Targeted Therapies for Adult Gliomas: A Guide to Recent Advances

Table of Contents

• Key Points
• Background: Why This Research Matters
• How Adult Gliomas Are Classified
• The Molecular Landscape of Adult Gliomas
• How This Review Was Conducted
• FDA-Approved Therapy: IDH Inhibitors (Vorasidenib)
• The INDIGO Trial: Detailed Results
• Important Limits of the INDIGO Findings
• FDA-Approved Therapy: BRAF and MEK Inhibitors
• FDA-Approved Therapy: NTRK Inhibitors
• FDA-Approved Therapy: Dordaviprone for H3K27M Gliomas
• Investigational Targeted Therapies
• New Strategies for Drug Delivery
• Persistent Challenges in the Field
• Clinical Implications for Patients
• Limitations of the Evidence
• Recommendations and Future Directions
• Frequently Asked Questions
• Source Information

Key Points

• Molecular testing of the tumor identifies IDH mutations, BRAF V600E mutations, NTRK fusions, or H3K27M mutations, which determine whether an FDA-approved targeted therapy is an option.
• In the INDIGO trial of 331 patients with grade 2, non-enhancing IDH1/2-mutant gliomas, median progression-free survival was 27.7 months with vorasidenib versus 11.1 months with placebo.
• The FDA approved dabrafenib plus trametinib for BRAF V600E-mutated gliomas; in the ROAR trial, objective response rates were 33% in high-grade and 54% in low-grade glioma cohorts.
• Dordaviprone was approved for H3K27M-mutant diffuse midline glioma with progressive disease after prior therapy; in 50 patients, objective response rate was 20% and disease control rate 40%.
• These targeted therapies help selected patients but are not curative, and most adult gliomas still lack an approved targeted treatment.

Background: Why This Research Matters

Gliomas are the most common primary malignant brain tumors in adults. These tumors are genetically heterogeneous, meaning that different cells within the same tumor can carry different genetic changes. Gliomas also infiltrate surrounding brain tissue, which makes them hard to remove completely with surgery. For these reasons, current therapies offer limited benefit.

Over the last decade, molecular diagnostics have changed how doctors classify and predict outcomes for adult gliomas. Molecular diagnostics are tests that look for specific gene changes in a tumor. One important example is the isocitrate dehydrogenase (IDH) mutation. IDH is a gene that normally helps cells produce energy.

Despite these advances in testing, turning molecular insights into effective treatments has been slow. Survival outcomes remain poor, especially for patients whose tumors have IDH-wildtype (IDH-wt) glioma. IDH-wildtype means the tumor does not carry an IDH mutation.

Encouragingly, this situation has begun to shift. Recent FDA approvals have introduced the first targeted agents for gliomas. These include vorasidenib for IDH-mutant diffuse gliomas. These include dabrafenib plus trametinib for BRAF V600E-mutated gliomas. These include neurotrophic tyrosine receptor kinase (NTRK) inhibitors for NTRK fusion-positive tumors. These include dordaviprone for recurrent H3K27M-mutant diffuse midline gliomas.

This review outlines the current classification and molecular landscape of adult gliomas. It also evaluates FDA-approved and investigational targeted therapies. Finally, it considers evolving drug delivery strategies, persistent challenges, and potential future directions.

How Adult Gliomas Are Classified

The classification of adult gliomas has undergone a paradigm shift over the last decade. Historically, doctors diagnosed gliomas based on histology, which is the appearance of tumor tissue under a microscope.

Molecular classification was first incorporated into the 2016 World Health Organization (WHO) Classification of Tumors of the Central Nervous System (CNS). It was refined further in the 2021 update. Together, these criteria introduced an "integrated diagnosis." In an integrated diagnosis, defining molecular alterations are considered alongside histopathology to designate distinct tumor types.

In the latest 2021 WHO classification, IDH1/2 mutation status is the primary molecular classifier of diffuse gliomas. This means the presence or absence of an IDH mutation is the first and most important distinction doctors make.

Glioblastoma (GBM) is a grade 4 tumor. Doctors define GBM by wild-type IDH status alongside characteristic histologic features. These features include microvascular proliferation (abnormal blood vessel growth) and necrosis (dead tissue). Molecular features can also define GBM. These include TERT promoter mutation, EGFR amplification, or chromosome 7 gain with chromosome 10 loss.

