Eflornithine plus lomustine produced superior OS and PFS outcomes vs lomustine in WHO grade 3 IDH-mutated astrocytoma.
The addition of eflornithine to lomustine (Gleostine) resulted in clinically meaningful overall survival (OS) and progression-free survival (PFS) benefits vs lomustine alone in patients with recurrent World Health Organization (WHO) 2021 criteria grade 3, IDH-mutated astrocytoma, according to updated data from the phase 3 STELLAR study (NCT02796261) presented during the
In the updated analysis, investigators reclassified patients from the original intention-to-treat population (n = 343) using updated WHO CNS5 molecular classification to identify a subset of patients (57%) who had WHO 2021 grade 3/4, IDH-mutated astrocytoma.
Patients with grade 3 or 4 disease who received the combination (n = 116) achieved a median OS of 28.5 months compared with 22.3 months among those who received lomustine monotherapy (n = 119; HR, 0.77; 95% CI, 0.55-1.05; P = .10). The median PFS values were 12.3 months and 7.3 months, respectively (HR. 0.68; 95% CI, 0.46-1.00; P = .05). Additionally, findings from a blinded independent central MRI review of PFS among patients with grade 3 disease revealed that the PFS benefit with eflornithine (HR, 0.61) was consistent with the investigator-assessed PFS benefit (HR, 0.57; P =.0305).
“This updated classification based on WHO 2021 [criteria] of the STELLAR population confirms the benefit of eflornithine in grade 3, IDH-mutant, CDK-intact population,” Howard Colman, MD, PhD, explained during the presentation. “The blinded independent review of the MRI results confirms the PFS benefit observed by investigators and the high correlation between the effect of PFS and OS in this subgroup. This is the first demonstration of a clinically significant OS and PFS benefit in a randomized study in this population.”
Colman is a Jon M. Huntsman Presidential Professor in the Department of Neurosurgery, a member of the multidisciplinary Brain Tumor Research Team, and the leader of the Center for Neurologic Cancers at Huntsman Cancer Institute (HCI) at the University of Utah. He is also an HCI investigator and a member of the Experimental Therapeutics program.
STELLAR was an open-label study that enrolled patients a surgical or biopsy-proven diagnosis of WHO grade 3 anaplastic astrocytoma.1,2 Patients were also required to have experienced their first instance of disease progression or recurrence at least 6 months after the completion of external beam radiation therapy (ERBT). Prior treatment with ERBT and temozolomide (Temodar) plus chemotherapy prior to the first instance of disease progression or recurrence was required, as was a Karnofsky Performance Status (KPS) of at least 70 and adequate organ function.1
“The STELLAR trial started in 2016 under the prior WHO diagnostic criteria, [and] this created several difficulties, but [an] extensive effort was made to gather historical archival tissue to reclassify the population based on 2021 WHO criteria,” Colman explained.
Patients were randomly assigned 1:1 to receive eflornithine plus lomustine (arm A) or lomustine monotherapy (arm B). Patients in arm A received eflornithine at 2.8 g/m2 on a 2-weeks-on, 1-week-off schedule for up to 24 months in combination with lomustine at 90 mg/m2 once on day 15 and once every 6 weeks during the eflornithine off weeks for up to 6 cycles or 12 months, whichever came first. Patients in arm B received lomustine at 100 mg/m2 once every 6 weeks for up to 6 cycles or 12 months, whichever came first.
The primary end point was OS.2 Secondary end points included PFS and objective response rate. Clinical benefit rate, 18-month OS rate, and pharmacokinetic measures were also assessed.
At baseline, the median age in the total population (n = 343) was 43.0 years (range, 19-78).1 Most patients were 45 years old or younger (56.0%), male (60.9%), underwent 1 or 2 surgical resections (86.0%), and had a KPS of at least 90 (68.0%). The median time from the last dose of radiation therapy to random assignment was 26.6 months (range, 1-197).
Previously reported for the ITT population showed that patients treated with the combination (n = 172) achieved a median OS of 23.4 months vs 20.3 months for those given lomustine alone (n = 171; HR, 0.94; 95% CI, 0.74-1.23; P = .7). The median PFS was 8.9 months vs 7.2 months, respectively (HR, 0.88; 95% CI, 0.65-1.20; P =.4).
In terms of safety, patients in the combination arm experienced grade 3 or higher treatment-emergent adverse effects (TEAEs) related to eflornithine or lomustine at respective rates of 50.9% and 45.6%. Grade 3 or higher TEAEs of relevance were reported at a rate of 63.9% and included myelosuppression (39.6%), hearing loss (23.7%), and diarrhea (9.5%). Serious TEAEs related to eflornithine or lomustine were reported at rates of 7.7% and 3.6%, respectively.
In the monotherapy arm, grade 3 or higher TEAEs related to lomustine occurred in 33.3% of patients. Grade 3 or higher TEAEs of relevance (30.0%) included myelosuppression (28.7%), seizure (1.3%), and nausea (0.7%). Serious TEAEs related to study treatment were also reported (2.7%).
“[The] toxicities were consistent with prior eflornithine; gastrointestinal [AEs] and decreased hearing were the notable toxicities,” Colman said.
Disclosures: Colman reported holding advisory board/consultant roles with Best Doctors/Teladoc, Orub Therapeutics, PPD/Climerix, Servier, Rigel, Jazz Therapeutics, and Bayer. He also received research funding from Orbus, GCAR, Bayer, CNS Pharms, Sumitomo Dainippon Pharma Oncology, Samus Therapeutics, Erasca, Antleart Therapeutics, Nuvation Bio, Novartis, Novocure, Tango Therapeutics, and Debiopharm.
