When compared against nivolumab alone, relatlimab plus nivolumab delayed progression in patients with unresectable stage III and IV untreated melanoma.
The randomized, double-blind phase 2/3 RELATIVITY-047 trial (NCT03470922) examining the experimental anti–LAG-3 antibody relatlimab plus nivolumab (Opdivo) versus nivolumab alone in patients with treatment-naïve metastatic or unresectable melanoma met its primary end point of progression-free survival, according to Bristol Myers Squibb who is responsible for developing the agent.1
The fixed-dose combination regimen of the trial’s experimental arm was well tolerated with no new apparent safety signals for either arm. Follow-up for the secondary end point of overall survival remains ongoing.
“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, MD, senior vice president and head of oncology development of Bristol Myers Squibb, said in a press 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.”
The trial is actively recruiting, with an enrollment goal of 700 participants. Secondary end points of the trial include overall survival, objective response rates for both phases 2 and 3, duration of response, and safety. To be eligible for enrollment, patients must have unresectable, histologically confirmed stage III or stage IV melanoma per the American Joint Committee on Cancer staging system; no prior systemic therapy for their disease; and tissue that is available for biomarker analysis. Patients cannot have any active brain metastases; uveal melanoma; and no active, known, or suspected autoimmune disease.
Results of RELATIVITY-047 will be made available for presentation at an upcoming medical meeting and will be discussed with regulatory authorities.
Data supporting the efficacy of the combination in patients with melanoma were previously presented at the European Society for Clinical Oncology 2017 Congress, which were taken from a phase 1/2 trial (NCT01968109) of relatlimab plus nivolumab in patients with disease progressing on prior anti–PD-1/L1 therapy.2
Seven of 61 evaluable patients (11.5%) had an objective response to therapy; alternatively, patients with LAG-3—positive tumors demonstrated a response rate of 18%. Stable disease was noted in 23 patients, resulting in a disease control rate (DCR) of 49%. In patients whose tumors expressed 1% or more LAG-3, the disease control rate was 64%, comprised of 1 complete response, 5 partial responses, and stable disease in 15.
Notably, patients whose tumors did not harbor a BRAF mutation had higher responses compared with those who did; the presence of LAG-3 expression (≥1%) in conjunction with a BRAF mutation made those patients more likely to respond.
LAG-3 is a cell-surface antigen that regulates an immune checkpoint pathway limiting activity of T cells, which can result in a reduced ability to attack tumor cells. Upregulation of LAG-3 is often noted in the presence of cancer, with dual inhibition with PD-1 potentially resulting in synergistic results of effect T cells, causing T-cell exhaustion.
1. 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/3ffwCnI
2. Ascierto PA, Bono P, Bhatia S, et al. 4998 - Efficacy of BMS-986016, a monoclonal antibody that targets lymphocyte activation gene-3 (LAG-3), in combination with nivolumab in pts with melanoma. Ann Oncol. 2017;28(suppl 5):v605-649. doi: 10.1093/annonc/mdx440