Part 01.

Treatment of Gliomas

The etiology of gliomas is still unclear. Currently identified risk factors include exposure to high-dose ionizing radiation and high penetrance genetic mutations associated with rare syndromes. The World Health Organization (WHO) classification of central nervous system (CNS) tumors (2021) categorizes adult diffuse astrocytic gliomas based on IDH status into: IDH-mutant astrocytoma, IDH-mutant and 1p/19q codeleted oligodendroglioma, and IDH-wildtype glioblastoma. Among primary malignant central nervous system (CNS) tumors, glioblastoma (GBM, WHO Grade IV) has the highest incidence rate, accounting for 46.6%. IDH-mutant gliomas exhibit a unique metabolic profile — notably decreased glycolysis, a metabolic hallmark of rapidly proliferating malignant tumors. The unique metabolic pathways in IDH-mutant gliomas not only explain the nature of this disease but also suggest that targeting strategies tailored to the IDH-mutant-specific metabolic pattern may be a valuable approach in the treatment of gliomas. NCCN guidelines have recommended the use of Ivosidenib in the treatment of gliomas accompanied by IDH mutations. Additionally, drug trials targeting multiple biomarkers are underway.

Part 02.

Efficacy of Vorasidenib in Low-Grade Gliomas with IDH1/2 Mutations

Vorasidenib is an oral formulation that inhibits IDH1/2 mutations and can penetrate the blood-brain barrier. INDIGO is a double-blind, Phase 3 clinical trial that enrolled a total of 331 patients with grade 2 gliomas harboring IDH mutations who had undergone surgery alone and had residual tumor or recurrence. Of these, 168 patients were assigned to the Vorasidenib group and 163 patients to the placebo group. The primary endpoint was progression-free survival based on imaging, with secondary endpoints including time to secondary tumor intervention. Patients in the placebo group were eligible to cross over to the Vorasidenib treatment group upon confirmation of disease progression based on imaging. Distribution of astrocytomas and oligodendrogliomas was similar between the two groups.

Progression-free survival and time to secondary intervention^[3]

In a follow-up period averaging 14.2 months, 226 patients (68.3%) continued to receive treatment with Vorasidenib or placebo. Compared to the placebo group, the Vorasidenib group showed a significant improvement in progression-free survival (median progression-free survival of 27.7 months vs. 11.1 months). Additionally, the time to the next intervention was significantly shortened in the Vorasidenib group compared to the placebo group. This phase III clinical trial yielded promising results, demonstrating that Vorasidenib can more than double the progression-free survival of patients with IDH 1/2-mutant grade 2 gliomas. The development of this therapy represents a breakthrough in the treatment of low-grade gliomas, offering hope to more patients with these conditions. It is worth mentioning that Vorasidenib has been granted Fast Track designation by the FDA, potentially making it the first targeted therapy for low-grade gliomas. Dr. Rimas V. Lukas, Associate Professor of Neurology and Neuro-oncology expert at Northwestern University Feinberg School of Medicine in Chicago, reviewed the key points of the phase III INDIGO trial (NCT04164901) presented at the 2023 ASCO Annual Meeting. Based on the trial results, he emphasized that adding Vorasidenib (AG-881) to the treatment regimen for IDH1/2-mutant gliomas is a feasible new targeted therapy approach.

Part 03.

Clinical Efficacy of ONC201 in H3K27M-Mutant Diffuse Midline Gliomas

There is currently no effective therapy for patients with H3K27M-mutant diffuse midline gliomas (DMGs). ONC201 has recently demonstrated efficacy in these patients. The small molecule ONC201 is a dopamine receptor D2 (drD2) antagonist, exerting its efficacy in H3K27M-DMGs by disrupting integrated metabolic and epigenetic pathways and reversing the pathological reduction of H3K27me3. The ONC 201-014 (NCT 03416530) trial included 30 patients, and the ONC 201-018 (NCT 03134131) trial included 41 patients. Although there were differences in the overall survival between the two trials, the median overall survival did not show statistical difference, with 21.7 months (n=24) in ONC201-014 and 13.9 months in ONC201-018. The median progression-free survival (PFS) also showed no statistical difference, with 9.4 months (n=24) in ONC201-014 and 4.8 months in ONC201-018.

