , & Transforming ras genes from human melanoma: a manifestation of tumour heterogeneity? Nature 308, 69–72 (1984).

  12. 12.

    et al. Disruption of the MMAC1/PTEN gene by deletion or mutation is a frequent event in malignant melanoma. Cancer Res. 57, 3660–3663 (1997).

  13. 13.

    et al. The genetic evolution of melanoma from precursor lesions. N. Engl. J. Med. 373, 1926–1936 (2015).

  14. 14.

    et al. BrafV600E cooperates with Pten loss to induce metastatic melanoma. Nat. Genet. 41, 544–552 (2009).

  15. 15.

    , , & Genomic alterations in spontaneous and carcinogen-induced murine melanoma cell lines. Oncogene 23, 2347–2356 (2004).

  16. 16.

    et al. A landscape of driver mutations in melanoma. Cell 150, 251–263 (2012).

  17. 17.

    , , & Somatic activation of KIT in distinct subtypes of melanoma. J. Clin. Oncol. 24, 4340–4346 (2006).

  18. 18.

    et al. Large-scale analysis of KIT aberrations in Chinese patients with melanoma. Clin. Cancer Res. 17, 1684–1691 (2011).

  19. 19.

    et al. PTEN loss confers BRAF inhibitor resistance to melanoma cells through the suppression of BIM expression. Cancer Res. 71, 2750–2760 (2011).

  20. 20.

    et al. Acquired resistance and clonal evolution in melanoma during BRAF inhibitor therapy. Cancer Discov. 4, 80–93 (2014).

  21. 21.

    et al. Tumor genetic analyses of patients with metastatic melanoma treated with the BRAF inhibitor dabrafenib (GSK2118436). Clin. Cancer Res. 19, 4868–4878 (2013).

  22. 22.

    et al. Prognostic and clinicopathologic associations of oncogenic BRAF in metastatic melanoma. J. Clin. Oncol. 29, 1239–1246 (2011).

  23. 23.

    et al. Distinguishing clinicopathologic features of patients with V600E and V600K BRAF-mutant metastatic melanoma. Clin. Cancer Res. 18, 3242–3249 (2012).

  24. 24.

    et al. BRAF inhibitor activity in V600R metastatic melanoma. Eur. J. Cancer 49, 1073–1079 (2013).

  25. 25.

    et al. Frequency and spectrum of BRAF mutations in a retrospective, single-institution study of 1112 cases of melanoma. J. Mol. Diagn. 15, 220–226 (2013).

  26. 26.

    et al. BRAFL597 mutations in melanoma are associated with sensitivity to MEK inhibitors. Cancer Discov. 2, 791–797 (2012).

  27. 27.

    et al. Recurrent BRAF kinase fusions in melanocytic tumors offer an opportunity for targeted therapy. Pigment Cell Melanoma Res. 26, 845–851 (2013).

  28. 28.

    et al. Activity of trametinib in K601E and L597Q BRAF mutation-positive metastatic melanoma. Melanoma Res. 24, 504–508 (2014).

  29. 29.

    et al. Kinase-impaired BRAF mutations in lung cancer confer sensitivity to dasatinib. Sci. Transl Med. 4, 136ra70 (2012).

  30. 30.

    , , , & Missense mutations of the BRAF gene in human lung adenocarcinoma. Cancer Res. 62, 7001–7003 (2002).

  31. 31.

    et al. Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. Cell 116, 855–867 (2004).

  32. 32.

    et al. BRAF mutants evade ERK-dependent feedback by different mechanisms that determine their sensitivity to pharmacologic inhibition. Cancer Cell 28, 370–383 (2015).

  33. 33.

    et al. KIT as a therapeutic target in metastatic melanoma. JAMA 305, 2327–2334 (2011).

  34. 34.

    et al. Imatinib for melanomas harboring mutationally activated or amplified KIT arising on mucosal, acral, and chronically sun-damaged skin. J. Clin. Oncol. 31, 3182–3190 (2013).

  35. 35.

    et al. 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, 2904–2909 (2011).

  36. 36.

    et al. Tumor-infiltrating lymphocyte grade in primary melanomas is independently associated with melanoma-specific survival in the population-based genes, environment and melanoma study. J. Clin. Oncol. 31, 4252–4259 (2013).

  37. 37.

    et al. Transcriptional profiling of melanoma sentinel nodes identify patients with poor outcome and reveal an association of CD30+ T lymphocytes with progression. Cancer Res. 74, 130–140 (2014).