GBM is the most common malignant primary brain tumor in adults. It accounts for approximately 51% of all malignant primary brain tumors. GBM primarily affects patients over 60 years old.

In contrast, IDH-mutant gliomas are less common. They account for roughly 15–20% of all adult gliomas. These tumors are more prevalent in younger patients, in their thirties and forties.

Within IDH-mutant glioma, co-deletion of the 1p and 19q chromosomal arms defines oligodendroglioma. Co-deletion means both copies of these chromosome arms are missing. Oligodendrogliomas often harbor alterations in TERT promoter, CIC, FUBP1, and NOTCH1. Doctors classify oligodendrogliomas as grade 2 or grade 3 based on histology.

IDH-mutant, 1p/19q-intact tumors are classified as astrocytoma. These tumors typically harbor ATRX and TP53 alterations. Doctors grade astrocytomas histologically as grade 2, 3, or 4. Notably, homozygous CDKN2A/B deletion in IDH-mutant astrocytoma yields a grade 4 designation. This is true regardless of histopathological features. Homozygous deletion means both copies of the gene are lost.

Besides GBM, IDH-wildtype adult gliomas include several "pediatric-type" diffuse gliomas and circumscribed gliomas. These tumors typically affect young adults and carry distinct molecular signatures.

One example is diffuse midline glioma (DMG), H3 K27-altered. This is a grade 4 tumor defined by its midline location, such as the thalamus, pons, or spinal cord. It is also defined by loss of H3K27 trimethylation. This loss is most commonly due to an H3 K27M mutation, abbreviated DMG-H3K27M.

Examples of low-grade circumscribed gliomas include pilocytic astrocytoma (PA) and pleomorphic xanthoastrocytoma (PXA).

The Molecular Landscape of Adult Gliomas

Beyond diagnostic classification, the molecular diversity of adult gliomas reveals distinct tumor biology and therapeutic vulnerabilities. In IDH-mutant gliomas, IDH1/2 mutations drive tumorigenesis, which is the formation of tumors.

In contrast, IDH-wildtype gliomas, especially GBM, are characterized by complex molecular architectures. These tumors frequently have alterations in receptor tyrosine kinases (RTKs), such as EGFR, PDGFRA, and FGFR. RTKs are proteins on the cell surface that receive growth signals.

These tumors also have alterations in RTK downstream cascades. These cascades include the phosphatidylinositol 3-kinase–protein kinase B–mechanistic target of rapamycin (PI3K-AKT-mTOR) pathway and the mitogen-activated protein kinase (MAPK) pathway. Alterations also occur in cell cycle regulation and DNA damage response.

These changes result in marked pathway redundancy and cross-talk. Pathway redundancy means that when one pathway is blocked, another can compensate. This redundancy makes treatment difficult.

Targeted therapies in glioma have been designed either to directly inhibit oncogenic drivers or to exploit vulnerabilities. Oncogenic drivers are the specific gene changes that push a cell to become cancerous. Vulnerabilities include DNA repair mechanisms and metabolic liabilities.

How This Review Was Conducted

This article is a narrative review, not a new clinical trial. The authors evaluated FDA-approved and investigational targeted therapies for adult gliomas. They examined the pivotal clinical trials that led to FDA approvals and reported glioma-specific data.

The authors also reviewed the current classification and molecular landscape of adult gliomas. They considered evolving drug delivery strategies and the persistent challenges that impede therapeutic progress.

Historically, adult glioma management has relied on surgery, radiotherapy, and cytotoxic chemotherapy. Cytotoxic chemotherapy means drugs that kill dividing cells. GBM is typically treated with maximal safe resection followed by chemoradiation. Maximal safe resection means removing as much tumor as possible without harming critical brain functions.

IDH-mutant gliomas have conventionally been managed with maximal safe resection followed by risk-adapted chemoradiation strategies. These strategies are based on tumor histology and grade.

Given the limited benefit and toxicities associated with these regimens, interest in targeting specific molecular alterations has grown. The sections that follow review FDA-approved targeted therapies for adult gliomas, examine supporting clinical trials, and highlight promising investigational agents.

