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Overcoming Challenges in the Treatment of Primary Brain Tumors

TOP - November 2022 Vol 15, No 6

Primary brain tumors, also known as gliomas, represent some of the greatest challenges in the management of patients with cancer. Despite aggressive surgical resections and recent advances in radiotherapy and chemotherapy, the prognosis for patients with these types of tumors is dismal. However, substantial progress has been made regarding the molecular characterization of gliomas, providing useful insights into the development of more effective targeted therapies. These treatments continue to be evaluated, with the hope of improving clinical outcomes. During a special symposium held during the European Society for Medical Oncology Congress 2022, experts discussed lessons learned in the diagnosis and treatment of patients with primary brain tumors and what is on the horizon.

“Primary brain tumors have many faces, and these make the development of precision treatment so challenging,” said Susan M. Chang, MD, Vice Chair of Neurological Surgery and Director of the Division of Neuro-Oncology, University of California, San Francisco.

Evaluating Response to Therapy

The fifth edition of the World Health Organization (WHO) Classification of Tumors of the Central Nervous System (CNS), published in 2021, incorporated molecular and histopathologic information into the diagnosis of brain tumors, which has enhanced diagnostic accuracy and helped to guide treatment decisions. In addition, the Response Assessment in Neuro-Oncology (RANO) working group identified current challenges related to response assessment, end point selection, and clinical trial design with the aim of improving the evaluation of novel agents in neuro-oncologic studies.

Dr Chang said that the biggest issue with response-based end points in trials is pseudoprogression, a phenomenon that occurs when radiochemotherapy leads to increased contrast agent uptake and enlargement of a residual tumor or the appearance of new lesions mimicking tumor progression. The ability to differentiate pseudoprogression as a result of treatment from true tumor progression remains a significant challenge, she added.

Factors to consider when evaluating response end points should include standardization of acquisition of imaging, standardization of patient assessments that are included in the response criteria, mechanism of action of the agent being evaluated (eg, antiangiogenic, targeted therapy, immunotherapy), modality of the treatment, and molecular and genomic characteristics of the tumor.

The RANO working group recognizes that the integration of molecular features to diagnose glioma can affect the imaging characteristics of patients eligible for trials and intends to remove barriers to inclusion in its 2.0 update, Dr Chang noted.

IDH Mutation–Positive Glioma

WHO 2021 classifies adult glioma based on IDH mutation. In adults, diffuse gliomas have been condensed into 3 types: astrocytoma, IDH mutation–positive; oligodendroglioma, IDH mutation–positive and 1p/19q-codeleted; and glioblastoma, IDH–wild-type.

IDH mutation is a super target in neuro-oncology, explained Anna Sophie S. Berghoff, MD, PhD, Head, CNS Tumor Unit, Medical University of

Vienna, Austria. “IDH mutation is not only a diagnostic biomarker, but we have inhibitors and it’s also an immunological target,” she said. “We can target it from so many angles.”

IDH mutation–positive glioma is a distinct entity that portends a more favorable prognosis than IDH–wild-type. IDH inhibitors are not proving to be effective in enhancing tumors, which tend to be more aggressive and fast growing, Dr Berghoff said.

Vorasidenib (AG-881) is a dual inhibitor of IDH1/2 with improved brain penetrance compared with ivosidenib (Tibsovo). In one study, 18% of patients with nonenhancing tumors had tumor shrinkage following treatment with vorasidenib. In the INDIGO trial, which is currently enrolling, patients with IDH mutation–positive nonenhancing gliomas are being randomized to vorasidenib 50 mg/day orally in continuous 28-day cycles or placebo. Crossover is permitted when radiographic progressive disease is documented and centrally confirmed.

IDH is also a target for immune-modulating therapies. “It’s a good target to explore a vaccination approach,” said Dr Berghoff. Preliminary data show immunogenicity but a low response to an IDH mutation–specific vaccine in patients with newly diagnosed astrocytoma, with a correlation between clinical response and biological T-cell response generated by the vaccine. The NOA21 window of opportunity trial is obtaining biologic information on the T-cell response after tumor resection and vaccination in patients with IDH mutation–positive gliomas and is assessing vaccination in combination with an immune checkpoint inhibitor.

Novel Treatment Approaches

Ahmed Idbaih, MD, PhD, Neuro-Oncologist at Hôpitaux Universitaires la Pitié-Salpêtrière, Paris, France, discussed novel treatment strategies for patients with glioblastoma, the most common and aggressive form of primary brain cancer in adults.

According to Dr Idbaih, standard first-line treatment for glioblastoma is maximal safe surgery and radiation with concurrent and adjuvant temozolomide (Temodar). However, this approach is associated with median overall survival (OS) of only 12 to 18 months, with virtually all patients experiencing disease recurrence. Second-line treatment approaches include surgery and/or second radiotherapy, and lomustine (Gleostine) alone, lomustine plus bevacizumab (Avastin), or bevacizumab alone, but this tends to extend median OS by only 6 to 9 months.

Molecular targeted therapies with broad activity currently being investigated include pan-receptor tyrosine kinase inhibitors. In a phase 2 study of patients with recurrent glioblastoma, treatment with regorafenib (Stivarga) led to improved OS versus lomustine, Dr Idbaih said.

Two phase 3 studies of nivolumab (Opdivo) in patients with newly diagnosed glioblastoma showed no advantage with the addition of this agent to standard therapy. “Some patients did respond; we need to find the best biomarkers of response,” he said. Two early-phase trials are assessing the utility of CAR T-cells in recurrent glioblastoma.

Immunotherapy using an oncolytic virus (poliovirus type 1, PVS-RIPO) showed some promise in a phase 1 trial of patients with recurrent glioblastoma. It “targets quite specifically tumor cells expressing CD155,” he said. “Twenty percent have long-term survival when treated with PVS-RIPO.”

Optune is a wearable, portable medical device approved by the FDA for the treatment of glioblastoma. It works by creating Tumor-Treating Fields, which are electric fields that disrupt cancer cell division. In a phase 3 trial, patients with newly diagnosed glioblastoma who were treated with a combination of Optune plus temozolomide had a longer median OS compared with those treated with temozolomide alone.

The FDA has also approved SonoCloud-9, a medical device that uses low-intensity pulsed ultrasound to temporarily disrupt the blood-brain barrier in patients with newly diagnosed glioblastoma, which allows enhanced penetration of therapeutic compounds. A phase 1 study in recurrent glioblastoma is ongoing.

Targeting Signaling

According to Paul Mischel, MD, Professor, Pathology, and Vice Chair, Research, Stanford University, CA, recent evidence points to actionable vulnerabilities and synthetic lethal targeting opportunities in lipid metabolism shaped by tumor genotype, brain physiology, and cell lineage. Sphingomyelin phosphodiesterase 1 (SMPD1), an enzyme that regulates the conversion of sphingomyelin to ceramide, has been identified as an actionable drug target in glioblastoma. The highly brain-penetrant antidepressant fluoxetine (Prozac), but not other selective serotonin reuptake inhibitors, potently inhibits SMPD1 activity, killing glioblastoma through inhibition of epidermal growth factor receptor signaling and via activation of lysosomal stress.

In mice, combining fluoxetine with temozolomide has resulted in increases in glioblastoma cell death and complete tumor regression. In addition, the incorporation of real-world evidence from electronic medical records from insurance databases has revealed significantly improved survival in patients with glioblastoma who were treated with fluoxetine, which was not seen in patients treated with other selective serotonin reuptake inhibitor antidepressants. This real-world evidence “suggests the efficacy of fluoxetine in combination with standard of care and sets the table for new drug development,” Dr Mischel concluded.

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