Nivolumab and LAG-3 blockade could be new standard of care in melanoma

Details of relatlimab’s success in treating first-line unresectable or metastatic melanoma with nivolumab have finally been released, supporting the drug’s addition to oncologists’ immunotherapeutic armamentarium, clinicians say.

The RELATIVITY-047 paper supplements Melanoma Institute Australia Co-Medical Director Professor Georgina Long’s ASCO 2021 presentation, which highlighted the combination therapy’s efficacy over nivolumab monotherapy.

The first-in-class lymphocyte-activation gene 3 (LAG-3) inhibitor relatlimab helped double median progression-free survival (PFS) when used with nivolumab (PD-1 inhibitor) versus nivolumab alone (10.1 months versus 4.6), the study involving 714 patients with previously untreated metastatic or unresectable melanom found.

It also saw 47% of relatlimab-nivolumab patients survive progression free at 12 months, while nearly two thirds of nivolumab-only patients had progressive disease.

The treatment has been compared to ipilimumab- (CTLA-4 inhibitor) nivolumab therapy, which has a similar median PFS at 11.5 months, but a seemingly worse safety profile, UK-based oncologists noted in an accompanying editorial.

“Although the progression-free survival times observed with the two combination therapies are similar, the safety profile of relatlimab–nivolumab appears more favorable than that of nivolumab–ipilimumab,” they wrote.

While more patients on relatlimab-nivolumab had grade 3 or 4 treatment-related adverse events than those on monotherapy (19% versus 10%) in RELATIVITY-047, they seemed greatly outnumbered by nivolumab–ipilimumab patients in CheckMate 067, 59% of whom had same-grade effects.

Although Professor Long and colleagues’ RELATIVITY-047 paper warned “cross-trial comparisons should be made with caution”, the editorial authors doubt there’ll be head-to-head trials for these combinations, given the “stark” difference between toxic effects.

“As the data from the RELATIVITY-047 trial mature, if the survival benefit of relatlimab-nivolumab is shown to be similar to or better than that of nivolumab-ipilimumab, this finding would reinforce the relatlimab-nivolumab regimen as the new standard of care for previously untreated patients with advanced melanoma,” the editorial read.

This might hold particularly true for patients with ≥1% LAG-3 expression, however, patients with lower LAG-3 levels may “derive more benefit from receiving [nivolumab-ipilimumab] as first-line therapy, followed by anti–LAG-3 as second-line therapy,” Professor Long and her team wrote.

LAG-3 is a cell-surface receptor found on T-cells which has binding sites with high-affinity for major histocompatibility complex class II and “functions to directly inhibit T-cell activation”, the paper and editorial explained.

It is upregulated in tumours such as melanoma and often co-expressed on tumour-infiltrating lymphocytes with PD-1 and so, contribute to T-cell exhaustion, Professor Long and co’s paper added.

By binding its receptor, human IgG4 antibody relatlimab blocks LAG-3 and “restores the effector function of exhausted T cells”.

The drug has shown synergistic activity when used with PD-1 inhibitors in pre-clinical trials, the RELATIVITY-047 paper noted.

While new biomarkers are needed to predict immune checkpoint inhibitors’ efficacy and safety in individual patients’, “these data further support the added benefit of dual checkpoint inhibition over monotherapy, add another immune checkpoint combination to the therapeutic armamentarium, and establish relatlimab–nivolumab as a potential new treatment option for patients with previously untreated metastatic or unresectable melanoma,” the articles concluded.

The study is available in the New England Journal of Medicine and was funded by Bristol Myers Squibb.

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