维莫非尼治疗 BRAF(V600) 突变转移性黑色素瘤患者：一项开放性、多中心、安全性研究。
Vemurafenib in patients with BRAF(V600) mutated metastatic melanoma: an open-label, multicentre, safety study.
机构信息
Royal Marsden Hospital NHS Foundation Trust, London, UK.
Department of Medical Oncology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Nazionale dei Tumori, Milan, Italy.
出版信息
Lancet Oncol. 2014 Apr;15(4):436-44. doi: 10.1016/S1470-2045(14)70051-8. Epub 2014 Feb 27.
BACKGROUND
The orally available BRAF kinase inhibitor vemurafenib, compared with dacarbazine, shows improved response rates, progression-free survival (PFS), and overall survival in patients with metastatic melanoma that has a BRAF(V600) mutation. We assessed vemurafenib in patients with advanced metastatic melanoma with BRAF(V600) mutations who had few treatment options.
METHODS
In an open-label, multicentre study, patients with untreated or previously treated melanoma and a BRAF(V600) mutation received oral vemurafenib 960 mg twice a day. The primary endpoint was safety. All analyses were done on the safety population, which included all patients who received at least one dose of vemurafenib. This report is the third interim analysis of this study. This study is registered with ClinicalTrials.gov, number NCT01307397.
FINDINGS
Between March 1, 2011, and Jan 31, 2013, 3226 patients were enrolled in 44 countries. 3222 patients received at least one dose of vemurafenib (safety population). At data cutoff, 868 (27%) patients were on study treatment and 2354 (73%) had withdrawn, mainly because of disease progression. Common adverse events of all grades included rash (1592 [49%]), arthralgia (1259 [39%]), fatigue (1093 [34%]), photosensitivity reaction (994 [31%]), alopecia (826 [26%]), and nausea (628 [19%]). 1480 (46%) patients reported grade 3 or 4 adverse events, including cutaneous squamous cell carcinoma (389 [12%]), rash (155 [5%]), liver function abnormalities (165 [5%]), arthralgia (106 [3%]), and fatigue (93 [3%]). Grade 3 and 4 adverse events were reported more frequently in patients aged 75 years and older (n=257; 152 [59%, 95% CI 53-65] and ten [4%, 2-7], respectively) than in those younger than 75 years (n=2965; 1286 [43%, 42-45] and 82 [3%, 2-3], respectively).
INTERPRETATION
Vemurafenib safety in this diverse population of patients with BRAF(V600) mutated metastatic melanoma, who are more representative of routine clinical practice, was consistent with the safety profile shown in the pivotal trials of this drug.
FUNDING
F Hoffmann-La Roche.
背景
与达卡巴嗪相比，口服 BRAF 激酶抑制剂维莫非尼可提高伴有 BRAF(V600)突变的转移性黑色素瘤患者的反应率、无进展生存期（PFS）和总生存期。我们评估了维莫非尼在伴有 BRAF(V600)突变且治疗选择有限的晚期转移性黑色素瘤患者中的疗效。
方法
在一项开放性、多中心研究中，未经治疗或既往治疗的黑色素瘤患者和 BRAF(V600)突变患者接受口服维莫非尼 960mg，每日两次。主要终点是安全性。所有分析均在安全性人群中进行，该人群包括至少接受过一次维莫非尼治疗的所有患者。本报告是该研究的第三次中期分析。该研究在 ClinicalTrials.gov 注册，编号为 NCT01307397。
结果
2011 年 3 月 1 日至 2013 年 1 月 31 日期间，来自 44 个国家的 3226 名患者入组。3222 名患者接受了至少一剂维莫非尼（安全性人群）。数据截止时，868 名（27%）患者正在接受研究治疗，2354 名（73%）已停药，主要原因是疾病进展。所有等级的常见不良事件包括皮疹（1592 例[49%]）、关节痛（1259 例[39%]）、疲劳（1093 例[34%]）、光敏反应（994 例[31%]）、脱发（826 例[26%]）和恶心（628 例[19%]）。1480 例（46%）患者报告了 3 级或 4 级不良事件，包括皮肤鳞状细胞癌（389 例[12%]）、皮疹（155 例[5%]）、肝功能异常（165 例[5%]）、关节痛（106 例[3%]）和疲劳（93 例[3%]）。年龄 75 岁及以上的患者（n=257）报告 3 级和 4 级不良事件的频率高于年龄 75 岁以下的患者（n=2965），分别为 152 例（59%，95%CI 53-65）和 10 例（4%，2-7）和 1286 例（43%，42-45）和 82 例（3%，2-3）。
结论
在更具代表性的常规临床实践中，BRAF(V600) 突变转移性黑色素瘤患者中维莫非尼的安全性与该药物关键性试验中的安全性一致。
资金来源
F Hoffmann-La Roche。
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