FDA-Approved Therapy: IDH Inhibitors (Vorasidenib)

A majority of IDH-mutant gliomas, over 90%, harbor a canonical heterozygous point mutation in IDH1. A point mutation is a change in a single building block of DNA. Heterozygous means the mutation is present in one of the two gene copies. This mutation leads to an arginine-to-histidine substitution at amino acid 132, abbreviated IDH1 R132H. A minority of these tumors harbor non-canonical IDH1 or IDH2 mutations.

These gain-of-function mutations in IDH1/2 induce the accumulation of the oncometabolite D-2-hydroxyglutarate (D-2HG). An oncometabolite is a substance that promotes cancer. D-2HG accumulation leads to DNA and histone hypermethylation and tumorigenesis. Histones are proteins that package DNA.

Mutant IDH inhibitors (mIDHIs) had previously received FDA approval for treatment of IDH1/2-mutant acute myeloid leukemia and IDH1-mutant cholangiocarcinoma. Building on promising preclinical studies, two mIDHIs, ivosidenib and vorasidenib, advanced into clinical trials in patients with IDH-mutant gliomas.

In phase 1 trials, both ivosidenib (an oral mIDH1 inhibitor) and vorasidenib (a dual mIDH1/2 inhibitor) demonstrated clinical activity in recurrent or progressive pre-treated IDH-mutant glioma. In a randomized window-of-opportunity trial comparing these two mIDHIs, both agents produced more than 90% suppression of D-2HG production.

However, vorasidenib achieved superior brain penetration and a slightly higher objective response rate (ORR) compared to ivosidenib. The objective response rate was 43% versus 36%. Vorasidenib was therefore selected for evaluation in the pivotal phase 3 INDIGO trial. INDIGO stands for INvestigating vorasiDenIb in GliOma.

The INDIGO Trial: Detailed Results

The INDIGO phase 3 trial was a double-blind, randomized, placebo-controlled study evaluating vorasidenib. Double-blind means neither patients nor doctors knew who received the drug. The trial enrolled 331 patients with residual or recurrent grade 2, non-enhancing IDH1/2-mutant gliomas. Residual means tumor remaining after treatment. Non-enhancing means the tumor does not take up contrast dye on imaging.

Participants were treatment-naïve except for prior surgery. Treatment-naïve means they had not received prior drug treatment. They were considered appropriate for a "watch-and-wait" approach.

In the primary analysis, the vorasidenib cohort had significantly longer median progression-free survival (mPFS). Progression-free survival is the time until the tumor grows or the patient dies. The median progression-free survival was 27.7 months for vorasidenib compared to 11.1 months for placebo.

The vorasidenib group also had delayed time to next intervention (TTNI) and lower tumor growth rates compared to placebo. Time to next intervention means the time until the next treatment is needed.

Vorasidenib was well tolerated. The most clinically significant adverse event was grade 3 or higher aminotransferase elevation in 9.6% of patients. Aminotransferases are liver enzymes, so this finding indicates liver irritation.

With an additional six months of follow-up, vorasidenib demonstrated continued efficacy. The INDIGO results led to FDA approval of vorasidenib in August 2024 for grade 2 IDH1/2-mutant glioma following surgery.

The INDIGO trial is the first randomized study to demonstrate the efficacy of targeted therapy in IDH-mutant gliomas. This marks a significant advance in neuro-oncology. Although its impact on overall survival (OS) is not yet established, vorasidenib can prolong progression-free survival and time to next intervention. In this way, vorasidenib delays chemoradiation and its associated toxicities.

This delay is particularly relevant for younger patients. For these patients, preserving neurocognitive function and quality of life is paramount.

Important Limits of the INDIGO Findings

The generalizability of INDIGO findings requires careful consideration. Generalizability means how well the results apply to patients outside the trial.

INDIGO only included tumors with measurable disease to allow for response assessment on MRI. However, vorasidenib is approved for use in gross-totally resected tumors, immediately after surgery. Gross-totally resected means the surgeon removed all visible tumor.

