Evolving pharmacotherapies for the treatment of metastatic melanoma

Clinical Medicine Insights: Oncology

Volumn 7, Issue , 2013, Pages 137-149

  Salama, April K S ^a  

^a DUKE UNIVERSITY MEDICAL CENTER   (United States)

Author keywords

BRAF; Ipilimumab; KIT; MEK; Metastatic melanoma; PD 1; Therapy

Indexed keywords

B RAF KINASE; B RAF KINASE INHIBITOR; CD134 ANTIGEN; CD137 ANTIGEN; CD40 ANTIGEN; CYTOTOXIC T LYMPHOCYTE ANTIGEN 4; DABRAFENIB; DACARBAZINE; GLYCOPROTEIN GP 100; IMATINIB; IMMUNOMODULATING AGENT; IPILIMUMAB; MITOGEN ACTIVATED PROTEIN KINASE; MITOGEN ACTIVATED PROTEIN KINASE INHIBITOR; MK 3475; NIVOLUMAB; PACLITAXEL; PHOSPHATIDYLINOSITOL 3 KINASE; PHOSPHATIDYLINOSITOL 3,4,5 TRISPHOSPHATE 3 PHOSPHATASE; PLACEBO; PLATELET DERIVED GROWTH FACTOR BETA RECEPTOR; PROGRAMMED DEATH 1 RECEPTOR; PROTEIN KINASE B; SOMATOMEDIN C RECEPTOR; STEM CELL FACTOR RECEPTOR; STEROID; TRAMETINIB; UNCLASSIFIED DRUG; VEMURAFENIB;

ACNEIFORM DERMATITIS; ADVANCED CANCER; ARTHRALGIA; CANCER COMBINATION CHEMOTHERAPY; CANCER IMMUNOTHERAPY; CANCER RESISTANCE; CANCER SURVIVAL; CD4 LYMPHOCYTE COUNT; COLITIS; COLORECTAL CARCINOMA; DERMATITIS; DIARRHEA; DOSE RESPONSE; DRUG BLOOD LEVEL; DRUG DOSE COMPARISON; DRUG DOSE ESCALATION; DRUG ERUPTION; DRUG FATALITY; DRUG FEVER; DRUG HALF LIFE; DRUG MECHANISM; DRUG MEGADOSE; DRUG RESPONSE; DRUG WITHDRAWAL; ENDOCRINE DISEASE; ENZYME INHIBITION; FATIGUE; GASTROINTESTINAL SYMPTOM; HUMAN; HYPERPROLIFERATIVE SKIN LESION; HYPOPHYSITIS; IMMUNOPATHOLOGY; KERATOACANTHOMA; LYMPHOCYTOPENIA; MELANOMA; METASTASIS; METASTATIC MELANOMA; MOLECULARLY TARGETED THERAPY; MONOTHERAPY; MUSCULOSKELETAL DISEASE; NAUSEA; NONHUMAN; PERIPHERAL EDEMA; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PHOTOSENSITIVITY; PRURITUS; RANDOMIZED CONTROLLED TRIAL (TOPIC); REVIEW; SIDE EFFECT; SKIN CARCINOMA; SKIN DISEASE; SOLID TUMOR; SYSTEMIC THERAPY; THYROIDITIS; TOXIC HEPATITIS; UNSPECIFIED SIDE EFFECT;

EID: 84879301507     PISSN: 11795549     EISSN: None     Source Type: Journal    
DOI: 10.4137/CMO.S9565     Document Type: Review

References (107)

