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LAG-3 and PD-1 blockade raises the bar for melanoma

Nature Cancer volume 2, pages 1251–1253 (2021)Cite this article

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Combination of approved immune checkpoint inhibitors has shown remarkable efficacy in the treatment of melanoma, but at the cost of high toxicity. After years of intensive research, inhibitors of the immune checkpoint molecule LAG-3 are now demonstrating promising results and favorable toxicity profiles in clinical trials in combination with inhibition of the checkpoint molecule PD-1.

For the past 10 years, melanoma has been at the forefront of advances in the development of immune checkpoint inhibitors (ICIs). Blockade of the immunoinhibitory receptor CTLA-4 with the monoclonal antibody ipilimumab was first to usher in the immunotherapy era, demonstrating an overall survival benefit in patients with metastatic melanoma, even with relatively low response rates (11–15%), and was approved by the US Food and Drug Administration in 2011 (ref. 1). Long-term remissions after treatment interruption suggested that ICIs could be curative for some patients with metastatic melanoma, but with this new therapy, a new toxicity spectrum of potentially severe immune-related adverse events (irAEs) (with grade 3 or 4 irAEs occurring in 24% of patients) also emerged. Both nivolumab and pembrolizumab, which are inhibitors of the checkpoint molecule PD-1, were approved in 2014, notably with an improved benefit/risk ratio relative to that of ipilimumab: response rates for both PD-1 inhibitors were around 40%, while grade 3 or 4 irAEs were seen in only ~15% patients2,3. Since then, these ICIs have become widely and routinely used to treat melanoma and many other tumor types.

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Fig. 1: Comparison of the combinations ipilimumab plus nivolumab and relatlimab plus nivolumab.

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Authors and Affiliations

  1. Department of Medicine, Dermatology Service, Gustave Roussy and Paris-Saclay University, INSERM U981, Villejuif, France

    Caroline Robert

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  1. Caroline Robert
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Correspondence to Caroline Robert.

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The author is a consultant for Bristol Myers Squibb, Merck Sharp & Dohme, Merck, Novartis, Roche, AstraZeneca, Pierre Fabre and Sanofi.

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Robert, C. LAG-3 and PD-1 blockade raises the bar for melanoma. Nat Cancer 2, 1251–1253 (2021). https://doi.org/10.1038/s43018-021-00276-8

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