Vorasidenib is also approved for use regardless of MRI contrast enhancement. However, INDIGO only included non-enhancing tumors. For patients with enhancing tumors, an individualized risk-benefit assessment is essential. This assessment should be informed by a multidisciplinary team and patient input.

Additionally, the utility of vorasidenib across tumor grades remains an area of ongoing investigation. Preliminary evidence suggests a potential benefit in select non-enhancing grade 3 gliomas.

Importantly, several outstanding questions remain. One question is the potential value of combining mIDHIs with other treatments such as chemoradiation or immunotherapies. Multiple clinical trials are underway to better characterize the benefits of these combination strategies.

FDA-Approved Therapy: BRAF and MEK Inhibitors

Alterations in the MAPK pathway are also targetable in adult gliomas. The BRAF gene is part of this pathway. A BRAF V600E point mutation occurs in approximately 1–2% of IDH-wildtype GBM. It occurs in approximately 10–12% of IDH-wildtype pilocytic astrocytoma (PA) and approximately 60% of IDH-wildtype pleomorphic xanthoastrocytoma (PXA).

BRAF fusions, such as KIAA1549-BRAF, occur in approximately 70% of IDH-wildtype PA. A fusion is a joining of two genes.

Dabrafenib is a BRAF inhibitor, and trametinib is a MEK inhibitor. The FDA approved dabrafenib plus trametinib in June 2022 for patients aged 6 years and older with unresectable or metastatic BRAF V600E-mutated solid tumors, including gliomas. Unresectable means the tumor cannot be removed by surgery. Metastatic means the cancer has spread.

This approval was based on the ROAR basket trial. A basket trial tests one drug across many cancer types that share a mutation. In the high-grade glioma (HGG) cohort, the objective response rate was 33%. Median progression-free survival was 5.5 months, median overall survival was 17.6 months, and median duration of response was 31.2 months. The HGG cohort included 45 patients.

In the low-grade glioma (LGG) cohort, the objective response rate was 54%. Median progression-free survival was not reached, median overall survival was not evaluable, and median duration of response was not reached. The LGG cohort included 13 patients.

A separate multi-cohort, open-label phase 1/2 trial evaluated dabrafenib and trametinib in children with refractory or recurrent malignancies, including BRAF-mutated gliomas. In this trial, the recommended phase 2 dose of trametinib produced an objective response rate of 15% and median progression-free survival of 16.4 months. The combination of dabrafenib plus trametinib produced an objective response rate of 25%, median progression-free survival of 36.9 months, and median duration of response of 33.6 months. This analysis included 49 patients, predominantly with low-grade glioma.

Tovorafenib is a type II pan-RAF inhibitor. The FDA approved tovorafenib in April 2024 for patients older than 6 months with relapsed or refractory pediatric low-grade glioma with a BRAF fusion, rearrangement, or V600 mutation. This approval was based on the FIREFLY-1 trial. In this trial of 137 patients, the objective response rate was 51%, median duration of response was 13.8 months, and median time to response was 5.3 months.

FDA-Approved Therapy: NTRK Inhibitors

NTRK fusions are rare in adult glioma, occurring in approximately 0.5–2% of cases. They occur in less than approximately 5% of pediatric gliomas, including IDH-wildtype GBM and pediatric high-grade gliomas. Examples include BCAN-NTRK1, BCR-NTRK2, and EML4-NTRK3 fusions.

Larotrectinib is an NTRK inhibitor. The FDA approved larotrectinib in November 2018 for adult and pediatric patients with NTRK fusion-positive solid tumors. The approval covers patients with metastatic disease or whose surgical resection would likely cause severe morbidity, and who have no satisfactory alternative treatments. It also covers patients whose cancer has progressed following treatment.

This approval was based on the SCOUT and NAVIGATE trials. A combined analysis included 33 patients: 7 adults and 26 pediatric patients with NTRK fusion-positive central nervous system primary malignancies that were recurrent or progressive. The objective response rate was 30%. The duration of response rate at 12 months was 75%. Progression-free survival at 12 months was 56%. Overall survival at 12 months was 85%. Median time to response was 1.9 months.

