辅助达布拉非尼联合曲美替尼治疗 III 期黑色素瘤的最终结果。
Final Results for Adjuvant Dabrafenib plus Trametinib in Stage III Melanoma.
机构信息
From the Melanoma Institute Australia, the University of Sydney, Royal North Shore Hospital, and Mater Hospital, Sydney (G.V.L.), Princess Alexandra Hospital, the Gallipoli Medical Research Foundation, and the University of Queensland, Woolloongabba (V.A.), and Alfred Hospital, Melbourne, VIC (A.H.) - all in Australia; the Department of Dermatology, University Hospital Schleswig-Holstein, Campus Kiel, Kiel (A.H.), and the German Cancer Consortium, National Center for Tumor Diseases, University Hospital Essen, Campus Essen, and the University Alliance Ruhr, Research Center One Health, University of Duisburg-Essen, Essen (D.S.) - all in Germany; Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan (M.S.), the Unit of Medical Oncology, Department of Oncology and Hematology, Papa Giovanni XXIII Cancer Center Hospital, Bergamo (B.M., M.M.), and Oncology 2, Veneto Institute of Oncology IOV-IRCCS, Padua (V.C.S.) - all in Italy; the Melanoma Program, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh (J.M.K.); Oslo University Hospital and the Norwegian Radium Hospital, Oslo (M.N.); Centre Hospitalier Universitaire de Bordeaux and Hôpital Saint-André, Bordeaux (C.D.), Gustave Roussy and Paris-Sud-Paris-Saclay University, Villejuif (C.R.), Université de Lille, INSERM Unité 1189, Lille (L.M.), and the Medical Oncology Department, Centre Eugène Marquis, Rennes (T.L.) - all in France; the Ella Lemelbaum Institute for Immuno Oncology and Melanoma, Sheba Medical Center, and the Sackler School of Medicine, Tel-Aviv University, Ramat Gan, Israel (J.S.); Northern Centre for Cancer Care, Freeman Hospital, and Newcastle University, Newcastle (R.P.), and the Royal Marsden National Health Services Foundation Trust, London (J.L.) - all in the United Kingdom; Novartis Pharmaceuticals, East Hanover, NJ (M.T.); Novartis Healthcare, Hyderabad, India (S.B.A., T.J.); and Novartis Pharma, Basel (P.B.), and the University Hospital Zürich Skin Cancer Center, Zurich (R.D.) - both in Switzerland.
出版信息
N Engl J Med. 2024 Nov 7;391(18):1709-1720. doi: 10.1056/NEJMoa2404139. Epub 2024 Jun 19.
BACKGROUND
The 5-year results of this trial showed that adjuvant therapy with dabrafenib plus trametinib resulted in longer relapse-free survival and distant metastasis-free survival than placebo among patients with V600-mutated stage III melanoma. Longer-term data were needed, including data regarding overall survival.
METHODS
We randomly assigned 870 patients with resected stage III melanoma with V600 mutations to receive 12 months of dabrafenib (150 mg twice daily) plus trametinib (2 mg once daily) or two matched placebos. Here, we report the final results of this trial, including results for overall survival, melanoma-specific survival, relapse-free survival, and distant metastasis-free survival.
RESULTS
The median duration of follow-up was 8.33 years for dabrafenib plus trametinib and 6.87 years for placebo. Kaplan-Meier estimates for overall survival favored dabrafenib plus trametinib over placebo, although the benefit was not significant (hazard ratio for death, 0.80; 95% confidence interval [CI], 0.62 to 1.01; P = 0.06 by stratified log-rank test). A consistent survival benefit was seen across several prespecified subgroups, including the 792 patients with melanoma with a V600E mutation (hazard ratio for death, 0.75; 95% CI, 0.58 to 0.96). Relapse-free survival favored dabrafenib plus trametinib over placebo (hazard ratio for relapse or death, 0.52; 95% CI, 0.43 to 0.63), as did distant metastasis-free survival (hazard ratio for distant metastasis or death, 0.56; 95% CI, 0.44 to 0.71). No new safety signals were reported, a finding consistent with previous trial reports.
CONCLUSIONS
After nearly 10 years of follow-up, adjuvant therapy with dabrafenib plus trametinib was associated with better relapse-free survival and distant metastasis-free survival than placebo among patients with resected stage III melanoma. The analysis of overall survival showed that the risk of death was 20% lower with combination therapy than with placebo, but the benefit was not significant. Among patients with melanoma with a V600E mutation, the results suggest that the risk of death was 25% lower with combination therapy. (Funded by GlaxoSmithKline and Novartis; COMBI-AD ClinicalTrials.gov number, NCT01682083; EudraCT number, 2012-001266-15.).
背景
这项试验的 5 年结果表明，与安慰剂相比，在 V600 突变的 III 期黑色素瘤患者中，辅助治疗用达拉非尼加曲美替尼可延长无复发生存期和远处无转移生存期。需要更长期的数据，包括总生存数据。
方法
我们随机分配 870 例接受过手术治疗的 III 期 V600 突变黑色素瘤患者，接受 12 个月的达拉非尼（每日两次，每次 150mg）加曲美替尼（每日一次，每次 2mg）或两种匹配的安慰剂治疗。在这里，我们报告了这项试验的最终结果，包括总生存、黑色素瘤特异性生存、无复发生存和远处无转移生存的结果。
结果
达拉非尼加曲美替尼组的中位随访时间为 8.33 年，安慰剂组为 6.87 年。Kaplan-Meier 估计总生存有利于达拉非尼加曲美替尼，尽管差异无统计学意义（死亡风险比，0.80；95%置信区间 [CI]，0.62 至 1.01；分层对数秩检验 P=0.06）。在几个预先指定的亚组中观察到一致的生存获益，包括 792 例 V600E 突变黑色素瘤患者（死亡风险比，0.75；95%CI，0.58 至 0.96）。无复发生存期达拉非尼加曲美替尼优于安慰剂（复发或死亡风险比，0.52；95%CI，0.43 至 0.63），远处无转移生存期也是如此（远处转移或死亡风险比，0.56；95%CI，0.44 至 0.71）。未报告新的安全性信号，这与之前的试验报告一致。
结论
近 10 年的随访结果显示，与安慰剂相比，接受达拉非尼加曲美替尼辅助治疗的 III 期黑色素瘤患者无复发生存期和远处无转移生存期更长。总生存分析显示，联合治疗组的死亡风险比安慰剂组低 20%，但差异无统计学意义。在 V600E 突变黑色素瘤患者中，结果表明联合治疗组的死亡风险降低了 25%。（由葛兰素史克和诺华公司资助；COMBI-AD 临床试验.gov 编号，NCT01682083；EudraCT 编号，2012-001266-15。）
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