近日，法国古斯塔夫·鲁西研究所教授Daniil Stroyakovskiy及其课题组，对达拉非尼联合曲米替尼治疗转移性黑色素瘤5年后的疗效进行了观察。 2019年8月15日出版的《新英格兰医学杂志》发表了这项成果。

为确定BRAF抑制剂和MEK抑制剂联合治疗BRAF V600E或V600K突变的、不可切除或转移性黑色素瘤患者的5年生存率和临床特征，课题组回顾分析了该临床试验的长期数据。

共有563例转移性黑色素瘤的患者接受达拉非尼联合曲米替尼治疗，并随机分配至COMBI-D组（211例）和COMBI-V组（352例），COMBI-D组的主要观察指标为无进展生存期，而COMBI-V组的主要观察指标为总生存期。平均随访22个月后，发现这些患者的4年无进展生存率为21%，5年无进展生存率为19%。4年总生存率为37%，5年总生存率为34%。

在多因素分析中，一些基线因素例如体力状态、年龄、性别、肿瘤转移器官的部位和数量、乳酸脱氢酶水平等均与无进展生存和总生存期显著相关。109例患者（19%）完全缓解，且预后良好，5年总生存率为71%。

该研究结果表明，对于患有BRAF V600E或V600K突变的不可切除或转移性黑色素瘤的患者，采用达拉非尼联合曲米替尼进行一线治疗，大约三分之一的患者可长期获益。

据了解，BRAF V600E或V600K突变的不可切除或转移性黑色素瘤患者在接受BRAF抑制剂和MEK抑制剂治疗后，无进展生存期和总生存期延长。然而，这些患者的长期临床效果仍不明确。

附：英文原文

Title: Five-Year Outcomes with Dabrafenib plus Trametinib in Metastatic Melanoma

Author: Caroline Robert, M.D., Ph.D., Jean J. Grob, M.D., Ph.D., Daniil Stroyakovskiy, M.D., Boguslawa Karaszewska, M.D., Axel Hauschild, M.D., Evgeny Levchenko, M.D., Vanna Chiarion Sileni, M.D., Jacob Schachter, M.D., Claus Garbe, M.D., Igor Bondarenko, M.D., Ph.D., Helen Gogas, M.D., Mario Mandalá, M.D., John B.A.G. Haanen, M.D., Ph.D., Celeste Lebbé, M.D., Andrzej Mackiewicz, M.D., Ph.D., Piotr Rutkowski, M.D., Ph.D., Paul D. Nathan, M.D., Antoni Ribas, M.D., Ph.D., Michael A. Davies, M.D., Ph.D., Keith T. Flaherty, M.D., Paul Burgess, M.Sci., Monique Tan, M.D., Eduard Gasal, M.D., Maurizio Voi, M.D., Dirk Schadendorf, M.D., and Georgina V. Long, M.B., B.S., Ph.D.

Issue&Volume: VOL. 381 NO. 7. 15 August 2019

Abstract: 

BACKGROUND
Patients who have unresectable or metastatic melanoma with a BRAF V600E or V600K mutation have prolonged progression-free survival and overall survival when receiving treatment with BRAF inhibitors plus MEK inhibitors. However, long-term clinical outcomes in these patients remain undefined. To determine 5-year survival rates and clinical characteristics of the patients with durable benefit, we sought to review long-term data from randomized trials of combination therapy with BRAF and MEK inhibitors.

METHODS
We analyzed pooled extended-survival data from two trials involving previously untreated patients who had received BRAF inhibitor dabrafenib (at a dose of 150 mg twice daily) plus MEK inhibitor trametinib (2 mg once daily) in the COMBI-d and COMBI-v trials. The median duration of follow-up was 22 months (range, 0 to 76). The primary end points in the COMBI-d and COMBI-v trials were progression-free survival and overall survival, respectively.

RESULTS
A total of 563 patients were randomly assigned to receive dabrafenib plus trametinib (211 in the COMBI-d trial and 352 in the COMBI-v trial). The progression-free survival rates were 21% (95% confidence interval [CI], 17 to 24) at 4 years and 19% (95% CI, 15 to 22) at 5 years. The overall survival rates were 37% (95% CI, 33 to 42) at 4 years and 34% (95% CI, 30 to 38) at 5 years. In multivariate analysis, several baseline factors (e.g., performance status, age, sex, number of organ sites with metastasis, and lactate dehydrogenase level) were significantly associated with both progression-free survival and overall survival. A complete response occurred in 109 patients (19%) and was associated with an improved long-term outcome, with an overall survival rate of 71% (95% CI, 62 to 79) at 5 years.

CONCLUSIONS
First-line treatment with dabrafenib plus trametinib led to long-term benefit in approximately one third of the patients who had unresectable or metastatic melanoma with a BRAF V600E or V600K mutation. 

DOI: 10.1056/NEJMoa1904059

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa1904059