Schadendorf Dirk, Long Georgina V, Stroiakovski Daniil, Karaszewska Boguslawa, Hauschild Axel, Levchenko Evgeny, Chiarion-Sileni Vanna, Schachter Jacob, Garbe Claus, Dutriaux Caroline, Gogas Helen, Mandalà Mario, Haanen John B A G, Lebbé Céleste, Mackiewicz Andrzej, Rutkowski Piotr, Grob Jean-Jacques, Nathan Paul, Ribas Antoni, Davies Michael A, Zhang Ying, Kaper Mathilde, Mookerjee Bijoyesh, Legos Jeffrey J, Flaherty Keith T, Robert Caroline
Department of Dermatology, University Hospital Essen, Hufelandstrasse 55, 45122 Essen, Germany; German Cancer Consortium, 69117 Heidelberg, Germany.
Melanoma Institute Australia, The University of Sydney, NSW, Australia; Mater Hospital, North Sydney, NSW, Australia; Royal North Shore Hospital, St Leonards, NSW, Australia.
Eur J Cancer. 2017 Sep;82:45-55. doi: 10.1016/j.ejca.2017.05.033. Epub 2017 Jun 22.
Understanding predictors of long-term benefit with currently available melanoma therapies is the key for optimising individualised treatments. A prior pooled analysis of dabrafenib plus trametinib (D + T)-randomised trials (median follow-up, 20.0 months) identified baseline lactate dehydrogenase (LDH) and number of organ sites with metastasis as predictive factors for progression-free (PFS) and overall (OS) survival. However, longer-term follow-up analyses are needed to confirm which patients treated with D + T can achieve maximum benefit.
Three-year landmark data were retrospectively pooled for D + T patients in phase 3 trials (COMBI-d [NCT01584648]; COMBI-v [NCT01597908]). Univariate and multivariate analyses assessed prognostic values of predefined baseline factors; regression tree analysis determined hierarchy and interactions between variables.
Long-term pooled outcomes were consistent with individual trial results (N = 563; 3-year PFS, 23%; 3-year OS, 44%). Baseline LDH level and number of organ sites remained strongly associated with and/or predictive of PFS and OS. In addition, baseline sum of lesion diameters (SLD) was identified as a predictor for progression. In the most favourable prognostic group (normal LDH, SLD <66 mm, <3 organ sites; n = 183/563 [33%]), 3-year PFS was 42%. Baseline number of organ sites was also predictive of outcomes in patients with PFS ≥ 6 months.
Using the largest phase 3 data set available for BRAF/MEK inhibitor combination therapy in melanoma, these results demonstrate that durable responses lasting ≥3 years are possible in subsets of patients with BRAF-mutant melanoma receiving D + T. Although the best predictive model evolved with longer follow-up, factors predicting clinical outcomes with the combination remained consistent with previous analyses.
了解当前可用的黑色素瘤疗法的长期获益预测因素是优化个体化治疗的关键。先前对达拉非尼联合曲美替尼（D+T）随机试验的汇总分析（中位随访时间为20.0个月）确定，基线乳酸脱氢酶（LDH）和转移器官部位数量是无进展生存期（PFS）和总生存期（OS）的预测因素。然而，需要进行长期随访分析，以确定哪些接受D+T治疗的患者能够获得最大获益。
回顾性汇总3期试验（COMBI-d [NCT01584648]；COMBI-v [NCT01597908]）中D+T患者的3年标志性数据。单因素和多因素分析评估了预定义基线因素的预后价值；回归树分析确定了变量之间的层次结构和相互作用。
长期汇总结果与各试验结果一致（N=563；3年PFS为23%；3年OS为44%）。基线LDH水平和器官部位数量仍然与PFS和OS密切相关和/或具有预测性。此外，基线病灶直径总和（SLD）被确定为进展的预测因素。在最有利的预后组（LDH正常，SLD<66mm，<3个器官部位；n=183/563 [33%]）中，3年PFS为42%。基线器官部位数量对PFS≥6个月的患者的预后也具有预测性。
利用黑色素瘤BRAF/MEK抑制剂联合治疗可用的最大规模3期数据集，这些结果表明，接受D+T治疗的BRAF突变型黑色素瘤患者亚组中可能出现持续≥3年的持久反应。尽管最佳预测模型随着随访时间延长而演变，但联合治疗临床结局的预测因素与先前分析一致。
