3 Things You Should Know About Targeted Therapies for Gliomas

LEARNING OBJECTIVES

Upon successful completion of this activity, you should be better prepared to:

• Integrate current classification criteria and diagnostic strategies for identifying adult and pediatric patients with glioma

• Incorporate genetic and molecular information to classify gliomas and develop personalized treatment plans accurately

• Evaluate the data for recent advancements in targeted agents, immunotherapies, and other innovative treatment methods for treating patients with gliomas

• Identify strategies to integrate targeted therapies, immunotherapies, and novel emerging treatment approaches for managing pediatric patients with gliomas

RELEASE DATE: June 10, 2026

EXPIRATION DATE: June 10, 2027

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This activity is supported by an educational grant from Jazz Pharmaceuticals.

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1. Read this activity in its entirety.

2. Go to https://www.gotoper.com/tb26glioma-postref to access and complete the posttest.

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Since its incorporation into the 2016 WHO Classification of Tumors of the Central Nervous System (CNS),¹ molecular testing has dramatically refined the classification of gliomas.² The molecular profile adds prognostic information and offers potential targets for an expanding inventory of new drugs.^3,4 Here are 3 things you should know about targeted therapies for gliomas.

1) The MAPK signaling pathway offers multiple targets for patients with pediatric low-grade glioma (pLGG).

The most common solid tumors in children are found in the CNS.⁵ Approximately 30% of childhood CNS tumors are pLGGs,⁵ which are most commonly driven by alterations along the MAPK/ERK pathway.^6,7 Multiple therapeutic targets along the MAPK signaling pathway have been identified, as shown in Figure 1.⁸

Combination dabrafenib plus trametinib is approved for patients 1 year or older with BRAFV600E–mutated LGG requiring systemic therapy.⁹ This approval was based on the superior frontline overall response rate (47% vs 11%; risk ratio, 4.31; 95% CI, 1.7-11.2; P < .001) and median progression-free survival (PFS; 20.1 vs 7.4 months; HR, 0.31; 95% CI, 0.17-0.55; P < .001) of this combination vs chemotherapy as demonstrated in a randomized phase 2 trial (NCT02684058).^9,10

Investigators for the phase 2 FIREFLY-1 trial (NCT04775485) evaluated the pan-RAF inhibitor tovorafenib in 137 patients aged 1 to 24 years with BRAF- (arm 1, n = 77) or RAF-altered (arm 2, n = 60) relapsed or refractory pLGG.⁷ Among FIREFLY-1 participants, 74% had pLGG with a KIAA1549::BRAF fusion, 16% had pLGG with a BRAFV600E mutation, and 61% had received a prior MEK and/or BRAF inhibitor. With a median follow-up of 40.6 months, tovorafenib was associated with a Response Assessment in Pediatric Neuro-Oncology (RAPNO) objective response rate (ORR) of 53% in arm 1.^11,12 The median time to response was 5.4 months, median duration of response was 19.4 months, and median time to next treatment was 42.6 months.¹² Tovorafenib received accelerated FDA approval for the treatment of patients 6 months or older with relapsed or refractory pLGG harboring a BRAF fusion or rearrangement, or BRAFV600 mutation, based on data from the FIREFLY-1 trial.¹³

2) IDH-targeting agents are expanding options for adult patients with LGG.

Gliomas harboring an IDH mutation include grade 2 to 4 astrocytomas and 1p/19q codeleted grade 2 to 3 oligodendrogliomas.¹⁴ IDH-mutant gliomas accounted for approximately 12% of all gliomas diagnosed in 2018 and are the most common malignant primary brain tumor in adults younger than 50 years. The most common IDH mutation in gliomas is a gain-of-function arginine-to-histidine substitution on IDH1 (IDH1 R132H), leading to an excess of D-2-hydroxyglutarate.¹⁵

Vorasidenib, a dual mutant IDH1 and IDH2 inhibitor, was approved to treat grade 2 astrocytomas or oligodendrogliomas with a susceptible IDH1 or IDH2 mutation in patients 12 years or older following surgery (eg, biopsy, subtotal resection, or gross total resection).¹⁶ This approval was based on results of the phase 3, double-blind INDIGO study (NCT04164901), in which 331 patients with an IDH1/2-mutant grade 2 astrocytoma or oligodendroglioma were randomly assigned to receive vorasidenib vs placebo following at least 1 prior surgery, but no additional anticancer treatment(s), for glioma.¹⁷ With a median follow-up of 20.1 months, participants who received vorasidenib achieved a superior median PFS and had a longer time to next intervention compared with the placebo group (Figure 2).¹⁸ In a prespecified exploratory analysis, participants who received vorasidenib were found to have lower seizure rates compared with the placebo group (18.2 vs 51.2 seizures per person-year). INDIGO study investigators noted that extended follow-up is necessary to capture overall survival, a secondary end point, given the biology of grade 2 gliomas.