FDA-Approved Therapy: Dordaviprone for H3K27M Gliomas

Dordaviprone is a dopamine subtype 2 receptor (D2DR) antagonist and caseinolytic protease P (ClpP) inducer. The FDA approved dordaviprone in August 2025 for patients aged 1 year and older with DMG-H3K27M with progressive disease following prior therapy.

This approval was based on several trials: ONC006, ONC013, ONC014, ONC016, ONC018. A combined analysis included 50 patients: 46 adults and 4 pediatric patients older than 2 years with recurrent, non-pontine and non-spinal DMG-H3K27M. All patients were more than 90 days post-radiotherapy, and their lesions were measurable with RANO-HGG criteria.

The objective response rate was 20%. The disease control rate was 40%. Median duration of response was 11.2 months. Median time to response was 8.3 months. Progression-free survival at 6 months was 35.1%. Median overall survival was 13.7 months.

Investigational Targeted Therapies

Several investigational agents target DNA repair and metabolic dependencies. These agents are not yet FDA-approved for glioma.

DNA damage response pathways are a key vulnerability. The ATM protein repairs double-strand breaks in DNA. The ATR protein coordinates DNA repair, including single-strand breaks. The DNA-PK protein repairs double-strand breaks via non-homologous end joining. The PARP protein repairs single-strand breaks. Inhibitors of ATM, ATR, DNA-PK, and PARP are under investigation. Blocking these proteins increases the accumulation of genetic damage, which can lead to genomic instability and cancer cell death.

Another vulnerability involves the mitochondrial protease ClpP. Targeting ClpP increases the integrated stress response, which increases p53-independent apoptosis (programmed cell death). It also decreases cell survival signaling. Dordaviprone works partly through this mechanism.

Transcriptional regulation is another target. Homozygous deletion of MTAP occurs in approximately 30–50% of IDH-wildtype GBM. This deletion often co-occurs with CDKN2A/B deletion. Loss of MTAP leads to accumulation of methylthioadenosine (MTA), which inhibits PRMT5. PRMT5 is a transcription regulator. Targeting tumors with homozygous MTAP deletion using PRMT5 inhibitors increases DNA damage sensitivity and decreases cell cycle control and gene regulation. MAT2A inhibitors are also under study.

Cell cycle control is another target. Focal amplification of CDK4 occurs in approximately 20% of IDH-wildtype GBM, and CDK6 amplification in approximately 5%. CDK4/6 inhibitors block the transition from G1 to S phase of the cell cycle, reducing cell proliferation.

Other pathways under investigation include PI3K, AKT, and mTOR. PIK3CA and PIK3R1 point mutations occur in approximately 5–10% of IDH-wildtype GBM and IDH-mutant tumors. PTEN mutations occur in approximately 30% of IDH-wildtype GBM. TSC1 and TSC2 mutations occur in approximately 85% of subependymal giant cell astrocytoma (SEGA). Inhibitors of PI3K, AKT, and mTOR are being studied.

EGFR alterations are common in IDH-wildtype GBM. EGFR focal amplification occurs in 45% of cases. The EGFRvIII in-frame deletion occurs in 25–30% of EGFR-amplified IDH-wildtype GBM. EGFR inhibitors are under investigation. PDGFRA focal amplification occurs in approximately 15% of IDH-wildtype GBM and approximately 30% of DMG-H3K27M. FGFR fusions such as FGFR3-TACC3 occur in approximately 3–8% of IDH-wildtype GBM.

New Strategies for Drug Delivery

Delivering drugs to brain tumors is a major challenge. The blood-brain barrier limits which drugs can reach the tumor. The review discusses evolving drug delivery strategies as a key area of investigation.

These strategies aim to improve how much drug reaches the tumor. Better delivery could increase the effectiveness of existing targeted therapies. This is an active area of research in neuro-oncology.

Persistent Challenges in the Field

Several challenges impede therapeutic progress in adult gliomas. Tumors with targetable alterations constitute a minority of adult gliomas. This means most patients do not have a tumor with an approved targeted therapy option.

Even when a target is present, the approved therapies are not curative. They can delay progression and delay the need for chemoradiation, but they do not eliminate the tumor.

Pathway redundancy and cross-talk limit the effectiveness of single-agent targeted therapies. When one pathway is blocked, tumor cells can use alternative pathways to survive. This is why combination strategies are under investigation.

