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What to Know About the Novel Anti–LAG-3 Checkpoint Inhibitor Relatlimab in Melanoma

Evan J. Lipson, MD

Associate Professor of Oncology
Melanoma and Cancer Immunology Programs
Bloomberg-Kimmel Institute for Cancer Immunotherapy
Johns Hopkins University School of Medicine
Sidney Kimmel Comprehensive Cancer Center
Baltimore, Maryland

Evan J. Lipson, MD, has received consulting fees from Array BioPharma, Bristol-Myers Squibb, EMD Serono, Genentech, MacroGenics, Merck, Novartis, Odonate Therapeutics, Regeneron, and Sanofi and funds for research support paid to his institution from Bristol-Myers Squibb, Merck, Regeneron, and Sanofi.

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Released: March 21, 2022

Drugs that target immune checkpoints, like PD‑1 and CTLA-4, have dramatically improved survival rates for patients with a wide variety of cancers including melanoma. Lymphocyte activation gene 3 (LAG-3) is an immune checkpoint protein present on activated T-cells that negatively regulates T-cell activation and proliferation. Binding of LAG-3 to the major histocompatibility complex class II leads to inhibitory modulation of the immune response. To build on the success of immunotherapies and to develop novel regimens that are safer and more effective, relatlimab, a LAG-3–blocking antibody, was studied in combination with nivolumab, an anti–PD-1 antibody, in patients with previously untreated advanced melanoma. Anti–LAG-3 and anti–PD-1 target distinct immune pathways, but they share a common goal, which is to activate antitumor T‑cells.

Why Combination Approaches
Relatlimab monotherapy appears to have limited antitumor efficacy. In support of a combination approach are results from previous clinical trials where the administration of relatlimab plus nivolumab caused tumor regression in some patients with advanced melanoma whose disease had already progressed on anti–PD-1 monotherapy with or without anti–CTLA-4.

RELATIVITY-047: Relatlimab Plus Nivolumab as Frontline Therapy in Advanced Melanoma
RELATIVITY‑047 is a global, double-blind, randomized phase II/III trial comparing relatlimab plus nivolumab vs nivolumab alone for patients with previously untreated, unresectable stage III/IV melanoma (N = 714). Patients with active brain metastases were excluded. Patients were randomized to receive the combination of relatlimab plus nivolumab or nivolumab monotherapy, which is a standard-of-care treatment for patients with metastatic melanoma. Relatlimab plus nivolumab was administered as a fixed-dose combination, meaning that both relatlimab and nivolumab were prepared in the same medication vial and administered as a single IV infusion. Fixed dosing reduces preparation times and minimizes the risk of administration errors. The primary endpoint was progression‑free survival (PFS) by blinded independent review. Secondary endpoints included overall survival (OS) and overall response rate (ORR).

In RELATIVITY-047, the median PFS was significantly improved with relatlimab plus nivolumab combination therapy; thus the trial met its primary endpoint. Patients receiving relatlimab plus nivolumab had a median PFS of 10.2 months compared with 4.6 months for those receiving nivolumab (HR: 0.78; 95% CI: 0.64-0.94). The PFS improvement associated with combination therapy was observed across prespecified patient subgroups such as age, baseline serum lactate dehydrogenase level, BRAF tumor mutation status, American Joint Committee on Cancer stage, and expression of PD-L1 and LAG-3 in the tumor microenvironment.

The OS analysis demonstrated a clinically meaningful improvement associated with relatlimab plus nivolumab vs nivolumab monotherapy at 19.3 months of follow-up with higher 12-, 24-, and 36-month OS rates for the combination; however, the difference did not reach statistical significance. A 10.3% improvement in ORR was seen with relatlimab plus nivolumab. Of note, the statistical plan called for hierarchical testing of the primary endpoint of PFS followed by OS and then ORR.

Safety Profile of Relatlimab Plus Nivolumab
The treatment‑related adverse events associated with relatlimab plus nivolumab therapy were manageable and reflected the safety profile we typically see with immune checkpoint inhibitors. Treatment‑related adverse events that led to discontinuation of therapy occurred in 15.2% of patients in the combination therapy group compared with 7.2% of patients who received nivolumab alone. Although the incidence of grade 3/4 treatment‑related toxicities was higher with combination therapy (21.1% vs 11.1%), these adverse events occurred at a lower rate than has been observed with other immunotherapy combinations. The most common immune-related adverse events in the combination group were hypothyroidism or thyroiditis, rash, and diarrhea or colitis.

How I Plan to Use Relatlimab Plus Nivolumab for Patients With Advanced Melanoma
Scientifically, the RELATIVITY-047 findings were an important advance not just in melanoma, but because this was the first phase III study to validate inhibition of the LAG-3 immune checkpoint as a therapeutic strategy for patients with cancer. The RELATIVITY-047 results established LAG-3 as the third immune checkpoint pathway in history, after CTLA-4 and PD‑1, for which blockade has clinical benefit.

In general, I think that the relatlimab plus nivolumab combination will be adopted largely as a replacement for anti–PD‑1 monotherapy in patients with advanced melanoma who do not have a clear indication—for example, brain metastases—for requiring ipilimumab plus nivolumab. The efficacy of relatlimab plus nivolumab in patients with active or untreated melanoma brain metastases is unknown. RELATIVITY‑047 included only a small number of patients with previously treated brain metastases.

One question that comes up frequently is whether relatlimab plus nivolumab could be used in patients whose disease has already progressed on anti–PD‑1 monotherapy. Although we have seen evidence of relatlimab efficacy in this patient population, I think that more work needs to be done to understand how to use this combination most effectively in that setting.

Relatlimab is being explored in other tumor types and settings. Data for relatlimab plus nivolumab in the neoadjuvant setting for patients with resectable melanoma have been presented and have demonstrated promising safety and efficacy profiles. Results from ongoing studies testing relatlimab in other tumor types will help us understand how broadly this new therapy might be applied in patients across the cancer landscape.

Your Thoughts?
How will you incorporate relatlimab into your clinical practice for your patients with advanced melanoma? Answer the polling question and join the conversation by posting a comment in the discussion section.

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