Eflornithine/Lomustine Prolongs Survival in Recurrent mIDH Grade 3 Astrocytoma

In the phase 3 STELLAR trial (NCT02796261), the ornithine decarboxylase inhibitor eflornithine (alpha-difluoromethylornithine) coupled with standard-of-care lomustine (Gleostine) demonstrated enhanced efficacy in patients with recurrent IDH-mutant grade 3 astrocytoma.¹

Compared with lomustine alone, the combination yielded clinically meaningful improvements in the study’s primary end point of overall survival (OS) and key secondary end point of progression-free survival (PFS) in a molecularly defined subset of the trial’s overall patient population, representing all diagnosed patients with grade 3 astrocytoma. Full results will be presented at the 2025 Society for Neuro-Oncology (SNO) Annual Meeting.

In a late-breaking abstract of STELLAR data previously presented at the 2024 SNO Annual Meeting, there was no significant OS benefit observed between the combination and control arms (median, 23.4 vs 20.3 months; HR, 0.94) in the overall in the intent-to-treat population (n = 343).² However, the analysis of the IDH-mutant subset revealed significant benefits by the combination in both OS (median, 34.9 vs 23.5 months; HR, 0.64; log-rank P =.016) and PFS (15.8 vs 7.2 months; HR, 0.58; log-rank P =.015).

In addition, the combination was generally well-tolerated. Adverse events (AEs) were expected and consistent with the known AE profile of the combination, with no new safety signals identified. The most common grade ≥3 treatment-emergent AEs pertained to myelosuppression and hearing impairment.

Of the total number of patients, more than half (57%; n = 196/343) had grade 3 astrocytoma tumors harboring IDH1/2 mutations, 2 oncogenes implicated in the development of gliomas.

“[The investigation into the clinical relevance of IDH mutations] was groundbreaking in terms of the understanding of gliomas writ large and specifically applies to grade 3 gliomas. When we look at this, this is now integrated in our standard testing,” said Arati Desai, MD, associate professor at the Perelman School of Medicine and director, Penn Brain Tumor Center at the University of Pennsylvania, in a 2020 interview with Targeted Oncology. “The most common mutation is something that we test for by immunohistochemistry. And then we can validate by next-generation sequencing quite easily. And in so doing, also evaluate IDH1 and IDH2 more comprehensively to look for other mutations beyond the most common one.”

This latest development in this subset of patients, who often face a challenging prognosis, offers hope for a new therapeutic option in the recurrent setting.

"In patients with recurrent WHO 2021 grade 3 IDH-mutant astrocytoma, eflornithine not only improved [OS] but, as determined by a blinded independent central review, improved [PFS] as well,” said Jason Levin, president and CEO of Orbus Therapeutics, in a news release.¹ “I believe these data, while taken from a subset analysis, represent one of the first meaningful advances for a patient population in which outcomes have been poor for years."

STELLAR Trial Overview

The randomized, global, open-label phase 3 STELLAR trial was initiated in 2016, setting out to evaluate the efficacy and safety of eflornithine combined with lomustine vs lomustine alone in 343 adult patients with anaplastic astrocytoma (AA) whose disease has recurred or progressed after irradiation and adjuvant temozolomide chemotherapy.³

AA was defined per the previous 2016 WHO CNS4 tumor classification system, encompassing patients with both grade 4 astrocytoma and glioblastoma and grade 3 astrocytoma. IDH mutational status was a key stratification factor in the analyses, defined by the updated 2021 WHO CNS5 tumor reclassification.

For treatment, patients were randomized to receive either eflornithine with lomustine (n = 172) or lomustine alone (n = 171). The regimen for the combination arm consisted of 2.8 g/m² of eflornithine every 8 hours on a 2 weeks on, 1 week off schedule, plus 90 mg/m² of lomustine once every 6 weeks, both administered orally. In the control arm, patients received 110 mg/m² of oral lomustine once every 6 weeks.

The study is assessing the primary end point of OS; key secondary end points include PFS and objective response rate.

REFERENCES

1. Orbus Therapeutics highlights phase 3 STELLAR clinical study results showing clinically meaningful benefits in rare brain tumor at Society for Neuro-Oncology (SNO) annual meeting. News release. Orbus Therapeutics. November 20, 2025. Accessed November 20, 2025. https://tinyurl.com/46kstrse

2. Colman H, Lombardi G, Wong E, et al. LTBK-01. Phase 3 STELLAR study shows eflornithine improves overall survival (OS) and progression-free survival (PFS) in patients with recurrent 2021 WHO astrocytoma, IDH-mutant grade 3. Neuro-Oncol. 2024;26(Supplement_8):viii1-viii1. doi:10.1093/neuonc/noae165.1301

3. Study to evaluate eflornithine + lomustine vs lomustine in recurrent anaplastic astrocytoma (AA) patients (STELLAR). ClinicalTrials.gov. Updated January 21, 2022. Accessed November 20, 2025. https://clinicaltrials.gov/study/NCT02796261