Neuro-Oncology Outlook: Advancements in Targeted Molecular Therapy for Low-Grade Gliomas—Challenging the Treatment Paradigm

Grade 2 astrocytomas and oligodendrogliomas account for approximately 12% of gliomas diagnosed each year.¹ They are classified by their histologic and molecular characteristics and are defined by the presence of a gain-of-function mutation in the isocitrate dehydrogenase (IDH) gene. IDH mutations contribute to genome-wide histone and DNA methylation alterations by increasing D-2-hydroxyglutarate (an oncometabolite), and they appear to drive low-grade glioma formation.^2-5 Advancements in the understanding of IDH mutations have led to the exploration of targeted therapies in neuro-oncology that may alter the natural history of these tumors. The application and success of these efforts has culminated in the landmark phase 3 clinical trial, Vorasidenib in IDH1- or IDH2-Mutant Low-Grade Glioma (INDIGO), the results of which were recently published in The New England Journal of Medicine.⁶

Grade 2 gliomas are often diagnosed in individuals age 30 to 45 years during workup for focal epilepsy, neurocognitive impairment, or symptoms related to elevated intracranial pressure.^2,7,8 Grade 2 gliomas are progressive and slow-growing; median survival ranges from 6 to 15 years.^1,9 The standard of care for grade 2 gliomas begins with maximal surgical resection. After resection, risk stratification based on age, tumor burden, and residual neurologic deficits is performed to determine next steps for therapy (Figure 1).^2,3 People deemed to have high-risk features (subtotal resection or age >40 y)¹⁰ are treated with radiation and chemotherapy; those who do not have high-risk features are often closely monitored with serial imaging (ie, watch and wait).² Radiation and chemotherapy are toxic and can substantially affect quality of life during active treatment. Alkylating chemotherapy can affect fertility, and radiation requires 6 weeks of near-daily treatments, disrupting the lives of individuals who are often midcareer or raising a family. These relatively young individuals may experience late effects of radiation, including radiation necrosis, stroke-like migraine attacks after radiation syndrome, and neurocognitive dysfunction.^2,8,11 In people with low-risk grade 2 gliomas, radiation and chemotherapy are often deferred and instead observed with serial imaging (watch and wait model) because of the prevalence of these effects.²

People with grade 2 gliomas under active surveillance are ideal candidates for an investigational agent that would alter the slow growth of these tumors. In addition, treatment implemented at this point in the disease course could allow for delayed initiation of toxic therapies, preserving quality of life while treating the cancer. Vorasidenib (Servier Pharmaceuticals; Boston, MA), a brain-penetrant, IDH 1/2 inhibitor, had previously been shown to have anti-tumor effects, presumably by its ability to reduce D-2-hydroxygluterate (oncometabolite) in a first-in-human phase 1 clinical trial in those with recurrent low grade gliomas.^6,12 For these reasons, the INDIGO trial studied the potential benefit of the targeted therapy vorasidenib in this population, exploring an intervention where one has not existed.

INDIGO Trial Design and Results

INDIGO was an international, double-blinded, randomized, placebo-controlled, phase 3 clinical trial performed in individuals with recurrent or residual grade 2 IDH mutant gliomas (oligodendrogliomas or astrocytomas) who had not received radiation or chemotherapy. Participants were randomized 1:1 to receive the investigational agent vorasidenib at 40 mg daily or a placebo. The individuals included in the trial were 12 years or older and had a Karnofsky Performance Status score of at least 80, indicating little to no disability. They must have had at least 1 surgery completed within the previous 1 to 5 years. The primary end point of this study was imaging-based progression-free survival from the time of randomization—which was monitored by blinded, independent radiologists—or death from any cause. Secondary end points included initiation of other anticancer treatments (including crossover to vorasidenib), objective response, health-related quality of life, and overall survival.⁶

The trial enrolled 331 individuals at 77 centers across 10 countries from January 2020 through February 2022. Of those, 163 individuals were assigned to the placebo group and 168 to the vorasidenib group. Participant characteristics in the 2 arms were similar. No participants were lost to follow-up, and no deaths occurred in either group. The median age was 39 years (range, 16 to 65 y) in the placebo group and 40.5 years (range, 21 to 71 y) in the vorasidenib group. Most participants (53% in both the placebo and treatment arms) had a Karnofsky Performance Status score of 100. Most tumors were in the frontal lobe (70.6% in the placebo arm and 63.7% in the vorasidenib arm). The mean time from diagnosis to randomization was 3.1±2.5 years in the placebo group and 3.3±2.4 years in the treatment group. Most individuals (82.2% in the placebo arm and 75% in the vorasidenib arm) had 1 resection, which occurred an average of 2.6±1.3 years before randomization into the placebo group and 2.7±1.1 years before randomization into the vorasidenib group. Imaging-based progression occurred in 54% of participants in the placebo group and 28% of participants in the vorasidenib group. The treatment arm demonstrated a significantly longer imaging-based progression-free survival. More specifically, the median progression-free survival was 11.1 months (95% CI, 11.0 to 13.7) in the placebo group and 27.7 months (95% CI, 17 to not estimated) in the vorasidenib group, with a hazard ratio of .39 (95% CI, .27 to .56; P<.001) (Figure 2A). In the placebo group, the probability of being alive and without progression at 18 months was 47.4% (95% CI, 35.8 to 58.2), and at 24 months was 27.0% (95% CI, 7.9 to 50.8). The treatment group fared significantly better, with a probability of being alive and without progression by 18 months of 85.6% (95% CI, 77.8 to 90.8), and by 24 months of 83.4% (95% CI, 74 to 89.6), with a hazard ratio for time to next intervention of 0.25 (95% CI, .15 to .4; P<.0001). In the placebo arm, 58 individuals (35.6%) required additional intervention; in the treatment arm, only 19 individuals (11.3%) received another anticancer therapy (Figure 2B).⁶

Vorasidenib was well-tolerated, with the most common adverse events being elevated alanine aminotransferase and aspartate aminotransferase levels (14.7% and 8.0%, respectively, in the placebo group, and 38.9% and 28.7% in the vorasidenib group). Other adverse events, such as fatigue, headache, diarrhea, nausea, dizziness, seizure, and constipation, were similar across treatment and placebo arms.⁶

Conclusion

Grade 2 gliomas are incurable, malignant tumors most commonly affecting individuals in their 30s to 40s.^2,7,8 They require aggressive treatments that have known acute and long-term side effects and toxicities that may substantially affect quality of life.^2,8,11 The ability to initiate a treatment that would delay the use of these toxic therapies provides an opportunity to advance the field of neuro-oncology. The INDIGO clinical trial has shown the ability to alter the disease course in individuals with recurrent or residual IDH mutant grade 2 gliomas by increasing the median progression-free survival by 16.6 months in individuals treated with vorasidenib. Treatment with this mutant IDH inhibitor also increased the time to next intervention. Along with being efficacious, vorasidenib was well-tolerated.⁶ These results provide a foundation as the first application of targeted therapies for IDH mutations in neuro-oncology. The results of the INDIGO trial challenge the current treatment paradigm in grade 2 glioma and provide phase 3 evidence that the role of surveillance (ie, watch and wait) in these tumors may no longer be appropriate. The encouraging results of this trial demonstrate a novel and effective therapeutic intervention for grade 2 gliomas.