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达拉非尼和曲美替尼联合治疗可改善黑色素瘤患者的总生存期。

Improved overall survival in melanoma with combined dabrafenib and trametinib.

机构信息

The authors' affiliations are listed in the Appendix.

出版信息

N Engl J Med. 2015 Jan 1;372(1):30-9. doi: 10.1056/NEJMoa1412690. Epub 2014 Nov 16.

DOI:10.1056/NEJMoa1412690

PMID:25399551

Abstract

BACKGROUND

The BRAF inhibitors vemurafenib and dabrafenib have shown efficacy as monotherapies in patients with previously untreated metastatic melanoma with BRAF V600E or V600K mutations. Combining dabrafenib and the MEK inhibitor trametinib, as compared with dabrafenib alone, enhanced antitumor activity in this population of patients.

METHODS

In this open-label, phase 3 trial, we randomly assigned 704 patients with metastatic melanoma with a BRAF V600 mutation to receive either a combination of dabrafenib (150 mg twice daily) and trametinib (2 mg once daily) or vemurafenib (960 mg twice daily) orally as first-line therapy. The primary end point was overall survival.

RESULTS

At the preplanned interim overall survival analysis, which was performed after 77% of the total number of expected events occurred, the overall survival rate at 12 months was 72% (95% confidence interval [CI], 67 to 77) in the combination-therapy group and 65% (95% CI, 59 to 70) in the vemurafenib group (hazard ratio for death in the combination-therapy group, 0.69; 95% CI, 0.53 to 0.89; P=0.005). The prespecified interim stopping boundary was crossed, and the study was stopped for efficacy in July 2014. Median progression-free survival was 11.4 months in the combination-therapy group and 7.3 months in the vemurafenib group (hazard ratio, 0.56; 95% CI, 0.46 to 0.69; P<0.001). The objective response rate was 64% in the combination-therapy group and 51% in the vemurafenib group (P<0.001). Rates of severe adverse events and study-drug discontinuations were similar in the two groups. Cutaneous squamous-cell carcinoma and keratoacanthoma occurred in 1% of patients in the combination-therapy group and 18% of those in the vemurafenib group.

CONCLUSIONS

Dabrafenib plus trametinib, as compared with vemurafenib monotherapy, significantly improved overall survival in previously untreated patients with metastatic melanoma with BRAF V600E or V600K mutations, without increased overall toxicity. (Funded by GlaxoSmithKline; ClinicalTrials.gov number, NCT01597908.).

摘要

背景

BRAF 抑制剂维莫非尼和达拉非尼在未经治疗的转移性黑色素瘤患者中具有疗效，这些患者的 BRAF V600E 或 V600K 突变。与单独使用达拉非尼相比，联合使用达拉非尼和 MEK 抑制剂曲美替尼可增强此类患者的抗肿瘤活性。

方法

在这项开放性、3 期临床试验中，我们将 704 例携带 BRAF V600 突变的转移性黑色素瘤患者随机分为两组，分别接受达拉非尼（每日 2 次，每次 150mg）和曲美替尼（每日 1 次，每次 2mg）联合治疗或维莫非尼（每日 2 次，每次 960mg）作为一线治疗。主要终点是总生存期。

结果

在计划的中期总生存分析中，在预计总事件发生的 77%时进行了分析，联合治疗组的 12 个月总生存率为 72%（95%置信区间[CI]，67 至 77），维莫非尼组为 65%（95%CI，59 至 70）（联合治疗组死亡风险比为 0.69；95%CI，0.53 至 0.89；P=0.005）。预先指定的中期停止边界已越过，该研究于 2014 年 7 月因疗效而停止。联合治疗组的中位无进展生存期为 11.4 个月，维莫非尼组为 7.3 个月（风险比为 0.56；95%CI，0.46 至 0.69；P<0.001）。联合治疗组的客观缓解率为 64%，维莫非尼组为 51%（P<0.001）。两组严重不良事件和停药率相似。联合治疗组有 1%的患者发生皮肤鳞状细胞癌和角化棘皮瘤，维莫非尼组有 18%的患者发生。