Dual checkpoint blockade beyond clinical trials: Real-world experience with nivolumab-relatlimab in advanced melanoma.

BACKGROUND: Nivolumab-relatlimab, a dual immune checkpoint inhibitor targeting PD-1 and LAG-3, has demonstrated improved outcomes compared with nivolumab monotherapy in previously untreated advanced melanoma. However, real-world data in broader and less selected populations remain limited. METHODS: We conducted a multicenter retrospective study across 10 oncology centers in Israel, including adults with unresectable or metastatic melanoma treated with first-line nivolumab-relatlimab. Endpoints included overall survival (OS), progression-free survival (PFS), melanoma-specific survival (MSS), objective response rate (ORR), and safety. Predictors of outcomes were explored using multivariable analyses. RESULTS: A total of 117 patients were included. The cohort was older and clinically frailer than those enrolled in pivotal trials (median age 75 years; 38% aged ≥80 years). The ORR was 69.8%, including a complete response rate of 43.6%. Median PFS was 18.6 months, while median OS and MSS were not reached; 12-month OS was 74.1%. Grade 3-4 adverse events occurred in 11% of patients, and treatment discontinuation due to toxicity in 14.5%, predominantly among patients aged ≥80 years. In multivariable analyses, liver and/or bone metastases and prior neo- or adjuvant therapy were associated with inferior outcomes. A higher-than-anticipated rate of neurologic toxicity was observed. CONCLUSIONS: In routine clinical practice, nivolumab-relatlimab demonstrated high response rates and durable disease control despite an older and frailer population than in clinical trials. These findings support its use as a frontline option while identifying subgroups with poorer outcomes who may benefit from alternative strategies.