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

Abstract 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.