The blood-brain barrier remains a barrier to effective drug delivery. Not all targeted agents penetrate the brain well. Vorasidenib was selected over ivosidenib partly because of superior brain penetration.

Resistance to targeted therapies can emerge over time. Combining a BRAF inhibitor with a MEK inhibitor is one strategy used to reduce the emergence of resistance.

Clinical Implications for Patients

Targeted therapies have begun to transform the management of molecularly defined subsets of adult glioma. This means that patients whose tumors carry specific mutations may have new treatment options.

For patients with grade 2 IDH1/2-mutant glioma after surgery, vorasidenib is now an FDA-approved option. The INDIGO trial showed a median progression-free survival of 27.7 months compared to 11.1 months for placebo. This represents a meaningful delay in tumor progression.

For patients with BRAF V600E-mutated gliomas, dabrafenib plus trametinib is FDA-approved. In high-grade glioma, the objective response rate was 33%. In low-grade glioma, the objective response rate was 54%.

For patients with NTRK fusion-positive tumors, larotrectinib is FDA-approved. In the combined analysis, the objective response rate was 30%.

For patients with DMG-H3K27M with progressive disease after prior therapy, dordaviprone is FDA-approved. In the combined analysis, the objective response rate was 20% and the disease control rate was 40%.

However, the clinical benefits of these therapies remain limited to date. They are not curative, and they apply only to patients whose tumors carry the relevant molecular alteration.

Limitations of the Evidence

The review identifies several limitations in the current evidence. The INDIGO trial only included non-enhancing tumors, but vorasidenib is approved regardless of contrast enhancement. This means the trial did not directly study enhancing tumors.

INDIGO only included tumors with measurable disease, but vorasidenib is approved for gross-totally resected tumors. The trial did not directly study patients with no measurable disease after surgery.

The impact of vorasidenib on overall survival is not yet established. Progression-free survival was prolonged, but it is not yet known whether this translates into longer overall survival.

The utility of vorasidenib across tumor grades remains under investigation. Preliminary evidence suggests a potential benefit in select non-enhancing grade 3 gliomas, but this is not yet confirmed.

For patients with enhancing tumors, an individualized risk-benefit assessment is essential. This assessment should be informed by a multidisciplinary team and patient input.

Many of the trials described are single-arm or basket trials, which have inherent limitations. Single-arm trials do not compare the drug to a placebo or standard treatment. Basket trials test one drug across many cancer types, which can make results harder to interpret for a specific tumor type.

Recommendations and Future Directions

Patients with adult glioma should discuss molecular testing of their tumor with their care team. Molecular testing identifies whether the tumor carries IDH mutations, BRAF V600E mutations, NTRK fusions, or H3K27M mutations. These results determine whether an FDA-approved targeted therapy is an option.

For patients with grade 2 IDH1/2-mutant glioma after surgery, vorasidenib may be considered. The decision should account for whether the tumor is enhancing or non-enhancing, and whether it was gross-totally resected. A multidisciplinary team and patient input should inform this decision.

For patients with enhancing tumors, an individualized risk-benefit assessment is essential. The INDIGO trial did not include enhancing tumors, so the benefit in this setting is less certain.

Several areas require further research. These include:

• Combining mIDHIs with chemoradiation or immunotherapies
• The utility of vorasidenib across tumor grades
• The impact of vorasidenib on overall survival
• Novel agents targeting DNA repair and metabolic dependencies
• Immune-based strategies
• Advanced strategies of drug delivery

Multiple clinical trials are underway to better characterize the benefits of combination strategies. The European Organization for Research and Treatment of Cancer and other groups are conducting these studies.

The field is moving toward more personalized treatment based on each tumor's molecular profile. As new targets are identified and new drugs are developed, more patients may gain access to targeted therapies. However, the benefits remain limited to date, and most adult gliomas still lack an approved targeted treatment.

Frequently Asked Questions

What molecular tests should I ask my care team about for my glioma?

Patients with adult glioma should discuss molecular testing of their tumor with their care team. Testing identifies whether the tumor carries IDH mutations, BRAF V600E mutations, NTRK fusions, or H3K27M mutations. These results determine whether an FDA-approved targeted therapy is an option. Molecular testing looks for specific gene changes in the tumor and now guides how doctors classify gliomas and predict outcomes.

