Treatment of Glioblastoma: A Potential Shift in Paradigm

Introduction
The evolution toward targeted therapies for glioblastoma multiforme (GBM) accelerated in 2021 when the World Health Organization (WHO) reclassified malignancies of the central nervous system.¹ By placing a greater emphasis on molecular rather than histological characteristics of brain cancers, the reclassification validated the progress in identifying potential targetable drivers of disease within GBM subtypes. At the time of this reclassification, the US Food and Drug Administration (FDA) was already granting more orphan drug designations to targeted small molecules and to immunotherapeutics than to cytotoxic drugs²; this evolution is ongoing. Several immunotherapeutic approaches look particularly promising in early clinical trials. For some GBM subtypes, a clinical trial might soon become a therapeutic choice, particularly in the second line.

Background
In the United States, the incidence of GBM is 3.23 cases per 100,000, representing nearly half (48.6%) of all primary malignant brain tumors.³ Relative to non-small cell lung cancer, which has an incidence of about 40 cases per 100,000,⁴ this incidence is a small burden, but GBM is highly lethal even relative to other aggressive tumors. Essentially all GBM patients relapse after first-line treatments, including patients with a complete response.⁵ The 5-year survival, which has changed little over decades, is estimated to be less than 5%.⁶

Following the 2021 WHO classification of tumors in the central nervous system (WHO CNS5),¹ the histologically oriented categories of pro-neural, neural, classical, and mesenchymal disease were replaced by 3 major types of GBM that can each be further characterized. These are astrocytoma mutant for isocitrate dehydrogenase (IDH), oligodendroglioma, and glioblastoma IDH-wildtype. For the first time, a separate classification system was also developed for pediatric GBM. Although brain cancer is the second most common type of malignancy in children, it is rare. Most cases of GBM occur in adults. More than half of new GBM diagnoses are in people older than 65 years.⁷ 

No standard method for molecular testing was described in WHO CNS5, but further molecular differentiation through biologic and genetic testing is recommended.⁸ Testing can be performed with transcription profiles, gene alterations, or DNA methylation.⁹ In addition to the evaluation of IDH status, mutations in α-thalassemia X-linked intellectual disability (ATRX), cyclin dependent kinase inhibitor 2A (CDKN2A/B), tumor suppressor gene (TP53), mitogen-activated protein kinases (MAPK), epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR), and histone H3 (H3) G34 have been identified as biomarkers with potential prognostic value.¹⁰ Some or all of these biomarkers might eventually prove targetable. Moreover, it is expected that more progress in describing the GBM molecular pathways will yield further modifications in prognostic assessment and, potentially, choice of treatment.

Despite the promise of some of these targets in laboratory and early clinical studies, none of the therapies in development have so far changed the standard of care, which is dominated by resection followed by radiation and temozolomide. However, several treatment categories support the premise that individualized therapies in GBM are plausible and might improve outcomes, including extended survival.

Selected Trials and Their Rationale
The distinction between IDH-wildtype GBM and IDH-mutant GBM, which has a better prognosis,¹¹ was one of many factors that changed the perception of GBM as a relatively homogeneous tumor type to one characterized by an array of intricate signaling pathways. Overall and in the context of glioma stem cells—which are a cell population in the GBM tumor microenvironment now suspected to play an important role in resistance and subsequent relapse,¹⁰—several pathways hold considerable promise for interfering with GBM progression. Studies of immunotherapies have been among the most encouraging. 

Following a substantial effort over the last decade to engage the immune response in the treatment of GBM through oncolytic virotherapy, the field, despite its promise, has yet to produce a viable treatment for GBM.^12,13 This effort includes multiple studies with dendritic cell vaccination, including a phase 3 trial published in 2023,¹⁴ but no therapy has yet to be approved.¹⁵ Although some of these trials did generate signals of activity, there are no approved treatments, and, recently, greater attention has been drawn to other strategies to engage the patient’s immune response, including chimeric antigen receptor (CAR) T-cells and checkpoint inhibitors.

