The ECOG-ACRIN E3F05 trial, a groundbreaking study in the field of neuro-oncology, has revealed significant insights into the treatment of low-grade gliomas (LGGs). This phase 3 trial, which began in 2009, aimed to explore the efficacy of combining temozolomide with radiotherapy in patients with IDH-mutant LGGs. The results, presented at the 2025 Society for Neuro-Oncology (SNO) Annual Meeting, have sparked excitement and important discussions within the medical community.
A Novel Approach to Treatment
The study’s key finding was that adding temozolomide to radiotherapy significantly improved overall survival (OS) and progression-free survival (PFS) compared to radiotherapy alone in patients with IDH-mutant LGGs without codeletions of 1q and 19q. This is a crucial development, as it suggests that a targeted approach to treatment can yield better outcomes for a specific subgroup of patients.
Unraveling the Data
The trial’s investigators employed methylation profiling to determine the IDH mutational status of enrolled patients. This allowed them to categorize patients into two groups: those with and without codeletions of 1q and 19q. The results showed that patients with IDH-mutated disease without codeletions experienced a statistically significant OS benefit when temozolomide was added to radiotherapy (HR, 0.15; 95% CI, 0.03-0.74; stratified log-rank P = .02).
Long-Term Benefits
The study’s long-term follow-up revealed that the 10-year OS rate was higher in the temozolomide plus radiotherapy arm (80%) compared to the radiotherapy alone arm (39%) among patients with IDH-mutated, non-codeleted disease. This highlights the potential for improved survival rates and a more promising outlook for patients with this specific diagnosis.
Evolution of Glioma Classification
The E3F05 trial’s design evolved as glioma classification systems progressed. Initially, the trial was activated before the advent of IDH testing in glioma. However, updated findings from the phase 2 RTOG 9802 trial suggested a benefit with the addition of chemotherapy, leading to a reevaluation of the control arm. This ethical dilemma resulted in the trial’s accrual being stopped with 172 enrolled patients.
Previous Efficacy Data
Previous reports from SNO 2024 revealed that the addition of temozolomide to radiotherapy significantly improved OS (HR, 0.54; 95% CI, 0.31-0.95) and PFS in the overall population. These findings were further refined at SNO 2025, showing a 5-year PFS rate of 76% in the temozolomide arm versus 53% in the radiotherapy alone arm for patients with IDH-mutated, non-codeleted disease.
Future Directions
The study’s lead author, David Schiff, emphasized the importance of these findings, particularly in the context of 10-year OS rates. He noted that the benefit of adding temozolomide in IDH-mutant astrocytomas is evident, and there is also a trend toward OS benefit in oligodendrogliomas. The study continues to provide valuable insights into the treatment of LGGs, offering hope for improved outcomes and a deeper understanding of this complex disease.