Eflornithine Plus Lomustine Demonstrates Clinically Meaningful Survival Benefits in Grade III IDH-Mutant Astrocytoma

Astrocytoma

Despite failing to improve survival outcomes in an overall population of patients with recurrent anaplastic astrocytoma, the addition of eflornithine to standard-of-care (SOC) lomustine did produce statistically significant and clinically meaningful improvements in overall survival (OS) and progression-free survival (PFS) vs lomustine for a subgroup of patients with recurrent grade 3, IDH-mutant astrocytoma per the 2021 World Health Organization (WHO) diagnostic criteria, according to Rimas V. Lukas, MD.^1,2

Findings from the phase 3 STELLAR trial (NCT02796261) presented at the 2024 Society for Neuro-Oncology (SNO) Annual Meeting demonstrated that in the intention-to-treat population (n = 343), no difference in OS was observed with the combination vs lomustine alone (HR, 0.94). However, in the recurrent grade 3 IDH-mutant astrocytoma subgroup (n = 194), the median OS with eflornithine plus lomustine was 34.9 months vs 23.5 months with lomustine alone (HR, 0.64; log-rank P = .016). Similarly, the median PFS of was 15.8 months vs 7.2 months with the combination vs lomustine, respectively (HR, 0.58; log-rank P = 0.015).

Regarding safety, the combination of eflornithine and lomustine was generally well tolerated with a toxicity profile consistent with that observed in previous studies. No unexpected safety signals were reported.

“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,” said Lukas, who is a neuro-oncologist at Northwestern Medicine and associate professor of Neurology at Northwestern University Feinberg School of Medicine in Chicago, Illinois.

In an interview with OncLive^®, Lukas discussed the rationale for evaluating eflornithine in combination with lomustine for patients with recurrent anaplastic astrocytoma, highlighted key efficacy and safety data with the agent from the STELLAR trial, and discussed the agent’s potential role for patients with IDH-mutant grade III astrocytoma.

OncLive: What was the rationale for evaluating eflornithine in combination with lomustine for patients with anaplastic astrocytoma?

Lukas: One of the concerns about what was termed anaplastic astrocytoma—and in large part represents IDH-mutant grade III astrocytoma in contemporary times—is that these tumors grow and progress. Regardless of what we do from a therapeutic perspective, there's an exceedingly high likelihood that there will be tumor progression at some point, and it's likely that these tumors may become more aggressive as time moves on, so they may move up in grade during the course of this disease.

[STELLAR used] an ornithine decarboxylase inhibitor, eflornithine. [The agent] had been looked at in several earlier, smaller studies and had demonstrated a possible signal for efficacy in a subgroup of gliomas called anaplastic astrocytomas without any obvious evidence of benefit in the glioblastoma patient population.

What was the design of the STELLAR trial?

[STELLAR] was a randomized phase 3 clinical trial comparing [lomustine] as the SOC for recurrent anaplastic astrocytoma vs lomustine plus eflornithine. The lomustine dosing was a bit different between the 2 arms: 110 mg/m² every 6 weeks in the control arm and 90 mg/m² in the investigational arm. That was because of early evidence of toxicity when [lomustine was] combined with eflornithine.

How did changes to the WHO classification system for anaplastic astrocytoma and the evolving understanding of molecular subtypes influence the interpretation of study results?

There are some important things to think about with regard to when this trial was initially planned, initiated, and conducted, and the changes that have occurred in the WHO classification system. [These circumstances] highlight the difficulty of conducting large, long-term clinical trials in this patient population. When this trial was initiated, the patient population was defined as anaplastic astrocytoma, a term which is no longer part of the WHO classification system.

If you look at the patients who were enrolled, [investigators] were able to look at the archival tissue and perform molecular analyses to begin classifying [patients] as [having] either IDH-mutant WHO grade III astrocytoma, which is the largest group and the one where the results are the most interesting. It is the group that the trial is designed to look at from my perspective. Then there were other tumors that proved to be IDH-mutant grade IV astrocytomas, [which comprised a] small population of those patients. Approximately a quarter of patients had IDH wild-type glioblastoma at this point. All those patients were treated together and then parceled out in an unplanned analysis after the fact.

What efficacy results were presented at the 2024 SNO Annual Meeting?

If you're looking at the overall results, which amalgamates all these different tumor types, this trial is a negative study. This is not surprising because a few different tumors were being addressed by this single modality, and that's just an artifact of the time when it was designed and conducted. Both OS and PFS did not show any statistically significant improvement with the combination therapy [in the ITT population], although there was a trend in that direction.

In some ways, the results [from the subgroup analyses] were not surprising because the early studies that led to the development of this phase 3 study had demonstrated no benefit [with eflornithine] in the glioblastoma patient population. [However, the largest subgroup] in the STELLAR trial, which was the IDH-mutant grade III astrocytoma [group], had a pretty clear separation of the curves in regard to both OS and PFS.

What are the safety and dosing considerations for eflornithine, and how might its frequent administration and extended treatment duration affect its real-world usage?

[From] a safety perspective, the results were [generally] aligned with [prior data and what was expected]. There is something to keep in mind from a dosing perspective. Eflornithine [is administered with] frequent dosing multiple times a day. One could imagine that in the real world, this could lead to suboptimal compliance, and it is a drug that was used for a much longer time interval than lomustine. Lomustine, both in the control arm and the investigational arm, was given over a total of 6 cycles, and [treatment with] eflornithine continued for up to 2 years.

Could eflornithine have a potential role for IDH wild-type tumors, and what other future research questions need to be answered to elucidate the utility of this combination?

I don't think there's going to be any role for this agent in the IDH wild-type patient population, and I'm not sure that it's worth investigating. One of the questions [to be answered through subsequent research] will be sequencing and even [its use] combination with other existing treatments for IDH-mutant tumors, specifically IDH inhibitors.

References

1. Coleman H, Lombardi G, Wong E, et al. 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. Presented at: 2024 SNO Annual Meeting; November 21-24, 2024; Houston, TX. Abstract LBTK-01.
2. Eflornithine and lomustine combination shows clinically meaningful improvements in overall survival (OS) and progression free survival (PFS) in patients with recurrent astrocytoma IDH mutant grade 3. News Release. Orbus. November 22, 2024. Accessed November 26, 2024. https://www.orbustherapeutics.com/blog