  38. 38.

    et al. The tyrosinase gene codes for an antigen recognized by autologous cytolytic T lymphocytes on HLA-A2 melanomas. J. Exp. Med. 178, 489–495 (1993).

  39. 39.

    , , , & CD4+ T cell recognition of MHC class II-restricted epitopes from NY-ESO-1 presented by a prevalent HLA DP4 allele: association with NY-ESO-1 antibody production. Proc. Natl Acad. Sci. USA 98, 3964–3969 (2001).

  40. 40.

    , , , & Use of an in vitro immunoselected tumor line to identify shared melanoma antigens recognized by HLA-A*0201-restricted T cells. Cancer Res. 61, 1089–1094 (2001).

  41. 41.

    et al. Recognition of shared melanoma antigens in association with major HLA-A alleles by tumor infiltrating T lymphocytes from 123 patients with melanoma. J. Immunother. 23, 17–27 (2000).

  42. 42.

    The blockade of immune checkpoints in cancer immunotherapy. Nat. Rev. Cancer 12, 252–264 (2012).

  43. 43.

    , & Regulatory circuits of T cell function in cancer. Nat. Rev. Immunol. 16, 599–611 (2016).

  44. 44.

    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. 1, 433–440 (2015).

  45. 45.

    et al. Pembrolizumab versus ipilimumab in advanced melanoma. N. Engl. J. Med. 372, 2521–2532 (2015).

  46. 46.

    et al. Analysis of BRAF and NRAS mutation status in advanced melanoma patients treated with anti-CTLA-4 antibodies: association with overall survival? PLoS ONE 10, e0139438 (2015).

  47. 47.

    et al. Phase III trial of carboplatin and paclitaxel with or without sorafenib in metastatic melanoma. J. Clin. Oncol. 31, 373–379 (2013).

  48. 48.

    et al. Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma. Nature 467, 596–599 (2010).

  49. 49.

    et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N. Engl. J. Med. 364, 2507–2516 (2011).

  50. 50.

    et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur. J. Cancer 45, 228–247 (2009).

  51. 51.

    et al. Safety and efficacy of vemurafenib in BRAFV600E and BRAFV600K mutation-positive melanoma (BRIM-3): extended follow-up of a phase 3, randomised, open-label study. Lancet Oncol. 15, 323–332 (2014).

  52. 52.

    et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet 380, 358–365 (2012).

  53. 53.

    et al. Improved survival with MEK inhibition in BRAF-mutated melanoma. N. Engl. J. Med. 367, 107–114 (2012).

  54. 54.

    & Resistance to BRAF inhibition in melanomas. N. Engl. J. Med. 364, 772–774 (2011).

  55. 55.

    & Ipilimumab, vemurafenib, dabrafenib, and trametinib: synergistic competitors in the clinical management of BRAF mutant malignant melanoma. Oncologist 18, 717–725 (2013).

  56. 56.

    et al. RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors. N. Engl. J. Med. 366, 207–215 (2012).

  57. 57.

    et al. RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth. Nature 464, 431–435 (2010).

  58. 58.

    et al. Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF. Cell 140, 209–221 (2010).

  59. 59.

    , , , & RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF. Nature 464, 427–430 (2010).

  60. 60.

    et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N. Engl. J. Med. 367, 1694–1703 (2012).

  61. 61.

    et al. Updated overall survival (OS) for BRF113220, a phase 1–2 study of dabrafenib (D) alone versus combined dabrafenib and trametinib (D+T) in pts with BRAF V600 mutation-positive (+) metastatic melanoma (MM). J. Clin. Oncol. 32 (Suppl.), abstr. 9010 (2014).

  62. 62.

    et al. Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial. Lancet 386, 444–451 (2015).

  63. 63.

    et al. Improved overall survival in melanoma with combined dabrafenib and trametinib. N. Engl. J. Med. 372, 30–39 (2015).

  64. 64.

    et al. Two year estimate of overall survival in COMBI-v, a randomized, open-label, phase III study comparing the combination of dabrafenib (D) and trametinib (T) with vemurafenib (Vem) as first-line therapy in patients (pts) with unresectable or metastatic BRAF V600E/K mutation-positive cutaneous melanoma [abstract 3301]. Eur. J. Cancer 51 (Suppl. 3), S663 (2015).

