对比纳武利尤单抗联合伊匹单抗与 BRAF 及 MEK 抑制剂治疗 BRAF 突变型晚期黑色素瘤的匹配调整间接比较。
A matching-adjusted indirect comparison of combination nivolumab plus ipilimumab with BRAF plus MEK inhibitors for the treatment of BRAF-mutant advanced melanoma.
机构信息
Departments of Cutaneous Oncology and Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, USA.
Evidence Synthesis and Decision Modeling, Precision HEOR, Vancouver, Canada.
出版信息
ESMO Open. 2021 Apr;6(2):100050. doi: 10.1016/j.esmoop.2021.100050. Epub 2021 Feb 6.
BACKGROUND
Approved first-line treatments for patients with BRAF V600-mutant advanced melanoma include nivolumab (a programmed cell death protein 1 inhibitor) plus ipilimumab (a cytotoxic T lymphocyte antigen-4 inhibitor; NIVO+IPI) and the BRAF/MEK inhibitors dabrafenib plus trametinib (DAB+TRAM), encorafenib plus binimetinib (ENCO+BINI), and vemurafenib plus cobimetinib (VEM+COBI). Results from prospective randomized clinical trials (RCTs) comparing these treatments have not yet been reported. This analysis evaluated the relative efficacy and safety of NIVO+IPI versus DAB+TRAM, ENCO+BINI, and VEM+COBI in patients with BRAF-mutant advanced melanoma using a matching-adjusted indirect comparison (MAIC).
PATIENTS AND METHODS
A systematic literature review identified RCTs for DAB+TRAM, ENCO+BINI, and VEM+COBI in patients with BRAF-mutant advanced melanoma. Individual patient-level data for NIVO+IPI were derived from the phase III CheckMate 067 trial (BRAF-mutant cohort) and restricted to match the inclusion/exclusion criteria of the comparator trials. Treatment effects for overall survival (OS) and progression-free survival (PFS) were estimated using Cox proportional hazards and time-varying hazard ratio (HR) models. Safety outcomes (grade 3 or 4 treatment-related adverse events) with NIVO+IPI and the comparators were compared.
RESULTS
In the Cox proportional hazards analysis, NIVO+IPI showed improved OS compared with DAB+TRAM (HR = 0.53; 95% confidence interval [CI], 0.39-0.73), ENCO+BINI (HR = 0.60; CI, 0.42-0.85), and VEM+COBI (HR = 0.50; CI, 0.36-0.70) for the overall study period. In the time-varying analysis, NIVO+IPI was associated with significant improvements in OS and PFS compared with the BRAF/MEK inhibitors 12 months after treatment initiation. There were no significant differences between NIVO+IPI and BRAF/MEK inhibitor treatment from 0 to 12 months. Safety outcomes favored DAB+TRAM over NIVO+IPI, whereas NIVO+IPI was comparable to VEM+COBI.
CONCLUSION
Results of this MAIC demonstrated durable OS and PFS benefits for patients with BRAF-mutant advanced melanoma treated with NIVO+IPI compared with BRAF/MEK inhibitors, with the greatest benefits noted after 12 months.
背景
批准的用于 BRAF V600 突变型晚期黑色素瘤患者的一线治疗方法包括纳武利尤单抗（一种程序性细胞死亡蛋白 1 抑制剂）加伊匹单抗（一种细胞毒性 T 淋巴细胞抗原 4 抑制剂；NIVO+IPI）和 BRAF/MEK 抑制剂达拉非尼加曲美替尼（DAB+TRAM）、恩考芬尼加比美替尼（ENCO+BINI）和维莫非尼加考比替尼（VEM+COBI）。尚未报告比较这些治疗方法的前瞻性随机临床试验（RCT）的结果。这项分析使用匹配调整间接比较（MAIC）评估了 NIVO+IPI 与 DAB+TRAM、ENCO+BINI 和 VEM+COBI 在 BRAF 突变型晚期黑色素瘤患者中的相对疗效和安全性。
患者和方法
系统文献检索确定了用于 BRAF 突变型晚期黑色素瘤患者的 DAB+TRAM、ENCO+BINI 和 VEM+COBI 的 RCT。纳武利尤单抗+伊匹单抗的个体患者水平数据来自 III 期 CheckMate 067 试验（BRAF 突变型队列），并限制为匹配比较试验的纳入/排除标准。使用 Cox 比例风险和时变风险比（HR）模型估计总生存期（OS）和无进展生存期（PFS）的治疗效果。比较了 NIVO+IPI 和比较药物的安全性结局（3 级或 4 级治疗相关不良事件）。
结果
在 Cox 比例风险分析中，与 DAB+TRAM（HR=0.53；95%置信区间 [CI]，0.39-0.73）、ENCO+BINI（HR=0.60；CI，0.42-0.85）和 VEM+COBI（HR=0.50；CI，0.36-0.70）相比，NIVO+IPI 显示出改善的 OS。在时变分析中，与 BRAF/MEK 抑制剂相比，NIVO+IPI 在治疗开始后 12 个月时与 OS 和 PFS 的显著改善相关。在 0 至 12 个月期间，NIVO+IPI 与 BRAF/MEK 抑制剂治疗之间没有显著差异。安全性结局有利于 DAB+TRAM 而非 NIVO+IPI，而 NIVO+IPI 与 VEM+COBI 相当。
结论
这项 MAIC 的结果表明，与 BRAF/MEK 抑制剂相比，NIVO+IPI 治疗 BRAF 突变型晚期黑色素瘤患者具有持久的 OS 和 PFS 获益，在治疗后 12 个月时获益最大。
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