The emerging role of lymphocyte-activation gene 3 targeting in the treatment of solid malignancies

PD-(L)1–based immune checkpoint inhibitor therapies have profoundly impacted the treatment of many solid malignancies. Although the addition of CTLA-4 checkpoint inhibitors can enhance anticancer activity, it also significantly increases the rate of immune-related adverse events. Therefore, there has been much interest in identifying additional immune checkpoints to improve the outcomes seen with PD-1–based therapy while minimizing additional side effects. One such target, lymphocyte-activation gene 3 (LAG-3), has long been recognized as an important inhibitor of T-cell function via modulation of the T-cell receptor pathway. Several drugs targeting LAG-3 have been developed, including most prominently the monoclonal antibody relatlimab. To date, the most significant demonstration of efficacy in targeting LAG-3 has been the use of relatlimab with the PD-1 inhibitor nivolumab in the treatment of advanced melanoma. The combination of nivolumab plus relatlimab is more efficacious compared to PD-1 inhibition alone, as has been previously seen with the combination of CTLA-4 inhibitor ipilimumab with nivolumab. However, nivolumab plus relatlimab offers a potentially more favorable toxicity profile. Here, the authors review the mechanism of the LAG-3 pathway and its rationale as a target for anticancer therapy as well as currently available data regarding the use of LAG-3 agents in treating melanoma and other solid tumors. Other investigational agents that target LAG-3 via novel mechanisms are also reviewed.