Targeted Therapy Arrives in Neuro-Oncology: Vorasidenib, Dordaviprone, and What's Actually Changing in Brain Tumor Care

Introduction: Neuro-Oncology Catches Up

Neuro-oncology has long been one of the last fields to benefit from the precision medicine revolution. Where colleagues in lung cancer, breast cancer, and hematology have had actionable molecular targets and approved targeted therapies for years, the brain tumor field has largely watched from the sidelines. That is changing. The last two years have brought the first FDA-approved targeted therapy for a primary brain tumor, a new option for one of the most devastating rare central nervous system malignancies, and important practice-clarifying data on chemotherapy duration and prophylaxis in glioblastoma.

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Glioma Classification: IDH Status Is Everything

Since the 2021 WHO classification update, IDH mutation status has become the organizing principle of glioma classification, replacing the old system based primarily on histology. Understanding this framework is essential for interpreting treatment decisions and prognosis.

Three major categories now define adult glioma:

Oligodendrogliomas are always IDH-mutant and carry the 1p/19q co-deletion. They can be grade 2 or 3 and carry a favorable prognosis.

Astrocytomas are also always IDH-mutant (without 1p/19q co-deletion) and span grades 2, 3, and 4. They have a better prognosis than IDH wild-type tumors.

Glioblastoma is always IDH wild-type and always grade 4. It has the worst prognosis.

This distinction matters enormously for both treatment planning and prognosis. IDH-mutant gliomas carry meaningfully better survival, tend to occur in younger patients — often in their 20s, 30s, and 40s — and frequently present with seizures. These are patients at the height of their careers and family lives, for whom the toxicities of chemoradiation carry particular weight.

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The INDIGO Trial: Vorasidenib — The First Targeted Therapy in Neuro-Oncology

For decades, the treatment of grade 2 IDH-mutant glioma following surgery was observation (watch and wait) or chemoradiation, the latter not curative and associated with significant long-term neurotoxicity including cognitive decline and secondary malignancies from radiation exposure.

Vorasidenib (Voranigo) changes that calculus. An oral inhibitor of both IDH1 and IDH2, vorasidenib was studied in the INDIGO trial: a phase 3, randomized, placebo-controlled study enrolling patients with grade 2 IDH-mutant gliomas who had undergone prior surgery only and had measurable non-enhancing disease without immediate need for chemoradiation. Patients were randomized to vorasidenib or placebo, with crossover permitted at progression.

The results were among the most striking data seen in neuro-oncology in years. Progression-free survival was 27.7 months with vorasidenib versus 11.1 months with placebo. Time to next intervention (meaning time until chemoradiation or other salvage therapy was needed) was not reached in the vorasidenib arm versus 17.8 months in the placebo arm. Vorasidenib also reduced tumor volume over time, decreased seizure frequency (a particularly meaningful outcome for younger patients), preserved neurocognitive function and quality of life, and was well tolerated with predominantly low-grade fatigue and GI side effects.

Vorasidenib received FDA approval in 2023 and has reshaped the treatment paradigm for grade 2 IDH-mutant gliomas. In current practice, vorasidenib is oftentimes offered as the first option for eligible grade 2 IDH-mutant patients after surgery after multidisciplinary discussion with radiation oncology. The drug is also being used off-label for higher-grade IDH-mutant gliomas (grade 3 and 4), a population not included in INDIGO but where the biological rationale for IDH inhibition is similar.

Important unanswered questions remain: the overall survival effect is difficult to assess because of the crossover design; the optimal duration of treatment is unknown; mechanisms of resistance have not been characterized; and the best approach for patients who received earlier-generation IDH inhibitors (ivosidenib, enasidenib) and whether to transition them to vorasidenib is undefined. These questions will take years to answer, but the core finding is clear: IDH inhibition delays progression, reduces tumor growth, and spares patients from the toxicities of chemoradiation for a meaningful period.

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Dordaviprone: A New Option for Diffuse Midline Gliomas

Diffuse midline gliomas with H3K27 alteration (DMGs) are rare, devastating tumors primarily affecting pediatric patients but also occurring in young adults. They arise in surgically inaccessible midline structures (thalamus, brainstem, pons, spinal cord) and carry a median overall survival of approximately one year. Chemotherapy has not been effective, and radiation is the only established treatment.