  65. 65.

    et al. Combination of vemurafenib and cobimetinib in patients with advanced BRAFV600-mutated melanoma: a phase 1b study. Lancet Oncol. 15, 954–965 (2014).

  66. 66.

    et al. Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N. Engl. J. Med. 371, 1867–1876 (2014).

  67. 67.

    et al. Impact of baseline genetic heterogeneities on progression-free survival (PFS) in patients (pts) with advanced BRAFV600-mutated melanoma treated with cobimetinib (COBI) + vemurafenib (VEM) in the phase 3 coBRIM study [abstract 25LBA]. Eur. J. Cancer 51 (Suppl. 3), S722–S723 (2015).

  68. 68.

    et al. Cobimetinib combined with vemurafenib in advanced BRAFV600-mutant melanoma (coBRIM): updated efficacy results from a randomised, double-blind, phase 3 trial. Lancet Oncol. 17, 1248–1260 (2016).

  69. 69.

    , & BRAF and MEK inhibition in melanoma. Expert Opin. Drug Saf. 14, 559–570 (2015).

  70. 70.

    , , & BRAF and MEK inhibition for the treatment of advanced BRAF mutant melanoma. Expert Opin. Pharmacother. 16, 1285–1297 (2015).

  71. 71.

    et al. MEK162 for patients with advanced melanoma harbouring NRAS or Val600 BRAF mutations: a non-randomised, open-label phase 2 study. Lancet Oncol. 14, 249–256 (2013).

  72. 72.

    et al. Results of NEMO: a phase III trial of binimetinib (BINI) versus dacarbazine (DTIC) in NRAS-mutant cutaneous melanoma. J. Clin. Oncol. 34 (Suppl.), abstr. 9500 (2016).

  73. 73.

    et al. Oncogenic NRAS signaling differentially regulates survival and proliferation in melanoma. Nat. Med. 18, 1503–1510 (2012).

  74. 74.

    et al. p53 rescue through HDM2 antagonism suppresses melanoma growth and potentiates MEK inhibition. J. Invest. Dermatol. 132, 356–364 (2012).

  75. 75.

    et al. Reversing melanoma cross-resistance to BRAF and MEK inhibitors by co-targeting the AKT/mTOR pathway. PLoS ONE 6, e28973 (2011).

  76. 76.

    et al. Melanoma. J. Natl Compr. Canc. Netw. 10, 366–400 (2012).

  77. 77.

    et al. Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 363, 711–723 (2010).

  78. 78.

    et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N. Engl. J. Med. 364, 2517–2526 (2011).

  79. 79.

    et al. Overall survival (OS) and safety results from a phase 3 trial of ipilimumab (IPI) at 3 mg/kg versus 10 mg/kg in patients with metastatic melanoma (MEL). Ann. Oncol. 27 (Suppl. 6), abstr.1106O (2016).

  80. 80.

    , & Management of immune-related adverse events and kinetics of response with ipilimumab. J. Clin. Oncol. 30, 2691–2697 (2012).

  81. 81.

    et al. Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin. Cancer Res. 15, 7412–7420 (2009).

  82. 82.

    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. 33, 1889–1894 (2015).

  83. 83.

    et al. Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial. Lancet Oncol. 13, 459–465 (2012).

  84. 84.

    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. 33, 3193–3198 (2015).

  85. 85.

    et al. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N. Engl. J. Med. 369, 134–144 (2013).

  86. 86.

    et al. Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab. J. Clin. Oncol. 32, 1020–1030 (2014).

  87. 87.

    et al. Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet Oncol. 16, 908–918 (2015).

  88. 88.

    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. 16, 375–384 (2015).

  89. 89.

    et al. Nivolumab in previously untreated melanoma without BRAF mutation. N. Engl. J. Med. 372, 320–330 (2014).

  90. 90.

    et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N. Engl. J. Med. 373, 23–34 (2015).

  91. 91.

    , , & PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors. Proc. Natl Acad. Sci. USA 107, 4275–4280 (2010).

  92. 92.

    et al. Nivolumab plus ipilimumab in advanced melanoma. N. Engl. J. Med. 369, 122–133 (2013).

  93. 93.

    et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N. Engl. J. Med. 372, 2006–2017 (2015).

  94. 94.

    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. 17, 1558–1568 (2016).

  95. 95.

    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. 17, 943–955 (2016).

  96. 96.

