Activity and safety of first-line treatments for advanced melanoma: A network meta-analysis

Background: 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 in-hibitors 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. Methods: Randomised clinical trials of previously untreated, advanced melanoma were in-cluded 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/nivo-lumab and relatlimab/nivolumab, and these combinations with all the other first-line treat-ment 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. Results: 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. Conclusion: Relatlimab/nivolumab showed similar PFS and ORR compared to ipilimumab/ nivolumab, with a trend for a better safety profile. (c) 2023 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Automated summary

The anti-LAG3 plus anti-PD-1 combination therapy has been approved as a treatment option for advanced melanoma. This study conducted a systematic review and network meta-analysis comparing different first-line treatment options in terms of progression-free survival, overall response rate, and treatment-related adverse events. The results showed that relatlimab/nivolumab had similar efficacy to ipilimumab/nivolumab but with a better safety profile.