Vorasidenib Shows Significant Improvement in Progression-Free Survival for Patients with IDH-Mutant Grade 2 Gliomas

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Grade 2 IDH-mutant glioma patients face a challenging journey as they navigate through the complexities of their diagnosis and treatment. Gliomas are a type of brain tumor that originate from glial cells, which are supportive cells in the central nervous system.

Among gliomas, grade 2 IDH-mutant gliomas are particularly notable due to their malignant nature and the significant impact they have on patients’ lives.

IDH mutations play a crucial role in the development of grade 2 gliomas. Isocitrate dehydrogenase (IDH) enzymes normally function to convert isocitrate to alpha-ketoglutarate in the citric acid cycle, a process that generates energy in cells.

However, mutations in the IDH1 or IDH2 genes result in a gain of function, leading to the production of an abnormal metabolite called 2-hydroxyglutarate (2-HG). This accumulation of 2-HG disrupts normal cellular processes and contributes to tumor development.

Grade 2 IDH-mutant gliomas are classified as low-grade tumors, indicating that they are less aggressive compared to higher-grade gliomas. However, they still pose significant challenges and can have a profound impact on patients’ quality of life.

These tumors typically grow slowly and have a propensity to infiltrate surrounding brain tissue, making complete surgical removal challenging. As a result, residual tumor cells often remain after surgery, leading to the potential for disease recurrence and progression.

The symptoms experienced by grade 2 IDH-mutant glioma patients can vary depending on the location of the tumor within the brain. Common symptoms may include headaches, seizures, cognitive difficulties, and motor impairments. These symptoms can significantly impact daily activities and overall well-being, leading to considerable disability and a decreased quality of life.

Traditionally, the management of grade 2 gliomas has involved a combination of surgical resection, radiation therapy, and chemotherapy. However, the emergence of targeted therapies has opened up new avenues for treatment. Vorasidenib, the oral brain-penetrant inhibitor of mutant IDH1 and IDH2 enzymes, has shown promise in clinical trials for IDH-mutant gliomas. By targeting the specific molecular abnormalities driving the tumor’s growth, vorasidenib aims to inhibit tumor progression and improve patient outcomes.

The recently conducted phase 3 trial evaluating vorasidenib in grade 2 IDH-mutant glioma patients demonstrated significant advancements in the treatment landscape. The trial randomized patients to receive either vorasidenib or a placebo and assessed key endpoints such as progression-free survival and the time to the next anticancer intervention. The results showed that vorasidenib significantly improved progression-free survival and delayed the need for additional interventions compared to the placebo group.

These findings provide hope for grade 2 IDH-mutant glioma patients and their healthcare providers. The ability of vorasidenib to target the specific genetic mutation driving tumor growth represents a personalized and precision medicine approach. By inhibiting the abnormal metabolic processes associated with IDH mutations, vorasidenib offers a novel therapeutic strategy that holds the potential to improve patient outcomes and prolong survival.

However, a recent phase 3 clinical trial has shown promising results for the treatment of these tumors.

Vorasidenib, an oral brain-penetrant inhibitor of mutant IDH1 and IDH2 enzymes, demonstrated preliminary activity in IDH-mutant gliomas.

The study, a double-blind trial, involved randomly assigning patients with residual or recurrent grade 2 IDH-mutant glioma, who had undergone no previous treatment other than surgery, to receive either oral vorasidenib (40 mg once daily) or a matched placebo in 28-day cycles.

The primary endpoint of the trial was imaging-based progression-free survival, as assessed by an independent review committee. The key secondary endpoint was the time to the next anticancer intervention. Patients on the placebo arm were allowed to switch to vorasidenib upon confirmation of imaging-based disease progression. Safety was also assessed throughout the trial.

A total of 331 patients were enrolled in the trial, with 168 patients receiving vorasidenib and 163 patients receiving placebo. At a median follow-up of 14.2 months, 226 patients (68.3%) were still receiving vorasidenib or placebo. The results demonstrated a significant improvement in progression-free survival in the vorasidenib group compared to the placebo group (median progression-free survival of 27.7 months vs. 11.1 months; hazard ratio for disease progression or death, 0.39; 95% confidence interval [CI], 0.27 to 0.56; P<0.001). Additionally, the time to the next intervention was significantly extended in the vorasidenib group compared to the placebo group (hazard ratio, 0.26; 95% CI, 0.15 to 0.43; P<0.001).

Regarding safety, adverse events of grade 3 or higher occurred in 22.8% of patients who received vorasidenib and in 13.5% of those who received placebo. An increased alanine aminotransferase level of grade 3 or higher occurred in 9.6% of patients who received vorasidenib and in none of the patients who received placebo.

The study’s findings have important implications for the treatment of grade 2 IDH-mutant glioma patients. Vorasidenib demonstrated significant improvements in progression-free survival and delayed the need for additional interventions. These results offer hope for patients with this aggressive form of brain cancer.

