A Phase II Trial of Concurrent Sunitinib, Temozolomide and Radiation Therapy Followed by Adjuvant Temozolomide for Newly Diagnosed Glioblastoma Patients with an Unmethylated MGMT Gene Promoter

Abstract

<h3>Purpose/Objective(s)</h3> Despite advances in treatment modalities, the overall prognosis of Glioblastoma remains dismal, particularly for patients with unmethylated MGMT promoter. In this phase II trial, we tested for the first time the combination of Sunitinib with radiotherapy and Temozolomide in newly diagnosed MGMT unmethylated Glioblastoma patients. We hypothesized that this combination therapy would be safe and yield superior survival outcomes than the current standard of care for MGMT unmethylated Glioblastoma patients. <h3>Materials/Methods</h3> 37 patients diagnosed with WHO-Grade IV Glioblastoma and unmethylated MGMT promoter, age 18-70 and KPS ≥70 were eligible from two institutions. Patients received 12.5 mg of daily Sunitinib for 7 days, followed by concurrent chemoradiation and 12.5 mg Sunitinib x6 weeks, then adjuvant Temozolomide x6 cycles. Primary objective was progression-free-survival (PFS) as per RANO criteria, secondary objectives were overall survival (OS), safety and Neutrophil-to-Lymphocyte ratio (NLR). <h3>Results</h3> Median follow-up time was 15.3 months (95% CI: 13.8-19.4). Median PFS was 7.15 months (95% CI: 5.4-10.5 months) and 6-month PFS was 54.0%. Median OS was 15.0 months (95% CI: 13.8-19.4 months) and 2-year OS was 17.1%. Having received >3 cycles of adjuvant Temozolomide and surgery at progression significantly predicted for better OS with hazard ratios of 0.32 (p=0.017) and 0.46 (p=0.049) respectively, whereas age >65 and post-treatment NLR>6 predicted for worse OS with hazard ratios of 3.92 (p=0.037) and 2.64 (p = 0.021) respectively. Grade ≥3 thrombocytopenia occurred in 22.9%, grade ≥3 neutropenia in 20% and grade ≥3 thromboembolic events in 14.3% of patients. There were no grade 5 events. <h3>Conclusion</h3> Addition of Sunitinib to RT and Temozolomide was safe and survival outcomes are promising compared to the standard of care for GBM patients with unmethylated MGMT promoter status.