ASCO Perspective
“Immunotherapy has transformed the outlook for patients with advanced melanoma. The success seen in this study by combining two immunotherapy drugs that act on different checkpoints, in this case PD-1 and LAG-3, adds support for additional investigation of this approach with other drugs that target other checkpoints,” said ASCO Chief Medical Officer and Executive Vice President Julie R. Gralow, MD, FACP, FASCO.

ALEXANDRIA, Va. – When compared to anti-PD-1 monotherapy, two immunotherapy agents blocking different checkpoints extended time to disease progression for patients with previously untreated, unresectable, or metastatic melanoma, new research found.

The study will be presented at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting.

Study at a Glance

Key Findings
Immune checkpoint inhibitor therapy has revolutionized the treatment of patients with advanced melanoma, significantly improving survival. Immune checkpoint inhibitor therapy works by blocking the interaction between specific proteins on the surface of cancer cells or immune cells in the tumor microenvironment, which prevents cancer cells from evading the body’s immune system.

Until now, phase III studies evaluating combinations of immune checkpoint inhibitors have only demonstrated clinical benefit by blocking the PD-1 and CTLA-4 pathways. Nivolumab acts on the PD-1 protein and is FDA-approved for the treatment of patients with melanoma and several other cancer types. Relatlimab is the first to bind to LAG-3 on T cells, reinvigorating their activity and potentially unleashing enhanced anti-tumor responses.

The RELATIVITY-047 study is the first randomized phase III trial to evaluate the immunotherapy agents nivolumab and relatlimab, administered as a fixed-dose combination (FDC), to patients with previously untreated, unresectable, or metastatic melanoma.

The researchers found that the median PFS was significantly longer with nivolumab and relatlimab compared with nivolumab alone, 10.1 versus 4.6 months, respectively. At 1 year, PFS rates were 47.7% for patients receiving the immunotherapy combination and 36.0% for those receiving nivolumab alone.

TRAEs associated with nivolumab and relatlimab were generally manageable and reflected the typical safety profile seen with immune checkpoint inhibitors. Grade 3/4 TRAEs were more common among patients receiving nivolumab and relatlimab (18.9%) versus nivolumab alone (9.7%). There were three treatment-related deaths among patients receiving the dual immunotherapy regimen and two in the nivolumab monotherapy group. TRAEs led to therapy discontinuation in 14.6% and 6.7% of patients, respectively.

“Our results demonstrate that combination therapy with nivolumab and relatlimab is a potential novel treatment option for patients with previously untreated, unresectable, or metastatic melanoma. This is the first phase III study to validate inhibition of the LAG-3 immune checkpoint as a 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,” said lead author Evan J. Lipson, MD, an associate professor of oncology at the Johns Hopkins Kimmel Cancer Center and Bloomberg-Kimmel Institute for Cancer Immunotherapy in Baltimore.

About the Study
RELATIVITY-047 is a global, multicenter, double-blind, randomized phase II/III trial. In all, 714 patients with previously untreated, unresectable, or metastatic melanoma were randomized 1:1 to receive either a fixed-dose combination of nivolumab and relatlimab or nivolumab alone. Nivolumab is a well-established standard of care for patients with advanced melanoma.

The primary endpoint was PFS for all study participants and for subgroups. Secondary endpoints were overall survival (OS) and objective response rate (ORR).

Next Steps
The researchers are awaiting ORR and OS outcomes.

View the full abstract

View the author disclosures: https://coi.asco.org/Report/ViewAbstractCOI?id=331037

For your readers:

• Guide to Melanoma
• Understanding Immunotherapy
• Cancer.Net Blog Post (English)
• Cancer.Net Blog Post (Spanish)

View the disclosures for the 2021 Cancer Communications Committee: https://www.asco.org/sites/new-www.asco.org/files/content-files/about-asco/pdf/2021-am-news-planning-team-disclosures.pdf

View the disclosures for Dr. Gralow: https://coi.asco.org/share/CKD-HYVM/Julie%20Gralow

View the disclosures for Dr. Pierce: https://coi.asco.org/share/Z2M-8YDX/Lori

ATTRIBUTION TO THE AMERICAN SOCIETY OF CLINICAL ONCOLOGY ANNUAL MEETING IS REQUESTED IN ALL COVERAGE.

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