晚期恶性黑色素瘤的新药治疗进展_West China Medical Journal

Authors：

 吴达军 ^1,2 ,  许峰 ¹

1. ;
2. ;

Corresponding author：

许峰, Email: fengxuster@gmail.com

Keywords：

恶性黑色素瘤; 晚期; 靶向治疗; 免疫治疗; 疗效

DOI：

10.7507/1002-0179.201600570

Video：

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Abstract Full text Figures/Tables Video References Cited by

恶性黑色素瘤是起源于神经嵴黑色素细胞的高度恶性肿瘤。近10年来，恶性黑色素瘤发病率日益增加。世界卫生组织报道全球每年新发皮肤恶性黑色素瘤大约13.2万例，而我国每年新发病例已超过1万例。恶性黑色素瘤易于远处转移和扩散，而晚期患者的治疗手段有限，预后极差。近年来，恶性黑色素瘤相关的研究进展迅速，已经发现遗传和免疫因素与恶性黑色素瘤的发生、发展密切相关，这为恶性黑色素瘤的靶向和免疫治疗奠定了基础。不断的新药临床研究取得了重要临床成果。该文就此进行了综述。

Citation： 吴达军, 许峰. 晚期恶性黑色素瘤的新药治疗进展. West China Medical Journal, 2016, 31(12): 2079-2083. doi: 10.7507/1002-0179.201600570 Copy

