Targeted therapy and immunotherapy in advanced melanoma: An evolving paradigm

Therapeutic Advances in Medical Oncology

Volumn 5, Issue 2, 2013, Pages 105-118

  Khattak, Muhammad ^a   Fisher, Rosalie ^a   Turajlic, Samra ^b   Larkin, James ^a  

^a INSTITUTE OF CANCER RESEARCH   (United Kingdom)

^b INSTITUTE OF CANCER RESEARCH   (United Kingdom)

Author keywords

BRAF inhibitor; cutaneous; immunotherapy; ipilimumab; melanoma; mutations

Indexed keywords

BEVACIZUMAB; CARBOPLATIN; DABRAFENIB; DACARBAZINE; DASATINIB; ENZASTAURIN; GLYCOPROTEIN GP 100; IMATINIB; INTERLEUKIN 2; IPILIMUMAB; PACLITAXEL; PLACEBO; SELUMETINIB; SORAFENIB; STEM CELL FACTOR RECEPTOR; SUNITINIB; TEMOZOLOMIDE; TICILIMUMAB; TRAMETINIB; VEMURAFENIB;

ALOPECIA; ANTIPROLIFERATIVE ACTIVITY; ARTHRALGIA; BLURRED VISION; CANCER IMMUNOTHERAPY; CARDIOTOXICITY; CHORIORETINOPATHY; CUTANEOUS MELANOMA; DIARRHEA; DISEASE COURSE; DRUG DOSE ESCALATION; DRUG EFFICACY; DRUG WITHDRAWAL; EYE TOXICITY; FATIGUE; FEVER; FOLLOW UP; GENE MUTATION; HEADACHE; HUMAN; HYPERKERATOSIS; INFLAMMATORY INFILTRATE; KERATOACANTHOMA; MELANOMA CELL; METASTATIC MELANOMA; MONOSOMY; MONOTHERAPY; NAUSEA; OVERALL SURVIVAL; PERIPHERAL EDEMA; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PHOTOSENSITIVITY; PRIORITY JOURNAL; PROGRESSION FREE SURVIVAL; RASH; REVIEW; SIGNAL TRANSDUCTION; SKIN CARCINOMA; SKIN PAPILLOMA; SOMATIC MUTATION; SURVIVAL RATE; TUMOR BIOPSY; UVEA MELANOMA; WILD TYPE; WORLD HEALTH ORGANIZATION;

EID: 84877912554     PISSN: 17588340     EISSN: 17588359     Source Type: Journal    
DOI: 10.1177/1758834012466280     Document Type: Review

References (97)

