Grimaldi Antonio Maria, Simeone Ester, Festino Lucia, Vanella Vito, Palla Marco, Ascierto Paolo Antonio
O.U. Melanoma, Cancer Immunotherapy and Innovative Therapies, National Cancer Institute of Naples "G. Pascale" Foundation, Naples, Italy.
Discov Med. 2015 Jun;19(107):455-61.
The development of novel treatments that selectively inhibit the RAS-RAF-MAPK pathway represents a milestone in the history of melanoma treatment. BRAF mutations occur in approximately 45% of cutaneous melanomas, while mutations in NRAS occur in 15-25%. Vemurafenib was the first BRAF inhibitor to be approved in 2011, based on the results of a phase III trial (BRIM-3) that showed higher progression-free survival and overall survival compared with dacarbazine chemotherapy in metastatic BRAF-mutated melanoma. Dabrafenib, another BRAF inhibitor, has shown similar results and was approved in 2013. Preclinical studies suggested that another novel group of agents, the MEK inhibitors, showed stronger inhibition of both mutated BRAF and NRAS cell cultures than vemurafenib. Trametinib was the first MEK inhibitor approved in 2014, both as a single agent and in combination with dabrafenib for the treatment of advanced BRAF-mutated melanoma. Other MEK inhibitors are also in development. Concomitant inhibition of both MEK and BRAF has shown more durable and greater tumor response than BRAF monotherapy, by overcoming the multiple genetic mechanisms of escape. Combined therapy prevents the development of acquired resistance as well as decreasing cutaneous toxicity secondary to paradoxical activation of the MAPK pathway induced by BRAF inhibitors. Various combinations of BRAF and MEK inhibitors have shown promising results. Moreover, triple combination therapies involved other agents with novel mechanisms of action are also being evaluated. These and other combination strategies involving immunotherapies and targeted therapies offer the hope of improving outcomes beyond those already achieved with anti-BRAF treatments.
选择性抑制RAS-RAF-MAPK通路的新型治疗方法的开发是黑色素瘤治疗史上的一个里程碑。BRAF突变约发生在45%的皮肤黑色素瘤中，而NRAS突变发生在15%-25%。维莫非尼是2011年首个获批的BRAF抑制剂，基于一项III期试验（BRIM-3）的结果，该试验显示与达卡巴嗪化疗相比，转移性BRAF突变黑色素瘤患者的无进展生存期和总生存期更长。另一种BRAF抑制剂达拉非尼也显示出类似结果，并于2013年获批。临床前研究表明，另一类新型药物MEK抑制剂对突变的BRAF和NRAS细胞培养物的抑制作用比维莫非尼更强。曲美替尼是2014年首个获批的MEK抑制剂，可单药使用或与达拉非尼联合用于治疗晚期BRAF突变黑色素瘤。其他MEK抑制剂也在研发中。同时抑制MEK和BRAF已显示出比BRAF单药治疗更持久、更强的肿瘤反应，通过克服多种逃逸的遗传机制。联合治疗可防止获得性耐药的发生，并降低BRAF抑制剂诱导的MAPK通路反常激活继发的皮肤毒性。BRAF和MEK抑制剂的各种联合已显示出有前景的结果。此外，涉及其他具有新作用机制药物的三联联合疗法也在评估中。这些以及其他涉及免疫疗法和靶向疗法的联合策略为改善治疗效果带来了希望，有望超越抗BRAF治疗已取得的成果。
