Chocarro de Erauso, LuisaBocanegra Gondán, Ana IsabelBlanco, EsterFernández Rubio, LeticiaArasanz Esteban, HugoEchaide Górriz, MíriamGarnica, MaiderRamos, PabloPiñeiro Hermida, SergioVera García, RuthEscors Murugarren, DavidKochan, Grazyna2022-12-302022-12-302022Chocarro-de-Erauso, L.; Bocanegra, A.; Blanco, E.; Fernández-Rubio, L.; Arasanz-Esteban, H.; Echaide-Gorriz, M.; Garnica, M.; Ramos, P.; Piñeiro-Hermida, S.; Vera, R.; Escors, D.; Kochan, G.. (2022). Cutting-edge: preclinical and clinical development of the first approved LAG-3 inhibitor. Cells. 11,15 1-24 .2073-440910.3390/cells11152351https://academica-e.unavarra.es/handle/2454/44509Immune checkpoint inhibitors (ICIs) have revolutionized medical practice in oncology since the FDA approval of the first ICI 11 years ago. In light of this, Lymphocyte-Activation Gene 3 (LAG-3) is one of the most important next-generation immune checkpoint molecules, playing a similar role as Programmed cell Death protein 1 (PD-1) and Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4). 19 LAG-3 targeting molecules are being evaluated at 108 clinical trials which are demonstrating positive results, including promising bispecific molecules targeting LAG-3 simultaneously with other ICIs. Recently, a new dual anti-PD-1 (Nivolumab) and anti-LAG-3 (Relatimab) treatment developed by Bristol Myers Squibb (Opdualag), was approved by the Food and Drug Administration (FDA) as the first LAG-3 blocking antibody combination for unresectable or metastatic melanoma. This novel immunotherapy combination more than doubled median progression-free survival (PFS) when compared to nivolumab monotherapy (10.1 months versus 4.6 months). Here, we analyze the large clinical trial responsible for this historical approval (RELATIVITY-047), and discuss the preclinical and clinical developments that led to its jump into clinical practice. We will also summarize results achieved by other LAG-3 targeting molecules with promising anti-tumor activities currently under clinical development in phases I, I/II, II, and III. Opdualag will boost the entry of more LAG-3 targeting molecules into clinical practice, supporting the accumulating evidence highlighting the pivotal role of LAG-3 in cancer.application/pdfapplication/zipeng© 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) licenseBMS-986016LAG-3NivolumabOpdualagPD-1Relatimabinfo:eu-repo/semantics/article2022-12-30info:eu-repo/semantics/openAccess