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. 2023 Jul:188:64-79.
doi: 10.1016/j.ejca.2023.04.010. Epub 2023 Apr 24.

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

Andrea Boutros  1 , Enrica Teresa Tanda  2 , Elena Croce  3 , Fabio Catalano  3 , Marcello Ceppi  4 , Marco Bruzzone  4 , Federica Cecchi  2 , Luca Arecco  5 , Matteo Fraguglia  6 , Paolo Pronzato  2 , Carlo Genova  5 , Lucia Del Mastro  5 , Matteo Lambertini  5 , Francesco Spagnolo  7
Affiliations

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

Andrea Boutros et al. Eur J Cancer. 2023 Jul.

Abstract

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 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.

Methods: 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.

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.

Keywords: Advanced; BRAF; CTLA-4; Immunotherapy; Ipilimumab; LAG-3; Melanoma; Nivolumab; PD-1; Relatlimab.

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Conflict of interest statement

Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Prof. Genova reported receipt of Grants from Italian Ministry of Health and BMS, and Honoraria from AstraZeneca, BMS, Eli Lilly, MSD, Roche, Sanofi, Takeda, ThermoFisher. Prof. Del Mastro reported receipt of speaker Honoraria from Roche, Novartis, Eli Lilly and MSD; Travel Grants from Roche, Pfizer and Celgene; participation on Advisory Board for Roche, Novartis, MSD, Pfizer, Ipsen, AstraZeneca, Genomic Health, Eli Lilly, Seattle Genetics, Eisai, Pierre Fabre, and Daiichi Sankyo. Prof. Lambertini reported receipt of personal fees (advisory role and/or speaker honoraria) from Roche, Takeda, Sandoz, Eli Lilly, Pfizer, AstraZeneca, Novartis Exact Sciences and Ipsen. Prof. Spagnolo reported receipt of Honoraria for presentations or lectures from Sanofi Genzyme, Roche, BMS, Novartis, Merk, Sun Pharma, MSD, Pierre Fabre; participation on Advisory Board for Novartis, Philogen SunPharma, and MSD. The remaining authors declare no conflict of interest.

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