Management of metastatic melanoma with combinations including PD-1 inhibitors

INTRODUCTION: Melanoma is among the most immunogenic malignancies. The advent of immune checkpoint inhibitors (ICIs) has revolutionized the landscape of melanoma treatment. Long-term durable cancer control is possible in nearly 50% of non-resectable, metastatic melanoma patients with anti-CTLA4 and anti-PD-1 antibodies. AREAS COVERED: This review provides a critical overview of the current data and future research directions on the management of metastatic melanoma with ICIs. We reviewed the efficacy and safety of combinations with PD-1 inhibitors through PubMed database research (Nov 2024-Mar 2025). EXPERT OPINION: A decade after ipilimumab's approval, challenges remain. To cure more patients, the development of combinations is warranted. Combinations with a limited number of ipilimumab applications improve the overall survival outcome by approximately 10%, with a dramatic increase in adverse events including fatal events. Anti-LAG3/nivolumab is a promising alternative, offering similar efficacy to ipilimumab/nivolumab with better tolerability. In our opinion, ipilimumab/nivolumab combination should be the first-line therapy for high-risk patients (high LDH, brain or liver metastasis), while nivolumab/relatlimab or PD-1 monotherapy may be preferable for lower-risk cases. However, treatment decisions are increasingly complex, since most patients nowadays are pretreated in the (neo)-adjuvant setting. The key limitation today is the lack of biomarkers to guide individualized treatment strategies.