Phase II Trial Demonstrates Benefit for Patients With Recurrent Meningiomas

February 1, 2020
Dylann Cohn-Emery

Patients with aggressive meningiomas presented with clinical and radiological activity when receiving a combination of everolimus&nbsp; and octreotide in the single-arm phase II CEVOREM trial.<br /> &nbsp;

Patients with aggressive meningiomas presented with clinical and radiological activity when receiving a combination of everolimus (Afinitor) and octreotide (Sandostatin) in the single-arm phase II CEVOREM trial.

The progression-free survival rate at 6 months (PFS6) was 55% in the intention-to-treat (ITT) population (95% CI, 31.3%-73.5%), and the rate of PFS at 12 months (PFS12) was 30% (95% CI, 12.2%-50.1%). The median PFS was 6.6 months (95% CI, 2.7-15.0). In the per protocol population (PP), PFS6 was 61.1% (95% CI, 35.3%-79.2%), and PFS12 was 33.3% (95% CI, 13.6%-54.5%). There were 2 patients who were not evaluable and therefore excluded in the PP population because their duration of treatment was <2 months.

Three patients had long-term (>2 years) tumor growth control. The ITT population exhibited an overall survival rate of 90% at 6 months (95% CI, 65.6%-97.4%) and 75% at 12 months (95% CI, 50.0%-88.7%).

In 1 patient, investigators observed the disappearance of 2 separate subcutaneous nodules, although there were no complete or partial responses in the trial defined by Response Assessment in Neuro-Oncology (RANO) criteria. A major decrease (>50%) in the growth rate was observed in in 78% of the tumors at 3 months. Before inclusion on the trial, the median tumor growth rate was 16.6% per 3 months, which decreased to 0.02% per 3 months at 3 months of treatment (P<.0002) and 0.48% per 3 months at 6 months (P<.0003).

“For meningiomas, we demonstrated that the adjunction of octreotide to everolimus in vitro decreased and reversed everolimus-induced Akt hyperphosphorylation and, thereby, improved the antiproliferative effect of everolimus,” the study investigators wrote. “In addition, the combination of everolimus and octreotide improved cell-cycle inhibitory effect compared with those of individual drugs.”

CEVOREM, an open-label, prospective, multicenter trial, which enrolled 20 patients, with 35 progressive meningiomas between them. Patients were treated with a fixed dose of everolimus at 10 mg per day. A dose reduction to 5 mg was allowed if the patient experienced adverse events (AEs). In combination with everolimus, 30 mg of long acting releasing octreotide was given monthly through intramuscular injection until the tumor progressed.

The safety profile showed that 11 of the 20 patients (55%) experienced stomatitis, which was the most common AE. Three patients had grade 3 somatitis which caused 1 patient to discontinue both drugs and another patient to discontinue everolimus only. Other common AEs were asthenia, fatigue (45%); abdominal pain, diarrhea (40%); and hypercholesterolemia (45%).

For this study, eligible progressive disease was defined as an increase in 2-dimensional (2D) tumor area of ≥5% per 3 months or ≥10% per 6 months, based on MRIs performed before inclusion on the trial. The largest tumor diameter and its largest perpendicular diameter on the same side made up the 2D tumor area.

The median age of the patients was 55 years old (range, 30-75). Each patient had a histologically confirmed meningioma, which was either a tumor of World Health Organization grade I (2 patients), II (10 patients), or III (8 patients). All patients had previous surgery and were no longer eligible for surgery or radiotherapy. Of the 20 patients, 4 harbored theNF2germline mutation.

Because meningiomas demonstrate a strong and constant expression of SSTR2A receptors and activation of the Pi3K/Akt/mTOR pathway, everolimus, an mTOR inhibitor, and octreotide, a somatostatin agonist were selected to treat these patients.

The investigators concluded that the clinical and radiological activity associated with this drug combination warrants further studies, including a potential decrease in the tumor volume growth rate as “a complementary and sensitive end point to select potentially effective drugs for recurrent meningiomas.”

Reference:

Graillon T, Sanson M, Campello C, et al. Everolimus and octreotide for patients with recurrent meningioma: results from the phase II CEVOREM trial.Clin Cancer Res. Published online January 22, 2020. Accessed January 31, 2020. doi: 10.1158/1078-0432.CCR-19-2109.