1. Ahmad M. Rees R.C. Ali S.A. (2004) Escape from immunotherapy: possible mechanisms that influence tumor regression/progression. Cancer Immunol Immunother 53: 844–854.
2. Alcala A. Flaherty K. (2012) BRAF inhibitors for the treatment of metastatic melanoma: clinical trials and mechanisms of resistance. Clin Cancer Res 18: 33–39.
3. Alegre M.L. Noel P.J. Eisfelder B.J. Chuang E. Clark M.R. Reiner S.L. et al. (1996) Regulation of surface and intracellular expression of Ctla 4 on Mouse T Cells. J Immunol 157: 4762–4770.
4. Ascierto P. Berking C. Agarwala S. Schadendorf D. van Herpen C. Queirolo P. et al. (2012) Efficacy and safety of oral MEK 162 in patients with locally advanced and unresectable or metastatic cutaneous melanoma harboring BRAFV 600 or NRAS mutations. J Clin Oncol 30: abstract 8511.
5. Atkins M. Kunkel L. Sznol M. Rosenberg S. (2000) High-dose recombinant interleukin-2 therapy in patients with metastatic melanoma: long-term survival update. Cancer J Sci Am 6(Suppl. 1): S11–S14.
6. Atkins M.B. Lotze M.T. Dutcher J.P. Fisher R.I. Weiss G. Margolin K. et al. (1999) 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.
7. Attia P. Phan G. Maker A. Robinson M. Quezado M. Yang J. et al. (2005) Autoimmunity correlates with tumor regression in patients with metastatic melanoma treated with anti-cytotoxic T-lymphocyte antigen-4. J Clin Oncol 23: 6043–6053.
8. Balch C. Gershenwald J. Soong S. Thompson J. Atkins M. Byrd D. et al. (2009) Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol 27: 6199–6206.
9. Bauer J. Kilic E. Vaarwater J. Bastian B.C. Garbe C. de Klein A. (2009) Oncogenic Gnaq mutations are not correlated with disease-free survival in Uveal Melanoma. Br J Cancer 101: 813–815.
10. Brahmer J. Tykodi S. Chow L. Hwu W. Topalian S. Hwu P. et al. (2012) Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 366: 2455–2465.
11. Camacho L. Antonia S. Sosman J. Kirkwood J. Gajewski T. Redman B. et al. (2009) Phase I / II trial of tremelimumab in patients with metastatic melanoma. J Clin Oncol 27: 1075–1081.
12. Carvajal R. Antonescu C. Wolchok J. Chapman P. Roman R. Teitcher J. et al. (2011) KIT as a therapeutic target in metastatic melanoma. JAMA 305: 2327–2334.
13. Chapman P.B. Einhorn L.H. Meyers M.L. Saxman S. Destro A.N. Panageas K.S. et al. (1999) Phase iii multicenter randomized trial of the Dartmouth Regimen Versus Dacarbazine in patients with metastatic Melanoma. J Clin Oncol 17: 2745–2751.
14. Chapman P. Hauschild A. Robert C. Haanen J. Ascierto P. Larkin J. et al. (2011) Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 364: 2507–2516.
15. Chapman P. Hauschild A. Robert C. Larkin J. Haanen J. Ribas A. et al. (2012) Updated overall survival (OS) results for BRIM-3, a phase III randomized, open-label, multicenter trial comparing BRAF inhibitor vemurafenib (vem) with dacarbazine (DTIC) in previously untreated patients with BRAFV600E-mutated melanoma. J Clin Oncol 30: abstract 8502.
16. Cheng S. Chu P. Hinshaw M. Smith K. Maize J. Sferruzza A. (2011) Frequency of mutations associated with targeted therapy in malignant melanoma patients J Clin Oncol 29: abstract 8597.
17. Cipponi A. Wieers G. van Baren N. Coulie P.G. (2011) Tumor-infiltrating lymphocytes: apparently good for Melanoma patients. But why? Cancer Immunol Immunother 60: 1153–1160.
18. Corcoran R. Settleman J. Engelman J. (2011) Potential therapeutic strategies to overcome acquired resistance to BRAF or MEK inhibitors in BRAF mutant cancers. Oncotarget 2: 336–346.
19. Curtin J.A. Busam K. Pinkel D. Bastian B.C. (2006) Somatic activation of kit in distinct subtypes of Melanoma. J Clin Oncol 24: 4340–4346.