1. Atallah E, Flaherty L. Treatment of metastatic malignant melanoma. Curr Treat Options Oncol. 2005;6(3):185-93.
2. Mouawad R, Sebert M, Michels J, Bloch J, Spano J-P, Khayat D. Treatment for metastatic malignant melanoma: Old drugs and new strategies. Crit Rev Oncol Hematol. 2010;74(1):27-39.
3. Middleton MR, Grob JJ, Aaronson N, etal. Randomized phase III study of temozolomide versus dacarbazine in the treatment of patients with advanced metastatic malignant melanoma. J Clin Oncol. 2000;18(1):158-66.
4. Rosenberg SA, Yang JC, Topalian SL, etal. Treatment of 283 consecutive patients with metastatic melanoma or renal cell cancer using high-dose bolus interleukin 2. JAMA. 1994;271(12):907-13.
5. Hodi FS, O'Day SJ, McDermott DF, etal. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363(8):711-23.
6. Davies H, Bignell GR, Cox C, etal. Mutations of the BRAF gene in human cancer. Nature. 2002;417(6892):949-54.
7. Chapman PB, Hauschild A, Robert C, etal. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364(26):2507-16.
8. Hauschild A, Grob JJ, Demidov LV, etal. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2012;380(9839):358-65.
9. Ronan SG, Eng AM, Briele HA, Shioura NN, Das Gupta TK. Thin malignant melanomas with regression and metastases. Arch Dermatol. 1987;123(10): 1326-30.
10. Gromet MA, Epstein WL, Blois MS. The regressing thin malignant melanoma: a distinctive lesion with metastatic potential. Cancer. 1978;42(5): 2282-92.
11. Tefany FJ, Barnetson RS, Halliday GM, McCarthy SW, McCarthy WH. Immunocytochemical analysis of the cellular infiltrate in primary regressing and non-regressing malignant melanoma. J Invest Dermatol. 1991;97(2): 197-202.
12. Cook MG. The significance of inflammation and regression in melanoma. Virchows Arch A Pathol Anat Histopathol. 1992;420(2):113-5.
13. Kalialis LV, Drzewiecki KT, Klyver H. Spontaneous regression of metastases from melanoma: review of the literature. Melanoma Res. 2009;19(5):275-82.
14. Valenzano Menada M, Moioli M, Garaventa A, etal. Spontaneous regression of transplacental metastases from maternal melanoma in a newborn: case report and review of the literature. Melanoma Res. 2010;20(6):443-9.
15. Salama AK, Hodi FS. Cytotoxic T-lymphocyte-associated antigen-4. Clin Cancer Res. 2011;17(14):4622-8.
16. Sharpe AH, Abbas AK. T-cell costimulation-biology, therapeutic potential, and challenges. N Engl J Med. 2006;355(10):973-5.
17. Rudd CE, Taylor A, Schneider H. CD28 and CTLA-4 coreceptor expression and signal transduction. Immunol Rev. 2009;229(1):12-26.
18. Robert C, Thomas L, Bondarenko I, etal. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011;364(26): 2517-26.
19. Fong L, Small EJ. Anti-cytotoxic T-lymphocyte antigen-4 antibody: the first in an emerging class of immunomodulatory antibodies for cancer treatment. J Clin Oncol. 2008;26(32):5275-83.
20. Tchekmedyian S, Glaspy J, Korman A, Keler T, Deo Y, Davis T. MDX-010 (human anti-CTLA4): a phase I trial in malignant melanoma. Proc Am Soc Clin Oncol. 2002;21(Abstract 56):223.
21. O'Day SJ, Maio M, Chiarion-Sileni V, etal. Efficacy and safety of ipilimumab monotherapy in patients with pretreated advanced melanoma: a multicenter single-arm phase II study. Ann Oncol. 2010;21(8):1712-7.
22. Wolchok JD, Neyns B, Linette G, etal. Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study. Lancet Oncol. 2010;11(2):155-64.
23. Boni A, Cogdill AP, Dang P, etal. Selective BRAFV600E inhibition enhances T-cell recognition of melanoma without affecting lymphocyte function. Cancer Res. 2010;70(13):5213-9.
