{"entity":{"id":"paper-relativity-047-nejm-2022","kind":"paper","name":"RELATIVITY-047: relatlimab plus nivolumab, the first LAG-3 checkpoint combination, in untreated advanced melanoma","aka":[],"tldr":"Adding an antibody against a second immune brake, LAG-3, to nivolumab delayed progression in advanced melanoma compared with nivolumab alone, with far fewer serious side effects than the ipilimumab combination.","summary":"Double-blind phase 3 trial of 714 patients with untreated advanced melanoma randomised to a fixed-dose combination of relatlimab (anti-LAG-3) and nivolumab or nivolumab alone. Primary endpoint was PFS by blinded review.\n\nMedian PFS was 10.1 vs 4.6 months (HR 0.75). Grade 3-4 treatment-related adverse events were 18.9% vs 9.7%, much lower than the roughly 55-59% seen with nivolumab plus ipilimumab. It validated LAG-3 as the third checkpoint target after CTLA-4 and PD-1, led to FDA approval of the combination (Opdualag) in 2022, and provided a gentler dual-checkpoint option.","asOf":"2026-09-08","links":[{"label":"NEJM 2022","url":"https://doi.org/10.1056/NEJMoa2109970"},{"label":"ClinicalTrials.gov NCT03470922","url":"https://clinicaltrials.gov/study/NCT03470922"}],"tags":[],"related":[],"cancers":["melanoma"],"sections":[],"technologies":["checkpoint-inhibitor"],"targets":["lag3","pd1"],"drugs":["relatlimab-nivolumab","nivolumab"],"companies":["bms"],"institutions":["md-anderson"],"pathways":[],"terms":["pfs","os","irae","first-line"],"trials":["checkmate-067"],"people":[],"bottlenecks":["b-immunotherapy-response","b-toxicity-qol","b-combination-space"],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2022,"doi":"10.1056/NEJMoa2109970","authors":"Tawbi HA, Schadendorf D, Lipson EJ, et al.","paperType":"rct","findings":["Median PFS 10.1 vs 4.6 months; HR 0.75 (95% CI 0.62-0.92); 12-month PFS 47.7% vs 36.0%.","Benefit consistent across LAG-3 and PD-L1 expression subgroups, so neither is used for selection.","Grade 3-4 treatment-related adverse events 18.9% vs 9.7%; discontinuation for toxicity 14.6% vs 6.7%.","Overall survival (updated analysis): median 51.0 vs 34.1 months, HR 0.80, not meeting the prespecified significance threshold.","Objective response 43.1% vs 32.6% in later analyses."],"whatItMeans":"Patients with newly diagnosed advanced melanoma have a dual-checkpoint option that improves on nivolumab alone with only a modest increase in serious side effects, making it attractive for those unable to tolerate or unwilling to risk the toxicity of ipilimumab. It did not prove superior survival, and it has not been compared with nivolumab plus ipilimumab, which remains preferred for patients with brain metastases or other high-risk features. LAG-3 is now an established target under study in many other cancers.","caveats":["Overall survival improvement did not reach statistical significance.","No head-to-head comparison with nivolumab plus ipilimumab; indirect comparisons suggest the ipilimumab combination may be more active in poor-prognosis subgroups.","Patients with active brain metastases were excluded.","Whether relatlimab adds benefit in other tumours is not yet demonstrated in phase 3."],"changedPractice":true,"participants":714},"route":"/key-papers/paper-relativity-047-nejm-2022/","neighbours":{"cancer":[{"id":"advanced-melanoma","kind":"cancer","name":"Advanced melanoma (unresectable stage III and stage IV)","route":"/cancers/advanced-melanoma/"},{"id":"melanoma","kind":"cancer","name":"Melanoma","route":"/cancers/melanoma/"}],"technology":[{"id":"checkpoint-inhibitor","kind":"technology","name":"Immune checkpoint inhibitors","route":"/technologies/checkpoint-inhibitor/"}],"target":[{"id":"lag3","kind":"target","name":"LAG-3","route":"/targets/lag3/"},{"id":"pd1","kind":"target","name":"PD-1","route":"/targets/pd1/"}],"drug":[{"id":"nivolumab","kind":"drug","name":"Nivolumab","route":"/drugs/nivolumab/"},{"id":"relatlimab-nivolumab","kind":"drug","name":"Relatlimab + nivolumab","route":"/drugs/relatlimab-nivolumab/"}],"company":[{"id":"bms","kind":"company","name":"Bristol Myers Squibb","route":"/companies/bms/"}],"institution":[{"id":"md-anderson","kind":"institution","name":"MD Anderson Cancer Center","route":"/institutions/md-anderson/"}],"term":[{"id":"irae","kind":"term","name":"Immune-related adverse events (irAEs)","route":"/terms/irae/"},{"id":"first-line","kind":"term","name":"Lines of therapy","route":"/terms/first-line/"},{"id":"os","kind":"term","name":"Overall survival (OS)","route":"/terms/os/"},{"id":"pfs","kind":"term","name":"Progression-free survival (PFS)","route":"/terms/pfs/"}],"trial":[{"id":"checkmate-067","kind":"trial","name":"CheckMate 067","route":"/trials/checkmate-067/"},{"id":"relativity-047","kind":"trial","name":"RELATIVITY-047","route":"/trials/relativity-047/"}],"bottleneck":[{"id":"b-immunotherapy-response","kind":"bottleneck","name":"No one can predict who responds to immunotherapy","route":"/bottlenecks/b-immunotherapy-response/"},{"id":"b-combination-space","kind":"bottleneck","name":"Too many combinations to test","route":"/bottlenecks/b-combination-space/"},{"id":"b-toxicity-qol","kind":"bottleneck","name":"Toxicity and quality of life are undervalued","route":"/bottlenecks/b-toxicity-qol/"}],"journal":[{"id":"nejm","kind":"journal","name":"New England Journal of Medicine","route":"/journals/nejm/"}],"person":[{"id":"hussein-tawbi","kind":"person","name":"Hussein A. Tawbi","route":"/people/hussein-tawbi/"}]}}