Investigators for a single-arm phase 2 study (NCT04458272) evaluated the efficacy of safusidenib erbumine, a selective mutant IDH1 inhibitor, in 27 patients with chemotherapy- and radiotherapy-naive, IDH1-mutated grade 2 gliomas.¹⁹ The Response Assessment in Neuro-Oncology (RANO) criteria for WHO grade 2 gliomas ORR was 44.4%. With a median follow-up of 28.0 months, the median PFS was not reached, with a 24-month event-free probability of 87.9%. Investigators for the 3-part phase 3 SIGMA trial (NCT05303519) are evaluating the efficacy and safety of safusidenib erbumine in patients with a variety of IDH1-mutated gliomas.²⁰ 

3) Dordaviprone is the first systemic therapy approved for the treatment of H3K27M-mutated diffuse midline gliomas (DMG) in children and adults.

An estimated 3940 people in the US, including 1380 children, are living with a DMG.²¹ Associated with a median survival of less than 1 year, DMGs are the most common cause of pediatric cancer-related deaths.²² Given their infiltrative nature and critical occupation in the thalamus, spinal cord, cerebellum, or pons, these grade 4 tumors are often unresectable.^21,23 Radiation therapy provides a modest survival benefit for some patients, and most traditional chemotherapies, including myeloablative regimens with stem cell transplantation, have proven ineffective for this disease.^23,24

The somatic H3K27M oncogenic missense mutation, occurring as either H3F3A (H3.3) or HIST1H3B (H3.1), is a poor prognostic feature detected in up to 80% of pediatric DMGs and up to 60% of adult diffuse gliomas.²² Dordaviprone is a first-in-class, oral, CNS-penetrant imipridone that acts as an allosteric agonist of mitochondrial ClpP serine protease.²⁵ This drug also selectively antagonizes the dopamine receptor D2/3, inhibiting intracellular DRD2 signaling pathways.²⁶ Dordaviprone’s unique mechanism of action disrupts metabolic and epigenetic pathways and reverses the pathognomonic loss of H3K27 trimethylation.²⁷

The authors of a pooled analysis of 46 adult and 4 pediatric patients with (nonpontine and nonspinal) recurrent, H3K27M-mutant DMGs who received single-agent dordaviprone reported an overall response rate (RANO-High Grade Glioma) of 22%.^12,28 The median time to response was 3.6 months, and the median duration of response was 10.3 months for the 11 patients who responded to dordaviprone. When limited to the prospectively defined trials of the analysis, dordaviprone demonstrated similar efficacy and safety.²⁹ Based on results from the 50-patient pooled analysis, the FDA granted accelerated approval for dordaviprone for patients 1 year or older with H3K27M-mutant DMG with progressive disease following prior therapy.³⁰

Key References

11. Kline C, Hargrave D, Khong-Quang DA, et al. CTP-17: clinical stability following tovorafenib treatment in relapsed/refractory pediatric low-grade glioma: updated results from the phase 2 FIREFLY-1 trial. Neuro Oncol. 2025;27(suppl 5):v149. doi:10.1093/neuonc/noaf201.0589

18. Cloughesy TF, van den Bent MJ, Touat M, et al. Vorasidenib in IDH1-mutant or IDH2-mutant low-grade glioma (INDIGO): secondary and exploratory endpoints from a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2025;26(12):1665-1675. doi:10.1016/s1470-2045(25)00472-3

28. Arrillaga-Romany I, Gardner SL, Odia Y, et al. ONC201 (dordaviprone) in recurrent H3 K27M-mutant diffuse midline glioma. J Clin Oncol. 2024;42(13):1542-1552. doi:10.1200/jco.23.01134

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CME Posttest Questions

1) Your patient is diagnosed with diffuse midline glioma. Molecular profiling is performed and reveals an H3 K27M mutation. The patient undergoes standard therapy; however, disease progression is noted 6 months after completion of radiation therapy (RT). Which of the following is the best option for this patient?

A. Dabrafenib/trametinib

B. Dordaviprone

C. Selumetinib

D. Vorasidenib

2) Based on updated results of the INDIGO trial, which of the following outcome measures were improved, in addition to progression-free survival, in adult patients with residual or recurrent IDH1/2-mutant low-grade glioma who were treated with vorasidenib compared with placebo?

A. Seizure rate in oligodendroglioma

B. Time to next intervention (TTNI)

C. Overall survival (OS)

D. TTNI and OS

E. TTNI and seizure rate

3) A tumor is confirmed to have both an IDH mutation and 1p/19q codeletion. Which principle best guides management?

A. Histology alone determines therapy

B. Molecular subtype directs treatment selection
C. All gliomas are treated the same
D. Surgery is sufficient

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To learn more about this topic, including information on additional MAPK pathway inhibiting drugs to treat pediatric gliomas, novel interventions for IDH-mutated gliomas, and a discussion of adult glioblastomas, go to https://www.gotoper.com/courses/tumor-board-clinical-integration-of-molecular-profiling-in-gliomatransforming-the-use-of-targeted-therapy

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