24. Hong DS, Vence L, Falchook G, etal. BRAF(V600) inhibitor GSK2118436 targeted inhibition of mutant BRAF in cancer patients does not impair overall immune competency. Clin Cancer Res. 2012;18(8):2326-35.
25. Wolchok JD, Hoos A, O'Day S, etal. Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res. 2009;15(23):7412-20.
26. Dong H, Zhu G, Tamada K, Chen L. B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion. Nat Med. 1999;5(12):1365-9.
27. Ishida M, Iwai Y, Tanaka Y, etal. Differential expression of PD-L1 and PD-L2, ligands for an inhibitory receptor PD-1, in the cells of lymphohematopoietic tissues. Immunol Lett. 2002;84(1):57-62.
28. Freeman GJ, Long AJ, Iwai Y, etal. 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(7):1027-34.
29. Dong H, Strome SE, Salomao DR, etal. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med. 2002;8(8):793-800.
30. Iwai Y, Ishida M, Tanaka Y, Okazaki T, Honjo T, Minato N. Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. Proc Natl Acad Sci U S A. 2002;99(19): 12293-7.
31. Thompson RH, Kuntz SM, Leibovich BC, etal. Tumor B7-H1 is associated with poor prognosis in renal cell carcinoma patients with long-term follow-up. Cancer Res. 2006;66(7):3381-5.
32. Hamanishi J, Mandai M, Iwasaki M, etal. Programmed cell death 1 ligand 1 and tumor-infiltrating CD8+ T lymphocytes are prognostic factors of human ovarian cancer. Proc Natl Acad Sci U S A. 2007;104(9):3360-5.
33. Brahmer JR, Drake CG, Wollner I, etal. Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol. 2010;28(19):3167-75.
34. Topalian SL, Hodi FS, Brahmer JR, etal. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366(26): 2443-54.
35. Hamid O. Efficacy and Safety of MK-3475in Patients with Advanced Melanoma. Paper presented at The Society for Melanoma Research 2012 Congress; Nov 8-11, 2012; Hollywood, CA.
36. Vonderheide RH, Glennie MJ. Agonistic CD40 antibodies and cancer therapy. Clin Cancer Res. 2013;19(5):1035-43.
37. Eliopoulos AG, Young LS. The role of the CD40 pathway in the pathogenesis and treatment of cancer. Curr Opin Pharmacol. 2004;4(4):360-7.
38. Melero I, Grimaldi AM, Perez-Gracia JL, Ascierto PA. Clinical development of immunostimulatory monoclonal antibodies and opportunities for combination. Clin Cancer Res. 2013;19(5):997-1008.
39. Paterson DJ, Jefferies WA, Green JR, etal. Antigens of activated rat T lymphocytes including a molecule of 50,000 Mr detected only on CD4 positive T blasts. Mol Immunol. 1987;24(12):1281-90.
40. Croft M. Control of immunity by the TNFR-related molecule OX40 (CD134). Annu Rev Immunol. 2010;28:57-78.
41. Mallett S, Fossum S, Barclay AN. Characterization of the MRC OX40 antigen of activated CD4 positive T lymphocytes-a molecule related to nerve growth factor receptor. EMBO J. 1990;9(4):1063-8.
42. Miller RE, Jones J, Le T, etal. 4-1BB-specific monoclonal antibody promotes the generation of tumor-specific immune responses by direct activation of CD8 T cells in a CD40-dependent manner. J Immunol. 2002; 169(4):1792-800.
43. May KF Jr, Chen L, Zheng P, Liu Y. Anti-4-1BB monoclonal antibody enhances rejection of large tumor burden by promoting survival but not clonal expansion of tumor-specific CD8+ T cells. Cancer Res. 2002;62(12): 3459-65.
44. Pollok KE, Kim YJ, Zhou Z, etal. Inducible T cell antigen 4-1BB. Analysis of expression and function. J Immunol. 1993;150(3):771-81.
45. Lin W, Voskens CJ, Zhang X, etal. Fc-dependent expression of CD137 on human NK cells: insights into "agonistic" effects of anti-CD137 monoclonal antibodies. Blood. 2008;112(3):699-707.
