CHECKPOINT blockade has transformed outcomes in metastatic melanoma. Combinations of PD-1 and CTLA-4 inhibitors, such as nivolumab plus ipilimumab, have achieved long-term survival rates exceeding those seen with nivolumab alone. More recently, attention has turned to LAG-3, which is often co-expressed with PD-1 on tumour-infiltrating lymphocytes and contributes to suppression of T-cell activity. Relatlimab, the first antibody developed to block LAG-3, has been combined with nivolumab in a fixed-dose regimen. This approach was shown to improve progression-free survival compared with nivolumab alone, with the benefit sustained at three years of follow-up. Overall survival also showed early signs of advantage, which became more pronounced over time.
The four-year analysis strengthens the evidence of durability across outcomes. Melanoma-specific survival at three years favoured the combination, and by four years, the overall survival advantage was clearer, with the survival curves continuing to separate. Median melanoma-specific survival had not yet been reached with the combination, compared with just under four years for nivolumab alone. Although rates of severe treatment-related adverse events were higher than with monotherapy, they remained substantially lower than those seen with other immunotherapy combinations, pointing to a more favourable balance between efficacy and tolerability.
Biomarker analyses continue to provide insights but have not yet established clear rules for patient selection. PD-L1 expression has not consistently predicted benefit, although recent data suggest a trend towards improved outcomes in tumours with PD-L1 expression of at least 1%. Similarly, patients with LAG-3–positive immune infiltrates tended to respond better across both treatment arms, reflecting the broader biology of inflamed tumours rather than predicting superiority of one regimen.
Safety findings have remained consistent with earlier reports, with clinical benefit often persisting even after treatment discontinuation due to side effects. Patterns of subsequent therapy use were similar across groups, though patients on monotherapy appeared to need more lines of follow-up treatment.
Taken together, the four-year results of RELATIVITY-047 confirm nivolumab plus relatlimab as a durable, less toxic dual-checkpoint option for patients with advanced melanoma, while highlighting the need for biomarkers to guide treatment choice between LAG-3/PD-1 and CTLA-4/PD-1 combinations.
Reference
Lipson EJ et al. Nivolumab plus relatlimab in advanced melanoma: RELATIVITY-047 4-year update. Eur J Cancer. 2025;225:115547.