    & Talimogene laherparepvec for the treatment of advanced melanoma. Clin. Cancer Res. 22, 3127–3131 (2016).

  97. 97.

    GM-CSF-based cancer vaccines. Immunol. Rev. 188, 147–154 (2002).

  98. 98.

    et al. Talimogene laherparepvec improves durable response rate in patients with advanced melanoma. J. Clin. Oncol. 33, 2780–2788 (2015).

  99. 99.

    et al. Up-regulation of PD-L1, IDO, and Tregs in the melanoma tumor microenvironment is driven by CD8+ T cells. Sci. Transl Med. 5, 200ra116 (2013).

  100. 100.

    et al. Association of response to programmed death receptor 1 (PD-1) blockade with pembrolizumab (MK-3475) with an interferon-inflammatory immune gene signature. J. Clin. Oncol. 33 (Suppl.), abstr. 3001 (2015).

  101. 101.

    et al. Talimogene laherparepvec in combination with ipilimumab in previously untreated, unresectable stage IIIB-IV melanoma. J. Clin. Oncol. 34, 2619–2626 (2016).

  102. 102.

    et al. Efficacy analysis of MASTERKEY-265 phase 1b study of talimogene laherparepvec (T-VEC) and pembrolizumab (pembro) for unresectable stage IIIB-IV melanoma. J. Clin. Oncol. 34, (Suppl.), abstr. 9568 (2016).

  103. 103.

    et al. Pembrolizumab versus ipilimumab for advanced melanoma: Final overall survival analysis of KEYNOTE-006. J. Clin. Oncol. 34 (Suppl.), abstr. 9504 (2016).

  104. 104.

    et al. Simultaneous suppression of MITF and BRAF V600E enhanced inhibition of melanoma cell proliferation. Cancer Sci. 100, 1863–1869 (2009).

  105. 105.

    et al. Inverse relationship of melanocyte differentiation antigen expression in melanoma tissues and CD8+ cytotoxic-T-cell responses: evidence for immunoselection of antigen-loss variants in vivo. Int. J. Cancer 66, 470–476 (1996).

  106. 106.

    et al. A melanocyte lineage program confers resistance to MAP kinase pathway inhibition. Nature 504, 138–142 (2013).

  107. 107.

    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. 19, 1225–1231 (2013).

  108. 108.

    et al. Selective BRAF inhibitors induce marked T-cell infiltration into human metastatic melanoma. Clin. Cancer Res. 18, 1386–1394 (2012).

  109. 109.

    et al. Distinct clinical patterns and immune infiltrates are observed at time of progression on targeted therapy versus immune checkpoint blockade for melanoma. Oncoimmunology 5, e1136044 (2016).

  110. 110.

    et al. Improved antitumor activity of immunotherapy with BRAF and MEK inhibitors in BRAFV600E melanoma. Sci. Transl Med. 7, 279ra41 (2015).

  111. 111.

    et al. BRAF inhibition stimulates melanoma-associated macrophages to drive tumor growth. Clin. Cancer Res. 21, 1652–1664 (2015).

  112. 112.

    et al. Phase I study combining anti-PD-L1 (MEDI4736) with BRAF (dabrafenib) and/or MEK (trametinib) inhibitors in advanced melanoma. J. Clin. Oncol. 33 (Suppl.), abstr. 3003 (2015).

  113. 113.

    et al. Preliminary safety and clinical activity of atezolizumab combined with cobimetinib and vemurafenib in BRAF V600-mutant metastatic melanoma. Ann. Oncol. 27 (Suppl. 6), abstr.1109PD (2016).

  114. 114.

    et al. Pembrolizumab (pembro) in combination with dabrafenib (D) and trametinib (T) for BRAF-mutant advanced melanoma: phase 1 KEYNOTE-022 study. J. Clin. Oncol. 34 (Suppl.), abstr. 3014 (2016).

  115. 115.

    , , & Targeting oncogenic BRAF and aberrant MAPK activation in the treatment of cutaneous melanoma. Crit. Rev. Oncol. Hematol. 96, 385–398 (2015).

  116. 116.

    et al. Acquired BRAF inhibitor resistance: a multicenter meta-analysis of the spectrum and frequencies, clinical behaviour, and phenotypic associations of resistance mechanisms. Eur. J. Cancer 51, 2792–2799 (2015).