It is worth noting that this phase 3 trial was funded by Servier, the pharmaceutical company that developed vorasidenib. The trial is registered on ClinicalTrials.gov with the identifier NCT04164901.

While these results are promising, it is essential to interpret them within the context of ongoing research and clinical practice. Further studies and long-term follow-up are necessary to assess the durability of the treatment response, potential side effects, and overall survival outcomes. However, the findings of this phase 3 trial provide a strong foundation for future investigations and potential therapeutic options for patients with IDH-mutant grade 2 gliomas.


Current Treatment of Lower-Grade Glioma.
The treatment of lower-grade glioma is based on a multimodality approach. It is important to note that the landmark studies that provide the foundation for the current treatment approach for LGG and anaplastic glioma were designed and conducted prior to current molecular classification of glioma being established and when modern surgical or radiotherapy techniques such as Intensity Modulated Radiotherapy or proton therapy were not available. As such, there are inherent limitations in trying to extrapolate results to the IDH mutated glioma subgroup. Future studies stratifying patients into homogeneous populations will be critical to assess the benefit of novel therapies.

Maximal safe, surgical resection remains the initial treatment for LGG to enable an accurate diagnosis and improve clinical outcomes such as progression-free survival, overall survival and risk of malignant transformation 42–44. The impact of maximal resection as first-line treatment may be more important for mIDH astrocytoma than oligodendroglioma 45. Improved surgical techniques such as intraoperative MRI and electrostimulation mapping during an awake craniotomy allow for more extensive resection while minimizing neurologic injury.

Radiation therapy is an important adjunct in the management of LGG and several studies have explored the optimal timing and dosing schedule. The European Organization for Research and Treatment of Cancer (EORTC) 22845 study comparing early RT after surgery vs RT delayed until time of progression, showed no significant difference in OS (7.4 years vs 7.2 years), but patients who received early RT had improvements in seizure control and median PFS (5.3 years vs 3.4 years with delayed RT)46. Two randomized studies evaluating high dose RT versus low dose RT did not show any significant differences in PFS and OS, but long-term analysis demonstrated improved quality of life in patients treated at the lower radiation dose 47–49.

The optimal use of RT and/or chemotherapy after surgery for low-grade gliomas continues to be defined. Several prognostic factors have been proposed to better identify patients at high risk for malignant transformation and may benefit from aggressive management with adjuvant chemoradiation. High-risk factors include age > 40 years, subtotal resection/biopsy only, astrocytic lineage (lack of 1p/19q codeletion), neurologic deficits prior to surgery, tumor diameter > 6 cm, tumor crossing the midline of the brain, and tumors located within or adjacent to eloquent areas of the brain 50–52.

Patients without these risk factors can be considered at low risk; therefore, after gross total resection, they are usually observed closely with regularly scheduled surveillance imaging to assess for intervention at the time of progression. The EORTC brain tumor group is conducting a phase 3 study for patients with IDH mutated 1p/19q intact lower grade glioma following resection, without a need for immediate post-operative treatment, to establish whether early adjuvant treatment with radiotherapy and adjuvant temozolomide in this clinically favorable group of patients will improve outcome compared to active surveillance. The primary endpoint is first intervention free survival with multiple secondary endpoints of PFS, OS, seizure control and health related quality of life. [EORTC-1635-BTG ClinicalTrials.gov Identifier: NCT03763422].

In an attempt to defer the adverse effects of RT, several studies have evaluated chemotherapy alone 53,54. A report of the EORTC 22033–26033 study of temozolomide versus RT in high risk LGG did not demonstrate a difference in PFS, but radiotherapy tended to be superior in mIDH astrocytoma. The results regarding the effects on OS are pending 55.

The survival benefit of adjuvant chemoradiotherapy for high-risk LGG was demonstrated in the Radiation Therapy Oncology Group 9802 phase III trial that randomized patients to receive RT or RT plus combination chemotherapy with PCV (procarbazine, lomustine, and vincristine). Based on the pivotal data showing an almost two-fold increase in OS for patients in the chemoradiation therapy arm compared with the RT alone arm (13.3 years vs 7.8 years), high-risk patients with low-grade gliomas should receive radiotherapy followed by adjuvant chemotherapy rather than RT alone 56 (Figure 3). This study was conducted prior to the molecular characterization of LGG. A post-hoc molecular analysis on a subgroup of patients from this trial 39 confirmed that patients with IDH mutated gliomas with or without 1p/19q codeletion benefited from the addition of PCV to radiotherapy, but suggested that patients with IDH wild-type astrocytomas may not benefit from this combination.

Figure 3.
Long-term follow-up of Progression-free survival (PFS) of RT/PCV versus RT alone in 1p/19q codel glioma patients (n=80) in EORTC 26951.