Dordaviprone (ONC201) is a dopamine receptor antagonist that reverses the pathognomonic loss of trimethylation at H3K27 seen in these tumors. Based on an integrated analysis of five clinical studies enrolling patients with recurrent H3K27-altered DMGs, the drug received FDA approval. The overall response rate was approximately 20%, time to response approximately eight months, and duration of response nearly one year. These are meaningful results in a disease with essentially no other options.

The limitations of the approval dataset are important to acknowledge: patients required a Karnofsky Performance Status of at least 60 and had to be at least 90 days from prior radiation — criteria that may exclude patients with the rapid functional decline typical of this disease. Patients with pontine and spinal tumors, as well as leptomeningeal metastases, were excluded. The analysis was not randomized or placebo-controlled. These constraints limit generalizability but do not diminish the significance of seeing any durable responses in this population.

The ACTION trial is currently evaluating dordaviprone in newly diagnosed H3K27-altered DMG, with overall survival as the primary endpoint. Results from this trial will determine whether dordaviprone can be incorporated into frontline treatment as well.

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Glioblastoma: Clarifying Two Common Questions

Glioblastoma treatment follows a well-established path: maximal safe surgical resection, followed by concurrent temozolomide and radiation for six weeks, followed by six months of adjuvant temozolomide. Two clinical questions arise frequently in this population.

How Many Cycles of Adjuvant Temozolomide?

The GEINO 14-01 trial addressed whether extending adjuvant temozolomide from six to twelve cycles improves outcomes. The answer is no. Six cycles and twelve cycles produced identical progression-free and overall survival, including in MGMT-methylated patients where one might hypothesize greater benefit. Patients who received twelve cycles had meaningfully higher rates of lymphopenia, thrombocytopenia, and nausea and vomiting. Six cycles of adjuvant temozolomide followed by surveillance is the standard. Extending chemotherapy does not improve survival and furthermore increases toxicity.

Is PCP Prophylaxis Necessary?

The recommendation for PCP prophylaxis during chemoradiation in glioblastoma appears on the FDA package insert for temozolomide, originating from an early trial where 2 of the first 15 patients developed PCP pneumonia. A 2022 study of over 200 patients receiving concurrent chemoradiation re-examined this question. Approximately 80% of patients did not receive prophylaxis. Of over 300 patients analyzed, 18 developed PCP pneumonia.

The number needed to treat to prevent one hospitalization from PCP pneumonia was 288. The number needed to harm, causing one episode of grade 3 or 4 neutropenia, was 39. There was no association between PCP prophylaxis and survival or hospitalization rates. Patients who developed PCP pneumonia had a notably lower lymphocyte count (0.39 vs. 0.74 in those who did not). Prophylaxis also increased the risk of missing adjuvant temozolomide doses.

Current practice based on this evidence: PCP prophylaxis is reserved for patients with severe lymphopenia (lymphocyte count consistently below 0.5) or those on prolonged corticosteroid therapy. For most patients, the harms of prophylaxis outweigh the benefits.

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Leptomeningeal Disease: Improving Diagnosis With CSF Liquid Biopsy

Leptomeningeal disease (LMD), spread of cancer cells to the leptomeninges and cerebrospinal fluid, is an aggressive, incurable complication with notoriously difficult diagnosis. Clinical symptoms, MRI findings (which are often subtle), and CSF cytology (gold standard but with limited sensitivity of around 50%) are the three traditional diagnostic pillars.

Liquid biopsy applied to the CSF (detecting circulating tumor cells (CTCs) and cell-free DNA) substantially improves diagnostic sensitivity over cytology alone. Technologies using antibody cocktails to isolate CTCs from CSF can then perform FISH, copy number variation analysis, and next-generation sequencing, providing a comprehensive molecular profile of the leptomeningeal disease.

Beyond diagnosis, CSF liquid biopsy has prognostic value: higher CTC burden correlates with worse survival. It also provides actionable molecular information; for example, identifying the "HER2 flip" phenomenon in which a patient with a HER2-negative primary tumor is found to have HER2-positive cells in the CSF, potentially qualifying the patient for HER2-directed therapy. Similar discordances are seen in NSCLC patients with leptomeningeal spread.

In current practice, an early lumbar puncture for CSF cytology plus CTC and cell-free DNA analysis can be clinically useful if LMD is suspected, rather than waiting for obvious MRI changes.