  117. 117.

    et al. The genetic landscape of clinical resistance to RAF inhibition in metastatic melanoma. Cancer Discov. 4, 94–109 (2014).

  118. 118.

    et al. BRAF inhibitor resistance mechanisms in metastatic melanoma: spectrum and clinical impact. Clin. Cancer Res. 20, 1965–1977 (2014).

  119. 119.

    et al. Increased MAPK reactivation in early resistance to dabrafenib/trametinib combination therapy of BRAF-mutant metastatic melanoma. Nat. Commun. 5, 5694 (2014).

  120. 120.

    et al. MAP kinase pathway alterations in BRAF-mutant melanoma patients with acquired resistance to combined RAF/MEK inhibition. Cancer Discov. 4, 61–68 (2014).

  121. 121.

    et al. Non-genomic and immune evolution of melanoma acquiring MAPKi resistance. Cell 162, 1271–1285 (2015).

  122. 122.

    et al. Circulating tumor DNA to monitor treatment response and detect acquired resistance in patients with metastatic melanoma. Oncotarget 6, 42008–42018 (2015).

  123. 123.

    et al. Isolation and molecular characterization of circulating melanoma cells. Cell Rep. 7, 645–653 (2014).

  124. 124.

    et al. Correlation of BRAF mutation status in circulating-free DNA and tumor and association with clinical outcome across four BRAFi and MEKi clinical trials. Clin. Cancer Res. 22, 567–574 (2016).

  125. 125.

    et al. Response of BRAF-mutant melanoma to BRAF inhibition is mediated by a network of transcriptional regulators of glycolysis. Cancer Discov. 4, 423–433 (2014).

  126. 126.

    et al. Inhibition of mTORC1/2 overcomes resistance to MAPK pathway inhibitors mediated by PGC1alpha and oxidative phosphorylation in melanoma. Cancer Res. 74, 7037–7047 (2014).

  127. 127.

    et al. The Hippo effector YAP promotes resistance to RAF- and MEK-targeted cancer therapies. Nat. Genet. 47, 250–256 (2015).

  128. 128.

    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 9, e101286 (2014).

  129. 129.

    et al. TORC1 suppression predicts responsiveness to RAF and MEK inhibition in BRAF-mutant melanoma. Sci. Transl Med. 5, 196ra98 (2013).

  130. 130.

    et al. BCL2A1 is a lineage-specific antiapoptotic melanoma oncogene that confers resistance to BRAF inhibition. Proc. Natl Acad. Sci. USA 110, 4321–4326 (2013).

  131. 131.

    et al. Oncogenic BRAF regulates oxidative metabolism via PGC1alpha and MITF. Cancer Cell 23, 302–315 (2013).

  132. 132.

    et al. Brn-2 represses microphthalmia-associated transcription factor expression and marks a distinct subpopulation of microphthalmia-associated transcription factor-negative melanoma cells. Cancer Res. 68, 7788–7794 (2008).

  133. 133.

    et al. A melanoma cell state distinction influences sensitivity to MAPK pathway inhibitors. Cancer Discov. 4, 816–827 (2014).

  134. 134.

    et al. Low MITF/AXL ratio predicts early resistance to multiple targeted drugs in melanoma. Nat. Commun. 5, 5712 (2014).

  135. 135.

    et al. Downregulation of the ubiquitin ligase RNF125 underlies resistance of melanoma cells to BRAF inhibitors via JAK1 deregulation. Cell Rep. 11, 1458–1473 (2015).

  136. 136.

    et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 515, 568–571 (2014).

  137. 137.

    , & Gene signature in melanoma associated with clinical activity: a potential clue to unlock cancer immunotherapy. Cancer J. 16, 399–403 (2010).

  138. 138.

    , & Innate and adaptive immune cells in the tumor microenvironment. Nat. Immunol. 14, 1014–1022 (2013).

  139. 139.

    et al. Chemokine expression in melanoma metastases associated with CD8+ T-cell recruitment. Cancer Res. 69, 3077–3085 (2009).

  140. 140.

    et al. An immune-active tumor microenvironment favors clinical response to ipilimumab. Cancer Immunol. Immunother. 61, 1019–1031 (2011).

  141. 141.

    et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N. Engl. J. Med. 366, 2443–2454 (2012).

  142. 142.

    et al. Inflamed-phenotype gene expression signatures to predict benefit from the anti-PD-1 antibody pembrolizumab in PD-L1+ head and neck cancer patients. J. Clin. Oncol. 33 (Suppl.), abstr. 6017 (2015).