46. Sznol M, Hodi FS, Margolin K, McDermott DF, Ernstoff MS, Kirkwood J. Phase I study of BMS-663513, a fully human anti-CD137 agnonist monoclonal antibody, in patients (pts) with advanced cancer (CA). Journal of Clinical Oncology. 26 2008(May 20Suppl; abstr 3007).
47. Melero I, Hirschhorn-Cymerman D, Morales-Kastresana A, Sanmamed MF, Wolchok JD. Agonist antibodies to TNFR molecules that costimulate T and NK cells. Clin Cancer Res. 2013;19(5):1044-53. PMID: 23460535.
48. Curtin JA, Fridlyand J, Kageshita T, etal. Distinct sets of genetic alterations in melanoma. N Engl J Med. 2005;353(20):2135-47.
49. Curtin JA, Busam K, Pinkel D, Bastian BC. Somatic activation of KIT in distinct subtypes of melanoma. J Clin Oncol. 2006;24(26):4340-6.
50. McCubrey JA, Steelman LS, Chappell WH, etal. Roles of the Raf/MEK/ERK pathway in cell growth, malignant transformation and drug resistance. Biochim Biophys Acta. 2007;1773(8):1263-84.
51. Hingorani SR, Jacobetz MA, Robertson GP, Herlyn M, Tuveson DA. Suppression of BRAF(V599E) in human melanoma abrogates transformation. Cancer Res. 2003;63(17):5198-202.
52. Ikenoue T, Hikiba Y, Kanai F, etal. Different effects of point mutations within the B-Raf glycine-rich loop in colorectal tumors on mitogen-activated protein/extracellular signal-regulated kinase kinase/extracellular signal-regulated kinase and nuclear factor κB pathway and cellular transformation. Cancer Res. 2004;64(10):3428-35.
53. Ikenoue T, Kanai F, Hikiba Y, etal. Functional consequences of mutations in a putative Akt phosphorylation motif of B-raf in human cancers. Mol Carcinog. 2005;43(1):59-63.
54. Menzies AM, Haydu LE, Visintin L, etal. Distinguishing clinicopathologic features of patients with V600E and V600K BRAF-mutant metastatic melanoma. Clin Cancer Res. 2012;18(12):3242-9.
55. Pollock PM, Harper UL, Hansen KS, etal. High frequency of BRAF mutations in nevi. Nat Genet. 2003;33(1):19-20.
56. Yazdi AS, Palmedo G, Flaig MJ, etal. Mutations of the BRAF gene in benign and malignant melanocytic lesions. J Invest Dermatol. 2003;121(5): 1160-2.
57. Wan PT, Garnett MJ, Roe SM, etal. Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. Cell. 2004;116(6):855-67.
58. Eisen T, Ahmad T, Flaherty KT, etal. Sorafenib in advanced melanoma: a Phase II randomised discontinuation trial analysis. Br J Cancer. 2006; 95(5):581-6.
59. Min CJ, Liebes LF, Escalon J, etal. Phase II trial of sorafenib (S[BAY 43-9006]) in metastatic melanoma (MM) including detection of BRAF with mutant specific-PCR (MS-PCR) and altered proliferation pathways-final outcome analysis. Journal of Clinical Oncology. 2008;26:(Suppl; abstr 9072).
60. Hauschild A, Agarwala SS, Trefzer U, etal. 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(17):2823-30.
61. Amaravadi RK, Schuchter LM, McDermott DF, etal. Phase II trial of temozolomide and sorafenib in advanced melanoma patients with or without brain metastases. Clin Cancer Res. 2009;15(24):7711-8.
62. Ott PA, Hamilton A, Min C, etal. A phase II trial of sorafenib in metastatic melanoma with tissue correlates. PLoS One. 2010;5(12):e15588.
63. Bollag G, Hirth P, Tsai J, etal. Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma. Nature. 2010; 467(7315):596-9.
64. Flaherty KT, Puzanov I, Kim KB, etal. Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med. 2010;363(9):809-19.
65. Sosman JA, Kim KB, Schuchter L, etal. Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. N Engl J Med. 2012; 366(8):707-14.
66. Chapman PB, Hauschild A, Robert C, etal. 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. Journal of Clinical Oncology. 2012;30(Suppl; abstr 8502).