I had surgery for a grade 2 IDH-mutant glioma. Am I eligible for vorasidenib?

Vorasidenib was approved by the FDA in August 2024 for grade 2 IDH1/2-mutant glioma following surgery. In the INDIGO trial of 331 patients with residual or recurrent grade 2, non-enhancing IDH1/2-mutant gliomas, median progression-free survival was 27.7 months with vorasidenib versus 11.1 months with placebo. The trial did not include enhancing tumors, so for enhancing tumors an individualized risk-benefit assessment with a multidisciplinary team is essential.

What does a progression-free survival of 27.7 months mean for me?

Progression-free survival is the time until the tumor grows or the patient dies. In the INDIGO trial, median progression-free survival was 27.7 months for vorasidenib compared to 11.1 months for placebo. This means half of the patients in the vorasidenib group had not progressed at 27.7 months. It does not mean the tumor is eliminated; these therapies are not curative.

What are the risks or side effects of vorasidenib?

In the INDIGO trial, vorasidenib was well tolerated. The most clinically significant adverse event was grade 3 or higher aminotransferase elevation in 9.6% of patients. Aminotransferases are liver enzymes, so this finding indicates liver irritation. Your care team can monitor for this. The trial did not include enhancing tumors, so the benefit in that setting is less certain and an individualized risk-benefit assessment is essential.

My tumor has a BRAF V600E mutation. What treatment is approved?

The FDA approved dabrafenib plus trametinib in June 2022 for patients aged 6 years and older with unresectable or metastatic BRAF V600E-mutated solid tumors, including gliomas. In the ROAR basket trial, the objective response rate was 33% in the high-grade glioma cohort of 45 patients and 54% in the low-grade glioma cohort of 13 patients. These therapies are not curative.

What is dordaviprone and who can receive it?

Dordaviprone is a dopamine subtype 2 receptor antagonist and ClpP inducer. The FDA approved it in August 2025 for patients aged 1 year and older with H3K27M-mutant diffuse midline glioma with progressive disease following prior therapy. In a combined analysis of 50 patients, the objective response rate was 20% and the disease control rate was 40%. Median overall survival was 13.7 months. It is not curative.

Are targeted therapies for glioma curative?

No. The review stresses that these therapies help selected patients but are not curative. They can delay progression and delay the need for chemoradiation, but they do not eliminate the tumor. Most adult gliomas still lack an approved targeted treatment. Tumors with targetable alterations constitute a minority of adult gliomas. Resistance to targeted therapies can emerge over time, and combination strategies are under investigation.

When should a patient with an adult glioma seek a second opinion about targeted therapy?

A second opinion is worth considering when molecular testing has not been reviewed, since IDH mutation status, BRAF V600E, NTRK fusions, and H3K27M determine whether an FDA-approved targeted therapy applies. It is also reasonable when vorasidenib is proposed for an enhancing or gross-totally resected tumor, because the INDIGO trial enrolled only non-enhancing, measurable, treatment-naïve grade 2 IDH-mutant gliomas, and an individualized risk-benefit assessment with a multidisciplinary team is essential. Diagnostic Detectives Network provides independent expert second opinions.

Source Information

Original article title: Recent Advances in Targeted Therapies for Adult Gliomas.

Authors: Lasica AB, Tang AR, Iqbal A, Nakhate V, Wen PY.

Author affiliations: Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Center For Tumors of the Nervous System, Mass General Brigham Cancer Institute, Boston, MA, USA

Publication: Current Neurology and Neuroscience Reports (2026) 26:20

DOI: https://doi.org/10.1007/s11910-026-01484-4

Received: 8 October 2025 / Accepted: 4 February 2026 / Published: © The Author(s) 2026

Article type: Review

Keywords: Glioma, Targeted therapy, IDH mutant, IDH wildtype, Glioblastoma, IDH inhibitor

This patient-friendly article is based on peer-reviewed research. It is intended for educational purposes and does not replace consultation with a qualified healthcare provider. Patients should discuss their individual diagnosis and treatment options with their care team.