Highlights on CNS

Dr Marika Rasschaert, a medical oncologist at the University Hospital Antwerp, Belgium, provided a comprehensive overview of critical studies presented at ASCO 2024 in the Central Nervous System Tumours session.

A German phase I/IIa umbrella trial was conducted to evaluate the safety, feasibility, and preliminary efficacy of targeted compounds in addition to standard radiotherapy for glioblastoma patients without MGMT promoter hypermethylation. Stratified into five subtrials based on molecular alterations, treatments included alectinib, idasanutlin, palbociclib, vismogedib, and temsirolimus. Patients without specific molecular alterations were randomized to subtrials with atezolizumab, asunercept, and temozolomide as standard care. The study demonstrated the clinical activity of temsirolimus in patients with tumours harbouring an activated mTOR pathway, though mTOR inhibition was necessary for prognostic benefit. However, no clinical activity was observed for asunercept and atezolizumab in non-molecularly selected patients.

The second abstract of interest is the TRIGGER trial, an elegant phase 0-1 study evaluating a PARP inhibitor for glioblastoma, WHO grade 4, without MGMT methylation. Historically, temozolomide is used in this context, but it is not highly effective. The trial explored the use of niraparib, a PARP inhibitor that targets the DNA repair mechanism, in these patients. In the phase 0 part of the trial, pharmacokinetics were assessed by administering niraparib for four days before surgery, followed by sequential harvesting of the tumour, blood, and CSF (with tumour samples collected post-surgery). Niraparib was detected in all 40 patients, showing very good clinical efficacy. The Phase 1 data outperformed historical data from the Stupp trial for temozolomide. Consequently, niraparib is moving into phase 3 trials, which will be conducted worldwide, including in Belgium. This trial represents a promising new option for treating this challenging malignancy, and patient enrollment is encouraged.

Another promising molecular agent for treating difficult brain diseases is abemaciclib, particularly in recurrent grade 2 and 3 meningiomas. These recurrent meningiomas can be as lethal as glioblastoma. Abemaciclib targets meningiomas exhibiting CDK mutations and has shown potential in this context. This drug is set to be investigated further in clinical trials, offering hope for managing this challenging disease.

Perhaps the most practice-changing study of this session was the French prospective cohort analysis, the POLA study. In this cohort, French investigators evaluated the efficacy of radiotherapy with temozolomide versus radiotherapy with PCV in patients with grade 3 oligodendroglioma. This analysis included 305 patients in a two-to-one ratio (not randomised, but prospective). The results indicate that PCV is the preferred treatment, showing a significant survival benefit. The five-year OS data showed a difference of about 10%, with PCV achieving approximately 98% compared to 75% for temozolomide. This finding supports the superiority of PCV, although a prospective randomized trial is still awaited for a definitive conclusion. For now, PCV seems to be the recommended treatment for grade 3 oligodendroglioma.