• 1
    Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin 2013; 63:1130.
  • 2
    Baker HW. Spontaneous regression of malignant melanoma. Am Surg 1964; 30:8259.
  • 3
    Tsao H, Cosimi AB, Sober AJ. Ultra-late recurrence (15 years or longer) of cutaneous melanoma. Cancer 1997; 79:236170.
  • 4
    Morton D, Eilber FR, Malmgren RA et al. Immunological factors which influence response to immunotherapy in malignant melanoma. Surgery 1970; 68:15863. discussion 163–4.
  • 5
    Morton DL, Eilber FR, Holmes EC et al. BCG immunotherapy of malignant melanoma: summary of a seven-year experience. Ann Surg 1974; 180:63543.
  • 6
    Mastrangelo MJ, Bellet RE, Berkelhammer J et al. Regression of pulmonary metastatic disease associated with intralesional BCG therapy of intracutaneous melanoma metastases. Cancer 1975; 36:13058.
  • 7
    Kirkwood JM, Ernstoff MS. Interferons in the treatment of human cancer. J Clin Oncol 1984; 2:33652.
  • 8
    Rosenberg SA, Lotze MT, Muul LM et al. Observations on the systemic administration of autologous lymphokine-activated killer cells and recombinant interleukin-2 to patients with metastatic cancer. N Engl J Med 1985; 313:148592.
  • 9
    Rosenberg SA, Mule JJ, Spiess PJ et al. Regression of established pulmonary metastases and subcutaneous tumor mediated by the systemic administration of high-dose recombinant interleukin 2. J Exp Med 1985; 161:116988.
  • 10
    Kirkwood JM, Strawderman MH, Ernstoff MS et al. Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: the Eastern Cooperative Oncology Group Trial EST 1684. J Clin Oncol 1996; 14:717.
  • 11
    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; 17:210516.
  • 12
    Atkins MB, Kunkel L, Sznol M et al. High-dose recombinant interleukin-2 therapy in patients with metastatic melanoma: long-term survival update. Cancer J Sci Am 2000; 6(Suppl. 1):S1114.
  • 13
    Brunet JF, Denizot F, Luciani MF et al. A new member of the immunoglobulin superfamily – CTLA-4. Nature 1987; 328:26770.
  • 14
    Walunas TL, Lenschow DJ, Bakker CY et al. CTLA-4 can function as a negative regulator of T cell activation. Immunity 1994; 1:40513.
  • 15
    Ishida Y, Agata Y, Shibahara K et al. Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. EMBO J 1992; 11:388795.
  • 16
    Freeman GJ, Long AJ, Iwai Y et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med 2000; 192:102734.
  • 17
    Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 2012; 12:25264.
  • 18
    Phan GQ, Yang JC, Sherry RM et al. Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma. Proc Natl Acad Sci USA 2003; 100:83727.
  • 19
    Hodi FS, O'Day SJ, McDermott DF et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010; 363:71123.
  • 20
    Robert C, Thomas L, Bondarenko I et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 2011; 364:251726.
  • 21
    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; 366:245565.
  • 22
    Hamid O, Robert C, Daud A et al. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med 2013; 369:13444.
  • 23
    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; 366:244354.
  • 24
    Hamid O, Sosman J, Lawrence D et al. Clinical activity, safety, and biomarkers of MPDL3280A, an engineered PD-L1 antibody in patients with locally advanced or metastatic melanoma (mM). Presented at the 2013 ASCO Annual Meeting, Chicago. J Clin Oncol 2013; 31 (Suppl.):abstr. 9010.
  • 25
    Davies H, Bignell GR, Cox C et al. Mutations of the BRAF gene in human cancer. Nature 2002; 417:94954.
  • 26
    Van Raamsdonk CD, Bezrookove V, Green G et al. Frequent somatic mutations of GNAQ in uveal melanoma and blue naevi. Nature 2009; 457:599602.
