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背景 BRAF激酶抑制剂vemurafenib(PLX4032)的1期和2期临床试验已证实其对伴BRAFV600E突变的转移性黑色素瘤患者的反应率超过50%。方法我们在675例既往未经治疗、伴BRAFV600E突变的转移性黑色素瘤患者中,实施了一项Ⅲ期随机化临床试验以比较vemurafenib和Dacarbazine(氮烯唑胺)。患者通过随机分配,分别接受vemurafenib(每次口服960mg,每天两次)或氮烯唑胺(每3周静脉注射1000mg·m-2体表面积)。本研究主要终点是比较总体生存率及无进展期生存率。次要终点包括反应率、反应持续时间以及安全性。计划在死亡98例患者时进行中期分析、死亡196例时进行最终分析。结果在治疗6个月后,vemurafenib组总体生存率为84%(95%置信区间[CI],78-89),而氮烯唑胺组为64%(95%CI,56-73)。在对总体生存率的中期分析及无进展期生存率的最终分析中,与氮烯唑胺相比,vemurafenib能相对减低63%的死亡风险,以及减低74%的死亡或者疾病进展风险(两种比较P<0.001)。通过数据及安全监督委员会进行独立中期分析审查后,建议氮烯唑胺组患者也转而服用vemurafenib。对Vemurafenib反应率是48%而氮烯唑胺只有5%。伴Vemurafenib常见不良反应为关节痛、皮疹、疲劳、脱发、角化棘皮瘤或鳞状细胞癌、光过敏、恶心和腹泻;38%的患者因为毒副作用要求调整剂量。结论 Vemurafenib能改善既往未经治疗、伴有BRAFV600E突变的黑色素瘤患者的总体及无进展期生存率。(本研究由瑞士罗氏制药有限公司资助;BRIM-3临床试验编号:NCT01006980)
Background Phase I and Phase II clinical trials of the BRAF kinase inhibitor vemurafenib (PLX4032) have demonstrated over 50% response to metastatic melanoma patients with the BRAFV600E mutation. Methods We conducted a phase III randomized clinical trial of 675 patients with metastatic melanoma who had previously untreated BRAFV600E mutations to compare vemurafenib and dacarbazine. Patients were randomized to receive either vemurafenib (960 mg orally twice daily) or dacarbazine (1000 mg · m-2 body surface every 3 weeks). The primary endpoint of this study was to compare overall survival and progression-free survival. Secondary endpoints included response rate, duration of response, and safety. An interim analysis is planned for 98 deaths and final analysis is performed when 196 patients die. Results Overall survival was 84% (95% confidence interval [CI], 78-89) in the vemurafenib group and 64% (95% CI, 56-73) in the dacarbazine group after 6 months of treatment. In a meta-analysis of overall survival and a final analysis of progression-free survival, vemurafenib reduced relative risk of death by 63% and risk of death by 74% or risk of disease progression compared to dacarbazine (both P <0.001 compared). Following an independent mid-term review by the Data and Safety Oversight Board, patients in the dacarbazine group were also advised to switch to vemurafenib. The response rate to Vemurafenib is 48% compared to 5% for dacarbazine. Common side effects with Vemurafenib are joint pain, rash, fatigue, alopecia, keratoacanthoma or squamous cell carcinoma, photosensitivity, nausea and diarrhea; 38% require dosage adjustments due to side effects. Conclusion Vemurafenib improves the overall and progression-free survival of previously untreated melanoma patients with the BRAFV600E mutation. (This study was funded by Roche Pharmaceuticals, Switzerland; BRIM-3 clinical trial number: NCT01006980)