Dordaviprone in Patients with Recurrent H3K27M-Mutant DMG

Funding support provided by Chimerix/Jazz Pharmaceuticals. Content independently developed and published by OncLive.

Dordaviprone represents a novel therapeutic option for diffuse midline gliomas with the H3K27M mutation, distinguished by its dual mechanism of action. It functions as an antagonist of dopamine receptor D2/3, disrupting signaling pathways that sustain glioma cell survival. At the same time, it acts as an agonist of the mitochondrial protease CLPP, triggering degradation of mitochondrial proteins, activation of the integrated stress response, metabolic disruption, and ultimately apoptosis. This combination of dopamine receptor inhibition and mitochondrial stress activation makes dordaviprone a unique therapy in the glioma space, targeting tumor survival from two distinct biological angles.

The FDA’s accelerated approval was based on pooled data from four clinical trials and one expanded access protocol, encompassing about 50 patients with recurrent disease. These patients had all failed prior radiotherapy and received dordaviprone as a single agent. Results showed an objective response rate of approximately 20% using high-grade RANO criteria, with responders often experiencing durable benefits lasting close to a year, and in some cases longer. Importantly, responses were accompanied by clinical improvements, such as reduced steroid dependence and enhanced performance status. Still, the majority of patients—around 60%—progressed despite treatment, underscoring both the significance of this advance and the continued need for more effective therapies.

In clinical practice, dordaviprone is currently reserved for patients with recurrent disease after radiotherapy, in line with its FDA label. Its safety profile has been favorable, with fatigue as the most common adverse effect, generally low-grade and manageable. The oral, once-weekly dosing makes it convenient and minimally disruptive to patients’ daily lives, an important consideration in a disease with limited survival. Physicians are encouraged to act promptly when progression is suspected, even if radiographic findings are subtle, given the drug’s tolerability and potential benefits. Looking forward, the results of ongoing phase III trials will clarify whether dordaviprone may eventually be integrated earlier in the treatment course, possibly as a maintenance therapy after initial radiation.