  • 27
    Van Raamsdonk CD, Griewank KG, Crosby MB et al. Mutations in GNA11 in uveal melanoma. N Engl J Med 2010; 363:21919.
  • 28
    Curtin JA, Fridlyand J, Kageshita T et al. Distinct sets of genetic alterations in melanoma. N Engl J Med 2005; 353:213547.
  • 29
    McArthur GA, Young RJ, Sheppard KE et al. Clinical significance of genomic alterations of the CDK4-pathway and sensitivity to the CDK4 inhibitor PD 0332991 in melanoma. Presented at the 2012 ASCO Annual Meeting, Chicago. J Clin Oncol 2012; 30 (Suppl.): abstr. 8520.
  • 30
    Dankort D, Curley DP, Cartlidge RA et al. Braf(V600E) cooperates with Pten loss to induce metastatic melanoma. Nat Genet 2009; 41:54452.
  • 31
    Tsao H, Zhang X, Benoit E et al. Identification of PTEN/MMAC1 alterations in uncultured melanomas and melanoma cell lines. Oncogene 1998; 16:3397402.
  • 32
    Amaravadi RK, Schuchter LM, McDermott DF et al. Phase II trial of temozolomide and sorafenib in advanced melanoma patients with or without brain metastases. Clin Cancer Res 2009; 15:771118.
  • 33
    Eisen T, Ahmad T, Flaherty KT et al. Sorafenib in advanced melanoma: a Phase II randomised discontinuation trial analysis. Br J Cancer 2006; 95:5816.
  • 34
    Flaherty KT, Schiller J, Schuchter LM et al. A phase I trial of the oral, multikinase inhibitor sorafenib in combination with carboplatin and paclitaxel. Clin Cancer Res 2008; 14:483642.
  • 35
    Hauschild A, Agarwala SS, Trefzer U et al. Results of a phase III, randomized, placebo-controlled study of sorafenib in combination with carboplatin and paclitaxel as second-line treatment in patients with unresectable stage III or stage IV melanoma. J Clin Oncol 2009; 27:282330.
  • 36
    Wyman K, Atkins MB, Prieto V et al. Multicenter Phase II trial of high-dose imatinib mesylate in metastatic melanoma: significant toxicity with no clinical efficacy. Cancer 2006; 106:200511.
  • 37
    Carvajal RD, Antonescu CR, Wolchok JD et al. KIT as a therapeutic target in metastatic melanoma. JAMA 2011; 305:232734.
  • 38
    Guo J, Si L, Kong Y 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 2011; 29:29049.
  • 39
    Wilhelm S, Carter C, Lynch M et al. Discovery and development of sorafenib: a multikinase inhibitor for treating cancer. Nat Rev Drug Discov 2006; 5:83544.
  • 40
    Wilhelm SM, Adnane L, Newell P et al. Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine kinase signaling. Mol Cancer Ther 2008; 7:312940.
  • 41
    Flaherty KT, Puzanov I, Kim KB et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med 2010; 363:80919.
  • 42
    Tsai J, Lee JT, Wang W et al. Discovery of a selective inhibitor of oncogenic B-Raf kinase with potent antimelanoma activity. Proc Natl Acad Sci USA 2008; 105:30416.
  • 43
    Chapman PB, Hauschild A, Robert C et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 2011; 364:250716.
  • 44
    Sosman JA, Kim KB, Schuchter L et al. Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. N Engl J Med 2012; 366:70714.
  • 45
    Falchook GS, Long GV, Kurzrock R et al. Dabrafenib in patients with melanoma, untreated brain metastases, and other solid tumours: a phase 1 dose-escalation trial. Lancet 2012; 379:1893901.
  • 46
    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; 380:35865.
  • 47
    Long GV, Trefzer U, Davies MA 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 2012; 13:108795.
  • 48
    Jelinek T, Catling AD, Reuter CW et al. RAS and RAF-1 form a signalling complex with MEK-1 but not MEK-2. Mol Cell Biol 1994; 14:821218.
