Trabectedin for recurrent WHO grade 2 or 3 meningioma: A randomized phase II study of the EORTC Brain Tumor Group (EORTC-1320-BTG)

Abstract

Background No systemic treatment has been established for meningioma progressing after local therapies. Methods This randomized, multicenter, open-label, phase 2 study included adult patients with recurrent WHO grade 2 or 3 meningioma. Patients were 2:1 randomly assigned to intravenous trabectedin (1.5 mg/m 2 every three weeks) or local standard of care (LOC). The primary endpoint was progression-free survival (PFS). Secondary endpoints comprised overall survival (OS), objective radiological response, safety, quality of life (QoL) assessment using the QLQ-C30 and QLQ-BN20 questionnaires, and we performed tissue-based exploratory molecular analyses. Results Ninety patients were randomized (n=29 in LOC, n=61 in trabectedin arm). With 71 events, median PFS was 4.17 months in the LOC and 2.43 months in the trabectedin arm (hazard ratio [HR]=1.42; 80% CI, 1.00-2.03; p=0.294) with a PFS-6 rate of 29.1% (95% CI, 11.9%-48.8%) and 21.1% (95% CI, 11.3%-32.9%), respectively. Median OS was 10.61 months in the LOC and 11.37 months in the trabectedin arm (HR=0.98; 95% CI, 0.54-1.76; p=0.94). Grade ≥3 adverse events occurred in 44.4% patients in the LOC and 59% of patients in the trabectedin arm. Enrolled patients had impeded global QoL and overall functionality and high fatigue before initiation of systemic therapy. DNA methylation class, performance status, presence of a relevant co-morbidity, steroid use, and right hemisphere involvement at baseline were independently associated with OS. Conclusions Trabectedin did not improve PFS and OS and was associated with higher toxicity than LOC treatment in patients with non-benign meningioma. Tumour DNA methylation class is an independent prognostic factor for OS.

Gemcitabine Cooperates with Everolimus to Inhibit the Growth of and Sensitize Malignant Meningioma Cells to Apoptosis Induced by Navitoclax, an Inhibitor of Anti-Apoptotic BCL-2 Family Proteins

“…Trabectedin, a chemotherapeutic agent used to treat advanced sarcoma, exhibited therapeutic activity for grade 2/3 meningioma cells in vitro [ 30 ]. However, a prospective randomized phase II clinical trial on patients with recurrent grade 2 or 3 meningiomas showed that trabectedin did not improve progression-free survival or overall survival [ 4 ]. A prospective phase II study on nivolumab, a programmed death 1 blocking antibody, among patients with grade 2/3 meningioma demonstrated that it failed to improve six-month progression-free survival; however, a minor subset of patients characterized by a high tumor mutation burden benefited from the treatment [ 31 ].…”

“…A number of chemotherapeutic reagents have been applied to the treatment of patients with meningioma; however, the efficacy of these reagents, including trabectedin, which was considered promising for meningioma, has mostly been small [ 3 , 4 ]. On the other hand, recent advances in our understanding of genomic alterations in meningioma have resulted in the introduction of potential therapeutic targets, such as mammalian target of rapamycin (mTOR), vascular endothelial growth factor receptor, the hedgehog pathway, focal adhesion kinase, AKT, and cyclin-dependent kinase [ 5 ].…”

Emerging systemic treatment options in meningioma

“…The efficacy of cytotoxic agents such as hydroxyurea [12][13][14][15], irinotecan [16], temozolomide [17,18], or combination regimens such as vincristine, adriamycin and cyclophosphamide (VAC) [19] has been evaluated, with overall limited efficacy (Table 1). Whereas the DNA-intercalating agent trabectedin has shown promising activity in vitro and in one heavily pretreated patient [20], a prospective randomized phase 2 trial (EORTC 1320) failed to meet its primary endpoint, with no difference to physician's choice in terms of antitumoral activity but significantly higher toxicity [21].…”

“…Other previously studied drugs include imatinib, erlotinib and gefitinib, with no relevant clinical activity [38][39][40][41]. These results which mainly stem from retrospective or small prospective studies could be substantiated in exploratory analyses of the EORTC 1320 study, where physician's choice was included as a control arm [21]. Control treatments included the cytotoxic compounds hydroxyurea, vincristine, cyclophosphamide, doxorubicin as well as bevacizumab and somatostatin analogs.…”

Advances in Molecular Biological and Translational Studies in World Health Organization Grades 2 and 3 Meningiomas: A Literature Review

“…140) However, in the EORTC Brain Tumor Group's randomized phase II trial (EORTC-1320-BTG), trabectedin did not improve overall survival in recurrent WHO grades 2 and 3 meningiomas. 141)…”