Targeting LAG-3 and PD-1 With Relatlimab and Nivolumab: A New Option Under Study in Advanced Melanoma

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Immune checkpoint inhibition has been established as an effective treatment for patients with metastatic melanoma. A novel immunotherapeutic combination—this one targeting the LAG-3 (lymphocyte-activation gene 3) and PD-1 immune checkpoints—delayed the time to disease progression significantly more than nivolumab (anti–PD-1) alone in a study presented at the 2021 ASCO Annual Meeting.1

Initial findings from the global, randomized, registrational phase III RELATIVITY-047 trial1 were presented at a press briefing prior to the meeting by Evan J. Lipson, MD, Associate Professor of Oncology at the Johns Hopkins Kimmel Cancer Center and Bloomberg~Kimmel Institute for Cancer Immunotherapy in Baltimore.

Evan J. Lipson, MD

Evan J. Lipson, MD

“Patients who received relatlimab plus nivolumab had a median progression-free survival of 10.1 months—more than double that of patients who received nivolumab alone (4.6 months). This significant improvement meant the study met its primary endpoint, with a hazard ratio of 0.75 and a P value of .0055,” Dr. Lipson said.

“The progression-free survival benefit appeared relatively early in the course of therapy. The curves separated at 12 weeks, which was when the first on-treatment imaging was performed.

“This is the first phase III study to confirm that targeting the LAG-3 immune checkpoint is a beneficial therapeutic strategy for patients with cancer. Our findings establish the LAG-3 pathway as the third immune checkpoint pathway in history, after CTLA-4 and PD-1, for which blockade has clinical benefit,” he added.

Mechanism of Action

LAG-3 is a component of an immune checkpoint pathway that inhibits T-cell activity. Relatlimab, a human IgG4 LAG-3–blocking antibody, restores the effector function of exhausted T cells, “reinvigorating T cells to attack cancer,” Dr. Lipson explained.

Relatlimab and nivolumab modulate potentially synergistic immune checkpoint pathways and can enhance antitumor immune responses. The two-drug combination has a generally manageable safety profile and can trigger durable tumor regressions in patients with melanoma whose disease has progressed after anti–PD-1 monotherapy, Dr. Lipson said.


RELATIVITY-047 is a global, double-blind, randomized, phase III study evaluating this novel immunotherapy approach as a fixed-dose combination in 714 patients with previously untreated, unresectable or metastatic melanoma. Its objective, according to Dr. Lipson, was to test a novel immune checkpoint inhibitor combination “that provides further benefit with manageable risk.”

Patients were randomly assigned 1:1 to receive every-4-week intravenous administration of relatlimab at 160 mg plus nivolumab at 480 mg or nivolumab at 480 mg, stratified by LAG-3 expression, PD-L1 expression, BRAF mutation status, and disease stage. Median follow-up was 13.2 months.

The study met its primary endpoint, with significantly better median progression-free survival achieved with the combination vs nivolumab alone: 10.1 vs 4.6 months (hazard ratio [HR] = 0.75; P = .0055). Progression-free survival rates at 12 months were 48% for patients receiving combination therapy vs 36% for nivolumab monotherapy. The combination was favored across key prespecified subgroups.

Dr. Lipson said the median progression-free survival of single-agent nivolumab observed in this study was “in the range” seen in historical studies (ie, 4–7 months). He cautioned against comparing progression-free survival across trials, which often differs in terms of the patient population, timing of scans, and blinded central review vs investigator assessment.

Safety Profile

“In general, treatment-related adverse events associated with relatlimab plus nivolumab were manageable and reflected the safety profile we typically see with immune checkpoint inhibitors. Although the incidence of grade 3 or 4 treatment-related adverse events was higher with the combination (18.9% vs 9.7%), they occurred at a lower rate than we observe with other immunotherapy combinations,” Dr. Lipson said.

Treatment-related adverse events led to treatment discontinuation in 14.6% and 6.7% of patients receiving combination and monotherapy, respectively. There were three treatment-related deaths with the combination (hemophagocytic lymphohistiocytosis, acute edema of the lungs, and pneumonitis) and two with nivolumab monotherapy (sepsis/myocarditis and worsening pneumonia).

Dr. Lipson called relatlimab plus nivolumab “a potential novel treatment option for patients with previously untreated unresectable or metastatic melanoma.” He noted that forthcoming trial data, including overall response and overall survival rates, will further inform clinical decision-making about the use of this combination in the context of other treatment options, including anti–PD-1 alone or with ipilimumab.

“The first-line treatment choice is a case-by-case decision. We are fortunate in melanoma to have an ever-expanding list of effective standard-of-care therapy options, and I think, at some point, this regimen will be added to that list,” he commented. 

DISCLOSURE:Dr. Lipson has served as a consultant or advisor to Array BioPharma, Bristol Myers Squibb, EMD Serono, Genentech, MacroGenics, Merck, Novartis, Odonate Therapeutics, Regeneron, and Sanofi; and has received institutional research funding from Bristol Myers Squibb, Merck, Regeneron, and Sanofi.


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.