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2.	WHO.Ultraviolet Radiation and the INTERSUN Programme[EB/OL].http://www.who.int/uv/intersunprogramme/en/.
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4.	李燕雏, 郑雪梅, 李平.沙利度胺联合三苯氧胺治疗Ⅳb期牙龈恶性黑色素瘤一例[J].华西医学, 2015, 30(10):1808-1809.
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6.	Ji ZY, Flaherty KT, Tsao H.Targeting the RAS pathway in melanoma[J].Trends Mol Med, 2012, 18(1):27-35.
7.	陈鹏亮, 郭进明, 赖文杰, 等.细胞程序性坏死的研究进展[J].华西医学, 2016, 31(8):1447-1452.
8.	Shah DJ, Dronca RS.Latest advances in chemotherapeutic, targeted, and immune approaches in the treatment of metastatic melanoma[J].Mayo Clin Proc, 2014, 89(4):504-519.
9.	Arkenau HT, Kefford R, Long GV.Targeting BRAF for patients with melanoma[J].Br J Cancer, 2011, 104(3):392-398.
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11.	Ascierto PA, Kirkwood JM, Grob J, et al.The role of BRAFV600 mutation in melanoma[J].J Transl Med, 2012, 10:85.
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18.	Hauschild A, Grob J, Demidov LV, et al.Dabrafenib in BRAF-mutated metastatic melanoma:a multicentre, openlabel, phase 3 randomised controlled trial[J].Lancet, 2012, 380(9839):358-365.
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21.	Lemech C, Infante J, Arkenau HT.Combination molecularly targeted drug therapy in metastatic melanoma:progress to date[J].Drugs, 2013, 73(8):767-777.
22.	Flaherty KT, Robert C, Hersey P, et al.Improved survival with MEK inhibition in BRAF-mutated melanoma[J].N Engl J Med, 2012, 367(2):107-114.
23.	Wright CJ, Mccormack PL.Trametinib:first global approval[J].Drugs, 2013, 73(11):1245-1254.
24.	Kirkwood JM, Bastholt L, Robert C, et al.Phase Ⅱ, openlabel, randomized trial of the MEK1/2 inhibitor selumetinib as monotherapy versus temozolomide in patients with advanced melanoma[J].Clin Cancer Res, 2012, 18(2):555-567.
25.	Robert C, Dummer R, Gutzmer R, et al.Selumetinib plus dacarbazine versus placebo plus dacarbazine as first-line treatment for BRAF-mutant metastatic melanoma:a phase 2 doubleblind randomised study[J].Lancet Oncol, 2013, 14(8):733-740.
26.	Larkin J, Ascierto PA, Dréno B, et al.Combined vemurafenib and cobimetinib in BRAF-mutated melanoma[J].N Engl J Med, 2014, 371(20):1867-1876.
27.	Ascierto PA, Schadendorf D, Berking CA, et al.MEK162 for patients with advanced melanoma harbouring NRAS or Val600 BRAF mutations:a non-randomised, open-label phase 2 study[J].Lancet Oncol, 2013, 14(3):249-256.
28.	Guo J, Si L, Kong Y, et al.Phase Ⅱ, open-label, single-arm trial of imatinibmesylate in patients withmetastaticmelanoma harboring c-Kit mutation or amplification[J].J Clin Oncol, 2011, 29(21):2904-2909.
29.	Curtin JA, Busam K, Pinkel D, et al.Somatic activation of KIT in distinct subtypes of melanoma[J].J Clin Oncol, 2006, 24(26):4340-4346.
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31.	US Food and Drug Administration.Trametinib and dabrafenib[EB/OL].(2014-08-20)[2016-01-01].http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm381451.htm.
32.	Glaxo SK.Dabrafenib plus trametinib vs vemurafenib alone in unresectable or metastatic BRAFV600E/K cutaneous melanoma (COMBI-v).Clinical Trials.Gov:NCT01597908.https://www.clinicaltrials.gov/show/NCT01597908.
33.	Sullivan RJ, Flaherty KT.Resistance to BRAF-targeted therapy in melanoma[J].Eur J Cancer, 2013, 49(6):1297-1304.
34.	Menzies AM, Long GV.Recent advances in melanoma systemic therapy.BRAF inhibitors, CTLA4 antibodies and beyond[J].Eur J Cancer, 2013, 49(15):3229-3241.
35.	Topalian SL, Drake CG, Pardoll DM.Targeting the PD-1/B7-H1(PD-L1) pathway to activate anti-tumor immunity[J].Curr Opin Immunol, 2012, 24(2):207-212.
