A single-arm phase II Austrian/German multicenter trial on continuous daily sunitinib in primary glioblastoma at first recurrence (SURGE 01-07)

Abstract

Background: Due to the redundancy of molecular pathways simultaneously involved in glioblastoma growth and angiogenesis, therapeutic approaches intervening at multiple levels seem particularly appealing.

Methods: This prospective, multicenter, single-arm phase II trial was designed to evaluate the antitumor activity of sunitinib, an oral small-molecule inhibitor of several receptor tyrosine kinases, in patients with first recurrence of primary glioblastoma using a continuous once-daily dosing regimen. Patients received a starting dose of sunitinib 37.5 mg, followed by a maintenance dose between 12.5 mg and 50 mg depending on drug tolerability. The primary endpoint was a 6-month progression-free survival (PFS) rate. Secondary endpoints included median PFS, overall survival (OS), safety/toxicity, quality of life, and translational studies on the expression of sunitinib target molecules.

Results: Forty participants were included in this study, and no objective responses were detected. PFS6 was 12.5%, median PFS 2.2 months, and median OS 9.2 months. Five participants (12.5%) showed prolonged stable disease ≥6 months with a median PFS of 16.0 months (range, 6.4-41.4 mo) and a median OS of 46.9 months (range, 21.2-49.2 mo) for this subgroup. c-KIT expression in vascular endothelial cells (n = 14 participants) was associated with improved PFS. The most common toxicities were fatigue/asthenia, mucositis/dermatitis, dysesthesias, gastrointestinal symptoms, cognitive impairment, leukoctopenia, and thrombocytopenia. Two participants (5%) terminated treatment due to toxicity.

Conclusion: Continuous daily sunitinib showed minimal antiglioblastoma activity and substantial toxicity when given at higher doses. High endothelial c-KIT expression may define a subgroup of patients who will benefit from sunitinib treatment by achieving prolonged PFS. ClinicalTrials.gov Identifier: NCT00535379.

Keywords: antitumor activity and safety; glioblastoma; molecular markers; quality of life; sunitinib.

Fig. 1.

c-KIT and PDGFR-α protein expression patterns in glioblastoma assessed by immunohistochemistry (magnification x400). (A) Expression of c-KIT in vascular endothelial cells. (B) PDGFR-α expression in tumor cells (magnification x200). The inset in (B) shows the expression of PDGFR-α in vascular cells in a different patient (magnification x400).

Fig. 2.

Kaplan—Meier survival curves showing progression-free survival (PFS) dependent on the expression of c-KIT in vascular endothelial cells, PDGFR-α in tumor cells, and MGMT promoter methylation status. Only high vascular endothelial c-KIT expression (A), but not absent or low PDGFR-α expression in tumor cells (B) or MGMT promoter methylation (C), was independently associated with prolonged PFS for sunitinib treatment. During first-line treatment, neither vascular endothelial c-KIT (D) nor tumoral PDGFR-α expression (E) were associated with improved PFS. As expected, MGMT promoter methylation (F) led to improved PFS during first-line radio-/chemotherapy (F). MGMT (M), methylated; MGMT (U), unmethylated.