Fixed-Dose Relatlimab Plus Nivolumab Shows First Signs of Benefit in Advanced Melanoma

The fixed-dose combination of relatlimab and nivolumab (Opdivo) compared to nivolumab alone was found to improve progression-free survival (PFS) in patients with previously untreated metastatic or unresectable melanoma, which met the primary endpoint of the phase 2/3 RELATIVITY-047 (CA224-047; NCT03470922) study.1

Relatlimab is an anti-lymphocyte-activation gene 3 (LAG-3) antibody, and these data are the first to be reported from a study evaluating the antibody, according to the drug developer Bristol Meyers Squib, in a press release. This is also the first fixed-dose combination to show a benefit for patients, and the company plans to share the full results at an upcoming medical meeting, along with discussing the results with regulators.

RELATIVITY-047 is a randomized, double-blind phase 2/3 study that looked at 714 patients with previously untreated metastatic or unresectable melanoma who were randomized 1:1 to either the fixed-dose combination of relatlimab and nivolumab or nivolumab alone. In addition to the primary end point, follow-up is still underway for the secondary end point of overall survival and objective response rate, duration of response, and safety determined by the occurrence of adverse events (AEs), serious AE, and AES leading to treatment discontinuation or death. PFS was determined by Blinded Independent Central Review.

Patients received either 160 mg of the fixed-dose combination or 480 mg of nivolumab alone by intravenous infusion every 4 weeks until disease recurrence, unacceptable toxicity, or withdrawal by consent. Eligible patients for the RELATIVITY-047 study were those with histologically confirmed stage III or IV melanoma who had not received prior systemic anticancer therapy for unresectable or metastatic melanoma and for whom tumor tissue was available for biomarker analyses. The study excluded patients who had active brain metastases or leptomeningeal metastases, uveal melanoma, or active, known, or suspected autoimmune disease.

Based on what has been observed in the study so far, there were no new safety signals to report in either the relatlimab and nivolumab combination arm or nivolumab monotherapy arm.

LAG-3 inhibits an immune checkpoint pathway which limits the activity of T cells that lead to an impaired ability from the immune system to attack tumor cells in the body. With the presence of chronic diseases, like cancer, T cells show signs of progressive exhaustion that are characterized by the inhibition of immune checkpoints such as PD-1 and LAG-3. According to the researchers, these are pathways that are distinct but could act synergistically on effector T cells that lead to T cell exhaustion. In the case of relatilmab, it is a LAG-3 blocking antibody that binds to LAG-3 on T cells restoring the function of the effector function of exhausted T cells.

“Immune checkpoint inhibitors alone or in combination have transformed treatment and improved survival rates for patients with metastatic or unresectable melanoma. However, there remain a considerable number of patients who could benefit from a novel combination therapy that leverages potentially complementary pathways to improve anti-tumor activity,” Jonathan Cheng, senior vice president and head of oncology development, Bristol Myers Squibb, concluded in the release. “The results of this study suggest that targeting the LAG-3 pathway in combination with PD-1 inhibition may be a key strategy to enhance the immune response and help improve outcomes for these patients.”

_Reference

_{Bristol Myers Squibb Announces RELATIVITY-047, a trial evaluating anti-LAG-3 antibody relatlimab and Opdivo (nivolumab) in patients with previously untreated metastatic or unresectable melanoma, meets primary endpoint of progression-free survival. News Release. Bristol Myers Squibb. March 25, 2021. Accessed March 25, 2021. https://bit.ly/3fjGpsT}