67. Kefford R, Arkenau H, Brown MP, etal. Phase I/II study of GSK2118436, a selective inhibitor of oncogenic mutant BRAF kinase, in patients with metastatic melanoma and other solid tumors Journal of Clinical Oncology. 2010;28:15s(Suppl; abstr 8503).
68. Trefzer U, Minor D, Ribas A, etal. BREAK-2: a phase IIA trial of the selective BRAF kinase inhibitor GSK2118436in patients with BRAF (V600E/K)-positive metastatic melanoma. Paper presented at: Presented at The Society for Melanoma Research 2011 Congress; Nov 9-13, 2011; Tampa, FL.
69. Su F, Viros A, Milagre C, etal. RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors. N Engl J Med. 2012; 366(3):207-15.
70. Whittaker S, Kirk R, Hayward R, etal. Gatekeeper mutations mediate resistance to BRAF-targeted therapies. Sci Transl Med. 2010;2(35):35-41.
71. Nazarian R, Shi H, Wang Q, etal. Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation. Nature. 2010; 468(7326):973-7.
72. Sosman JA, Pavlick AC, Schuchter LM, etal. Analysis of molecular mechanisms of response and resistance to vemurafenib (vem) in BRAFV600E melanoma. Journal of Clinical Oncology. 2012;30(Suppl; abstr 8503).
73. Emery CM, Vijayendran KG, Zipser MC, etal. MEK1mutations confer resistance to MEK and B-RAF inhibition. Proc Natl Acad Sci U S A. 2009; 106(48):20411-6.
74. Johannessen CM, Boehm JS, Kim SY, etal. COT drives resistance to RAF inhibition through MAP kinase pathway reactivation. Nature. 2010; 468(7326):968-72.
75. Garcia-Echeverria C, Sellers WR. Drug discovery approaches targeting the PI3K/Akt pathway in cancer. Oncogene. 2008;27(41):5511-26.
76. Boisvert-Adamo K, Aplin AE. B-RAF and PI-3 kinase signaling protect melanoma cells from anoikis. Oncogene. 2006;25(35):4848-56.
77. Stahl JM, Sharma A, Cheung M, etal. Deregulated Akt3 activity promotes development of malignant melanoma. Cancer Res. 2004;64(19):7002-10.
78. Paraiso KH, Xiang Y, Rebecca VW, etal. PTEN loss confers BRAF inhibitor resistance to melanoma cells through the suppression of BIM expression. Cancer Res. 2011;71(7):2750-60.
79. Hilmi C, Larribere L, Giuliano S, etal. IGF1 promotes resistance to apoptosis in melanoma cells through an increased expression of BCL2, BCL-X(L), and survivin. J Invest Dermatol. 2008;128(6):1499-505.
80. Villanueva J, Vultur A, Lee JT, etal. 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(6):683-95.
81. Flaherty KT, Robert C, Hersey P, etal. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med. 2012;367(2):107-14.
82. Solit DB, Garraway LA, Pratilas CA, etal. BRAF mutation predicts sensitivity to MEK inhibition. Nature. 2006;439(7074):358-62.
83. Kirkwood JM, Bastholt L, Robert C, etal. Phase II, open-label, randomized trial of the MEK1/2inhibitor selumetinib as monotherapy versus temozolomide in patients with advanced melanoma. Clin Cancer Res. 2012;18(2):555-67.
84. Lorusso PM, Adjei AA, Varterasian M, etal. Phase I and pharmacodynamic study of the oral MEK inhibitor CI-1040in patients with advanced malignancies. J Clin Oncol. 2005;23(23):5281-93.
85. LoRusso PM, Krishnamurthi SS, Rinehart JJ, etal. Phase I pharmacokinetic and pharmacodynamic study of the oral MAPK/ERK kinase inhibitor PD-0325901in patients with advanced cancers. Clin Cancer Res. 2010; 16(6):1924-37.
86. Haura EB, Ricart AD, Larson TG, etal. A phase II study of PD-0325901, an oral MEK inhibitor, in previously treated patients with advanced non-small cell lung cancer. Clin Cancer Res. 2010;16(8):2450-7.