20. Curtin J. Fridlyand J. Kageshita T. Patel H. Busam K. Kutzner H. et al. (2005) Distinct sets of genetic alterations in melanoma. N Engl J Med 353: 2135–2147.
21. Davies H. Bignell G. Cox C. Stephens P. Edkins S. Clegg S. et al. (2002) Mutations of the BRAF gene in human cancer. Nature 417: 949–954.
22. Dong H. Strome S.E. Salomao D.R. Tamura H. Hirano F. Flies D.B. et al. (2002) Tumor-associated B7-H1 promotes T-Cell apoptosis: a potential mechanism of immune evasion. Nat Med 8: 793–800.
23. Downey S. Klapper J. Smith F. Yang J. Sherry R. Royal R. et al. (2007) Prognostic factors related to clinical response in patients with metastatic melanoma treated by CTL-associated antigen-4 blockade. Clin Cancer Res 13: 6681–6688.
24. Eggermont A. Kirkwood J. (2004) Re-evaluating the role of dacarbazine in metastatic melanoma: what have we learned in 30 years? Eur J Cancer 40: 1825–1836.
25. Eggermont A. Schadendorf D. (2009) Melanoma and immunotherapy. Hematol Oncol Clin North Am 23: 547–564.
26. Eisen T. Marais R. Affolter A. Lorigan P. Robert C. Corrie P. et al. (2011) Sorafenib and dacarbazine as first-line therapy for advanced melanoma: phase I and open-label phase II studies. Br J Cancer 105: 353–359.
27. Emery C.M. Vijayendran K.G. Zipser M.C. Sawyer A.M. Niu L. Kim J.J. et al. (2009) Mek 1 mutations confer resistance to Mek and B-Raf inhibition. Proc Natl Acad Sci U S A 106: 20411–20416.
28. Flaherty K. Puzanov I. Kim K. Ribas A. McArthur G. Sosman J. et al. (2010) Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med 363: 809–819.
29. Flaherty K. Robert C. Hersey P. Nathan P. Garbe C. Milhem M. et al. (2012) Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med 367: 107–114.
30. Freeman G.J. Long A.J. Iwai Y. Bourque K. Chernova T. Nishimura H. et al. (2000) Engagement of the Pd-1 immunoinhibitory receptor by a Novel B 7 family member leads to negative regulation of lymphocyte activation. J Exp Med 192: 1027–1034.
31. Garnett M. Marais R. (2004) Guilty as charged: B-RAF is a human oncogene. Cancer Cell 6: 313–319.
32. Gilmartin A. Bleam M. Groy A. Moss K. Minthorn E. Kulkarni S. et al. (2011) GSK 1120212 (JTP-74057) is an inhibitor of MEK activity and activation with favorable pharmacokinetic properties for sustained in vivo pathway inhibition. Clin Cancer Res 17: 989–1000.
33. Goel V. Lazar A. Warneke C. Redston M. Haluska F. (2006) Examination of mutations in BRAF, NRAS, and PTEN in primary cutaneous melanoma. J Invest Dermatol 126: 154–160.
34. Gopal Y.N. Deng W. Woodman S.E. Komurov K. Ram P. Smith P.D. et al. (2010) Basal and treatment-induced activation of Akt mediates resistance to cell death by Azd 6244 (Arry-142886) in Braf-Mutant human Cutaneous Melanoma cells. Cancer Res 70: 8736–8747.
35. Gowrishankar K. Snoyman S. Pupo G. Becker T. Kefford R. Rizos H. (2012) Acquired resistance to BRAF inhibition can confer cross-resistance to combined BRAF / MEK inhibition. J Invest Dermatol 132: 1850–1859.
36. Guo J. Si L. Kong Y. Flaherty K. Xu X. Zhu Y. et al. (2011) 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.
37. Hadrup S.R. Bakker A.H. Shu C.J. Andersen R.S. van Veluw J. Hombrink P. et al. (2009) Parallel detection of antigen-specific T-Cell responses by multidimensional encoding of Mhc multimers. Nat Methods 6: 520–526.
38. Harbour J. Onken M. Roberson E. Duan S. Cao L. Worley L. et al. (2010) Frequent mutation of BAP 1 in metastasizing uveal melanomas. Science 330: 1410–1413.
39. Harris N.L. Ronchese F. (1999) The role of B 7 costimulation in T-Cell immunity. Immunol Cell Biol 77: 304–311.
40. Hauschild A. Agarwala S. Trefzer U. Hogg D. Robert C. Hersey P. et al. (2009) 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 27: 2823–2830.
