A Shift in the Treatment of Advanced Melanoma

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Answers to questions about first-line treatment of metastatic melanoma are “going to be shifting,” Jason J. Luke, MD, told The ASCO Post, with the change coming on the heels of the phase III RELATIVITY-047 trial reported at the 2021 ASCO Annual Meeting.1

That abstract reported that using two immunotherapy agents blocking different checkpoints—nivolumab blocking PD-1 and relatlimab blocking LAG-3 (lymphocyte-activation gene 3)—produced a statistically significant benefit in progression-free survival compared with nivolumab alone in patients with advanced melanoma. The median progression-free survival was 10.1 months with nivolumab plus relatlimab vs 4.6 months with nivolumab alone.

“That is probably going to become the new first-line standard of care for melanoma,” commented Dr. Luke, who was the discussant for the abstract. “It sets up a paradigm where we have a very robust regimen of inhibition of the PD-1 and LAG-3 pathways as first-line therapy, and it will make a lot of sense then to go to second line with inhibition of the PD-1 and CTLA-4 pathways,” using a low-dose anti–CTLA-4 antibody.

Dr. Luke is Director of the Cancer Immunotherapeutics Center and Associate Professor of Medicine at UPMC Hillman Cancer Center in Pittsburgh and corresponding author of a recently reported study finding that nearly 30% of patients with advanced melanoma refractory to an anti–PD-1/L1 antibody responded to pembrolizumab plus low-dose ipilimumab.2

In an interview with The ASCO Post prior to the 2021 ASCO Annual Meeting, Dr. Luke noted: “One of the interesting questions [in RELATIVITY-047] was whether patients who experience disease progression on adjuvant postsurgical treatment would be given a LAG-3 combination or a CTLA-4 combination. In those patients, I might still defer to giving the PD-1/CTLA-4 regimen, because we have more historical experience than just this new abstract for LAG-3. Those patients tend to be at very high risk,” and as noted in the study report, “the therapy seems to be pretty active across the different clinical cohorts. Even in high-risk disease, we saw long-term responders, so, I am going to be a little bit cautious about going away from that to the new combination until there are more robust data to support it.” 


1. Lipson EJ, Tawbi HAH, Schadendorf K, et al: Relatlimab plus nivolumab versus nivolumab in first-line advanced melanoma: Primary phase III results from RELATIVITY-047 (CA224-047). 2021 ASCO Annual Meeting. Abstract 9503. Presented June 6, 2021.

2. Olson DJ, Eroglu Z, Brockstein B, et al: Pembrolizumab plus ipilimumab following anti-PD-1/L1 failure in melanoma. J Clin Oncol. May 4, 2012 (early release online).

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