A phase II study of bevacizumab and erlotinib after radiation and temozolomide in MGMT unmethylated GBM patients

Abstract

Survival for glioblastoma (GBM) patients with an unmethyated MGMT promoter in their tumor is generally worse than methylated MGMT tumors, as temozolomide (TMZ) response is limited. How to better treat patients with unmethylated MGMT is unknown. We performed a trial combining erlotinib and bevacizumab in unmethylated GBM patients after completion of radiation (RT) and TMZ. GBM patients with an unmethylated MGMT promoter were trial eligible. Patient received standard RT (60 Gy) and TMZ (75 mg/m2 × 6 weeks) after surgical resection of their tumor. After completion of RT they started erlotinib 150 mg daily and bevacizumab 10 mg/kg every 2 weeks until progression. Imaging evaluations occurred every 8 weeks. The primary endpoint was overall survival. Of the 48 unmethylated patients enrolled, 46 were evaluable (29 men and 17 women); median age was 55.5 years (29–75) and median KPS was 90 (70–100). All patients completed RT with TMZ. The median number of cycles (1 cycle was 4 weeks) was 8 (2–47). Forty-one patients either progressed or died with a median progression free survival of 9.2 months. At a follow up of 33 months the median overall survival was 13.2 months. There were no unexpected toxicities and most observed toxicities were categorized as CTC grade 1 or 2. The combination of erlotinib and bevacizumab is tolerable but did not meet our primary endpoint of increasing survival. Importantly, more trials are needed to find better therapies for GBM patients with an unmethylated MGMT promoter.

DNA repair genes in astrocytoma tumorigenesis, progression and therapy resistance

“…Although studies of new drugs take more time and are more laborious, they are also extremely important and largely conducted worldwide. New drugs for GBM treatment, such as bevazicumab, erlotinib (Raizer et al, 2016), 1,3-bis (2-chloroethyl)-1 nitrosourea (BCNU) (Vinjamuri et al, 2009), and gliadel (Xing et al, 2015), are being massively exploited with good results and some of them have already reached phase II clinical trials. In phase III trials, the implantation of gliadel and BCNU wafers in the after surgery tumor bed was assessed and improved overall survival average in 2 months (Westphal et al, 2003).…”

EGFR as a Target for Glioblastoma Treatment: An Unfulfilled Promise

“…For the leading representatives of this group, erlotinib, gefitinib, afatinib, and lapatinib, trials have not shown efficacy either alone or in combination. Erlotinib showed no efficacy and unacceptable side effects as a single agent in newly diagnosed glioblastoma [ 25 ] and later studies combining it for recurrent glioblastoma with mechanistic target of rapamycin (mTOR) blockers or bevacizumab were unsuccessful [ 26 – 28 ]. Gefitinib did not result in improved overall survival in a phase II trial in recurrent glioblastoma [ 29 ] or in a phase I/II trial in combination with radiation in newly diagnosed glioblastoma [ 30 ].…”

New Directions in Anti-Angiogenic Therapy for Glioblastoma

“…Additional phase 2 trials have evaluated bevacizumab in combination with irinotecan, cetuximab, carboplatin, etoposide, fotemustine, sorafenib, temozolomide, erlotinib, panobinostat, and temsirolimus [66,[69][70][71][72][73][74][75][76][77][78][79][80][81][82][83][84][85][86][87][88]. There have also been trials evaluating bevacizumab and re-irradiation [89][90][91].…”