41. Hauschild A. Grob J. Demidov L. Jouary T. Gutzmer R. Millward M. et al. (2012) Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet 380: 358–365.
42. Hirano F. Kaneko K. Tamura H. Dong H. Wang S. Ichikawa M. et al. (2005) Blockade of B7-H1 and Pd-1 by monoclonal antibodies potentiates cancer therapeutic immunity. Cancer Res 65: 1089–1096.
43. Hocker T. Singh M. Tsao H. (2008) Melanoma genetics and therapeutic approaches in the 21st century: moving from the benchside to the bedside. J Invest Dermatol 128: 2575–2595.
44. Hodi F. Friedlander M. Atkins M. McDermott D. Lawrence D. Ibrahim N. et al. (2011) A phase I trial of ipilimumab plus bevacizumab in patients with unresectable stage III or stage IV melanoma. J Clin Oncol 29: abstract 8511.
45. Hodi F. O'Day S. McDermott D. Weber R. Sosman J. Haanen J. et al. (2010) Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363: 711–723.
46. Hunder N.N. Wallen H. Cao J. Hendricks D.W. Reilly J.Z. Rodmyre R. et al. (2008) Treatment of metastatic Melanoma with autologous Cd4+ T Cells against Ny-Eso-1. N Engl J Med 358: 2698–2703.
47. Jakob J. Bassett R. Ng C. Lazar A. Alvarado G. Rohlfs M. (2011) Clinical characteristics and outcomes associated with BRAF and NRAS mutations in metastatic melanoma. J Clin Oncol 29: abstract 8500.
48. Jiang X. Zhou J. Yuen N.K. Corless C.L. Heinrich M.C. Fletcher J.A. et al. (2008) Imatinib targeting of Kit-Mutant Oncoprotein in Melanoma. Clin Cancer Res 14: 7726–7732.
49. Johannessen C.M. Boehm J.S. Kim S.Y. Thomas S.R. Wardwell L. Johnson L.A. et al. (2010) Cot drives resistance to Raf inhibition through map kinase pathway reactivation. Nature 468: 968–972.
50. Kalialis L. Drzewiecki K. Klyver H. (2009) Spontaneous regression of metastases from melanoma: review of the literature. Melanoma Res 19: 275–282.
51. Kefford R. Arkenau H. Brown M. Millward M. Infante J. Long G. et al. (2010) Phase I / II study of GSK2118436, a selective inhibitor of oncogenic mutant BRAF kinase, in patients with metastatic melanoma and other solid tumors. J Clin Oncol 28(15 Suppl.): abstract 8503.
52. Kim K.B. Eton O. Davis D.W. Frazier M.L. Mcconkey D.J. Diwan A.H. et al. (2008) Phase ii trial of Imatinib Mesylate in patients with metastatic Melanoma. Br J Cancer 99: 734–740.
53. Kirkwood J. Bastholt L. Robert C. Sosman J. Larkin J. Hersey P. et al. (2012) Phase II, open-label, randomized trial of the MEK1/2 inhibitor selumetinib as monotherapy versus temozolomide in patients with advanced melanoma. Clin Cancer Res 18: 555–567.
54. Kluger H.M. Dudek A.Z. Mccann C. Ritacco J. Southard N. Jilaveanu L.B. et al. (2011) A phase 2 trial of Dasatinib in advanced Melanoma. Cancer 117: 2202–2208.
55. Koivunen J. Aaltonen V. Peltonen J. (2006) Protein kinase C (PKC) family in cancer progression. Cancer Lett 235: 1–10.
56. Kong Y. Si L. Zhu Y. Xu X. Corless C. Flaherty K. et al. (2011) Large-scale analysis of KIT aberrations in Chinese patients with melanoma. Clin Cancer Res 17: 1684–1691.
57. Krasagakis K. Tholke D. Farthmann B. Eberle J. Mansmann U. Orfanos C. (1998) Elevated plasma levels of transforming growth factor (TGF)-beta1 and TGF-beta2 in patients with disseminated malignant melanoma. Br J Cancer 77: 1492–1494.
58. Lee J. Choi J. Kim Y. (2011) Frequencies of BRAF and NRAS mutations are different in histological types and sites of origin of cutaneous melanoma: a meta-analysis. Br J Dermatol 164: 776–784.
59. Lee P.P. Yee C. Savage P.A. Fong L. Brockstedt D. Weber J.S. et al. (1999) Characterization of circulating T Cells specific for tumor-associated antigens in Melanoma patients. Nat Med 5: 677–685.