  143. 143.

    et al. Pembrolizumab (MK-3475) for advanced urothelial cancer: updated results and biomarker analysis from KEYNOTE-012. J. Clin. Oncol. 33 (Suppl.), abstr. 4502 (2015).

  144. 144.

    et al. Correlation of gene expression signatures and clinical outcomes in patients with advanced gastric cancer treated with pembrolizumab (MK-3475). J. Clin. Oncol. 33 (Suppl.), abstr. 3026 (2015).

  145. 145.

    , & Melanoma-intrinsic β-catenin signalling prevents anti-tumour immunity. Nature 523, 231–235 (2015).

  146. 146.

    et al. Loss of PTEN promotes resistance to T cell-mediated immunotherapy. Cancer Discov. 6, 202–216 (2016).

  147. 147.

    et al. Mutations associated with acquired resistance to PD-1 blockade in melanoma. N. Engl. J. Med. 375, 819–829 (2016).

  148. 148.

    et al. Primary resistance to PD-1 blockade mediated by JAK1/2 mutations. Cancer Discov. 7, 188–201 (2017).

  149. 149.

    & Progression-free survival landmark analysis: a critical endpoint in melanoma clinical trials. Lancet Oncol. 17, 1037–1039 (2016).

  150. 150.

    et al. Final version of 2009 AJCC melanoma staging and classification. J. Clin. Oncol. 27, 6199–6206 (2009).

  151. 151.

    et al. Baseline and postbaseline characteristics associated with treatment benefit across dabrafenib and trametinib registration pooled data [abstract]. Pigment Cell Melanoma Res. 28, 793 (2015).

  152. 152.

    et al. Baseline tumor size as an independent prognostic factor for overall survival in patients with metastatic melanoma treated with the anti-PD-1 monoclonal antibody MK-3475. J. Clin. Oncol. 32 (Suppl.), abstr. 3015 (2014).

  153. 153.

    et al. Efficacy and safety in key patient subgroups of nivolumab (NIVO) alone or combined with ipilimumab (IPI) versus IPI alone in treatment-naïve patients with advanced melanoma (MEL) (CheckMate 067) [abstract 3303]. Eur. J. Cancer 51 (Suppl. 3), S664–S665 (2015).

  154. 154.

    et al. Three-year overall survival for patients with advanced melanoma treated with pembrolizumab in KEYNOTE-001. J. Clin. Oncol. 34 (Suppl.), abstr. 9503 (2016).

  155. 155.

    et al. Three-year estimate of overall survival in COMBI-v, a randomized phase 3 study evaluating first-line dabrafenib (D) + trametinib (T) in patients (pts) with unresectable or metastatic BRAF V600E/K–mutant cutaneous melanoma. J. Clin. Oncol. 27 (Suppl. 6), abstr. LBA40 (2016).

  156. 156.

    et al. Genomic analysis and 3-y efficacy and safety update of COMBI-d: a phase 3 study of dabrafenib (D) + trametinib (T) versus D monotherapy in patients (pts) with unresectable or metastatic BRAF V600E/K-mutant cutaneous melanoma. J. Clin. Oncol. 34 (Suppl.), abstr. 9502 (2016).

  157. 157.

    et al. Lesion-specific patterns of response and progression with anti-PD-1 treatment in metastatic melanoma (MM). J. Clin. Oncol. 32 (5s Suppl.), abstr. 9077 (2015).

  158. 158.

    et al. Factors predictive of response, disease progression, and overall survival after dabrafenib and trametinib combination treatment: a pooled analysis of individual patient data from randomised trials. Lancet Oncol. 17, 1743–1754 (2016).

  159. 159.

    et al. Update on overall survival (os) and follow-on therapies in BREAK-3, a phase III, randomized trial: dabrafenib (D) versus dacarbazine (DTIC) in patients (pts) with BRAF V600E mutation-positive metastatic melanoma (MM) [abstract 1092PD]. Ann. Oncol. 25, iv378 (2014).

  160. 160.

    et al. Updated overall survival (OS) results for BRF113220, a phase I–II study of dabrafenib alone versus combined dabrafenib and trametinib in patients with BRAF V600 metastatic melanoma (MM). J. Clin. Oncol. 33 (Suppl.), abstr. 9036 (2015).

