RTOG 0625: A phase II study of bevacizumab with irinotecan in recurrent glioblastoma (GBM)

Abstract

2011 Background: Angiogenesis is a hallmark of GBM, making the tumor vasculature an attractive therapeutic target. In gliomas, vascular endothelial growth factor (VEGF) promotes both angiogenesis and invasion of tumor cells. Bevacizumab is a humanized monoclonal antibody against VEGF-A that rapidly reduces the concentration of VEGF in the circulation. Irinotecan may enhance efficacy by synergistic tumor endothelial cell death or improved tumor delivery of the chemotherapy via “normalized” tumor vasculature. Prior studies of this combination demonstrated high radiographic response and 6-month progression free (6-mPFS) rates. This study was designed to determine the efficacy and safety of this regimen in the cooperative group setting. Methods: Eligibility included age ≥ 18, centrally confirmed GBM or gliosarcoma, progressive or recurrent disease. Enzyme-inducing anticonvulsants were not allowed. Treatment was intravenous bevacizumab 10 mg/kg and irinotecan 200 mg/m2 every 2 weeks. Accrual goal was 57 eligible patients. Primary endpoint was 6-mPFS rate where an estimate of ≥ 35% would define efficacy (15% improvement over historical data). Results: Full enrollment (57) was achieved, median age was 57, median KPS was 80; all had prior radiation and temozolomide treatment. The 6m-PFS rate was 37% (95% CI: 24–50%), with 21 of 57 patients progression-free at 6 months. Moderate toxicity was noted with 21(37%) grade 3, seven (12%) grade 4, and one (<2%) treatment-related death (intracranial hemorrhage). There were six episodes of venous thrombosis, 14 episodes of grade 3 or 4 hematologic toxicity, predominantly lymphopenia (7), and neutropenia (4), no opportunistic infections or febrile neutropenia were noted. Other toxicities included fatigue (9), diarrhea (2), and hypertension (2). Conclusions: These results, in the cooperative group context, corroborate the efficacy of the bevacizumab and irinotecan combination for recurrent GBM with the 6m-PFS surpassing the predetermined efficacy threshold. Previously described toxicities were confirmed with a moderately high rate of venous thrombosis, one intracranial hemorrhage, and moderate hypertension. Studies to determine the contribution of the cytotoxic agent to efficacy and the role of bevacizumab in newly diagnosed GBM are planned. [Table: see text]

Bevacizumab for the Treatment of Recurrent Glioblastoma

“…31–34,46,48,50,53 While the reported rate of grade 2 or higher bleeding events has been as high as 5.3%, life-threatening intracranial hemorrhages have occurred in only a small percentage (≤3%) of patients treated with bevacizumab. 31–34,37,46,50 This latter incidence rate falls within the expected range for spontaneous events in patients with GBM (approximately 2%–3%). 54,55 Relatively high rates of thromboembolism ie, deep vein thrombosis and pulmonary embolism have been reported in studies evaluating bevacizumab-containing therapy in recurrent GBM (ranging from 1.6%–12.5%).…”

“…34 In retrospective analyses and additional phase 2 studies, investigator determined response rates with bevacizumab-based combination therapy have ranged between 19% and 62%, and PFS-6 rates have ranged between 30% and 46% in patients with recurrent GBM, representing an apparent and significant improvement compared with historical outcomes. 31,32,37,46,47 An apparent improvement (50%) in median OS (ranging from 31 weeks to 42 weeks) has also been observed with bevacizumabbased regimens relative to historical controls. 33,34,46,47 In a recent pilot study, the combination of bevacizumab and concurrent radiotherapy (re-radiation) was shown to be active and well tolerated in recurrent malignant glioma.…”

“…26 These encouraging results prompted the investigation of bevacizumab with irinotecan in subsequent prospective phase 2 studies. [32][33][34][35][36][37] Several mechanisms of action have been suggested for the anti-GBM effect of bevacizumab, including direct inhibition of tumorassociated angiogenesis, a direct anti-GBM effect on VEGF receptor-expressing GBM cells, disruption of the glioma stem cell microvascular niche, and improved vascular function or normalization. 13,39,42,44 The glioma stem cell microvascular niche may represent an important target of antiangiogenic agents, because the resident glioma stem cells are a population of CD133+, nestin+, self-renewing, multipotent GBM-initiating cells that are relatively radio-and chemoresistant.…”

“…34 Cross-trial comparisons also suggest that single-agent bevacizumab is associated with a lower rate of grade 3 adverse events than bevacizumab-containing combinations for GBM; however, these observations are subject to differences in study design and patient populations. 37,49 The most common adverse events attributable to bevacizumab treatment in recurrent GBM include low-grade bleeding (ie, epistaxis), hypertension, impaired wound healing, and proteinuria, [32][33][34] which are similar to bevacizumab associated toxicities in other cancer types. 26,28,29 The majority of these toxicities appear to be due to on-target, classspecific actions of angiogenic inhibition, and reflect disruption of VEGF in normal tissue.…”

Activity and Safety of Bevacizumab Plus Fotemustine for Recurrent Malignant Gliomas

“…In phase II trials regarding the association of bevacizumab with chemotherapeutic agents including also irinotecan, the response rates ranged from 38% to 57% [ 12 , 16 ] and activity achieved a percentage of about 32% [ 9 ]. Among the experiences with bevacizumab combination regimens in GBM, the 6-month PFS ranged from 37% to 50% [ 9 , 12 , 16 , 19 , 20 ]. Bevacizumab is also active as a single agent in patients with recurrent GBM reporting objective response rate ranging from 25% to 42% and 6-month PFS of 29–42% [ 12 , 13 , 21 , 22 ].…”