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BACKGROUND. Relatlimab plus nivolumab (anti-lymphocyte-activation gene 3 plus anti-programmed death 1 [anti- [LAG3.sup.+]anti-PD-1]) has been approved by the FDA as a first-line therapy for stage III/IV melanoma, but its detailed effect on the immune system is unknown. METHODS. We evaluated blood samples from 40 immunotherapy-naive or prior immunotherapy-refractory patients with metastatic melanoma treated with anti-LAG-3+anti-PD-1 in a phase I trial using single-cell RNA and T cell receptor sequencing (scRNA+TCR[alpha][beta]-Seq) combined with other multiomics profiling. RESULTS. The highest LAG3 expression was noted in NK cells, Tregs, and [CD8.sup.+] T cells, and these cell populations underwent the most significant changes during the treatment. Adaptive NK cells were enriched in responders and underwent profound transcriptomic changes during the therapy, resulting in an active phenotype. [LAG3.sup.+] Tregs expanded, but based on the transcriptome profile, became metabolically silent during the treatment. Last, higher baseline TCR clonality was observed in responding patients, and their expanding [CD8.sup.+] T cell clones gained a more cytotoxic and NK-like phenotype. CONCLUSION. Anti-LAG-3+anti-PD-1 therapy has profound effects on NK cells and Tregs in addition to [CD8.sup.+] T cells. TRIAL REGISTRATION. ClinicalTrials.gov (NCT01968109) FUNDING. Cancer Foundation Finland, Sigrid Juselius Foundation, Signe and Ane Gyllenberg Foundation, Relander Foundation, State funding for university-level health research in Finland, a Helsinki Institute of Life Sciences Fellow grant, Academy of Finland (grant numbers 314442, 311081, 335432, and 335436), and an investigator-initiated research grant from BMS., Introduction Even though immune checkpoint inhibitor therapies have revolutionized the treatment of metastatic melanoma, a majority of patients fail to achieve sustainable responses. As currently available immune checkpoint inhibitor therapies [...]

Aim: First-line (1L) immunotherapy has yielded superior overall survival (OS) in metastatic melanoma (MM) but some patients are ineligible for immunotherapy or need rapid response with 1L targeted therapy (TT). Materials & methods: Retrospective cohort study of real-world patients treated with 1L immunotherapy (144 BRAF wild type, 85 BRAF -mutated) or 1L TT (143 BRAF -mutated) for MM in Finland during 2014-2021. Results: Baseline brain metastases, liver metastases and elevated LDH were less common, 2-year OS rates were higher (60.3-63.5% vs. 33.8%) and more patients were alive without the next-line treatment (38.0-43.8% vs. 23.3%) in patients with 1L immunotherapy. Conclusion: Real-world patients with 1L immunotherapy for MM had favorable baseline characteristics and better treatment outcomes than observed in patients with 1L TT.