Survival results of H3K27M-DMG trial patients treated with ONC201^[4]

Explored comparative analysis with historical cohorts. (Historical control data are derived from previously published meta-analyses of new diagnostic H3K27M mutant DMG cases and survival data from recurrent H3K27M mutant DMG patients). After adjusting for potential confounding factors in multivariate Cox analysis, ONC201 treatment still exhibited significance. Survival analysis comparing non-recurrent DMG patients receiving ONC201 treatment with publicly reported untreated H3K27M-DMG historical controls demonstrated a significant increase in overall survival (median OS of 21.7 months for the ONC201 treatment group from diagnosis compared to 12 months for historical controls, median OS of 9.3 months for recurrent DMG patients receiving ONC201 treatment compared to 8.1 months for historical controls).

This comprehensive study integrating clinical, radiological, and molecular analyses demonstrated the efficacy of ONC201 in H3K27M-DMG and supports ONC201 as a first-line monotherapy, improving the efficacy of H3K27M-DMG by simultaneously inhibiting key energy production pathways and reversing the pathological reduction of H3K27M. Further research is underway through a combination phase II trial (NCT05009992), a placebo-controlled phase III trial (NCT05580562), and other ONC201-related compounds (ONC206 and ONC212) that may improve central nervous system penetration and/or therapeutic effects for DMG patients.

Part 04.

PTPRZ1-MET Fusion: A multicenter, randomized, open-label phase II/III trial

PTPRZ1-MET fusion is associated with the progression of gliomas from low to high grade and is a target of the MET inhibitor vebreltinib. This multicenter, randomized, open-label, controlled trial aims to evaluate the safety and efficacy of vebreltinib in patients with sGBM/IDH-mutant glioblastomas carrying the ZM fusion gene. A total of 84 patients carrying the ZM fusion gene with sGBM or IDH-mutant glioblastomas were recruited. They were randomly assigned in a 1:1 ratio to the vebreltinib and control groups (temozolomide or cisplatin combined with temozolomide). The primary endpoint is overall survival (OS). Secondary endpoints include progression-free survival (PFS) and objective response rate (ORR). Patient recruitment was completed in March 2023.

Research process^[5]

Part 05.

Type II RAF inhibitor tovorafenib

FIREFLY-1 is an open-label phase II study. The trial results show that in 69 pediatric patients with recurrent or progressive low-grade glioma carrying BRAF mutations, monotherapy with Tovorafenib resulted in tumor shrinkage in 67% of patients, with complete disappearance of tumors in 17% of patients. Additionally, disease stabilization was observed in 26% of patients, resulting in an overall clinical benefit rate of 93%. The median duration of efficacy was 16.6 months. These data suggest that Tovorafenib may be an effective drug for pediatric patients with recurrent or progressive low-grade gliomas carrying BRAF mutations.

A patient's maximum change in tumor size can be assessed ^[6]

Part 06: Facing the Challenges

Gliomas originate from the glial cells of the brain and are the most common primary intracranial tumors. The treatment of gliomas primarily involves surgical resection, combined with radiotherapy, chemotherapy, and other comprehensive treatment methods. Compared to other tumors, targeted therapy for gliomas has been slow to develop, and currently, there are no specifically approved targeted drugs. Guidelines also recommend broad-spectrum targets such as NTRK. However, molecular markers have already played an important role in the auxiliary diagnosis and grading of gliomas, and research on targeted drugs has never ceased. Gliomas, as a type of intracranial tumor, have their own characteristics, but with the continuous advancement of related research in the future, it is believed that glioma patients will soon have their own targeted drugs, bringing new changes to the treatment plans for glioma patients.

References:

1. Guidelines for the Diagnosis and Treatment of Gliomas (2022 edition)

2. Central Nervous System Cancers 2023.v1

3. Br J Cancer. 2020 May;122(11):1580-1589.

4. Cancer Discov. 2023 Nov 1;13(11):2370-2393.

5. Chin Neurosurg J. 2023 Jul 14;9(1):21.

6. Nat Med. 2024 Jan;30(1):207-217.

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