Phase II trials of erlotinib or gefitinib in patients with recurrent meningioma

Abstract

There are no established treatments for recurrent meningioma when surgical and radiation options are exhausted. The epidermal growth factor receptor (EGFR) is often over-expressed in meningiomas and may promote tumor growth. In open label, single arm phase II studies of the EGFR inhibitors gefitinib (NABTC 00-01) and erlotinib (NABTC 01-03) for recurrent malignant gliomas, we included exploratory subsets of recurrent meningioma patients. We have pooled the data and report the results here. Patients with recurrent histologically confirmed meningiomas with no more than 2 previous chemotherapy regimens were treated with gefitinib 500 mg/day or erlotinib 150 mg/day until tumor progression or unacceptable toxicity. Twenty-five eligible patients were enrolled with median age 57 years (range 29–81) and median Karnofsky performance status (KPS) score 90 (range 60–100). Sixteen patients (64%) received gefitinib and 9 (36%) erlotinib. Eight patients (32%) had benign tumors, 9 (36%) atypical, and 8 (32%) malignant. For benign tumors, the 6-month progression-free survival (PFS6) was 25%, 12-month PFS (PFS12) 13%, 6-month overall survival (OS6) 63%, and 12-month OS (OS12) 50%. For atypical and malignant tumors, PFS6 was 29%, PFS12 18%, OS6 71%, and OS12 65%. The PFS and OS were not significantly different by histology. There were no objective imaging responses, but 8 patients (32%) maintained stable disease. Although treatment was well-tolerated, neither gefitinib nor erlotinib appear to have significant activity against recurrent meningioma. The role of EGFR inhibitors in meningiomas is unclear. Evaluation of multi-targeted inhibitors and EGFR inhibitors in combination with other targeted molecular agents may be warranted.

Kinetics of tumor size and peritumoral brain edema before, during, and after systemic therapy in recurrent WHO grade II or III meningioma

“…A recent systematic analysis proposed a PFS-6 rate of 26% as the benchmark for historical comparisons. 14 Considering this benchmark, hydroxyurea, octreotide analogues, gefitinib, and erlotinib were deemed ineffective, 4,13,16 while anti-angiogenic drugs, including bevacizumab, vatalanib, and sunitinib showed potential activity, with PFS-6 rates of 37.5% to 64.3%. 11,14,17 -19 Interestingly, our data support a potential role of anti-angiogenic treatment in recurrent WHO grades II and III meningioma, as the most pronounced decrease of tumor growth rates was observed in patients put on bevacizumab therapy.…”

An evidence-based treatment algorithm for the management of WHO Grade II and III meningiomas

“…Gefitinib, erlotinib, and imatinib, which target platelet-derived growth factor receptor (PDGFR) and epidermal growth factor receptor (EGFR), respectively, have generally been ineffective for AM and MM. 56,66,82 Although imatinib in combination with hydroxyurea did achieve a modest effect in Grade II and III meningiomas with a 6-month PFS of 46%, the 12-month PFS was only 8%. 66 Several authors have suggested antiangiogenic agents for the treatment of AM and MM.…”

“…Pa-tients with these refractory tumors typically have a median overall survival of only 6-33 months. 9,38,56 Modern trials have looked at the possible utility of receptor tyrosine kinase (RTK) inhibitors. Gefitinib, erlotinib, and imatinib, which target platelet-derived growth factor receptor (PDGFR) and epidermal growth factor receptor (EGFR), respectively, have generally been ineffective for AM and MM.…”

“…39,65 This relative success must be tempered, however, by the high rate of side effects and the low median overall survival (OS) with chemotherapy for these surgery-and radiation-refractory Grade II and III meningiomas, at approximately 24 months. 39,55,56,65 Chemotherapy for AMs shows promise but should only be considered for select refractory tumors as salvage therapy.…”

“…Conversely, select trials have suggested that angiogenesis inhibitors may play a role in salvage therapy for recurrent or refractory MMs (EBM Level 2, Grade 2B recommendation). 39,55,56,65 Clearly, additional studies are needed for these formidable meningiomas.…”