Phase II trial of sunitinib for recurrent and progressive atypical and anaplastic meningioma

Meningioma is the most common primary brain tumor, comprising 35% of all CNS tumors in the United States.1 Approximately 80% of meningiomas are World Health Organization (WHO) grade I and may be observed expectantly or treated successfully with surgery or radiotherapy. However, the remaining 20% are either WHO grade II (atypical) or grade III (anaplastic or “malignant”) and have high recurrence rates, exceeding 50% for atypical tumors and 80% for anaplastic tumors. Despite maximal surgical resection and radiotherapy, a subset of these patients will recur and require additional treatment, but there is no proven effective chemotherapy for patients with aggressive meningiomas. Studies investigating traditional chemotherapies (temozolomide, hydroxyurea, irinotecan, and triple therapy with cyclophosphamide + doxorubicin + vincristine), hormonal therapies (progesterone and estrogen modulators, somatostatin analogues), interferon alfa-2b, and molecularly targeted therapies, including inhibitors of platelet-derived growth factor receptors (PDGFRs; imatinib) and epidermal growth factor receptor (gefitinib and erlotinib), have all been disappointing.2–19 Although the natural history of these tumors is not well established, the 6-month progression-free survival (PFS6) rate for these patients is poor. A phase II study of imatinib in recurrent meningioma demonstrated a PFS6 of 0% in the atypical/anaplastic cohort.19 PDGF is a ubiquitous growth factor driving cell proliferation in normal development as well as numerous neoplasms, including meningiomas.20–25 Administration of PDGF-BB to meningioma cells in culture results in stimulation of tumor growth, while administration of anti–PDGF-BB antibodies inhibits proliferation.26,27 Vascular endothelial growth factor (VEGF) is upregulated in almost all meningiomas and has been associated with neovascularization, tumor growth, and the development of edema.28,29 Targeting VEGF with different agents has proved effective in several different cancers, including malignant gliomas.30,31 Targeting this pathway may have therapeutic potential in meningioma. Sunitinib malate (SU011248, Sutent, Pfizer) is an orally administered tyrosine kinase inhibitor targeting VEGF receptor (VEGFR), PDGFR, and KIT.32 Inhibiting these targets represents an attractive therapeutic approach for recurrent meningiomas. The FDA-approved and recommended dose for sunitinib in renal cell carcinoma and gastrointestinal stromal tumor is 50 mg daily for 4 of every 6 weeks. We selected this dose because meningiomas are extraparenchymal tumors. Given (i) the strong preclinical rationale for targeting PDGFR and VEGFR in meningiomas, (ii) the efficacy of sunitinib cotargeting VEGFR2 and PDGFR, and (iii) its safety in adults with other solid tumors, we investigated sunitinib in this phase II study for recurrent and progressive meningiomas that had failed prior surgery and radiation.