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Seizure Prophylaxis in Brain Tumor Patients

A related clinical question worth addressing: should brain tumor patients without a prior seizure receive prophylactic antiseizure medication? There is not enough high quality evidence to support the use of empiric antiseizure medications in brain tumor patients without a seizure history. Although newer medications such as Keppra (levetiracetam) are better tolerated than older ones (valproic acid, phenytoin), there can still be side effects that can impact quality of life in patients who are already managing a brain tumor diagnosis.

Current practice: no empiric antiseizure medication for brain tumor patients who have never had seizures. If a patient has a first seizure with a known brain mass, they meet the definition of tumor-related epilepsy and should be remain on antiseizure medication indefinitely.  

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For Patients

If you or a family member has been diagnosed with a brain tumor, the molecular characteristics of the tumor — particularly IDH mutation status and H3K27 alteration status — now directly influence treatment decisions and prognosis. For patients with IDH-mutant grade 2 glioma, a new FDA-approved oral targeted therapy (vorasidenib) can delay tumor progression and postpone the need for radiation and chemotherapy. Ask your neuro-oncologist whether vorasidenib is appropriate for your situation. For patients with glioblastoma, six cycles of adjuvant chemotherapy is the standard; more does not help. And if you are experiencing symptoms that might suggest cancer has spread to the spinal fluid, ask about CSF liquid biopsy — it can provide more information than standard cytology alone.

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Key Takeaways

• IDH mutation status defines glioma classification per WHO 2021 criteria; IDH-mutant tumors have substantially better prognosis and different treatment implications than IDH wild-type glioblastoma.

• Vorasidenib (INDIGO trial): first FDA-approved targeted therapy in neuro-oncology; PFS 27.7 vs 11.1 months in grade 2 IDH-mutant glioma; delays need for chemoradiation, reduces tumor volume, decreases seizures, preserves cognition; now first-line option before radiation oncology referral.

• Dordaviprone: FDA-approved for recurrent H3K27-altered DMGs; ORR ~20%, durable responses in a disease with median OS of ~1 year; ACTION trial ongoing for newly diagnosed.

• GAINO 14-01: 12 cycles of adjuvant temozolomide in GBM is not superior to 6 cycles and increases toxicity; 6 cycles is the standard.

• PCP prophylaxis in GBM chemoradiation: NNT to prevent one hospitalization = 288; NNH for grade 3/4 neutropenia = 39; reserve for patients with severe lymphopenia or prolonged steroid use.

• CSF liquid biopsy (CTCs + cell-free DNA) substantially improves LMD diagnostic sensitivity over cytology and provides molecular information that can guide treatment decisions.

• No empiric antiseizure medication for brain tumor patients without prior seizure; first seizure warrants indefinite antiseizure therapy.

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About the Author

Toni Cao, MD, is an attending neuro-oncologist at Stanford Health Care and an instructor in the Department of Neurology and Neurological Sciences at Stanford University School of Medicine. She completed her neurology training at Northwestern University in Chicago and her neuro-oncology fellowship at Stanford, where she joined the faculty. Her clinical and research interests include neuroimaging, clinical trials for primary brain tumors, and advancing precision medicine in neuro-oncology.

References

1. Mellinghoff IK, et al. (INDIGO trial). Vorasidenib in IDH-mutant, grade 2 glioma. New England Journal of Medicine, 2023. (https://www.nejm.org)

2. Dordaviprone (ONC201) integrated analysis. FDA approval 2024. (https://www.fda.gov)

3. ACTION trial. Dordaviprone in newly diagnosed H3K27-altered DMG. ClinicalTrials.gov. (https://clinicaltrials.gov)

4. GAINO 14-01 study. Six vs twelve cycles adjuvant temozolomide in GBM. Neuro-Oncology, 2024. (https://academic.oup.com/neuro-oncology)

5. PCP prophylaxis in glioblastoma chemoradiation. Journal of Neuro-Oncology, 2022. (https://link.springer.com/journal/11060)

6. CSF liquid biopsy for leptomeningeal disease. Cancer Research, 2023. (https://cancerres.aacrjournals.org)

7. Cao T. "Advances in CNS Tumors." Presented at the 2026 Alaska Hematology Oncology Conference, Anchorage, AK, May 2026.

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