1. Samson, Kurt

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Researchers have successfully used two immunotherapy drugs to target and block different protein checkpoints, significantly increasing the time before melanoma progressed in new patients with previously untreated, unresectable, or metastatic disease. Results of the RELATIVITY-047 clinical trial were presented at the 2021 ASCO Annual Meeting (Abstract 9503).

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The study is a randomized, global, Phase III trial to evaluate the immunotherapy agents nivolumab and relatlimab, administered as a fixed-dose combination, targeting the lymphocyte-activation gene 3 (LAG-3) checkpoint in patients with previously untreated, unresectable, or metastatic melanoma. LAG-3 regulates an immune checkpoint pathway that inhibits T-cell activity and is upregulated in many tumor types, including 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 investigator Evan J. Lipson, MD, Associate Professor of Oncology at the Johns Hopkins Kimmel Cancer Center and Bloomberg-Kimmel Institute for Cancer Immunotherapy in Baltimore.


"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."


According to Lipson, Phase III studies that have been conducted to evaluate combination of immune checkpoint inhibitors have only demonstrated clinical benefit by targeting and blocking the programmed death-1 (PD-1) and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) pathways. CTLA-4, also known as CD152, is a protein receptor immune checkpoint activator that downregulates immune responses to tumor cells.


Nivolumab acts on the PD-1 protein and is approved by the FDA for the treatment of patients with melanoma and several other cancers. Relatlimab is the first to bind to LAG-3 on T cells, reinvigorating their activity and potentially unleashing enhanced antitumor responses. It is a human IgG4 LAG-3-blocking antibody which has the ability to reinvigorate "exhausted" T cells. Combined with nivolumab, it acts synergistically on immune checkpoint pathways to promote immune responses to tumors. The RELATIVITY-047 study evaluated the fixed-dose combination to patients with previously untreated, unresectable, or metastatic melanoma.


The researchers tested the combination by randomly assigning combination treatment in a group of 714 patients as either a fixed-dose combination of nivolumab and relatlimab or nivolumab alone.


Doubled Time Before Progression

With the combination, they discovered that the median time until disease progression was significantly longer compared with nivolumab alone-10.1 versus 4.6 months. Progression-free survival (PFS) rates at 1 year were 47.7 percent in the combined group compared with 36.0 percent in patients treated with just nivolumab alone.


Adverse events associated with the combination were generally manageable and similar to the safety profile seen with other immune checkpoint inhibitors. Grade 3/4 reactions were more common in the combination arm at 18.9 percent versus nivolumab alone at 9.7 percent.


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 percent and 6.7 percent of patients, respectively.


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.


"First-line treatment with [the combination] demonstrated a statistically significant PFS benefit compared to nivolumab monotherapy and was well-tolerated with a manageable safety profile and without unexpected safety signals," noted Lipsom, adding that this is the first Phase III study of a novel fixed-dose combination to demonstrate a clinically meaningful benefit by dual inhibition of the LAG-3 and PD-1 pathways.


Commenting on the study findings, ASCO Chief Medical Officer and Executive Vice President Julie R. Gralow, MD, said the results are encouraging.


"Immunotherapy has transformed the outlook for patients with advanced melanoma," she noted. "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."


Kurt Samson is a contributing writer.