Vemurafenib in patients with BRAFV600 mutated metastatic melanoma: an open-label, multicentre, safety study
Vemurafenib in patients with BRAFV600 mutated metastatic melanoma: an open-label, multicentre, safety study
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DOI：
10.1016/s1470-2045(14)70051-8
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发表时间：
2014-04-01
期刊：
影响因子：
51.1
通讯作者：
Blank, Christian U.
中科院分区：
文献类型：
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作者：
Larkin, James;Del Vecchio, Michele;Blank, Christian U.
口服BRAF激酶抑制剂维罗非尼与达卡巴嗪相比，在BRAF（V600）突变的转移性黑色素瘤患者中显示出改善的缓解率、无进展生存期（PFS）和总生存期。我们评估vemurafenib在晚期转移性黑色素瘤患者BRAF（V600）突变谁有几个治疗选项。方法在一项开放标签，多中心研究，未经治疗或以前治疗的黑色素瘤和BRAF（V600）突变的患者接受口服vemurafenib 960毫克，每天两次。主要终点是安全性。所有分析均针对安全性人群进行，其中包括至少接受一剂维罗菲尼的所有患者。本报告是本研究的第三次中期分析。该研究在ClinicalTrials.gov注册，编号NCT 01307397。结果在2011年3月1日至2013年1月31日期间，在44个国家招募了3226名患者。3222例患者接受了至少一剂维罗非尼（安全性人群）。在数据截止时，868例（27%）患者正在接受研究治疗，2354例（73%）患者退出研究，主要原因是疾病进展。所有级别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%]）和疲乏（93例[3%]）。年龄≥ 75岁的患者更常报告3级和4级不良事件（n= 257; 152 [59%，95% CI 53- 65]和10 [4%，2- 7]）（n= 2965;分别为1286 [43%，42- 45]和82 [3%，2- 3]）。解释维罗非尼在BRAF（V600）突变转移性黑色素瘤患者（更能代表常规临床实践）的多样化人群中的安全性与该药物关键试验中显示的安全性特征一致。
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 At data cutoff, 868 (27%) patients were on study treatment and 2354 (73%) had withdrawn, mainly because of disease progression.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.