36.	Ribas A.Tumor immunotherapy directed at PD-1[J].N Engl J Med, 2012, 366(26):2517-2519.
37.	Hodi FS, O'day SJ, Mcdermott DF, et al.Improved survival with ipilimumab in patients with metastatic melanoma[J].N Engl J Med, 2010, 363(8):711-723.
38.	Robert C, Thomas L, Bondarenko I, et al.Ipilimumab plus dacarbazine for previously untreated metastatic melanoma[J].N Engl J Med, 2011, 364(26):2517-2526.
39.	Hodi FS, Lee S, Mcdermott DF, et al.Ipilimumab plus sargramostim vs ipilimumab alone for treatment of metastatic melanoma a randomized clinical trial[J].JAMA, 2014, 312(17):1744-1753.
40.	Margolin K, Ernstoff MS, Hamid O, et al.Ipilimumab in patients with melanoma and brain metastases:an open-label, phase 2 trial[J].Lancet Oncol, 2012, 13(5):459-465.
41.	Ribas A, Hodi FS, Callahan M, et al.Hepatotoxicity with combination of vemurafenib and ipilimumab[J].N Engl J Med, 2013, 368(14):1365-1366.
42.	Camacho LH, Antonia S, Sosman J, et al.PhaseⅠ/Ⅱ trial of tremelimumab in patients with metastatic melanoma[J].J Clin Oncol, 2009, 27(7):1075-1081.
43.	Ribas A, Kefford R, Marshall MA, et al.Phase Ⅲ randomized clinical trial comparing tremelimumab with Standard-of-Care chemotherapy in patients with advanced melanoma[J].J Clin Oncol, 2013, 31(5):616-622.
44.	Robert C, Long GV, Brady B, et al.Nivolumab in previously untreated melanoma without BRAF mutation[J].N Engl J Med, 2015, 372(4):320-330.
45.	US Food and Drug Administration.FDA approves opdivo for advanced melanoma[EB/OL].(2014-12-24)[2016-01-01].http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm427716.htm.
46.	Wolchok JD, Kluger H, Callahan MK, et al.Nivolumab plus ipilimumab in advanced melanoma[J].N Engl J Med, 2013, 369(2):122-133.
47.	Chapman PB.D'angelo SP, Wolchok JD.Rapid eradication of a bulky melanoma mass with one dose of immunotherapy[J].N Engl J Med, 2015, 372(21):2073-2074.
48.	Hamid O, Robert C, Daud A, et al.Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma[J].N Engl J Med, 2013, 369(2):134-144.
49.	Bagcchi S.Pembrolizumab for treatment of refractory melanoma[J].Lancet Oncol, 2014, 15(10):E419.
50.	Pazdur R.Drug administration pembrolizumab[EB/OL].FDA, 2014:1-8.www.accessdata.fda.gov/drugsatfda_docs/appletter/2014/125514Orig1s000ltr.pdf..
51.	Robert C, Schachter J, Long GV, et al.Pembrolizumab versus ipilimumab in advanced melanoma[J].N Engl J Med, 2015, 372(26):2521-2532.
52.	Atkins MB, Kudchadkar RR, Sznol M, et al.Phase 2, multicenter, safety and efficacy study of pidilizumab in patients with metastatic melanoma[J].J Clin Oncol, 2014, 32(Suppl 5):9001a.
53.	Nishino M, Sholl LM, Hodi FS.Anti-PD-1-Related pneumonitis during cancer immunotherapy[J].N Engl J Med, 2015, 373(3):288-290.
54.	Hamid O, SosmanJA, Lawrence DP, et al.Clinical activity, safety, and biomarkers of MPDL3280A, an engineered PDL1 antibody in patients with locally advanced or metastatic melanoma[J].J Clin Oncol, 2013, 31(Suppl 15):9010a.
55.	Brahmer JR, Tykodi SS, Chow LQ, et al.Safety and activity of anti-PD-L1 antibody in patients with advanced cancer[J].N Engl J Med, 2012, 366(26):2455-2465.
56.	MedImmune LLC.A phase 1/2 study to evaluate MEDI4736[EB/OL].2015:NCT01693562.https://www.clinicaltrials.gov/ct2/show/NCT01693562.
57.	Heery CR, O'Sullivan Coyne GH, Madan RA, et al.Phase Ⅰ open-label, multiple ascending dose trial ofMSB0010718C, an anti-PD-L1 monoclonal antibody, in advanced solid malignancies[J].J Clin Oncol, 2014, 32(Suppl 5):3064a.
58.	Infante JR, Powderly JD, Burris HA, et al.Clinical and pharmacodynamic (PD) results of a phase Ⅰ trial with AMP-224(B7-DC Fc) that binds to the PD-1 receptor[J].J Clin Oncol, 2013, 31(Suppl):3044a.

