BRAF V600E 突变型黑色素瘤患者采用威罗菲尼治疗后生存改善。
Improved survival with vemurafenib in melanoma with BRAF V600E mutation.
机构信息
Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
出版信息
N Engl J Med. 2011 Jun 30;364(26):2507-16. doi: 10.1056/NEJMoa1103782. Epub 2011 Jun 5.
BACKGROUND
Phase 1 and 2 clinical trials of the BRAF kinase inhibitor vemurafenib (PLX4032) have shown response rates of more than 50% in patients with metastatic melanoma with the BRAF V600E mutation.
METHODS
We conducted a phase 3 randomized clinical trial comparing vemurafenib with dacarbazine in 675 patients with previously untreated, metastatic melanoma with the BRAF V600E mutation. Patients were randomly assigned to receive either vemurafenib (960 mg orally twice daily) or dacarbazine (1000 mg per square meter of body-surface area intravenously every 3 weeks). Coprimary end points were rates of overall and progression-free survival. Secondary end points included the response rate, response duration, and safety. A final analysis was planned after 196 deaths and an interim analysis after 98 deaths.
RESULTS
At 6 months, overall survival was 84% (95% confidence interval [CI], 78 to 89) in the vemurafenib group and 64% (95% CI, 56 to 73) in the dacarbazine group. In the interim analysis for overall survival and final analysis for progression-free survival, vemurafenib was associated with a relative reduction of 63% in the risk of death and of 74% in the risk of either death or disease progression, as compared with dacarbazine (P<0.001 for both comparisons). After review of the interim analysis by an independent data and safety monitoring board, crossover from dacarbazine to vemurafenib was recommended. Response rates were 48% for vemurafenib and 5% for dacarbazine. Common adverse events associated with vemurafenib were arthralgia, rash, fatigue, alopecia, keratoacanthoma or squamous-cell carcinoma, photosensitivity, nausea, and diarrhea; 38% of patients required dose modification because of toxic effects.
CONCLUSIONS
Vemurafenib produced improved rates of overall and progression-free survival in patients with previously untreated melanoma with the BRAF V600E mutation. (Funded by Hoffmann-La Roche; BRIM-3 ClinicalTrials.gov number, NCT01006980.).
背景
BRAF 激酶抑制剂 vemurafenib（PLX4032）的 I 期和 II 期临床试验显示，携带 BRAF V600E 突变的转移性黑色素瘤患者的反应率超过 50%。
方法
我们进行了一项 III 期随机临床试验，比较了 vemurafenib 与达卡巴嗪在 675 例未经治疗的转移性黑色素瘤患者中的疗效，这些患者携带 BRAF V600E 突变。患者被随机分配接受 vemurafenib（每天口服 2 次，每次 960mg）或达卡巴嗪（每平方米体表面积静脉注射 1000mg，每 3 周 1 次）。主要终点是总生存率和无进展生存率。次要终点包括反应率、反应持续时间和安全性。在 196 例死亡后进行最终分析，在 98 例死亡后进行中期分析。
结果
在 6 个月时，vemurafenib 组的总生存率为 84%（95%置信区间[CI]，78 至 89），达卡巴嗪组为 64%（95%CI，56 至 73）。在中期分析的总生存率和最终分析的无进展生存率中，与达卡巴嗪相比，vemurafenib 降低了 63%的死亡风险和 74%的死亡或疾病进展风险（两者均<0.001）。在一个独立的数据和安全监测委员会对中期分析进行审查后，建议从达卡巴嗪交叉使用 vemurafenib。vemurafenib 的反应率为 48%，达卡巴嗪为 5%。与 vemurafenib 相关的常见不良反应包括关节痛、皮疹、乏力、脱发、角化棘皮瘤或鳞状细胞癌、光敏性、恶心和腹泻；由于毒性作用，38%的患者需要调整剂量。
结论
vemurafenib 提高了未经治疗的携带 BRAF V600E 突变的黑色素瘤患者的总生存率和无进展生存率。（由 Hoffmann-La Roche 资助；BRIM-3 ClinicalTrials.gov 编号，NCT01006980）。
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