NRAS突变黑素瘤的靶向治疗
NRAS突变可激活MAPK与PI3K通路，从而促进肿瘤增殖和生长。MEK162是一种小分子MEK1/2抑制剂，与NRAS突变黑素瘤患者的某些活动有关，[155]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;14:249-256.http://www.ncbi.nlm.nih.gov/pubmed/23414587?tool=bestpractice.comIII期临床试验正在进行中。MEK和PI3K抑制剂的早期联合试验亦在进行中。
KIT突变黑素瘤的靶向治疗
在肢端黑素瘤中4q染色体近端扩增引出了KIT癌基因在黑素瘤中可能发生了突变或异常表达的假说。[156]Curtin JA, Fridlyand J, Kageshita T, et al. Distinct sets of genetic alterations in melanoma. N Engl J Med. 2005;353:2135-2147.http://www.nejm.org/doi/full/10.1056/NEJMoa050092#t=articlehttp://www.ncbi.nlm.nih.gov/pubmed/16291983?tool=bestpractice.comKIT基因直接测序结果显示KIT的突变见于21%的黏膜型黑素瘤、11%肢端黑素瘤和17%继发于慢性日光性损害的黑素瘤。但是继发于间断光照皮肤的黑素瘤发生KIT基因突变的不到1%。[156]Curtin JA, Fridlyand J, Kageshita T, et al. Distinct sets of genetic alterations in melanoma. N Engl J Med. 2005;353:2135-2147.http://www.nejm.org/doi/full/10.1056/NEJMoa050092#t=articlehttp://www.ncbi.nlm.nih.gov/pubmed/16291983?tool=bestpractice.com在一项开放式II期临床研究中，具有KIT基因突变或增殖的患者使用KIT抑制剂伊马替尼治疗后，表现出16%的总体持久反应率，且整个过程平均需要12周。[157]Carvajal R, Antonescu C, Wolchok J, et al. KIT as a therapeutic target in metastatic melanoma. JAMA. 2011;305:2327-2334.http://www.ncbi.nlm.nih.gov/pubmed/21642685?tool=bestpractice.com另外两项II期临床试验也证实了伊马替尼的疗效。[158]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;29:2904-2909.http://ascopubs.org/doi/full/10.1200/jco.2010.33.9275http://www.ncbi.nlm.nih.gov/pubmed/21690468?tool=bestpractice.com[159]Hodi FS, Corless CL, Giobbie-Hurder A, et al. Imatinib for melanomas harboring mutationally activated or amplified KIT arising on mucosal, acral, and chronically sun-damaged skin. J Clin Oncol. 2013;3:3182-3190.http://ascopubs.org/doi/full/10.1200/jco.2012.47.7836http://www.ncbi.nlm.nih.gov/pubmed/23775962?tool=bestpractice.com原发性和继发性耐药机制正在阐明。其他几种KIT抑制剂，包括舒尼替尼、达沙替尼、尼罗替尼都在临床试验积极研究中。TEAM试验，是一项比较尼洛替尼与达卡巴嗪治疗不能手术切除、KIT基因突变的患者疗效的随机III期临床试验，此类患者正在积极积累中。
司美替尼治疗Gq/11突变的葡萄膜黑素瘤
葡萄膜黑素瘤通常在GNAQ和GNA11基因上发生突变、易转移扩散至肝脏、预后差，且全身治疗疗效不大。近日，一项关于司美替尼的II期临床试验显示其有50%的肿瘤消退率，RECIST（实体瘤疗效评价标准）反应率为15%（N=46），以及平均作用时间为23周。[160]Carvajal RD, Sosman JA, Quevedo F, et al. Phase II study of selumetinib (sel) versus temozolomide (TMZ) in gnaq/Gna11 (Gq/11) mutant (mut) uveal melanoma (UM) J Clin Oncol. 2013;31:Abstract CRA9003.
靶向和免疫疗法联合治疗
若干项对靶向治疗与免疫疗法结合治疗进行评估的试验正在进行中。[161]ClinicalTrials.gov. A study of the safety and efficacy of pembrolizumab (MK-3475) in combination with trametinib and dabrafenib in participants with advanced melanoma (MK-3475-022/KEYNOTE-022). NCT02130466. November 2016. https://clinicaltrials.gov/ (last accessed 10 November 2016).https://clinicaltrials.gov/ct2/show/NCT02130466[162]ClinicalTrials.gov. Phase 1 safety and tolerability of MEDI4736 in combination with dabrafenib and trametinib or with trametinib alone. NCT02027961. July 2016. https://clinicaltrials.gov/ (last accessed 10 November 2016).https://clinicaltrials.gov/ct2/show/NCT02027961
新型分子和免疫靶标
目前正针对其他几个遗传畸变进行研究，单独或联合，用于各种黑素瘤分子亚型。新的目标包括PI3K通路/细胞周期调节因子（CDK4/6）、MAPK通路下游（ERK）。其他免疫细胞受体检查点也正在研究中，包括 LAG3 和 GITR。
辅助和新辅助治疗
若干项关于辅助和新辅助治疗的试验正在进行中，包括辅助性派姆单抗 (pembrolizumab)、[163]ClinicalTrials.gov. Study of pembrolizumab (MK-3475) versus placebo after complete resection of high-risk stage III melanoma (MK-3475-054/KEYNOTE-054). NCT02362594. September 2016. https://clinicaltrials.gov/ (last accessed 10 November 2016).https://clinicaltrials.gov/ct2/show/NCT02362594[164]ClinicalTrials.gov. High-dose recombinant interferon alfa-2B, ipilimumab, or pembrolizumab in treating patients with stage III-IV high risk melanoma that has been removed by surgery. NCT02506153. November 2016. https://clinicaltrials.gov/ (last accessed 10 November 2016).https://clinicaltrials.gov/ct2/show/NCT02506153尼鲁单抗 (nivolumab)[165]ClinicalTrials.gov. Efficacy study of nivolumab compared to ipilimumab in prevention of recurrence of melanoma after complete resection of stage IIIb/c or stage IV melanoma (CheckMate 238). NCT02388906. https://clinicaltrials.gov/ (last accessed 10 November 2016).https://clinicaltrials.gov/ct2/show/NCT02388906和 BRAF/MEK 抑制剂。[166]ClinicalTrials.gov. A study of the BRAF inhibitor dabrafenib in combination with the MEK inhibitor trametinib in the adjuvant treatment of high-risk BRAF V600 mutation-positive melanoma after surgical resection (COMBI-AD). NCT01682083. October 2016. https://clinicaltrials.gov/ (last accessed 10 November 2016).https://clinicaltrials.gov/ct2/show/NCT01682083[167]ClinicalTrials.gov. BRIM8: a study of vemurafenib adjuvant therapy in patients with resected cutaneous BRAF mutant melanoma. NCT01667419. November 2016. https://clinicaltrials.gov/ (last accessed 10 November 2016).https://clinicaltrials.gov/ct2/show/NCT01667419
