Ugurel Selma, Röhmel Joachim, Ascierto Paolo A, Flaherty Keith T, Grob Jean Jacques, Hauschild Axel, Larkin James, Long Georgina V, Lorigan Paul, McArthur Grant A, Ribas Antoni, Robert Caroline, Schadendorf Dirk, Garbe Claus
Department of Dermatology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
Bremen, Germany.
Eur J Cancer. 2017 Sep;83:247-257. doi: 10.1016/j.ejca.2017.06.028. Epub 2017 Aug 23.
The treatment of metastatic melanoma is still undergoing a process of major change. The two most important novel therapeutic strategies, selective kinase inhibitors and immune checkpoint blockers, both significantly prolong survival times of patients with advanced metastatic disease. Different agents, dose regimens and combinations have been tested against each other vigorously within these two groups. However, results from prospective head-to-head comparative studies of both strategies are still lacking. We performed an exploratory analysis of survival data from selected clinical trials representative for the new treatment strategies in advanced metastatic melanoma. Eighty-three Kaplan-Meier survival curves from 25 trials were digitised and grouped by therapeutic strategy and treatment line. For each of these groups, mean survival curves were generated for progression-free (PFS) and overall survival (OS) by weighted averaging. Survival curves grouped together by therapeutic strategy revealed a high concordance, particularly in the first-line setting. For kinase inhibitors, the most favourable PFS and OS in all therapy lines were observed for combined BRAF plus MEK inhibition. For immune checkpoint inhibitors, combined PD-1 plus CTLA-4 inhibition demonstrated the best survival outcome in all categories except for OS in first-line therapy. For the latter, combined PD-1 plus CTLA-4 inhibition showed similar outcomes as single-agent PD-1 inhibition. Comparison of kinase inhibitors and checkpoint blockers revealed a superiority of combined BRAF plus MEK inhibition within the first 6 months, later changing to a superiority of PD-1 blockers alone or in combination with CTLA-4 blockers. These results need confirmation by prospective clinical trials.
转移性黑色素瘤的治疗仍在经历重大变革。两种最重要的新型治疗策略，即选择性激酶抑制剂和免疫检查点阻断剂，均能显著延长晚期转移性疾病患者的生存时间。在这两组治疗方法中，不同的药物、剂量方案及联合用药都已进行了激烈的相互测试。然而，这两种策略的前瞻性头对头比较研究结果仍很缺乏。我们对晚期转移性黑色素瘤新治疗策略的代表性临床试验的生存数据进行了探索性分析。对25项试验中的83条Kaplan-Meier生存曲线进行数字化处理，并按治疗策略和治疗线分组。对于这些组中的每一组，通过加权平均生成无进展生存期（PFS）和总生存期（OS）的平均生存曲线。按治疗策略分组的生存曲线显示出高度一致性，尤其是在一线治疗中。对于激酶抑制剂，在所有治疗线中，联合BRAF和MEK抑制观察到最有利的PFS和OS。对于免疫检查点抑制剂，联合PD-1和CTLA-4抑制在除一线治疗OS外的所有类别中均显示出最佳生存结果。对于后者，联合PD-1和CTLA-4抑制与单药PD-1抑制显示出相似的结果。激酶抑制剂和检查点阻断剂的比较显示，在最初6个月内联合BRAF和MEK抑制具有优势，之后则变为单独使用PD-1阻断剂或与CTLA-4阻断剂联合使用具有优势。这些结果需要前瞻性临床试验予以证实。