  • 49
    Delord J, Houede N, Awada A. First-in-human phase I safety, pharmacokinetic (PK), and pharmacodynamic (PD) analysis of the oral MEK-inhibitor AS703026 (two regimens [R]) in patients (pts) with advanced solid tumors. Presented at the 2010 ASCO Annual Meeting, Chicago. J Clin Oncol 2010; 28 (Suppl. 15S):abstr. 2504.
  • 50
    Banerji U, Camidge DR, Verheul HM et al. The first-in-human study of the hydrogen sulfate (Hyd-sulfate) capsule of the MEK1/2 inhibitor AZD6244 (ARRY-142886): a phase I open-label multicenter trial in patients with advanced cancer. Clin Cancer Res 2010; 16:161323.
  • 51
    Adjei AA, Cohen RB, Franklin W et al. Phase I pharmacokinetic and pharmacodynamic study of the oral, small-molecule mitogen-activated protein kinase kinase 1/2 inhibitor AZD6244 (ARRY-142886) in patients with advanced cancers. J Clin Oncol 2008; 26:213946.
  • 52
    Lorusso PM, Adjei AA, Varterasian M et al. Phase I and pharmacodynamic study of the oral MEK inhibitor CI-1040 in patients with advanced malignancies. J Clin Oncol 2005; 23:528193.
  • 53
    Boasberg PD, Redfern CH, Daniels GA et al. Pilot study of PD-0325901 in previously treated patients with advanced melanoma, breast cancer, and colon cancer. Cancer Chemother Pharmacol 2011; 68:54752.
  • 54
    LoRusso PM, Krishnamurthi SS, Rinehart JJ et al. Phase I pharmacokinetic and pharmacodynamic study of the oral MAPK/ERK kinase inhibitor PD-0325901 in patients with advanced cancers. Clin Cancer Res 2010; 16:192437.
  • 55
    Falchook GS, Lewis KD, Infante JR et al. Activity of the oral MEK inhibitor trametinib in patients with advanced melanoma: a phase 1 dose-escalation trial. Lancet Oncol 2012; 13:7829.
  • 56
    Flaherty KT, Robert C, Hersey P et al. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med 2012; 367:10714.
  • 57
    Ascierto PA, Schadendorf D, Berking C et al. MEK162 for patients with advanced melanoma harbouring NRAS or Val600 BRAF mutations: a non-randomised, open-label phase 2 study. Lancet Oncol 2013; 14:24956.
  • 58
    Ascierto PA, Berking C, Agawala SS et al. Efficacy and safety of oral MEK162 in patients with locally advanced and unresectable or metastatic cutaneous melanoma harboring BRAFV600 or NRAS mutations. Presented at the 2012 ASCO Annual Meeting, Chicago. J Clin Oncol 2012; 30 (Suppl.):abstr. 8511.
  • 59
    Hatzivassiliou G, Song K, Yen I et al. RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth. Nature 2010; 464:4315.
  • 60
    Poulikakos PI, Zhang C, Bollag G et al. RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF. Nature 2010; 464:42730.
  • 61
    Su F, Viros A, Milagre C et al. RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors. N Engl J Med 2012; 366:20715.
  • 62
    Ackerman A, McDermott DF, Lawrence DP et al. Outcomes of patients with malignant melanoma treated with immunotherapy prior to or after vemurafenib. Presented at the 2012 ASCO Annual Meeting, Chicago. J Clin Oncol 2012; 30 (Suppl.):abstr. 8569.
  • 63
    Ascierto PA, Simeone E, Giannarelli D et al. Sequencing of BRAF inhibitors and ipilimumab in patients with metastatic melanoma: a possible algorithm for clinical use. J Transl Med 2012; 10:107.
  • 64
    Smith FO, Goff SL, Klapper JA et al. Risk of bowel perforation in patients receiving interleukin-2 after therapy with anti-CTLA 4 monoclonal antibody. J Immunother 2007; 30:130.
