The combination of eflornithine and lomustine has demonstrated a clinically meaningful improvement in overall survival (OS) and progression-free survival (PFS) in patients with recurrent grade 3 IDH-mutant astrocytoma, according to findings from the Phase 3 STELLAR trial presented at the 2024 Society for Neuro-Oncology (SNO) Annual Meeting. The study, which evaluated the efficacy and safety of eflornithine in combination with lomustine compared to lomustine alone, offers a potential new treatment option for this rare and difficult-to-treat form of malignant glioma. The results are particularly significant given that the last FDA approval of a chemotherapeutic agent for this patient population was 25 years ago.
STELLAR Trial: Key Findings
The STELLAR trial (NCT02796261) enrolled 343 patients with anaplastic astrocytoma that recurred after surgery, irradiation, and adjuvant temozolomide chemotherapy. A significant subset of these patients (n = 194) had grade 3 IDH-mutant astrocytoma, as defined by the 2021 World Health Organization (WHO) diagnostic criteria. While the primary efficacy endpoint of overall survival (OS) in the intention-to-treat population did not reach statistical significance (HR = 0.94), the subgroup analysis revealed compelling results.
In the recurrent grade 3 IDH-mutant astrocytoma subgroup, the median OS with eflornithine plus lomustine was 34.9 months, compared to 23.5 months with lomustine alone (HR = 0.64; log-rank P = 0.016). Similarly, the median PFS was 15.8 months with the combination therapy versus 7.2 months with lomustine alone (HR = 0.58; log-rank P = 0.015).
Safety and Tolerability
The combination of eflornithine and lomustine was generally well-tolerated, with a safety profile consistent with previous studies. No unexpected safety signals were reported. The most common Grade 3+ treatment-emergent adverse events were related to myelosuppression and hearing impairment, which were expected based on the known side effect profiles of the individual agents.
Expert Commentary
"When the current grade 3 astrocytoma population—the IDH-mutant, CDKN2-intact population—was analyzed, there was a very clinically significant and statistically significant benefit in terms of OS and PFS [with eflornithine plus lomustine vs lomustine alone]," said Howard Colman, MD, PhD, FAAN, the Jon M. Huntsman Presidential Chair in Neuro-Oncology at the Huntsman Cancer Institute at the University of Utah.
Rimas V. Lukas, MD, a neuro-oncologist at Northwestern Medicine, also commented on the positive results, stating, "I would view this as a positive study for the IDH-mutant, grade III astrocytoma patient population. Ideally, regulatory bodies will feel the same way, and we hopefully will have something that these patients are able to utilize in that recurrent disease setting."
Implications for Treatment
These findings suggest that the combination of eflornithine and lomustine could become a valuable treatment option for patients with recurrent grade 3 IDH-mutant astrocytoma. Further research may explore the sequencing of this combination with other existing treatments, such as IDH inhibitors, to optimize patient outcomes.
