Improved survival with vemurafenib in melanoma with BRAF V600E mutation.
Improved survival with vemurafenib in melanoma with BRAF V600E mutation.
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DOI：
10.1056/nejmoa1103782
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发表时间：
2011-06-30
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影响因子：
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通讯作者：
BRIM-3 Study Group
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作者：
Chapman PB;Hauschild A;Robert C;Haanen JB;Ascierto P;Larkin J;Dummer R;Garbe C;Testori A;Maio M;Hogg D;Lorigan P;Lebbe C;Jouary T;Schadendorf D;Ribas A;O'Day SJ;Sosman JA;Kirkwood JM;Eggermont AM;Dreno B;Nolop K;Li J;Nelson B;Hou J;Lee RJ;Flaherty KT;McArthur GA;BRIM-3 Study Group
BRAF激酶抑制剂vemurafenib（PLX 4032）的1期和2期临床试验显示，BRAF V600 E突变转移性黑色素瘤患者的缓解率超过50%。我们进行了一项3期随机临床试验，在675例BRAF V600 E突变的既往未经治疗的转移性黑色素瘤患者中比较vemurafenib和达卡巴嗪。患者被随机分配接受vemurafenib（960 mg，口服，每日两次）或达卡巴嗪（每平方米体表面积1000 mg，静脉注射，每3周一次）。共同主要终点是总生存率和无进展生存率。次要终点包括缓解率、缓解持续时间和安全性。计划在196例死亡后进行最终分析，在98例死亡后进行中期分析。6个月时，维罗非尼组的总生存率为84%（95%置信区间[CI]，78 - 89），达卡巴嗪组为64%（95% CI，56 - 73）。在总生存期的中期分析和无进展生存期的最终分析中，与达卡巴嗪相比，vemurafenib与死亡风险相对降低63%和死亡或疾病进展风险相对降低74%相关（两项比较均P<0.001）。在独立数据和安全性监测委员会审查中期分析后，建议从达卡巴嗪交叉至维罗非尼。vemurafenib的应答率为48%，达卡巴嗪为5%。与vemurafenib相关的常见不良事件为关节痛、皮疹、疲劳、脱发、角化棘皮瘤或鳞状细胞癌、光敏性、恶心和腹泻; 38%的患者因毒性作用需要调整剂量。Vemurafenib提高了BRAF V600 E突变的既往未经治疗的黑色素瘤患者的总体和无进展生存率。（由Hoffmann-La Roche资助; BRIM-3 ClinicalTrials.gov编号，NCT 01006980。）
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. 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. 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. 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.)