60. Long G. Menzies A. Nagrial A. Haydu L. Hamilton A. Mann G. et al. (2011) Prognostic and clinicopathologic associations of oncogenic BRAF in metastatic melanoma. J Clin Oncol 29: 1239–1246.
61. Maldonado J. Fridlyand J. Patel H. Jain A. Busam K. Kageshita T. et al. (2003) Determinants of BRAF mutations in primary melanomas. J Natl Cancer Inst 95: 1878–1890.
62. Marshall M. Ribas A. Huang B. (2010) Evaluation of baseline serum C-reactive protein (CRP) and benefit from tremelimumab compared to chemotherapy in first-line melanoma. J Clin Oncol 28: abstract 2609.
63. McDermott D. Sosman J. Gonzalez R. Hodi F. Linette G. Richards J. et al. (2008) Double-blind randomized phase II study of the combination of sorafenib and dacarbazine in patients with advanced melanoma: a report from the 11715 Study Group. J Clin Oncol 26: 2178–2185.
64. Melero I. Hervas-Stubbs S. Glennie M. Pardoll D.M. Chen L. (2007) Immunostimulatory monoclonal antibodies for cancer therapy. Nat Rev Cancer 7: 95–106.
65. Minor D. Kashani-Sabet M. Garrido M. O'Day S. Hamid O. Bastian B. (2012) Sunitinib therapy for melanoma patients with KIT mutations. Clin Cancer Res 18: 1457–1463.
66. Nazarian R. Shi H. Wang Q. Kong X. Koya R. Lee H. et al. (2010) Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation. Nature 468: 973–977.
67. Njauw C. Kim I. Piris A. Gabree M. Taylor M. Lane A. et al. (2012) Germline BAP 1 inactivation is preferentially associated with metastatic ocular melanoma and cutaneous-ocular melanoma families. PloS ONE 7: e35295.
68. Onken M.D. Worley L.A. Long M.D. Duan S. Council M.L. Bowcock A.M. et al. (2008) Oncogenic mutations in Gnaq occur early in Uveal Melanoma. Invest Ophthalmol Vis Sci 49: 5230-5234.
69. Paraiso K.H. Fedorenko I.V. Cantini L.P. Munko A.C. Hall M. Sondak V.K. et al. (2010) Recovery of Phospho-Erk activity allows Melanoma cells to escape from Braf inhibitor therapy. Br J Cancer 102: 1724-1730.
70. Patel S. Bedikian A. Papadopoulos N. Hwu W. Kim K. Homsi J. et al. (2011) Ipilimumab plus temozolomide in metastatic melanoma. J Clin Oncol 29: abstract 8579.
71. Poulikakos P.I. Persaud Y. Janakiraman M. Kong X. Ng C. Moriceau G. et al. (2011) Raf inhibitor resistance is mediated by dimerization of aberrantly spliced Braf(V600e). Nature 480: 387–390.
72. Prescher G. Bornfeld N. Hirche H. Horsthemke B. Jockel K. Becher R. (1996) Prognostic implications of monosomy 3 in uveal melanoma. Lancet 347: 1222–1225.
73. Prieto P. Yang J. Sherry R. Hughes M. Kammula U. White D. et al. (2010) Cytotoxic T lymphocyte-associated antigen 4 blockage with ipilimumab: long-term follow-up of 179 patients with metastatic melanoma. J Clin Oncol 28(15 Suppl.): abstract 8544.
74. Ribas A. Hauschild A. Kefford R. Punt C. Haanen J. Marmol M. et al. (2008) Phase III, open-label, randomized, comparative study of tremelimumab (CP-675,206) and chemotherapy (temozolomide or dacarbazine) in patients with advanced melanoma. J Clin Oncol 26: abstract LBA9011.
75. Robert C. Thomas L. Bondarenko I. O'Day S. Weber J. Garbe C. et al. (2011) Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 364: 2517–2526.
76. Rosenberg S.A. Yang J.C. Sherry R.M. Kammula US Hughes M.S. Phan G.Q. et al. (2011) Durable complete responses in heavily pretreated patients with metastatic Melanoma using T-Cell transfer immunotherapy. Clin Cancer Res 17: 4550–4557.
77. Rosenberg S.A. Yang J.C. Topalian S.L. Schwartzentruber D.J. Weber J.S. Parkinson D.R. et al. (1994) Treatment of 283 consecutive patients with metastatic Melanoma or renal cell cancer using high-dose bolus interleukin 2. JAMA 271: 907–913.
78. Shao Y. Aplin A.E. (2010) Akt3-mediated resistance to apoptosis in B-Raf-targeted Melanoma cells. Cancer Res 70: 6670–6681.