87. Gilmartin AG, Bleam MR, Groy A, etal. GSK1120212 (JTP-74057) is an inhibitor of MEK activity and activation with favorable pharmacokinetic properties for sustained in vivo pathway inhibition. Clin Cancer Res. 2011; 17(5):989-1000.
88. Infante JR, Fecher LA, Falchook GS, etal. Safety, pharmacokinetic, pharmacodynamic, and efficacy data for the oral MEK inhibitor trametinib: a phase 1 dose-escalation trial. Lancet Oncol. 2012;13(8):773-81.
89. Falchook GS, Lewis KD, Infante JR, etal. Activity of the oral MEK inhibitor trametinib in patients with advanced melanoma: a phase 1 dose-escalation trial. Lancet Oncol. 2012.
90. Kim KB, Lewis K, Pavlick AC, etal. A Phase II study of the MEK1/MEK2inhibitor GSK1120212in metastatic BRAF V600E or K mutant cutaneous melanoma patients previously treated with or without a BRAF inhibitor. Pigment Cell & Melanoma Research. 2011;24(5):1021(Abst. LBA 1021-3).
91. Flaherty KT, Infante JR, Daud A, etal. Combined BRAF and MEK inhibition in melanoma with BRAF V600mutations. N Engl J Med. 2012;367(18): 1694-703.
92. Infante JR, Falchook GS, Lawrence DP, etal. Phase I/II study to assess safety, pharmacokinetics, and efficacy of the oral MEK 1/2 inhibitor GSK1120212 (GSK212) dosed in combination with the oral BRAF inhibitor GSK2118436 (GSK436). Journal of Clinical Oncology. 2011:29(Suppl; abstr CRA8503).
93. Beadling C, Jacobson-Dunlop E, Hodi FS, etal. KIT gene mutations and copy number in melanoma subtypes. Clin Cancer Res. 2008;14(21):6821-8.
94. Demetri GD, von Mehren M, Blanke CD, etal. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med. 2002;347(7):472-80.
95. Hou L, Panthier JJ, Arnheiter H. Signaling and transcriptional regulation in the neural crest-derived melanocyte lineage: interactions between KIT and MITF. Development. 2000;127(24):5379-89.
96. Wehrle-Haller B. The role of Kit-ligand in melanocyte development and epidermal homeostasis. Pigment Cell Res. 2003;16(3):287-96.
97. Alexeev V, Yoon K. Distinctive role of the cKit receptor tyrosine kinase signaling in mammalian melanocytes. J Invest Dermatol. 2006;126(5): 1102-1110.
98. Wyman K, Atkins MB, Prieto V, etal. Multicenter Phase II trial of high-dose imatinib mesylate in metastatic melanoma: significant toxicity with no clinical efficacy. Cancer. 2006;106(9):2005-11.
99. Ugurel S, Hildenbrand R, Zimpfer A, etal. Lack of clinical efficacy of imatinib in metastatic melanoma. Br J Cancer. 2005;92(8):1398-405.
100. Kim KB, Eton O, Davis DW, etal. Phase II trial of imatinib mesylate in patients with metastatic melanoma. Brit J Cancer. 2008;99(5):734-40.
101. Hodi FS, Friedlander P, Corless CL, etal. Major response to imatinib mesylate in KIT-mutated melanoma. J Clin Oncol. 2008;26(12):2046-51.
102. Lutzky J, Bauer J, Bastian BC. Dose-dependent, complete response to imatinib of a metastatic mucosal melanoma with a K642E KIT mutation. Pigment Cell Melanoma Res. 2008;21(4):492-3.
103. Antonescu CR, Busam KJ, Francone TD, etal. L576P KIT mutation in anal melanomas correlates with KIT protein expression and is sensitive to specific kinase inhibition. Int J Cancer. 2007;121(2):257-64.
104. Ashida A, Takata M, Murata H, Kido K, Saida T. Pathological activation of KIT in metastatic tumors of acral and mucosal melanomas. Int J Cancer. 2009;124(4):862-8.
105. Jiang X, Zhou J, Yuen NK, etal. Imatinib targeting of KIT-mutant oncoprotein in melanoma. Clin Cancer Res. 2008;14(23):7726-32.
106. Guo J, Si L, Kong Y etal. 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;29:2904-2909.
107. Carvajal RD, Antonescu CR, Wolchok JD, etal. KIT as a therapeutic target in metastatic melanoma. JAMA. 2011;305(22):2327-34.