  • 65
    Wolchok JD, Kluger H, Callahan MK et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med 2013; 369:12233.
  • 66
    Bollag G, Hirth P, Tsai J et al. Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma. Nature 2010; 467:5969.
  • 67
    Halaban R, Zhang W, Bacchiocchi A et al. PLX4032, a selective BRAF(V600E) kinase inhibitor, activates the ERK pathway and enhances cell migration and proliferation of BRAF melanoma cells. Pigment Cell Melanoma Res 2010; 23:190200.
  • 68
    Johannessen CM, Boehm JS, Kim SY et al. COT drives resistance to RAF inhibition through MAP kinase pathway reactivation. Nature 2010; 468:96872.
  • 69
    Montagut C, Sharma SV, Shioda T et al. Elevated CRAF as a potential mechanism of acquired resistance to BRAF inhibition in melanoma. Cancer Res 2008; 68:485361.
  • 70
    Poulikakos PI, Persaud Y, Janakiraman M et al. RAF inhibitor resistance is mediated by dimerization of aberrantly spliced BRAF(V600E). Nature 2011; 480:38790.
  • 71
    Shi H, Moriceau G, Kong X et al. Melanoma whole-exome sequencing identifies (V600E)B-RAF amplification-mediated acquired B-RAF inhibitor resistance. Nat Commun 2012; 3:724.
  • 72
    Wagle N, Emery C, Berger MF et al. Dissecting therapeutic resistance to RAF inhibition in melanoma by tumor genomic profiling. J Clin Oncol 2011; 29:308596.
  • 73
    Wang H, Daouti S, Li WH et al. Identification of the MEK1(F129L) activating mutation as a potential mechanism of acquired resistance to MEK inhibition in human cancers carrying the B-RafV600E mutation. Cancer Res 2011; 71:553545.
  • 74
    Nathanson KL, Martin A, Letrero R et al. Tumor genetic analyses of patients with metastatic melanoma treated with the BRAF inhibitor GSK2118436 (GSK436). Presented at the 2011 ASCO Annual Meeting, Chicago. J Clin Oncol 2011; 29 (Suppl.):abstr. 8501.
  • 75
    Straussman R, Morikawa T, Shee K et al. Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion. Nature 2012; 487:5004.
  • 76
    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; 18:68395.
  • 77
    Wilson TR, Fridlyand J, Yan Y et al. Widespread potential for growth-factor-driven resistance to anticancer kinase inhibitors. Nature 2012; 487:5059.
  • 78
    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; 31:4829.
  • 79
    Flaherty KT, Infante JR, Daud A et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med 2012; 367:1694703.
  • 80
    Gonzalez R, Ribas A, Daud A et al. Phase IB study of vemurafenib in combination with the MEK inhibitor, GDC-0973, in patients (pts) with unresectable or metastatic BRAFV600 mutated melanoma (BRIM7). Presented at the 37th European Society for Medical Oncology Congress, Vienna, 28 September 2012; abstr. 2744.
  • 81
    Kefford R, Miller WH Jr, Tan DS-W et al. Preliminary results from a phase Ib/II, open-label, dose-escalation study of the oral BRAF inhibitor LGX818 in combination with the oral MEK1/2 inhibitor MEK162 in BRAF V600-dependent advanced solid tumors. Presented at the 2013 ASCO Annual Meeting, Chicago. J Clin Oncol 2013; 31 (Suppl.):abstr. 9029.
  • 82
    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; 19:122531.
  • 83
    Boni A, Cogdill AP, Dang P et al. Selective BRAFV600E inhibition enhances T-cell recognition of melanoma without affecting lymphocyte function. Cancer Res 2010; 70:521319.
  • 84
    Ribas A, Hodi FS, Callahan M et al. Hepatotoxicity with combination of vemurafenib and ipilimumab. N Engl J Med 2013; 368:13656.