A single-institution phase II trial of radiation (RT), temozolomide (TMZ), erlotinib, and bevacizumab for initial treatment of glioblastoma (GBM).

Abstract

2026 Background: Standard treatment for GBM includes surgery followed by RT and TMZ, rarely a curative treatment. Both the EGFR and VEGF pathways are frequently overactive in GBM; we previously added erlotinib, an EGFR inhibitor, to RT and TMZ, with modest improvement in survival. The present study combined bevacizumab, a VEGF inhibitor, and erlotinib with RT and TMZ, with the goal of improving overall survival (OS). Methods: Treatment consisted of fractionated RT to 60 Gy with daily TMZ at 75 mg/m2/d and erlotinib 150-200 mg/d (or 500-600 mg/d for patients on enzyme-inducing antiepileptic drugs [EIAEDs]). Bevacizumab was given at 10 mg/kg every 2 wks, starting ≥ 4 wks after surgery. After RT, adjuvant TMZ was given at 200 mg/m2/d x 5d per 28d cycle, with unchanged erlotinib and bevacizumab doses. Treatment was continued until progression or for 12 mo, with an option to continue for up to 24 mo. OS and progression-free survival (PFS) from initial diagnosis were compared against institutional historical controls (recent prior up-front clinical trials including RT and TMZ). Results: 59 pts were enrolled; 12 were receiving EIAEDs. Median age was 54 yrs; median KPS was 90. 33% underwent gross total resection and 53% subtotal resection. 16 pts had tumors with methylated MGMT (mMGMT), 26 with unmethylated MGMT (umMGMT), and 17 with unknown status. The most frequent related grade 3/4 AEs were lymphopenia (68%) thrombocytopenia (24%), neutropenia (10%), diarrhea (14%), weight loss (14%), and fatigue (12%). 1 pt died of aspergillosis. Median OS and PFS were 19.8 mo and 13.5 mo, respectively, vs. 18 mo and 8.6 mo for the historical control. The hazard ratio (adj for age, KPS, and extent of surgery) for PFS was 0.7 (95% CI 0.49-0.99, p=0.04). Median OS in pts with mMGMT was 20.9 mo, vs. 17.5 mo in pts with umMGMT; median PFS was 14 mo vs. 12.4 mo, respectively. Conclusions: The combination of bevacizumab, erlotinib, TMZ, and RT showed improved PFS but not OS vs. historical controls. Though the numbers were small, PFS and OS for pts with umMGMT were not significantly different from pts with mMGMT, suggesting that this combination may be more effective than standard therapy alone for pts with unMGMT tumors.