辅助达拉非尼联合曲美替尼治疗 BRAF 突变型 III 期黑色素瘤。
Adjuvant Dabrafenib plus Trametinib in Stage III BRAF-Mutated Melanoma.
机构信息
From the Melanoma Institute Australia, University of Sydney, Royal North Shore and Mater Hospitals (G.V.L.), and Macquarie University, Melanoma Institute Australia, University of Sydney, and Westmead Hospital (R.K.), Sydney, Princess Alexandra Hospital, Gallipoli Medical Research Foundation, University of Queensland, Brisbane (V.A.), and Alfred Hospital, Melbourne, VIC (A. Haydon) - all in Australia; University Hospital Schleswig-Holstein, Kiel (A. Hauschild), and University Hospital Essen, Essen, and the German Cancer Consortium, Heidelberg (D.S.) - all in Germany; Fondazione Istituto Nazionale Tumori, Milan (M.S.), Papa Giovanni XXIII Cancer Center Hospital, Bergamo (M.M.), and the Melanoma Oncology Unit, Veneto Oncology Institute, Padua (V.C.-S.) - all in Italy; Rikshospitalet-Radiumhospitalet, Oslo (M.N.); Centre Hospitalier Universitaire de Bordeaux, Hôpital Saint-André, Bordeaux (C.D.), Institute Gustave Roussy, Paris (C.R.), Université de Lille, INSERM Unité 1189, Centre Hospitalier Régional Universitaire de Lille, Lille (L.M.), and the Medical Oncology Department, Centre Eugène Marquis, Rennes (T.L.) - all in France; Ella Institute for Melanoma, Sheba Medical Center, Tel Hashomer, Israel (J.S.); Royal Marsden NHS Foundation Trust, London (J. Larkin), and Northern Centre for Cancer Care, Freeman Hospital, Newcastle upon Tyne (R.P.) - both in the United Kingdom; Novartis Pharmaceuticals, East Hanover, NJ (R.J., P.Z., B.M., J. Legos); University Hospital Zürich Skin Cancer Center, Zurich, Switzerland (R.D.); and the Melanoma Program, Hillman UPMC Cancer Center, University of Pittsburgh, Pittsburgh (J.M.K.).
出版信息
N Engl J Med. 2017 Nov 9;377(19):1813-1823. doi: 10.1056/NEJMoa1708539. Epub 2017 Sep 10.
BACKGROUND
Combination therapy with the BRAF inhibitor dabrafenib plus the MEK inhibitor trametinib improved survival in patients with advanced melanoma with BRAF V600 mutations. We sought to determine whether adjuvant dabrafenib plus trametinib would improve outcomes in patients with resected, stage III melanoma with BRAF V600 mutations.
METHODS
In this double-blind, placebo-controlled, phase 3 trial, we randomly assigned 870 patients with completely resected, stage III melanoma with BRAF V600E or V600K mutations to receive oral dabrafenib at a dose of 150 mg twice daily plus trametinib at a dose of 2 mg once daily (combination therapy, 438 patients) or two matched placebo tablets (432 patients) for 12 months. The primary end point was relapse-free survival. Secondary end points included overall survival, distant metastasis-free survival, freedom from relapse, and safety.
RESULTS
At a median follow-up of 2.8 years, the estimated 3-year rate of relapse-free survival was 58% in the combination-therapy group and 39% in the placebo group (hazard ratio for relapse or death, 0.47; 95% confidence interval [CI], 0.39 to 0.58; P<0.001). The 3-year overall survival rate was 86% in the combination-therapy group and 77% in the placebo group (hazard ratio for death, 0.57; 95% CI, 0.42 to 0.79; P=0.0006), but this level of improvement did not cross the prespecified interim analysis boundary of P=0.000019. Rates of distant metastasis-free survival and freedom from relapse were also higher in the combination-therapy group than in the placebo group. The safety profile of dabrafenib plus trametinib was consistent with that observed with the combination in patients with metastatic melanoma.
CONCLUSIONS
Adjuvant use of combination therapy with dabrafenib plus trametinib resulted in a significantly lower risk of recurrence in patients with stage III melanoma with BRAF V600E or V600K mutations than the adjuvant use of placebo and was not associated with new toxic effects. (Funded by GlaxoSmithKline and Novartis; COMBI-AD ClinicalTrials.gov, NCT01682083 ; EudraCT number, 2012-001266-15 .).
背景
BRAF 抑制剂达拉非尼联合 MEK 抑制剂曲美替尼的联合治疗改善了携带 BRAF V600 突变的晚期黑色素瘤患者的生存。我们旨在确定在接受完全切除的 III 期黑色素瘤且携带 BRAF V600E 或 V600K 突变的患者中，辅助使用达拉非尼联合曲美替尼是否会改善结局。
方法
在这项双盲、安慰剂对照、3 期临床试验中，我们将 870 例完全切除的 III 期黑色素瘤且携带 BRAF V600E 或 V600K 突变的患者随机分配，分别接受每日两次 150mg 达拉非尼联合每日一次 2mg 曲美替尼（联合治疗组，438 例）或每日两次安慰剂片（432 例）治疗 12 个月。主要终点是无复发生存。次要终点包括总生存、远处无转移生存、无复发和安全性。
结果
中位随访 2.8 年后，联合治疗组的 3 年无复发生存率为 58%，安慰剂组为 39%（复发或死亡的风险比，0.47；95%置信区间[CI]，0.39 至 0.58；P<0.001）。联合治疗组的 3 年总生存率为 86%，安慰剂组为 77%（死亡风险比，0.57；95%CI，0.42 至 0.79；P=0.0006），但这一改善水平未达到预先设定的 P=0.000019 的中期分析界值。联合治疗组的远处无转移生存率和无复发率也高于安慰剂组。达拉非尼联合曲美替尼的安全性与转移性黑色素瘤患者的联合治疗一致。
结论
与安慰剂辅助治疗相比，BRAF V600E 或 V600K 突变的 III 期黑色素瘤患者接受达拉非尼联合曲美替尼辅助治疗可显著降低复发风险，且不会产生新的毒性作用。（由葛兰素史克和诺华公司资助；COMBI-AD，ClinicalTrials.gov，NCT01682083；EudraCT 编号，2012-001266-15）。
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