PL3.2 Trabectedin for recurrent WHO grade II or III meningioma: a randomized phase II study of the EORTC Brain Tumor Group (EORTC-1320-BTG)

Abstract

BACKGROUND EORTC-1320-BTG investigated the activity, safety and quality of life of therapy with the tetrahydroisoquinoline alkaloid trabectedin (Yondelis®) in patients with recurrent higher-grade meningiomas. Trabectedin was originally derived from the Caribbean sea squirt, Ecteinascidia turbinata, and currently is manufactured by total synthesis. METHODS Adult patients with histological diagnosis of WHO grade II or III meningioma and radiologically documented progression after maximal feasible surgery and radiotherapy were randomly assigned in a 2:1 ratio to receive intravenous trabectedin (1.5 mg/m2every three weeks) or local standard of care (LOC). The primary endpoint was progression-free survival (PFS). RESULTS Within 22.1 months, we randomized a total of 90 patients (n=29 in LOC arm, n=61 in trabectedin arm) in 35 institutions and nine countries. In the LOC arm, the following treatments were administered: hydroxyurea (n=11), bevacizumab (n=9), none (n=4), chemotherapy (n=3), somatostatin analogue (n=1), combined chemotherapy and somatostatin analogue (n=1). With 71 PFS events, median PFS was 4.17 months in the LOC and 2.43 months in the trabectedin arm (hazard ratio [HR] for progression, 1.42; 80% CI, 1.00–2.03; p=0.204) with a PFS-6 rate of 29.1% (95% CI, 11.9%-48.8%) in the LOC and 21.1% (95% CI, 11.3%-32.9%) in the trabectedin arm. Median OS was 10.61 months in the LOC and 11.37 months in the trabectedin arm (HR for death, 0.98; 95% CI, 0.54–1.76; p=0.94).Grade 3 to 5 adverse events occurred in 44.4% (18.5% related, 4 serious adverse events, 0 lethal events) of the patients in the LOC and 59% (32.8% related, 57 serious adverse events and 2 toxic deaths) of patient in the trabectedin arm. CONCLUSIONS In this first prospective randomized trial performed in recurrent grade II or III meningioma, trabectedin did not improve PFS and OS and was associated with significantly higher toxicity as compared to LOC treatment. The data collected in this study may serve as benchmark for future clinical trials in this setting.

Prognostic factors and Doxorubicin involved in malignant progression of meningioma

“…The chemotherapy methods of malignant meningioma were limited. There are some reported clinical trials, but the effect was unsatisfactory 8,47 . We used the CMap website to select compound drugs that may have effect on meningioma with specificity 48 .…”

“…Presently, the main treatment of meningioma was the surgery, and the adjuvant treatment (radiosurgery or fractionated external beam RT). And, several studies have shown that trabectedin, multi-kinase inhibitors, and bevacizumab could be used as the adjuvant treatment, but the results were unsatisfactory [8][9][10] .…”

High Grade Meningiomas: Current Therapy Based on Tumor Biology

“…Also, the median OS was 10.61 months in the local standard care arm and was 11.37 months in the trabectedin arm (HR for death, 0.98; 95% CI, 0.54-1.76; p = 0.94). In 44.4% of the local standard care arm patients occurred adverse events (4 serious adverse events, 0 lethal events) and 59% of the trabectidin arm presented adverse events (57 serious adverse events and 2 toxic deaths) [79]. Trabectedin did not improve PFS and OS and was associated with significantly higher toxicity.…”

Chemotherapy and targeted therapies for meningiomas: what is the evidence?

“…Randomized trials are obviously recommended to improve the level of reliability but the rare patients and the lack of referent and consensual control drugs challenge the setting of such trials. For instance, in Preusser et al EORTC trial, control drugs varied depending on the centers so that control drugs included bevacizumab, somatostatin agonist, hydroxyurea which may limits the value of the control [41 ▪▪ ].…”

“…Preusser et al report a case of tumor stabilization of a WHO III grade meningioma [54]. Unfortunately, the EORTC prospective randomized trial including 90 patients with recurrent high-grade meningiomas concluded to the lack of improvement of both PFS and OS together with significant toxicity [41 ▪▪ ]. Different phase II studies testing alkylating agent temodal, an PDGF-R inhibitor imatinib, and EGRF inhibitor erlotinib and gefitinib were disappointing [55–58].…”