Background
Phase III double-blind RCT (RELATIVITY-047), N=714 untreated unresectable/metastatic melanoma. Stratified by PD-L1, BRAF V600 status, metastatic stage (M1a/M1b vs M1c/M1d), ECOG PS. 103 sites, enrolled 2019–2020. Relatlimab is an anti-LAG-3 antibody; relatlimab+nivolumab fixed-dose combination (Opdualag) is the first approved LAG-3 checkpoint inhibitor.
Interventions and follow up
Arm A: Relatlimab 160 mg + nivolumab 480 mg fixed-dose combination IV q4wk
Arm B: Nivolumab 480 mg IV q4wk
Primary endpoint: PFS
mFollow up: 33.8 mo (3-yr update, JCO 2025)
Arm B: Nivolumab 480 mg IV q4wk
Primary endpoint: PFS
mFollow up: 33.8 mo (3-yr update, JCO 2025)
Results
mPFS (primary, NEJM 2022): 10.1 vs 4.6 mo, HR 0.75 (95% CI 0.62–0.92), P=.006
mPFS (3-yr update): 10.2 vs 4.6 mo, HR 0.79 (95% CI 0.66–0.95)
mOS (3-yr update): 51.0 vs 34.1 mo, HR 0.80 (95% CI 0.66–0.99) — OS HR upper bound now <1
ORR: 43.7% vs 33.7%
mPFS (3-yr update): 10.2 vs 4.6 mo, HR 0.79 (95% CI 0.66–0.95)
mOS (3-yr update): 51.0 vs 34.1 mo, HR 0.80 (95% CI 0.66–0.99) — OS HR upper bound now <1
ORR: 43.7% vs 33.7%
Adverse events
Grade ≥3 AEs: 18.9% vs 9.7%
Immune-mediated AEs any grade: 35.3% vs 23.5%; grade ≥3: 7.7% vs 4.0%
Most common grade ≥3 immune AEs: hepatitis, rash, colitis
Discontinuation due to AE: 10.8% vs 5.4%; toxicity favorable vs ipi+nivo
Immune-mediated AEs any grade: 35.3% vs 23.5%; grade ≥3: 7.7% vs 4.0%
Most common grade ≥3 immune AEs: hepatitis, rash, colitis
Discontinuation due to AE: 10.8% vs 5.4%; toxicity favorable vs ipi+nivo
Conclusions
Relatlimab plus nivolumab significantly improved PFS vs nivolumab alone in untreated advanced melanoma (HR 0.75, P=.006). Three-year follow-up confirms sustained benefit with OS now significantly favoring the combination (HR 0.80, upper CI <1), establishing LAG-3 blockade as a clinically meaningful second checkpoint target.
Key Limitations
No head-to-head with nivolumab+ipilimumab (CheckMate 067), the most active doublet. OS benefit (HR 0.80) consistent but modest; superiority over PD-1 monotherapy in biomarker-unselected or LAG-3-high tumors not fully clarified. Comparator is nivolumab monotherapy. LAG-3 expression not required for enrollment; LAG-3-high subgroup benefit was retrospective, not pre-specified.
Clinical Context
FDA approved relatlimab+nivolumab fixed-dose combination (Opdualag) for unresectable/metastatic melanoma in March 2022 — the first LAG-3 checkpoint inhibitor approval in any cancer. Occupies a niche between PD-1 monotherapy (less effective, less toxic) and ipi+nivo (more effective, more toxic), favorable for patients not candidates for full-dose ipi+nivo. ESMO-MCBS: not yet scored at time of entry.