KPT-9274 + nivolumab

KPT-9274 + nivolumab is an investigational combination therapy comprising KPT-9274, an oral first-in-class small molecule dual inhibitor of p21-activated kinase 4 (PAK4) and nicotinamide phosphoribosyltransferase (NAMPT), and nivolumab, an anti-PD-1 monoclonal antibody checkpoint inhibitor. KPT-9274 exerts anti-tumor activity by inhibiting PAK4 (implicated in immune evasion and tumor signaling) and NAMPT, which is essential for NAD synthesis and cellular metabolism in cancer cells. This dual inhibition depletes NAD, impairs DNA repair, induces cell cycle arrest, suppresses β-catenin signaling (enhancing immune cell activation), and triggers apoptosis. Nivolumab is a PD-1 receptor antibody that blocks immune checkpoint signaling, promoting restoration of T cell-mediated anti-tumor responses. The combination is being investigated primarily for advanced solid malignancies, including melanoma, where KPT-9274 may sensitize tumors to immune checkpoint therapy[1][5][9].