The CATNON trial investigated concurrent and adjuvant temozolomide in anaplastic glioma and observed only benefit of the adjuvant treatment in mIDH anaplastic astrocytoma, not in IDHwt anaplastic astrocytoma. In mIDH tumors, adjuvant temozolomide improved outcome (HR 0.48, 95% CI (0.35, 0.67); p < 0.0001), 5 year survival increased from 62.0% (95% CI: 54.4, 68.7) to 81.6% (95% CI: 75.5, 86.4) 57.

With the introduction of temozolomide as the standard of care for glioblastoma 58 and based on the improved safety profile compared to nitrosoureas, in clinical practice, patients are commonly treated with temozolomide. The ongoing CODEL phase III study randomizes patients with 1p/19q co-deleted WHO grade II and III gliomas to receive either RT followed by PCV or RT with concurrent and then adjuvant temozolomide to address the comparison of these 2 chemotherapy regimens. [ClinicalTrials.gov Identifier: NCT00887146].

Development of mIDH Inhibitors.
Inhibiting the aberrant activity of mutant enzymes represents an established pharmacological strategy for the treatment of human cancer, exemplified by the class of kinase inhibitors 59. Cancer-associated mutant IDH enzymes represent attractive drug targets for the development of mutant-selective inhibitors because these mutations cluster in key arginine residues within the enzymes’ active sites (R132 of IDH1 and R140 or R172 of IDH2) and because successful inhibition of the mutant enzyme can readily be ascertained through measurements of 2-HG in tumor biopsies 10 60. In patients with acute myeloid leukemia (AML) or cholangiocarcinoma, two other human cancers with frequent IDH mutations, 2-HG can also be detected in patient serum 61 62. Non-invasive imaging approaches for the detection of 2-HG in patients with glioma have been reported 63 64, but their utility for clinical practice and clinical drug development remains to be defined.

Preclinical studies demonstrated that inhibition of mutant IDH enzymes retards tumor growth in experimental models of glioma, leukemia, and cholangiocarcinoma 65–67.

The clinical development of inhibitors of mIDH proceeded most expeditiously for AML where, unlike in glioma, IDH2 mutations are more common than IDH1 mutations. Enasidenib, the first-in-class inhibitor of mIDH2, produced clinical responses in approximately 40% of patients with advanced mIDH2 AML 68,69. Ivosidenib, the first-in-class inhibitor of the mIDH1 enzyme, similarly induced remissions in patients with advanced mIDH1 AML 70. Both drugs have received regulatory approval for the treatment of mIDH AML.

A phase I study with ivosidenib in subjects with mIDH1 advanced solid tumors, including previously treated glioma (ClinicalTrials.gov identifier: NCT02073994), reported no dose-limiting toxicities, and the maximum tolerated dose was not reached. A dose of 500 mg once daily was selected for expansion based on the pharmacokinetic/pharmacodynamic data from all solid tumor cohorts. This trial showed early signs of clinical activity in IDH1-mutant glioma, with a reduction in tumor volume growth rates (i.e., compared with pretreatment growth rates) and tumor shrinkage in several patients71. In patients with IDH1-mutant advanced cholangiocarcinoma, ivosidenib was also well tolerated and showed preliminary evidence for antitumor activity72. The clinical benefit of targeting IDH1 mutations in advanced, mIDH1 cholangiocarcinoma was subsequently confirmed in a Phase 3 trial 73.

Vorasidenib (AG-881) is a first-in-class, dual inhibitor of mIDH1 and mIDH2 that was developed for improved penetration across the blood-brain barrier 74. In a phase I study (ClinicalTrials.gov identifier: NCT02481154), Vorasidenib showed a favorable safety profile at doses <100 mg QD in previously treated patients with non-enhancing glioma. Many patients remained on treatment after several years of continuous treatment and tumor shrinkage was observed in multiple patients with non-enhancing glioma 75. In a follow-up perioperative phase I study in patients with non-enhancing glioma (ClinicalTrials.gov, NCT03343197), vorasidenib 50 mg QD resulted in >90% reduction in intratumoral 2-HG concentrations compared with untreated controls, indicating near complete inhibition of the enzyme 60.

Since a watch-and-wait approach following surgery remains a treatment option for patients with low-risk LGG, there is an opportunity to explore the activity of mIDH inhibitors during the active observation period. Vorasidenib (50 mg QD) is now being tested versus placebo in the ongoing, randomized, phase III INDIGO study (ClinicalTrials.gov, NCT04164901) which enrolls patients with grade II non-enhancing mIDH glioma treated with surgery only.

Several other inhibitors targeting the mIDH enzymes are in earlier stages of clinical development for mIDH human cancers, including glioma.


reference link : https://www.nejm.org/doi/full/10.1056/NEJMoa2304194

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9549919/

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