辅助达布拉非尼联合曲美替尼治疗 III 期黑色素瘤的 5 年分析。
Five-Year Analysis of Adjuvant Dabrafenib plus Trametinib in Stage III Melanoma.
机构信息
From University Hospital Zurich Skin Cancer Center, Zurich, Switzerland (R.D.); University Hospital Schleswig-Holstein, Kiel (A. Hauschild), University Hospital Essen, Essen (D.S.), and German Cancer Consortium, Heidelberg (D.S.) - all in Germany; Fondazione IRCCS Istituto Nazionale dei Tumori, Milan (M.S.), Papa Giovanni XXIII Cancer Center Hospital, Bergamo (M.M.), and the Melanoma Oncology Unit, Veneto Oncology Institute-IRCCS, Padua (V.C.S.) - all in Italy; Princess Alexandra Hospital, Gallipoli Medical Research Foundation, University of Queensland, Brisbane (V.A.), Alfred Hospital, Melbourne, VIC (A. Haydon), and Melanoma Institute Australia, University of Sydney, and Royal North Shore and Mater Hospitals, Sydney (G.V.L.) - all in Australia; the Melanoma Program, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh (J.M.K.); Royal Marsden NHS Foundation Trust, London (J.L.), and the Northern Centre for Cancer Care, Freeman Hospital and Newcastle University, Newcastle upon Tyne (R.P.) - both in the United Kingdom; Oslo University Hospital, the Norwegian Radium Hospital, Oslo (M.N.); Centre Hospitalier Universitaire de Bordeaux, 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; Ella Lemelbaum Institute for Immuno-Oncology and Melanoma, Sheba Medical Center, Tel Hashomer, and Sackler School of Medicine, Tel-Aviv University, Tel-Aviv - both in Israel (J.S.); Novartis Healthcare, Hyderabad, India (K.D.); and Novartis Pharmaceuticals, East Hanover, NJ (E.G., M.T.).
出版信息
N Engl J Med. 2020 Sep 17;383(12):1139-1148. doi: 10.1056/NEJMoa2005493. Epub 2020 Sep 2.
BACKGROUND
In the previously reported primary analysis of this phase 3 trial, 12 months of adjuvant dabrafenib plus trametinib resulted in significantly longer relapse-free survival than placebo in patients with resected stage III melanoma with V600E or V600K mutations. To confirm the stability of the relapse-free survival benefit, longer-term data were needed.
METHODS
We randomly assigned 870 patients who had resected stage III melanoma with V600E or V600K mutations to receive 12 months of oral dabrafenib (at a dose of 150 mg twice daily) plus trametinib (2 mg once daily) or two matched placebos. The primary end point was relapse-free survival. Here, we report 5-year results for relapse-free survival and survival without distant metastasis as the site of the first relapse. Overall survival was not analyzed, since the required number of events to trigger the final overall survival analysis had not been reached.
RESULTS
The minimum duration of follow-up was 59 months (median patient follow-up, 60 months for dabrafenib plus trametinib and 58 months for placebo). At 5 years, the percentage of patients who were alive without relapse was 52% (95% confidence interval [CI], 48 to 58) with dabrafenib plus trametinib and 36% (95% CI, 32 to 41) with placebo (hazard ratio for relapse or death, 0.51; 95% CI, 0.42 to 0.61). The percentage of patients who were alive without distant metastasis was 65% (95% CI, 61 to 71) with dabrafenib plus trametinib and 54% (95% CI, 49 to 60) with placebo (hazard ratio for distant metastasis or death, 0.55; 95% CI, 0.44 to 0.70). No clinically meaningful between-group difference in the incidence or severity of serious adverse events was reported during the follow-up period.
CONCLUSIONS
In the 5-year follow-up of a phase 3 trial involving patients who had resected stage III melanoma with V600E or V600K mutations, 12 months of adjuvant therapy with dabrafenib plus trametinib resulted in a longer duration of survival without relapse or distant metastasis than placebo with no apparent long-term toxic effects. (Funded by GlaxoSmithKline and Novartis; COMBI-AD ClinicalTrials.gov number, NCT01682083; EudraCT number, 2012-001266-15.).
背景
在这项 3 期试验的先前报告的主要分析中，与安慰剂相比，接受 12 个月辅助达布拉非尼联合曲美替尼治疗的 III 期黑色素瘤伴 V600E 或 V600K 突变患者，无复发生存期显著延长。为了确认无复发生存获益的稳定性，需要更长期的数据。
方法
我们将 870 例 III 期黑色素瘤伴 V600E 或 V600K 突变患者随机分配，接受 12 个月的口服达布拉非尼（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。主要终点是无复发生存。在此，我们报告无复发生存和无远处转移生存（首次复发部位）的 5 年结果。由于尚未达到最终总生存分析所需的事件数，因此未分析总生存。
结果
随访的最短时间为 59 个月（中位患者随访时间，达布拉非尼联合曲美替尼为 60 个月，安慰剂为 58 个月）。5 年时，无复发生存的患者比例分别为达布拉非尼联合曲美替尼组为 52%（95%置信区间[CI]，48 至 58），安慰剂组为 36%（95% CI，32 至 41）（复发或死亡的风险比为 0.51；95%CI，0.42 至 0.61）。无远处转移的患者比例分别为达布拉非尼联合曲美替尼组为 65%（95%CI，61 至 71），安慰剂组为 54%（95%CI，49 至 60）（远处转移或死亡的风险比为 0.55；95%CI，0.44 至 0.70）。在随访期间，未报告组间严重不良事件的发生率或严重程度有任何临床意义的差异。
结论
在 III 期黑色素瘤伴 V600E 或 V600K 突变患者的 3 期试验 5 年随访中，与安慰剂相比，达布拉非尼联合曲美替尼辅助治疗 12 个月可延长无复发或远处转移的生存时间，且无明显的长期毒性作用。（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。）
Zotero 插件