BRAF抑制劑併用MEK抑制劑用於BRAF基因突變陽性黑色素細胞癌的系統性回顧與統合分析及臨床試驗計畫書

Abstract

晚期腫瘤無法切除或轉移的黑色素細胞癌帶有BRAF V600E基因突變的患者，給予BRAF抑制劑合併MEK抑制劑比上單獨使用BRAF抑制劑，能增加腫瘤緩解率(response rate)、疾病無惡化存活期(progression free survival)及整體存活期(overall survival)。目前對於帶有BRAF基因突變的黑色素細胞癌沒有直接比較不同組合的BRAF抑制劑合併MEK抑制劑之間療效與安全性差異的臨床試驗。 藉由網絡統合分析(network meta-analysis)比較三組不同的BRAF抑制劑合併MEK抑制劑 (dabrafenib-trametinib, vemurafenib-cobimetinib, and encorafenib- binimetinib)，各組之間療效與安全性的差異。經由系統性回顧，針對四個皆是BRAF抑制劑合併MEK抑制劑比上單獨使用BRAF抑制劑用於帶有BRAF基因突變的晚期黑色素細胞癌之臨床試驗進行統合分析。 統合分析主要針對疾病無惡化存活期(PFS)及整體存活期(OS)的風險比值(hazard ratio)與安全性的危險比值(risk ratio)，進行三組藥物的比較。疾病無惡化存活期及整體存活期的風險比值在三組藥物治療間，無統計上的顯著差異。在安全性的部分，dabrafenib-trametinib與單獨使用vemurafenib (RR 1.19, 95% CI 1.03–1.37)治療相比，以及與vemurafenib-cobimetinib (RR 1.47, 95% CI 1.22–1.77) 及encorafenib-binimetinib (RR 1.24, 95% CI 1.01–1.51) 相比，產生嚴重度3-5的不良事件(Grades 3-5 AE)風險最低，並且達到統計上的顯著差異。 因為目前沒有直接比較不同組合的BRAF抑制劑合併MEK抑制劑之間療效與安全性差異的臨床試驗，經由統合分析以間接比較的方式可以了解各組之間療效與安全性的差異，對於臨床上的運用可以作為一個參考依據。

For patients with unresectable advanced or metastatic melanoma with BRAF V600E mutation, administration of BRAF inhibitor combined with MEK inhibitor can improve response rate, progression free survival and overall survival when the combination compares to the single agent of BRAF inhibitor. However, BRAF inhibitor and MEK inhibitor combined treatments for BRAF-mutant melanoma are not placed in head-to-head clinical trials to compare efficacy and safety. This network meta-analysis evaluates the efficacy and safety of three combination therapies (dabrafenib plus trametinib, vemurafenib plus cobimetinib, and encorafenib plus binimetinib). We conducted a systematic review and meta-analysis of four clinical trials of BRAF inhibitor plus MEK inhibitor vs. BRAF inhibitor in the treatment of BRAF-mutant advanced malignant melanoma. Hazard ratio (HR) for overall survival (OS), progression free survival (PFS), and risk ratio (RR) for safety, along with 95% credible intervals (95% CI), are used to compare the treatments in this network meta-analysis. No significant differences were observed in OS and PFS among these three combined regimens. Lower risk of Grades 3-5 AE in the treatment of dabrafenib-trametinib is statistically significant in comparing with vemurafenib (RR 1.19, 95% CI 1.03–1.37), vemurafenib-cobimetinib (RR 1.47, 95% CI 1.22–1.77) and encorafenib-binimetinib (RR 1.24, 95% CI 1.01–1.51). No head-to-head studies have compared the combination of BRAFi and MEKi in BRAF-mutant melanoma. This analysis to characterize differences in efficacy and safety may be valuable for therapeutic decision making.