1. Desantis CE, Lin CC, Mariotto AB, et al.Cancer treatment and survivorship statistics, 2014[J].CA Cancer J Clin, 2014, 64(4):252-271.
2. WHO.Ultraviolet Radiation and the INTERSUN Programme[EB/OL].http://www.who.int/uv/intersunprogramme/en/.
3. Agarwala SS.Novel immunotherapies as potential therapeutic partners for traditional or targeted agents:cytotoxic T-lymphocyte antigen-4 blockade in advanced melanoma[J].Melanoma Res, 2010, 20(1):1-10.
4. 李燕雏, 郑雪梅, 李平.沙利度胺联合三苯氧胺治疗Ⅳb期牙龈恶性黑色素瘤一例[J].华西医学, 2015, 30(10):1808-1809.
5. Sullivan RJ, Flaherty KT.BRAF in melanoma:pathogenesis, diagnosis, inhibition, and resistance[J].J Skin Cancer, 2011:423239.
6. Ji ZY, Flaherty KT, Tsao H.Targeting the RAS pathway in melanoma[J].Trends Mol Med, 2012, 18(1):27-35.
7. 陈鹏亮, 郭进明, 赖文杰, 等.细胞程序性坏死的研究进展[J].华西医学, 2016, 31(8):1447-1452.
8. Shah DJ, Dronca RS.Latest advances in chemotherapeutic, targeted, and immune approaches in the treatment of metastatic melanoma[J].Mayo Clin Proc, 2014, 89(4):504-519.
9. Arkenau HT, Kefford R, Long GV.Targeting BRAF for patients with melanoma[J].Br J Cancer, 2011, 104(3):392-398.
10. Inumaru J, Gordo K, Fraga Junior AC, et al.Analysis of the BRAF V600E mutation in primary cutaneous melanoma[J].Genet Mol Res, 2014, 13(2):2840-2848.
11. Ascierto PA, Kirkwood JM, Grob J, et al.The role of BRAFV600 mutation in melanoma[J].J Transl Med, 2012, 10:85.
12. Glud M, Gniadecki R.MicroRNAs in the pathogenesis of malignant melanoma[J].J Eur Acad Dermatol Venereol, 2013, 27(2):142-150.
13. Flaherty KT, Puzanov I, Kim KB, et al.Inhibition of mutated, activated BRAF in metastatic melanoma[J].N Engl J Med, 2010, 363(9):809-819.
14. Sosman JA, Kim KB, Schuchter L, et al.Survival in BRAFV600-mutant advanced melanoma treated with vemurafenib[J].N Engl J Med, 2012, 366(8):707-714.
15. Mcarthur GA, Chapman PB, Robert C, 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[J].Lancet Oncol, 2014, 15(3):323-332.
16. Swaika A, Crozier JA, Joseph RW.Vemurafenib:an evidence-based review of its clinical utility in the treatment of metastatic melanoma[J].Drug Des Devel Ther, 2014, 8:775-787.
17. Ascierto PA, Minor D, Ribas A, et al.Phase Ⅱ trial (BREAK-2) of the BRAF inhibitor dabrafenib (GSK2118436) in patients with metastatic melanoma[J].J Clin Oncol, 2013, 31(26):3205.
18. Hauschild A, Grob J, Demidov LV, et al.Dabrafenib in BRAF-mutated metastatic melanoma:a multicentre, openlabel, phase 3 randomised controlled trial[J].Lancet, 2012, 380(9839):358-365.
19. Long GV, Trefzer U, Davies MA, et al.Dabrafenib in patientswithVal600Glu orVal600Lys BRAF-mutantmelanoma metastatic to the brain (BREAK-MB):amulticentre, open-label, phase 2 trial[J].Lancet Oncol, 2012, 13(11):1087-1095.
20. GlaxoSmithKline.Two new GSK oral oncology treatments, BRAF-inhibitor Tafinlar^®(dabrafenib) capsules and the first MEK-inhibitor Mekinist^TM(trametinib) tablets, approved by FDA as single-agent therapies[EB/OL].(2013-05-29)[2016-01-01].https://us.gsk.com/en-us/media/press-releases/2013/two-new-gsk-oral-oncology-treatments-braf-inhibitor-tafinlardabrafenib-capsules-and-the-first-mek-inhibitor-mekinist-trametinib-tablets-approved-by-fda-as-single-agent-therapies/.
21. Lemech C, Infante J, Arkenau HT.Combination molecularly targeted drug therapy in metastatic melanoma:progress to date[J].Drugs, 2013, 73(8):767-777.
22. Flaherty KT, Robert C, Hersey P, et al.Improved survival with MEK inhibition in BRAF-mutated melanoma[J].N Engl J Med, 2012, 367(2):107-114.
23. Wright CJ, Mccormack PL.Trametinib:first global approval[J].Drugs, 2013, 73(11):1245-1254.
24. Kirkwood JM, Bastholt L, Robert C, et al.Phase Ⅱ, openlabel, randomized trial of the MEK1/2 inhibitor selumetinib as monotherapy versus temozolomide in patients with advanced melanoma[J].Clin Cancer Res, 2012, 18(2):555-567.
25. Robert C, Dummer R, Gutzmer R, et al.Selumetinib plus dacarbazine versus placebo plus dacarbazine as first-line treatment for BRAF-mutant metastatic melanoma:a phase 2 doubleblind randomised study[J].Lancet Oncol, 2013, 14(8):733-740.
26. Larkin J, Ascierto PA, Dréno B, et al.Combined vemurafenib and cobimetinib in BRAF-mutated melanoma[J].N Engl J Med, 2014, 371(20):1867-1876.
27. Ascierto PA, Schadendorf D, Berking CA, et al.MEK162 for patients with advanced melanoma harbouring NRAS or Val600 BRAF mutations:a non-randomised, open-label phase 2 study[J].Lancet Oncol, 2013, 14(3):249-256.
28. Guo J, Si L, Kong Y, et al.Phase Ⅱ, open-label, single-arm trial of imatinibmesylate in patients withmetastaticmelanoma harboring c-Kit mutation or amplification[J].J Clin Oncol, 2011, 29(21):2904-2909.
29. Curtin JA, Busam K, Pinkel D, et al.Somatic activation of KIT in distinct subtypes of melanoma[J].J Clin Oncol, 2006, 24(26):4340-4346.
