Department of Medical Oncology, Oncologia Medica 2, IRCCS Ospedale Policlinico San Martino, Genoa, Italy; Department of Internal Medicine and Medical Specialties (DiMI), School of Medicine, University of Genova, Genoa, Italy.
Department of Medical Oncology, Oncologia Medica 2, IRCCS Ospedale Policlinico San Martino, Genoa, Italy.
Eur J Cancer. 2023 Jul;188:64-79. doi: 10.1016/j.ejca.2023.04.010. Epub 2023 Apr 24.
Treatment options for advanced melanoma have increased with the US Food and Drug Administration approval of the anti-LAG3 plus anti-PD-1 relatlimab/nivolumab combination. To date, ipilimumab/nivolumab is the benchmark of overall survival, despite a high toxicity profile. Furthermore, in BRAF-mutant patients, BRAF/MEK inhibitors and the atezolizumab/vemurafenib/cobimetinib triplet are also available treatments, making the first-line therapy selection more complex. To address this issue, we conducted a systematic review and network meta-analysis of the available first-line treatment options in advanced melanoma.
Randomised clinical trials of previously untreated, advanced melanoma were included if at least one intervention arm contained a BRAF/MEK or an immune-checkpoint inhibitor (ICI). The aim was to indirectly compare the ICIs combinations ipilimumab/nivolumab and relatlimab/nivolumab, and these combinations with all the other first-line treatment options for advanced melanoma (irrespective of BRAF status) in terms of activity and safety. The coprimary end-points were progression-free survival (PFS), overall response rate (ORR) and grade ≥3 treatment-related adverse events (≥ G3 TRAEs) rate, defined according to Common Terminology Criteria for Adverse Events.
A total of 9070 metastatic melanoma patients treated in 18 randomised clinical trials were included in the network meta-analysis. No difference in PFS and ORR was observed between ipilimumab/nivolumab and relatlimab/nivolumab (HR = 0.99 [95% CI 0.75-1.31] and RR = 0.99 [95% CI 0.78-1.27], respectively). The PD-(L)1/BRAF/MEK inhibitors triplet combinations were superior to ipilimumab/nivolumab in terms of both PFS (HR = 0.56 [95% CI 0.37-0.84]) and ORR (RR = 3.07 [95% CI 1.61-5.85]). Ipilimumab/nivolumab showed the highest risk of developing ≥ G3 TRAEs. Relatlimab/nivolumab trended to a lower risk of ≥ G3 TRAEs (RR = 0.71 [95% CI 0.30-1.67]) versus ipilimumab/nivolumab.
Relatlimab/nivolumab showed similar PFS and ORR compared to ipilimumab/nivolumab, with a trend for a better safety profile.
随着美国食品和药物管理局批准抗 LAG3 联合抗 PD-1 的 relatlimab/nivolumab 组合，晚期黑色素瘤的治疗选择有所增加。迄今为止，尽管毒性较高，但 ipilimumab/nivolumab 仍是总生存期的基准。此外，在 BRAF 突变型患者中，BRAF/MEK 抑制剂和 atezolizumab/vemurafenib/cobimetinib 三联疗法也是可用的治疗方法，这使得一线治疗选择更加复杂。为了解决这个问题，我们对晚期黑色素瘤的现有一线治疗选择进行了系统评价和网络荟萃分析。
如果至少有一个干预臂包含 BRAF/MEK 或免疫检查点抑制剂（ICI），则纳入未经治疗的晚期黑色素瘤的随机临床试验。目的是间接比较 ICI 联合 ipilimumab/nivolumab 和 relatlimab/nivolumab 以及这些联合疗法与所有其他晚期黑色素瘤的一线治疗选择（无论 BRAF 状态如何）在活性和安全性方面的差异。主要终点是无进展生存期（PFS）、总缓解率（ORR）和≥3 级治疗相关不良事件（≥G3 TRAE）发生率，根据不良事件常用术语标准定义。
共有 18 项随机临床试验中 9070 例转移性黑色素瘤患者纳入网络荟萃分析。Ipilimumab/nivolumab 和 relatlimab/nivolumab 之间在 PFS 和 ORR 方面无差异（HR=0.99[95%CI 0.75-1.31]和 RR=0.99[95%CI 0.78-1.27]）。PD-(L)1/BRAF/MEK 抑制剂三联疗法在 PFS（HR=0.56[95%CI 0.37-0.84]）和 ORR（RR=3.07[95%CI 1.61-5.85]）方面均优于 ipilimumab/nivolumab。Ipilimumab/nivolumab 发生≥G3 TRAE 的风险最高。与 ipilimumab/nivolumab 相比，Relatlimab/nivolumab 有降低发生≥G3 TRAE 风险的趋势（RR=0.71[95%CI 0.30-1.67]）。
Relatlimab/nivolumab 与 ipilimumab/nivolumab 相比，PFS 和 ORR 相似，且安全性更好。
