Most primary brain tumors are called gliomas, and the most common glioma are glioblastomas which is very aggressive a high-grade tumor. Unfortunately, it carries very poor prognosis with a median survival of approximately 16 months following treatment. The two-year survival rate is approximately 30 %. Its treatment consists of initially maximal safe tumor resection followed by radiotherapy combined with an alkylating agent called Temozolomide and 6 adjuvant cycles of Temozolomide alone. Thew that study showed that Temozolomide improved median survival with a couple of months was published 20 years ago. Every phase 3 study in the following 2 decades failed to demonstrate a further survival benefit for this patient group.
A complete resection in these tumors is impossible, because of the infiltrating grow pattern causing inevitable residual tumor. To my opinion Improvement of local therapy i.e. surgery and radiotherapy is not likely to improve survival in a significant way. Innovative systemic therapy is more likely to improve the treatment outcome in this patient group.
A particular challenge for developing systemic therapy for gliomas, but actually for every brain disease, is the Blood Brain Barrier, in short, the BBB. The BBB regulates the passage of substances from the blood stream to the brain and it blocks the penetrance of toxic substances to the brain causing a lack of brain penetrance for a very large majority of medication.
The molecular characterization of gliomas has been developed during the last 20 years and has been implemented since 2016 in the WHO classification and defines new tumor entities. One of the molecular features has been the IDH1/2 mutation which has become a very important tumor marker, but it also considered as an oncogene and druggable target. And indeed, recently a brain penetrant novel drug targeting the IDH mutation has been developed for low grade gliomas, which almost always carry the IDH mutation. Preclinical data of this compound, now called Vorasidenib, was published in 2020 and already in 2023 a clinical study in the New England Journal of Medicine demonstrated a substantial increase of progression free survival, which was the basis for fast track registration in the US in 2024. Registration in Europe is expected this year. Importantly the compound was especially developed to penetrate the BBB, which was confirmed with phase 0 or window of opportunity studies. The collaboration of academic preclinical scientists and Pharma and early involvement of clinical researchers made fast translation from bench to bedside possible. It is a great example the way the field can and should advance.
In 2007 I established the Neuro-oncology research group in the CCA, and we work on liquid biopsy/biomarkers, target and drug discovery for glioma, especially high grade gliomas. The ultimate goal is achieving a translation from bench to bedside, similar to the recent Vorasidenib story.