Study results establish LAG-3 inhibition as therapeutically relevant third immune checkpoint pathway
The combination of immune checkpoint inhibitors relatlimab and nivolumab doubled the progression-free survival benefit compared with nivolumab alone for individuals with untreated, advanced melanoma, according to the results of the RELATIVITY-047 trial, a phase 2/3 clinical trial. The median progression-free survival was 10.1 months in the combination arm and 4.6 months in the monotherapy. After 12 months’ follow-up, the progression-free survival rate was 47.7% in the combination arm versus 36% in the monotherapy arm.
Additionally, there was a 25% lower risk of disease progression or death in the combination arm.
“The results from this global effort advance the field of immunotherapy by establishing a third class of immune checkpoint inhibitors through the LAG-3 pathway and have the potential to be practice-changing,” Hussein Tawbi, MD, PhD, professor of Melanoma Medical Oncology at the University of Texas MD Anderson Cancer Center, said in a statement.
“We’ve seen historic developments in melanoma treatment over the last decade with the combination of PD-1 and CTLA-4 inhibitors, which work well but also carry substantial toxicity. This study represents a significant and long-awaited next step toward providing patients with effective and safer treatment options,” Tawbi said.
The benefit of the combination therapy was observed across pre-specified subgroups, and the FDA granted priority review to the combination in September 2021, based on the results of the RELATIVITY-047 trial.
Relatlimab is a novel antibody that blocks lymphocyte-activation gene 3 (LAG-3), an immune checkpoint found on the surface of T cells. LAG-3 is often upregulated in melanoma, as is programmed death-1 (PD-1), the immune checkpoint inhibited by nivolumab.
These data represent the first phase 2/3 clinical trial results of a third-generation checkpoint inhibitor and the first clinical trial designed to compare combination checkpoint inhibitor therapy versus nivolumab monotherapy in melanoma.
The PD-1 and CTLA-4 inhibitor monotherapy and combination therapy are approved frontline treatment options for metastatic melanoma. The combination therapies benefit more individuals than monotherapy. However, there is a great effect on the quality of life, with toxicity rates of more than 50%.
In the RELATIVITY-047 study, grade 3 or 4 treatment-related adverse events (AEs) occurred in 18.9% of individuals and 9.7% in the monotherapy arm.
The most common grade 3 or 4 AEs included fatigue and levels of liver and pancreatic enzymes. Investigators determined there were 3 deaths in the combination arm and 2 deaths in the monotherapy arm that were treatment related.
Immune-meditated adverse events included colitis, hypothyroidism, rash, and thyroiditis.
There were no new safety signals identified, and individuals rated their health-related quality of life similarly across both treatment arms.
The trial had 714 individuals with untreated, unresectable state 3 or 4 melanoma across 111 international sites between May 2018 and December 2020. The individuals were randomized to receive either the combination or the monotherapy once every 4 weeks.
Sixty individuals received prior targeted therapy or immunotherapy as adjuvant therapy at least 6 months before recurrence or received interferon 6 weeks before randomization. The median age of individuals was 63. Approximately, 41.7% were female, and 96% were white.
The top reason for discontinuation was disease progression, with 36.3% of individuals in the combination arm and 46% in the monotherapy arm. The median follow-up was 13.2 months, with 470 individuals having discontinued treatment by the cut-off date of March 9, 2021.
The study met its primary endpoint of blinded independent central review-assessed progression-free survival, with progression defined as tumor growth or death due to any cause.
The benefit was sustained across pre-defined subgroups, including BRAF status, tumor stage, lactate dehydrogenase levels, LAG-3, and PD-1 progression.
The combination has a manageable safety profile.
The results were published in the New England Journal of Medicine.
Relatlimab plus nivolumab improves progression-free survival in metastatic melanoma. EurekAlert. News release. January 5, 2022. Accessed January 6, 2022. https://www.eurekalert.org/news-releases/939167