Treatment options for advanced melanoma have recently increased with the introduction of the anti-LAG3 and anti-PD-1 relatlimab/nivolumab combination. To date, ipilimumab/nivolumab is the benchmark of overall survival (OS), 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 (RCTs) 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 co-primary endpoints were progression-free survival (PFS), overall response rate (ORR) and grade ≥3 treatment-related adverse events (TRAEs) rate, defined according to Common Terminology Criteria for Adverse Events (CTCAE).
A total of 9070 patients treated in 18 first-line clinical trials of metastatic melanoma were included in the network meta-analysis. No difference in PFS nor ORR between ipilimumab/nivolumab and relatlimab/nivolumab was observed (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 was superior to ipilimumab/nivolumab in terms of PFS (HR=0.56 [95%CI 0.37 – 0.84]) and ORR (RR=3.07 [95%CI 1.61 – 5.85]). Relatlimab/nivolumab showed a trend to a lower risk of grade ≥3 TRAEs (RR=0.71 [95%CI 0.30 – 1.67]) compared to ipilimumab/nivolumab, which showed the highest probability of grade ≥3 TRAEs.
Relatlimab/nivolumab showed similar PFS and ORR compared to ipilimumab/nivolumab, with a trend for a better safety profile. The PD-(L)1/BRAF/MEK inhibitors triplet combinations showed the highest probability to achieve better PFS and ORR.
PROSPERO registration number: CRD42022303279.
The authors.
Has not received any funding.
L. Del Mastro: Financial Interests, Personal, Invited Speaker, Educational meeting: Novartis, Symposia, Andromeda E20, Vyvamed srl; Financial Interests, Personal, Invited Speaker, Lecture: Ipsen; Financial Interests, Personal, Advisory Board, Her2+ and TN breast cancer: Roche; Financial Interests, Personal, Invited Speaker, Consultancy for TNBC text: Roche; Financial Interests, Personal, Advisory Board, denosumab: Amgen; Financial Interests, Personal, Advisory Board, Early and metastatic BC: Eli Lilly; Financial Interests, Personal, Invited Speaker, CDK4-6 inhibitors: Eli Lilly; Financial Interests, Personal, Advisory Board, tucatinib: Seagen Int; Financial Interests, Personal, Advisory Board, Oncotype dx: Exact sciences, Havas life; Financial Interests, Personal, Advisory Board, Neratinib: Pierre Fabre; Financial Interests, Personal, Invited Speaker, Internal training: MSD; Financial Interests, Personal, Invited Speaker, Educational meetings: Accademia Nazionale Medicina; Financial Interests, Personal, Invited Speaker, Author for BC text: Pensiero Scientifico Editore; Financial Interests, Personal, Advisory Board, Breast cancer: Uvet; Financial Interests, Personal, Other, Author slide kits and interviews: Think2it; Financial Interests, Personal, Advisory Board, Palbociclib: Pfizer; Financial Interests, Personal, Invited Speaker, Breast cancer: Aristea, Meeting SrL; Financial Interests, Personal, Other, Author slide kits: Forum service; Financial Interests, Personal, Other, Author text about biosimilars: Edizioni Minerva Medica; Financial Interests, Personal, Other, consultant: Kardo srl; Financial Interests, Personal, Invited Speaker, Breast cancer meetings: Delphi international, Over srl; Financial Interests, Personal, Invited Speaker: Prex Srl, Editree; Financial Interests, Personal, Advisory Board: Uvet, Collage SpA, Daiichi Sankyo, AstraZeneca; Financial Interests, Personal, Other, Interview: Infomedica srl; Financial Interests, Personal, Other, Consultant: Sharing progress in cancer care - Switzerland; Financial Interests, Institutional, Funding, National coordinating PI: Roche; Financial Interests, Institutional, Funding, Local PI: AstraZeneca, Roche, Eli Lilly, Daiichi Sankyo, Novella Clinical, Novartis; Non-Financial Interests, Institutional, Product Samples, Genomic Test: FoundationOne. M. Lambertini: Financial Interests, Personal, Advisory Board: Roche, AstraZeneca, Lilly, Novartis, Exact Sciences, MSD, Seagen, Gilead; Financial Interests, Personal, Invited Speaker: Pfizer, Takeda, Sandoz, Ipsen, Libbs, Knight. F. Spagnolo: Financial Interests, Personal, Invited Speaker: Sanofi Genzyme, Roche, BMS, Novartis, Merck, Sunpharma, MSD, Pierre Fabre; Financial Interests, Personal, Advisory Board: Novartis, Philogen, Sunpharma, MSD. All other authors have declared no conflicts of interest.