79. Sharfman W. Hodi S. Lawrence D. Flaherty K. Amaravadi R. Kim K. et al. (2011) Results from the first-in-human (FIH) phase I study of the oral RAF inhibitor RAF 265 administered daily to patients with advanced cutaneous melanoma. J Clin Oncol 29: abstract 8508.
80. Shi H. Moriceau G. Kong X. Koya R.C. Nazarian R. Pupo G.M. et al. (2012) Preexisting Mek 1 Exon 3 mutations in V600e/Kbraf Melanomas do not confer resistance to Braf inhibitors. Cancer Discov 2: 414–424.
81. Siegel R. Naishadham D. Jemal A. (2012) Cancer statistics, 2012. CA Cancer J Clin 62: 10–29.
82. Solit D. Rosen N. (2011) Resistance to BRAF inhibition in melanomas. N Engl J Med 364: 772–774.
83. Sosman J. Kim K. Schuchter L. Gonzalez R. Pavlick A. Weber J. et al. (2012) Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. N Engl J Med 366: 707–714.
84. Topalian S. Hodi F. Brahmer J. Gettinger S. Smith D. McDermott D. et al. (2012) Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 366: 2443–2454.
85. Ugurel S. Hildenbrand R. Zimpfer A. La Rosee P. Paschka P. Sucker A. et al. (2005) Lack of clinical efficacy of Imatinib in metastatic Melanoma. Br J Cancer 92: 1398–1405.
86. van Raamsdonk C. Bezrookove V. Green G. Bauer J. Gaugler L. O'Brien J. et al. (2009) Frequent somatic mutations of GNAQ in uveal melanoma and blue naevi. Nature 457: 599–602.
87. van Raamsdonk C.D. Griewank K.G. Crosby M.B. Garrido M.C. Vemula S. Wiesner T. et al. (2010) Mutations in Gna 11 in Uveal Melanoma. N Engl J Med 363: 2191–2199.
88. Villanueva J. Vultur A. Lee J.T. Somasundaram R. Fukunaga-Kalabis M. Cipolla A.K. et al. (2010) 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 18: 683–695.
89. Wagle N. Emery C. Berger M.F. Davis M.J. Sawyer A. Pochanard P. et al. (2011) Dissecting therapeutic resistance to Raf inhibition in Melanoma by tumor genomic profiling. J Clin Oncol 29: 3085–3096.
90. Weber J. Flaherty K. Infante J. Falchook G. Kefford R. Daud A. et al. (2012) Updated safety and efficacy results from a phase I / II study of the oral BRAF inhibitor dabrafenib (GSK2118436) combined with the oral MEK 1 / 2 inhibitor trametinib (GSK1120212) in patients with BRAFi-naive metastatic melanoma. J Clin Oncol 30: abstract 8510.
91. Whittaker S. Kirk R. Hayward R. Zambon A. Viros A. Cantarino N. et al. (2010) Gatekeeper mutations mediate resistance to Braf-targeted therapies. Sci Transl Med 2: 35ra41.
92. Wolchok J.D. Hoos A. O'day S. Weber J.S. Hamid O. Lebbe C. et al. (2009) Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res 15: 7412–7420.
93. Wolchok J.D. Neyns B. Linette G. Negrier S. Lutzky J. Thomas L. et al. (2010) Ipilimumab monotherapy in patients with pretreated advanced Melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study. Lancet Oncol 11: 155–164.
94. Wong C.W. Fan Y.S. Chan T.L. Chan A.S. Ho L.C. Ma T.K. et al. (2005) Braf and Nras mutations are uncommon in Melanomas arising in diverse internal organs. J Clin Pathol 58: 640–644.
95. Wu X. Zhu M. Fletcher J. Giobbie-Hurder A. Hodi F. (2012) The protein kinase C inhibitor enzastaurin exhibits antitumor activity against uveal melanoma. PloS ONE 7: e29622.
96. Wyman K. Atkins M.B. Prieto V. Eton O. Mcdermott D.F. Hubbard F. et al. (2006) Multicenter phase ii trial of high-dose Imatinib mesylate in metastatic Melanoma: significant toxicity with no clinical efficacy. Cancer 106: 2005–2011.
97. Yeh T. Marsh V. Bernat B. Ballard J. Colwell H. Evans R. et al. (2007) Biological characterization of ARRY-142886 (AZD6244), a potent, highly selective mitogen-activated protein kinase kinase 1 / 2 inhibitor. Clin Cancer Res 13: 1576–1583.