30. Flaherty KT, Infante JR, Daud A, et al.Combined BRAF and MEK inhibition in melanoma with BRAFV600 mutations[J].N Engl J Med, 2012, 367(18):1694-1703.
31. US Food and Drug Administration.Trametinib and dabrafenib[EB/OL].(2014-08-20)[2016-01-01].http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm381451.htm.
32. Glaxo SK.Dabrafenib plus trametinib vs vemurafenib alone in unresectable or metastatic BRAFV600E/K cutaneous melanoma (COMBI-v).Clinical Trials.Gov:NCT01597908.https://www.clinicaltrials.gov/show/NCT01597908.
33. Sullivan RJ, Flaherty KT.Resistance to BRAF-targeted therapy in melanoma[J].Eur J Cancer, 2013, 49(6):1297-1304.
34. Menzies AM, Long GV.Recent advances in melanoma systemic therapy.BRAF inhibitors, CTLA4 antibodies and beyond[J].Eur J Cancer, 2013, 49(15):3229-3241.
35. Topalian SL, Drake CG, Pardoll DM.Targeting the PD-1/B7-H1(PD-L1) pathway to activate anti-tumor immunity[J].Curr Opin Immunol, 2012, 24(2):207-212.
36. Ribas A.Tumor immunotherapy directed at PD-1[J].N Engl J Med, 2012, 366(26):2517-2519.
37. Hodi FS, O'day SJ, Mcdermott DF, et al.Improved survival with ipilimumab in patients with metastatic melanoma[J].N Engl J Med, 2010, 363(8):711-723.
38. Robert C, Thomas L, Bondarenko I, et al.Ipilimumab plus dacarbazine for previously untreated metastatic melanoma[J].N Engl J Med, 2011, 364(26):2517-2526.
39. Hodi FS, Lee S, Mcdermott DF, et al.Ipilimumab plus sargramostim vs ipilimumab alone for treatment of metastatic melanoma a randomized clinical trial[J].JAMA, 2014, 312(17):1744-1753.
40. Margolin K, Ernstoff MS, Hamid O, et al.Ipilimumab in patients with melanoma and brain metastases:an open-label, phase 2 trial[J].Lancet Oncol, 2012, 13(5):459-465.
41. Ribas A, Hodi FS, Callahan M, et al.Hepatotoxicity with combination of vemurafenib and ipilimumab[J].N Engl J Med, 2013, 368(14):1365-1366.
42. Camacho LH, Antonia S, Sosman J, et al.PhaseⅠ/Ⅱ trial of tremelimumab in patients with metastatic melanoma[J].J Clin Oncol, 2009, 27(7):1075-1081.
43. Ribas A, Kefford R, Marshall MA, et al.Phase Ⅲ randomized clinical trial comparing tremelimumab with Standard-of-Care chemotherapy in patients with advanced melanoma[J].J Clin Oncol, 2013, 31(5):616-622.
44. Robert C, Long GV, Brady B, et al.Nivolumab in previously untreated melanoma without BRAF mutation[J].N Engl J Med, 2015, 372(4):320-330.
45. US Food and Drug Administration.FDA approves opdivo for advanced melanoma[EB/OL].(2014-12-24)[2016-01-01].http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm427716.htm.
46. Wolchok JD, Kluger H, Callahan MK, et al.Nivolumab plus ipilimumab in advanced melanoma[J].N Engl J Med, 2013, 369(2):122-133.
47. Chapman PB.D'angelo SP, Wolchok JD.Rapid eradication of a bulky melanoma mass with one dose of immunotherapy[J].N Engl J Med, 2015, 372(21):2073-2074.
48. Hamid O, Robert C, Daud A, et al.Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma[J].N Engl J Med, 2013, 369(2):134-144.
49. Bagcchi S.Pembrolizumab for treatment of refractory melanoma[J].Lancet Oncol, 2014, 15(10):E419.
50. Pazdur R.Drug administration pembrolizumab[EB/OL].FDA, 2014:1-8.www.accessdata.fda.gov/drugsatfda_docs/appletter/2014/125514Orig1s000ltr.pdf..
51. Robert C, Schachter J, Long GV, et al.Pembrolizumab versus ipilimumab in advanced melanoma[J].N Engl J Med, 2015, 372(26):2521-2532.
52. Atkins MB, Kudchadkar RR, Sznol M, et al.Phase 2, multicenter, safety and efficacy study of pidilizumab in patients with metastatic melanoma[J].J Clin Oncol, 2014, 32(Suppl 5):9001a.
53. Nishino M, Sholl LM, Hodi FS.Anti-PD-1-Related pneumonitis during cancer immunotherapy[J].N Engl J Med, 2015, 373(3):288-290.
54. Hamid O, SosmanJA, Lawrence DP, et al.Clinical activity, safety, and biomarkers of MPDL3280A, an engineered PDL1 antibody in patients with locally advanced or metastatic melanoma[J].J Clin Oncol, 2013, 31(Suppl 15):9010a.
55. Brahmer JR, Tykodi SS, Chow LQ, et al.Safety and activity of anti-PD-L1 antibody in patients with advanced cancer[J].N Engl J Med, 2012, 366(26):2455-2465.
56. MedImmune LLC.A phase 1/2 study to evaluate MEDI4736[EB/OL].2015:NCT01693562.https://www.clinicaltrials.gov/ct2/show/NCT01693562.
57. Heery CR, O'Sullivan Coyne GH, Madan RA, et al.Phase Ⅰ open-label, multiple ascending dose trial ofMSB0010718C, an anti-PD-L1 monoclonal antibody, in advanced solid malignancies[J].J Clin Oncol, 2014, 32(Suppl 5):3064a.
58. Infante JR, Powderly JD, Burris HA, et al.Clinical and pharmacodynamic (PD) results of a phase Ⅰ trial with AMP-224(B7-DC Fc) that binds to the PD-1 receptor[J].J Clin Oncol, 2013, 31(Suppl):3044a.

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