Immunotherapy with immune checkpoint inhibitors (ICIs) has transformed the outlook for patients with advanced melanoma. In order to optimize the benefit/risk profile of ICI combinations, a novel combination of ICIs targeting programmed cell death protein 1 (PD-1) and lymphocyte-activation gene 3 (LAG-3) has been investigated. LAG-3 is a transmembrane molecule that is expressed on effector T-cells and regulatory T-cells (Tregs) and is upregulated in many tumor types, including melanoma. LAG-3 regulates an inhibitory immune checkpoint pathway that limits the activity of T-cells, resulting in an impaired ability to attack tumor cells. Relatlimab, a novel ICI, blocks LAG-3 and its combination with nivolumab, which targets the PD-1 receptor, may act synergistically to restore the effector function of exhausted T-cells.

During the oral abstract session on melanoma/skin cancers at this year’s ASCO Annual Meeting, Dr Evan J. Lipson (Bloomberg~Kimmel Institute for Cancer Immunotherapy and the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, Massachusetts, US) presented primary results from the global, randomized, double-blind, phase II/III RELATIVITY-047 trial, the first trial to evaluate a fixed-dose combination (FDC) of relatlimab and nivolumab in patients with previously untreated, unresectable or metastatic melanoma. A total of 714 patients with performance status 0-1 were randomly assigned to receive either an FDC of relatlimab 160 mg plus nivolumab 480 mg intravenously (IV) every 4 weeks, or nivolumab monotherapy 480 mg IV every 4 weeks. Patients were stratified by LAG-3 expression, PD-L1 expression, BRAF mutation status, and American Joint Committee on Cancer (AJCC) stage. Median follow-up was 13.2 months. The trial met its primary endpoint, with a more than doubled improvement in median PFS by blinded independent central review (BICR) for the relatlimab plus nivolumab combination compared with nivolumab alone: mPFS was 10.1 months versus 4.6 months, respectively (hazard ratio [HR], 0.75; P=0.0055). At 1 year, the PFS rates were 47.7% for patients receiving the combination therapy and 36.0% for those receiving nivolumab alone. Notably, PFS was improved across all prespecified subgroups and regardless of stratification factors. Follow-up for overall survival (OS) and overall response rates (ORR) is ongoing. There were no unexpected safety signals with the relatlimab plus nivolumab combination, and treatment-related adverse events (TRAEs) were generally manageable. Grade 3/4 TRAEs occurred in 18.9% of patients in the combination arm, a lower rate of AEs relative to other ICI combinations, and in 9.7% of patients treated with nivolumab alone. TRAEs leading to discontinuation of treatment occurred in 14.6% versus 6.7% of patients, respectively. There were 3 treatment-related deaths in the combination arm and 2 in the nivolumab alone arm.  

Dr Lipson concluded that relatlimab plus nivolumab is a potential novel treatment option for patients with previously untreated, unresectable, or metastatic melanoma. He added that the trial results further validate the LAG-3 immune checkpoint as a therapeutic target in cancer and support the continued development of relatlimab in patients with other malignancies. Dr Jason Luke (UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, Pennsylvania, US), a discussant for the abstract, agreed that the combination is a new standard of care that should replace anti-PD-1 monotherapy. However, given the current lack of OS and ORR data, he would recommend using ipilimumab plus nivolumab combination as first-line therapy for patients who are rapid progressors/high LDH and those with brain, liver and bone metastases, or have bulky disease. He would also choose ipilimumab plus nivolumab for patients progressing on adjuvant anti-PD-1 antibody, while for the niche population of patients with severe autoimmune disease, there may still be a role for nivolumab or pembrolizumab monotherapy. Dr Luke noted that, in the future, we can expect clinical trial results of relatlimab plus nivolumab in the adjuvant and neoadjuvant setting (stage II/III melanoma), as well as in combination with low-dose ipilimumab (triplet regimen) in patients with advanced disease.

Reference

Lipson, EJ, et al. ASCO 2021; Abstract 9503.