A Breakthrough Against an Unstoppable Brain Tumor?

In an interview with Targeted Oncology, Patrick Wen, MD, director of the Center for Neuro-Oncology at Dana-Farber Cancer Center and professor of neurology at Harvard Medical School, discusses the research that led to the FDA approval of dordaviprone (Modeyso) as well the clinical implications and benefits of having this option available for patients.

Diffuse midline gliomas with the H3 K27M mutation are among the most challenging brain tumors to treat. Located in the brain's midline, they cannot be surgically removed, making a simple biopsy the only option. Standard chemotherapy is also ineffective, as the tumors typically have an unmethylated MGMT gene. For a long time, the only available treatment has been radiation, which offers a temporary reprieve of a few months before the tumor inevitably returns, leading to a grim prognosis where most patients survive for only about a year.

Finding a new, effective treatment has been a significant challenge. Traditional clinical trials, which rely on long-term outcomes like progression-free or overall survival, are unreliable for these aggressive tumors. A different approach was needed. A unique study was conducted, combining data from five separate trials, to gather a total of 50 patients with measurable disease. This method, developed in collaboration with the FDA, allowed researchers to assess if the treatment had an immediate impact on the tumor, a crucial shift from the standard, fixed-end point trial model.

A key difficulty in evaluating these new treatments has been the complex response criteria. Early criteria like RANO high-grade glioma only showed a 20% response rate because they focused on enhancing tumors, while many of these gliomas are nonenhancing. When researchers looked at non-enhancing tumors, the response rate was 26%. Combining both types of tumors using the newer RANO 2.0 criteria increased the response rate to 30%. While the overall response rate is still low, a positive response is often durable. It can take up to eight months to see a response, but once it occurs, the tumor can remain stable for nearly 2 years. This represents a significant step forward in a disease with very limited options.