Dr Franson on the Mechanism of Action of Tovorafenib and Its Emerging Role for pLGG Management

“Tovorafenib is first in class, at least on the clinical side for a pan-RAF inhibitor, inhibiting part of the Ras-Raf-MEK-ERK pathway, and has a different mechanism of action than previous type I RAF inhibitors. [Tovorafenib] is a type II [RAF inhibitor].”

Andrea Franson, MD, a clinical associate professor of pediatrics, fellowship director of Pediatric Hematology/Oncology, and a pediatric oncologist in the Department of Pediatrics at the University of Michigan Medical School, discussed the mechanism of action of tovorafenib (Ojemda) and where this agent fits within the evolving treatment paradigm for pediatric low-grade glioma (pLGG), a disease defined by aberrations in the MAPK signaling pathway.

Tovorafenib represents a first-in-class agent in clinical practice as a pan-RAF inhibitor with activity across RAF isoforms, targeting dysregulated signaling within the Ras-Raf-MEK-ERK cascade, Franson began. Unlike earlier-generation type I RAF inhibitors that bind the active conformation of RAF and may paradoxically activate downstream signaling in certain molecular contexts, tovorafenib is classified as a type II RAF inhibitor, she stated.

From a tolerability standpoint, Franson noted that the safety profile of tovorafenib appears consistent with that of other agents targeting the MAPK pathway, although with features specific to tovorafenib’s unique mechanism of action. Cutaneous toxicities are among the most frequently observed adverse effects (AEs), she explained. Laboratory abnormalities are also common, many of which are asymptomatic but require routine monitoring, she said. Hematologic AEs, including mild anemia related to reductions in hemoglobin levels, have been observed with long-term or continuous dosing, underscoring the importance of longitudinal surveillance in pediatric patients receiving chronic therapy, she noted. Fatigue has also been reported, although it is generally manageable. Looking ahead, Franson suggested that tovorafenib is likely to play an increasingly central role in both frontline and relapsed pLGG settings, particularly as oncologists seek to defer or avoid more toxic interventions.