  161. 161.

    et al. Dabrafenib in patients with Val600Glu or Val600Lys BRAF-mutant melanoma metastatic to the brain (BREAK-MB): a multicentre, open-label, phase 2 trial. Lancet Oncol. 13, 1087–1095 (2012).

  162. 162.

    et al. Dabrafenib in patients with melanoma, untreated brain metastases, and other solid tumours: a phase 1 dose-escalation trial. Lancet 379, 1893–1901 (2012).

  163. 163.

    et al. Vemurafenib in patients with BRAFV600 mutation-positive melanoma with symptomatic brain metastases: final results of an open-label pilot study. Eur. J. Cancer 50, 611–621 (2014).

  164. 164.

    et al. Circulating tumor DNA (ctDNA) to track responses and to capture the genomic heterogeneity of metastatic melanoma. J. Clin. Oncol. 34 (Suppl.), abstr. 9582 (2016).

  165. 165.

    et al. Outcomes of patients with metastatic melanoma treated with immunotherapy prior to or after BRAF inhibitors. Cancer 120, 1695–1701 (2014).

  166. 166.

    et al. Sequential treatment with ipilimumab and BRAF inhibitors in patients with metastatic melanoma: data from the Italian cohort of the ipilimumab expanded access program. Cancer Invest. 32, 144–149 (2014).

  167. 167.

    et al. Genomic and transcriptomic features of response to anti-PD-1 therapy in metastatic melanoma. Cell 165, 35–44 (2016).

  168. 168.

    Adaptive immune resistance: how cancer protects from immune attack. Cancer Discov. 5, 915–919 (2015).

  169. 169.

    et al. Pembrolizumab (pembro) plus ipilimumab (ipi) for advanced melanoma: results of the KEYNOTE-029 expansion cohort. J. Clin. Oncol. 34 (Suppl.), abstr. 9506 (2016).

  170. 170.

    et al. Preliminary results from a Phase I/II study of epacadostat (incb024360) in combination with pembrolizumab in patients with selected advanced cancers [abstract]. J. Immunother. Cancer 3 (Suppl. 2), O7 (2015).

  171. 171.

    et al. Pembrolizumab for patients with melanoma or non-small-cell lung cancer and untreated brain metastases: early analysis of a non-randomised, open-label, phase 2 trial. Lancet Oncol. 17, 976–983 (2016).

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J.J.L. has received funding from the Paul Calabresi Career Development in Clinical Oncology Award (NIH 1K12CA139160-05) and the Arthur J Schreiner Family Melanoma Research Fund.

Author information


  1. Department of Medicine, Division of Hematology/Oncology, University of Chicago Comprehensive Cancer Center, 5841 South Maryland Avenue MC2115, Chicago, Illinois 60637, USA.

    • Jason J. Luke
  2. Department of Medicine, Harvard Medical School, Massachusetts General Hospital Cancer Center, 55 Fruit Street, Boston, Massachusetts 02114, USA.

    • Keith T. Flaherty
  3. Department of Medicine, Division of Hematology/Oncology, University of California Los Angeles Jonsson Comprehensive Cancer Center, 10833 Le Conte Avenue, Los Angeles, California 90024, USA.

    • Antoni Ribas
  4. Melanoma Institute Australia, The University of Sydney, and The Mater Hospital, Rocklands Road, North Sydney, New South Wales 2060, Australia.

    • Georgina V. Long
  5. Royal North Shore Hospital, Reserve Road, St Leonards, New South Wales 2065, Australia.

    • Georgina V. Long


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All authors made substantial contributions to researching data for the article, discussions of content, and writing and reviewing/editing of the manuscript before submission.

Competing interests

J.J.L. has acted as a consultant for Amgen, Array, AstraZeneca, BeneVir, Bristol-Myers Squibb, CheckMate, EMD Serono, Gilead, Novartis, and Merck (non-paid). K.T.F. has been a consultant for Amgen, BMS, Merck, Novartis, and Roche. A.R. has acted as a consultant for Amgen, Array, BMS, Genentech-Roche, Merck MSD, and Novartis, and is a stock holder in Advaxis, Compugen, CytomX, Five Prime Therapeutics, and Kite Pharma. G.V.L. has been a consultant for Amgen, Array, BMS, Merck MSD, Novartis, Pierre-Fabre, and Roche.

Corresponding author

Correspondence to Jason J. Luke.

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