Eflornithine Plus Lomustine vs Lomustine Monotherapy for Recurrent Grade 3 Astrocytoma: Phase 3 STELLAR Trial
Key Clinical Takeaways:
Key Outcomes: In patients with recurrent IDH-mutant, grade 3 astrocytoma, eflornithine plus lomustine significantly improved outcomes versus lomustine alone, doubling median PFS (15.8 vs 7.2 months; HR 0.57) and prolonging median OS (34.9 vs 23.5 months; HR 0.64); no benefit was observed in grade 4 disease.
Design / Population: STELLAR was a phase 3 randomized, open-label trial enrolling adults with recurrent grade 3 astrocytoma after prior radiotherapy and temozolomide, with post hoc molecular reclassification per WHO CNS5 identifying a prespecified IDH-mutant grade 3 subgroup (n = 196) driving clinical benefit.
Clinical Relevance: These findings support eflornithine plus lomustine as a clinically meaningful treatment option in recurrent IDH-mutant grade 3 astrocytoma, highlighting the importance of molecular classification and aligning with the cytostatic mechanism of eflornithine.
Eflornithine combined with lomustine significantly prolonged both progression-free and overall survival in patients with recurrent IDH-mutant, grade 3 astrocytoma following prior radiotherapy and temozolomide, compared with lomustine monotherapy, according to results from the phase 3 STELLAR trial.
The randomized, open-label study evaluated eflornithine plus lomustine versus lomustine alone in adults with recurrent grade 3 astrocytoma. Eligible patients were ≥ 18 years old with anaplastic astrocytoma per the 2016 WHO CNS classification, experienced first recurrence at least six months after radiotherapy and temozolomide, had a Karnofsky performance status ≥ 70, and showed no radiographic features of glioblastoma. Patients were randomized 1:1 and stratified by IDH mutation status, age, extent of resection, and geographic region.
Treatment consisted of oral eflornithine (2.8 g/m² every 8 hours, administered on a 2-weeks-on/1-week-off schedule) combined with lomustine (90 mg/m² every 6 weeks), or lomustine monotherapy (110 mg/m² every 6 weeks). The primary endpoint was overall survival (OS).
Among 343 patients enrolled across 74 sites in 8 countries, no statistically significant OS difference was observed in the overall study population (median OS 23.4 months with combination therapy versus 20.3 months with lomustine alone; HR 0.94). However, following updates to tumor classification in the 2021 WHO CNS criteria, a pre-specified subset analysis—conducted prior to unblinding—focused on patients with IDH-mutant, grade 3 astrocytoma (n = 196). In this molecularly defined cohort, eflornithine plus lomustine demonstrated clinically meaningful improvements in median OS (34.9 vs 23.5 months; HR 0.64) and progression-free survival (15.8 vs 7.2 months; HR 0.57). No benefit was observed in patients reclassified as CNS grade 4 disease.
Grade ≥ 3 treatment-emergent adverse events were primarily related to reversible myelosuppression (42% with combination therapy vs 29% with lomustine alone) and hearing impairment (24% vs 0%). No new safety concerns emerged.
Overall, eflornithine combined with lomustine significantly prolonged both progression-free and overall survival in patients with recurrent IDH-mutant, grade 3 astrocytoma following prior radiotherapy and temozolomide, consistent with the cytostatic mechanism of eflornithine. No efficacy was observed in grade 4 tumors.
“In conclusion, patients with recurrent grade 3 astrocytoma (IDH-mut, without CDKN2A/B homozygous deletion) randomly assigned to eflornithine [plus] lomustine had substantially longer PFS and OS than with lomustine monotherapy,” study authors concluded.
“This is a clinically meaningful result, representing a potential new treatment option in this patient population with considerable unmet need,” they added.
Source:
Colman H, Lombardi G, Wong E, et al. STELLAR: Phase III, randomized, open-label study of eflornithine plus lomustine versus lomustine alone in patients with recurrent grade 3 astrocytoma. J Clin Oncol. Published online December 1, 2025. doi:10.1200/JCO-25-01204
