Robust Results Encourage the Use of Vorasidenib in the Treatment of IDH1/2-Mutant Gliomas

The INDIGO study highlights vorasidenib as a significant advancement in the treatment of IDH1/2-mutant gliomas, offering improved progression-free survival, a favorable safety profile, and enhanced quality of life. At this weekend’s Society of Neuro-Oncology Conference in Houston, a new wave of data from the groundbreaking INDIGO trial was revealed. Its incorporation into clinical practice may help reshape treatment strategies for patients with this subtype of glioma, focusing on delaying aggressive therapies while maintaining patient well-being.

The results have “a huge impact because patients with IDH1/2-mutant gliomas … represent a huge volume of young adult, adolescent patients, pediatric patients, and adult patients,” Dr. Erin Dunbar, a neuro-oncologist at Piedmont Healthcare in Atlanta, Georgia, tells SurvivorNet Connect. “And those patients, when they get a biopsy or resection and it’s time to start a therapy, now we have a new indication that we can put patients on — a well-tolerated oral medication that can slow down time to progression [and] definitely slow down time to next intervention.”

This new data shows updated results after 6 months of follow-up since the previous release in September 2023, reaching a median follow-up of 20.1 months. During this period, the authors reported only one death, which was not related to vorasidenib, and no patients were lost to overall survival follow-up. The longer follow-up endorsed the statistically significant improved progression-free survival (PFS) observed at the time of the second interim analysis (IA2), which had a data cutoff date of September 2022 (HR, 0.39; 95% CI, 0.27-0.56).

Notably, the patients in the vorasidenib arm presented with fewer seizure episodes than the placebo group (IA2: HR, 0.26; 95% CI, 0.15-0.43). The median time to next intervention (TTNI) with vorasidenib was not estimable (NE) (95% CI, NE-NE) compared to 20.1 months (95% CI, 17.5-27.1) with placebo (HR, 0.25; 95% CI, 0.16-0.40; P = 4.8 × 10⁻¹²).

To analyze the consistency of the results, the investigators further analyzed the data in subgroups, including age, chromosome 1p19q alteration, presence of prior surgery, the type of most recent surgery, and tumor size. Vorasidenib improved outcomes regardless of baseline tumor volume or tumor growth rate (TGR), which supports its broader applicability across different glioma patient populations​. The PFS benefit provided with vorasidenib vs placebo proved to be consistent across all subgroups analyzed.

Impact on Clinical Practice 

• Delayed Progression and Treatment Intervention: Vorasidenib’s significant impact on PFS and TTNI could alter treatment paradigms for patients with IDH-mutant gliomas by providing an effective therapeutic option that delays progression and reduces the need for immediate radiotherapy or chemotherapy. This is particularly beneficial in younger patients or those who seek to maintain functional status and quality of life for as long as possible.
• Potential for Earlier Intervention: Given the favorable safety profile and the ability to significantly reduce TGR vorasidenib could be integrated earlier in the treatment strategy for grade 2 gliomas. Its role in managing tumor growth could help delay more aggressive interventions, such as radiotherapy, which carries long-term risks, especially in younger patients.
• Enhanced Quality of Life: The reduced rate of seizures and fewer severe adverse events contribute to improved quality of life. Vorasidenib could therefore be considered not just for its survival benefit but also for its ability to manage symptoms that severely affect patients’ day-to-day lives.
• Targeted Therapy as Standard: The results of this study reinforce the role of targeted therapy in IDH1/2-mutant gliomas. As more evidence emerges, targeted treatments like vorasidenib may become a standard part of care, reducing the reliance on non-specific and often more toxic therapies like chemotherapy.

“I think this is really game-changing and the idea is that we’re trying to shift and prolong their life and the quality of their life for as long as we possibly can,” Dr. Alexandra Miller, a neuro-oncologist at NYU Langone Health, tells SurvivorNet Connect. “So these additional treatments, they make it so that the treatments we know exist already — radiation, chemotherapeutic agents — can be done later, and these patients are able to maintain normalcy really for a much longer period of time.”

The trial’s design allowed patients to continue vorasidenib until disease progression or unacceptable toxicity occurred. This approach indicates that, in clinical practice, patients may stay on the drug as long as it remains effective and tolerable. However, the optimal duration of therapy is still under investigation. 

The safety profile of vorasidenib remained stable after an additional six months of follow-up. Nearly all patients receiving vorasidenib (98.8%) experienced treatment-emergent adverse events (TEAEs), compared to 95.1% of those on placebo. Among these, Grade 3 or higher TEAEs were observed in 26.9% of patients receiving vorasidenib and 16.0% in the placebo group. 

Specific Grade 3 or higher TEAEs included increased alanine aminotransferase (10.2% for vorasidenib vs. 1.2% for placebo), increased aspartate aminotransferase (4.8% vs. 0%), seizures (4.2% vs. 3.1%), and increased gamma-glutamyltransferase (3.0% vs. 1.2%).

Dose reductions and interruptions due to TEAEs were more common in the vorasidenib group, affecting 11.4% and 32.9% of patients, respectively, compared to 4.3% and 25.2% for those on placebo. Additionally, 4.2% of patients receiving vorasidenib discontinued treatment due to TEAEs, versus 1.2% in the placebo group. Importantly, no treatment-related fatalities were reported.

Vorasidenib & Ivosidenib in IDH1-Mutant Diffuse Glioma

The updated results from the phase 1 trial evaluating vorasidenib (VOR) and ivosidenib (IVO) in IDH1-mutant diffuse gliomas demonstrate sustained clinical benefit with approximately 3.5 years of additional follow-up.

Vorasidenib showed durable disease control, with a median progression-free survival (PFS) of 41.4 months, compared to 38.6 months for ivosidenib.

Both drugs achieved significant reductions in tumor 2-hydroxyglutarate (2-HG) levels and exhibited favorable safety profiles, consistent with prior findings. Importantly, no new safety concerns were identified, reinforcing the therapeutic potential of VOR and IVO in this patient population. These results align with and expand upon the phase III INDIGO study findings, emphasizing the role of these agents in managing non-enhancing gliomas post-surgery.

Promising Advances in Neuro-Oncology

Larotrectinib Shows Promising Results in Pediatric CNS Tumors with NTRK Fusions

Larotrectinib, a selective TRK inhibitor, has demonstrated rapid and durable responses in pediatric patients with central nervous system (CNS) tumors harboring NTRK gene fusions. According to data presented, children treated with larotrectinib experienced significant tumor shrinkage and clinical improvement. The therapy was well-tolerated with manageable side effects, offering a promising treatment option for a patient population with limited effective therapies.

Nano2 Combined with Radiation and Temozolomide Under Investigation for Glioblastoma

A phase 3 clinical trial is exploring the use of Nano2, a nanotechnology-based therapeutic agent, in combination with radiation therapy and temozolomide for patients with newly diagnosed glioblastoma. Glioblastoma is an aggressive brain tumor with a poor prognosis, and current standard treatments provide limited survival benefits. The addition of Nano2 aims to enhance the effectiveness of chemoradiation therapy, potentially improving patient outcomes and offering new hope for those affected by this challenging condition.

Eflornithine Plus Lomustine Improves Survival in IDH-Mutant Anaplastic Astrocytoma

Eflornithine, an inhibitor of the enzyme ornithine decarboxylase, showed promising results when combined with lomustine, extending progression-free and overall survival compared to standard therapies. The combination was generally well-tolerated, suggesting it could become a valuable addition to treatment protocols for patients with this specific type of brain tumor.