A phase 1 study published in April 2024 showed that a novel engineered CAR T-cell product called CARv3-TEAM-E elicited dramatic radiographic regression of tumors in all 3 patients treated within days of intravenous administration.¹⁶ Although only 1 of the responses was sustained over follow-up, this result showed that clinically significant responses can be achieved in patients with advanced intraparenchymal disease. The tested CAR T construct included T-cell engaging antibody molecules (TEAMS) against wildtype EGFR, which was credited with inducing a radiological response not seen with a prior CAR T-cell construct. Other CAR T-cell studies are ongoing. In another trial published this year, results were less promising. It also targeted EGFR as well as the interleukin-13 receptor alpha 1, but none of the reductions in tumor size met criteria for an objective response.¹⁷

The theoretical promise of checkpoint inhibitors in GBM has not yet been realized in studies so far, despite numerous case reports and small series supporting activity. For example, overall survival was not improved with the programmed cell death protein 1 (PD-1) inhibitor nivolumab relative to the vascular endothelial growth factor (VEGF) inhibitor bevacizumab in a phase 3 controlled trial conducted in patients with recurrent GBM.¹⁸ However, preclinical research suggests combination strategies, including checkpoint inhibitors added to other types of therapeutics, might yield greater activity.¹⁹ The unprecedented responses with checkpoint inhibitors in other solid tumors is one reason that this approach is still being pursued avidly in GBM.¹³

For all forms of pharmacologic therapy and immunotherapies, providing adequate levels of therapeutic agent to the location of the tumor has been challenging. Convection-enhanced delivery (CED) is an example of a novel approach supported by clinical studies. By bypassing the blood-brain barrier, CED involves the delivery of a drug through a catheter placed into
the tumor.²⁰ While this method increases the concentration of the treatment at the malignancy, it also reduces the risk of systemic adverse effects. CED drug delivery for GBM has been evaluated across a diverse array of strategies, including oncolytic viruses, nucleotide-based therapies, and monoclonal antibodies, as well as immunotherapies. One potential advantage of pump-based CED is sustained drug delivery, which might prove to be an important variable in treatment success for a tumor that relapses almost uniformly after therapy.²¹

Despite the disappointments in the past, the enormous increase in the number of drugs and immunotherapies along with the array of available and potential GBM mechanisms is, by itself, a source of encouragement. This is because the growth in possible targets is representative of advances in GBM biology leading to new potential targets for disease control. For example, small molecule pathway inhibitors that have reached clinical trials include P13K pathway inhibitors, inhibitors of HGFR/MET and SGX532, and inhibitors of EGFR and PDGFR.¹² 

Unfortunately, the failures of promising drugs in phase 3 trials have also continued. For example, the VEGF-targeted monoclonal antibody bevacizumab, did not provide an overall survival benefit despite an encouraging degree of activity in early clinical studies.²² Recently, the antibody-drug conjugate depatuxizumab mafodotin also failed to demonstrate a survival benefit in a recent phase 3 trial despite an improvement in progression-free survival.²³ However, the failure of these drugs to extend survival as single agents does not preclude benefit in further studies when they are combined with other strategies or administered with novel methods of drug delivery. The poor response to conventional therapies has led to consideration of alternative strategies such as tumor-treating fields where low-intensity electrical fields delivered via an FDA-approved portable wearable device demonstrated a modest effect on survival when combined with temozolomide.²⁴

Why Optimism for Advances in GBM Is Warranted
The standard for the first-line treatment of GBM has remained unchanged since the introduction of temozolomide about 25 years ago. The combination of surgical debulking, radiation, temozolomide, and adjuvant chemotherapy is recommended in joint guidelines from the Society of Neuro-Oncology and the European Society of Neuro-Oncology.²⁵ This strategy also remains a recommendation in the most recent guidelines on central nervous system cancers from the National Comprehensive Cancer Network® (NCCN®).²⁶

The absence of new treatment standards belies the substantial new detail in which the pathophysiology is understood and with which GBM is being characterized. In this short review, only a proportion of the work in this field could be included. The combination approaches being pursued in relapsed disease is an example of promising work that was not addressed.

Yet, a focus on first-line therapies might be particularly appropriate in GBM. In this malignancy, for which relapse after the standard therapy almost always occurs, the identification of effective early treatment might be the only practical opportunity to increase survival meaningfully. For most cancer types, patients are typically offered experimental therapies only after progression on the standard of care. With advances in understanding the biology and molecular pathways of GBM progression, a paradigm shift might be appropriate. For a tumor type that is rarely, if ever, controlled on the current standard, trials of promising therapies, individualized to the underlying biology of GBM, might be warranted in tumors newly diagnosed and at an early stage.

Read more from the 2024 Rare Diseases Report: Hematology and Oncology.