The STELLAR trial: a phase II/III randomized trial of high-dose, intermittent sunitinib in patients with recurrent glioblastoma

Abstract

Previously, the tyrosine kinase inhibitor sunitinib failed to show clinical benefit in patients with recurrent glioblastoma. Low intratumoural sunitinib accumulation in glioblastoma patients was reported as a possible explanation for the lack of therapeutic benefit. We designed a randomized phase II/III trial to evaluate whether a high-dose intermittent sunitinib schedule, aimed to increase intratumoural drug concentrations, would result in improved clinical benefit compared to standard treatment with lomustine. Patients with recurrent glioblastoma were randomized 1:1 to high-dose intermittent sunitinib 300 mg once weekly (Q1W, part 1) or 700 mg once every two weeks (Q2W, part 2) or lomustine. The primary end-point was progression-free survival. Based on the pre-planned interim analysis, the trial was terminated for futility after including 26 and 29 patients in parts 1 and 2. Median progression-free survival of sunitinib 300 mg Q1W was 1.5 months (95% CI 1.4-1.7) compared to 1.5 months (95% CI 1.4-1.6) in the lomustine arm (P = 0.59). Median progression-free survival of sunitinib 700 mg Q2W was 1.4 months (95% CI 1.2-1.6) versus 1.6 months (95% CI 1.3-1.8) for lomustine (P = 0.70). Adverse events (≥grade 3) were observed in 25%, 21% and 31% of patients treated with sunitinib 300 mg Q1W, sunitinib 700 mg Q2W and lomustine, respectively (P = 0.92). To conclude, high-dose intermittent sunitinib treatment failed to improve the outcome of patients with recurrent glioblastoma when compared to standard lomustine therapy. Since lomustine remains a poor standard treatment strategy for glioblastoma, innovative treatment strategies are urgently needed.

Keywords: glioblastoma; high-dose; lomustine; sunitinib; tyrosine kinase inhibitors.

Graphical Abstract

Figure 1

CONSORT diagram of patients invited to participate and included in the STELLAR trial. Overview of patient enrolment and availability for analysis. All evaluable patients, defined as those completing at minimum six weeks of treatment, were included in the analysis.

Figure 2

Progression-free survival and overall survival. Progression-free survival (A) and overall survival (B) in part 1. Part 1: lomustine n = 14, high-dose intermittent sunitinib n = 12. Progression-free survival (C) and overall survival (D) in part 2. Part 2: lomustine n = 15, high-dose intermittent sunitinib n = 14. PFS, progression-free survival; HR, hazard ratio; OS, overall survival.

Figure 3

Efficacy lomustine cohort. (A) Progression-free survival of patients treated with lomustine (n = 29). (B) Overall survival of patients treated with lomustine (n = 29). PFS, progression-free survival; OS, overall survival.

Figure 4

MGMT status in relation to PFS and OS. (A) MGMT status in relation to OS in patients treated with lomustine (n = 27). (B) MGMT status in relation to OS in patients treated with sunitinib (n = 22). (C) MGMT status in relation to PFS in patients treated with lomustine (n = 27). (D) MGMT status in relation to PFS in patients treated with sunitinib (n = 22). In the lomustine arm, n = 9 had methylated MGMT and n = 18 unmethylated MGMT. In the high-dose intermittent sunitinib arm, n = 11 had methylated MGMT and n = 11 unmethylated MGMT. MGMT, O⁶-methylguanine-DNA methyl-transferase; HR, hazard ratio; PFS, progression-free survival; OS, overall survival.