Editorial
What have we learned from trials on antiangiogenic agents in glioblastoma? Expert Review of Neurotherapeutics Downloaded from informahealthcare.com by Michigan State University on 03/01/15 For personal use only.
Expert Rev. Neurother. 14(1), 1–3 (2014)
Riccardo Soffietti Author for correspondence: Department of Neuro-Oncology, University and City of Health and Science Hospital of Turin, Turin, Italy [email protected]
Elisa Trevisan Department of Neuro-Oncology, University and City of Health and Science Hospital of Turin, Turin, Italy
Roberta Ruda` Department of Neuro-Oncology, University and City of Health and Science Hospital of Turin, Turin, Italy
Trials on recurrent glioblastoma have shown that bevacizumab alone is able to increase response rate on MRI, median and 6-month progression-free survival (PFS), and modestly overall survival, allowing an improvement of neurological function and a reduction of steroids. Any drug combination was not superior over bevacizumab alone. A synergistic effect of CCNU has been suggested when added to bevacizumab (BELOB trial), but excluded when added to cediranib (REGAL trial). Phase III trials on bevacizumab in newly diagnosed glioblastoma have shown an improvement of PFS of 3–4 months, but failed to prolong overall survival. The AVAglio trial has reported an improvement of quality of life, while the RTOG 0825 did not, and suggested a negative impact on neurocognitive functions. The GLARIUS trial, focusing on newly diagnosed glioblastoma without MGMT methylation, suggested an advantage for bevacizumab plus irinotecan. The Phase III CENTRIC trial has excluded any role for cilengitide in addiction to standard treatment in newly diagnosed glioblastoma.
The standard management of newly diagnosed glioblastoma multiforme (GBM; Grade IV WHO) involves maximal safe surgical resection, followed by radiotherapy with concomitant and adjuvant temozolomide and treatment options at relapse are limited [1]. GBM has the highest degree of vascular proliferation among solid tumors, and angiogenesis is a crucial step in the development and progression. VEGF is a key growth factor in promoting angiogenesis in gliomas: endothelial cells express and upregulate VEGF and its receptors, resulting in both paracrine and autocrine loops that drive endothelial cells permeability, proliferation and invasion. The main mechanism of action of anti-VEGF agents, such as bevacizumab (monoclonal antibody against VEGF) or cediranib (oral pan VEGF inhibitor), consists in a transient normalization of the abnormal tumor vasculature, leading to a reduction of the vasogenic edema [2]. The normalization of tumor vessels may theoretically improve the efficacy of chemotherapy by increasing the exposure of tumor cells to cytotoxic drugs and the
efficacy of radiotherapy by reducing tumor hypoxia. However, this vascular normalization is time-limited, as the restoration of blood–brain barrier integrity could lead to ischemia and hypoxia thereafter. In a multi-institutional randomized noncomparative Phase II trial for recurrent GBM (BRAIN Study), 167 patients were assigned either bevacizumab or bevacizumab combined with irinotecan [3]. For those patients on bevacizumab alone, 6-month progression-free survival (PFS) was 43%, objective response rate 28% and median overall survival (OS) 9 months. For those patients on bevacizumab and irinotecan, 6-month PFS was 50%, objective response rate 38% and median OS 8.7 months. Overall, when comparing the results of available Phase II trials on bevacizumab, alone or in combination with irinotecan, with those of standard cytotoxic chemotherapy (i.e., temozolomide, nitrosoureas) in the setting of recurrence, several findings are clear: bevacizumab alone has activity and clearly increases response rate on MRI, PFS at 6 months and median PFS; conversely, the impact of bevacizumab on OS is less clear. The improved
KEYWORDS: bevacizumab • cediranib • cilengitide • glioblastoma • VEGF
www.expert-reviews.com
10.1586/14737175.2014.873277
2014 Informa UK Ltd
ISSN 1473-7175
1
Expert Review of Neurotherapeutics Downloaded from informahealthcare.com by Michigan State University on 03/01/15 For personal use only.
Editorial
` Soffietti, Trevisan & Ruda
objective response and PFS at 6 months rates observed in the BRAIN study resulted in May 2009 in the accelerated approval by US FDA of single-agent bevacizumab for patients with recurrent GBM after standard treatment, while EMA rejected the approval in the EU due to the lack of an OS advantage resulting from Phase III comparative studies: thus, bevacizumab in the EU is still an off-label drug. The use of bevacizumab has been shown to quickly decrease peritumoral edema, thereby reducing the requirement for chronic corticosteroid use in up to 70% of patients and allowing a reduction of side effects. None of the drug combinations employed so far have demonstrated superiority over bevacizumab alone. This is true for irinotecan, carboplatin, etoposide, dose-intense temozolomide, cetuximab or erlotinib. A possible synergistic effect, in terms of OS, when adding CCNU to bevacizumab, has been recently reported in Dutch randomized Phase II study (BELOB study) [4]: a Phase III EORTC trial has been launched to confirm this finding. On the other hand, a randomized Phase III trial (REGAL) on recurrent GBM has not found any advantage for the addition of CCNU to cediranib [5]. Two Phase III trials on newly diagnosed glioblastoma, evaluating the role of bevacizumab added to standard radiotherapy and temozolomide, have just been completed. The AVAglio trial (registration trial mainly conducted in Europe) has shown a significant advantage for bevacizumab-treated patients in terms of PFS (6.2 vs 10.6 months) and quality of life maintenance [6], but has failed to demonstrate an advantage in terms of OS (16.8 vs 16.7 months). Confirmed pseudoprogression has been found in 2.2 versus 9.3% for bevacizumab-treated versus nonbevacizumab-treated patients. The results of RTOG 0825 (USA) [7] in terms of PFS and OS are similar to those of AVAglio; conversely, the US trial has reported that quality of life, symptom burden and cognitive functions worsened during PFS in bevacizumab-treated patients. These differences could be at least in part due to some differences in the selection criteria of the two trials: AVAglio included a large proportion of patients with a residual tumor burden after biopsy or incomplete resection, while RTOG 0825 excluded patients with a biopsy only and had a greater number of large resections. Cognitive tests were performed in a minority of patients only and were analyzed longitudinally up to 46 weeks only. As it stands, the OS data from both trials do not support the routine use of bevacizumab in the upfront treatment setting in all patients. The risk of a cognitive impairment after bevacizumab, as suggested by the RTOG trial, must be carefully evaluated in future studies, especially within the best prognostic subgroups of patients; for example, newly diagnosed GBMs after extensive resection and with methylguanine methyltransferase [MGMT] promoter methylation. In this regard, one must pay attention that there are experimental studies suggesting an important role of VEGF in maintaining neurogenesis and cognition [8].
2
An open issue is whether any subgroup of patients could benefit most from bevacizumab. This did not emerge from a subgroup analysis of AVAglio trial; on the other hand, a retrospective review on recurrent GBM reported that patients aged ‡55 years had an improved PFS when treated with bevacizumab, and this was related to a higher VEGF expression in tumor specimens [9]. A randomized Phase II trial (ARTE Trial) is being conducted in Switzerland on newly diagnosed GBM patients aged >65 years. Interestingly, a randomized Phase II trial restricted to newly diagnosed GBM patients without MGMT promoter methylation (Glarius trial) has shown a significant increase in both PFS and OS when adding bevacizumab plus irinotecan to standard radiotherapy and temozolomide [10]. GBMs invariably relapse after initial response to anti-VEGF therapy. There are different mechanisms by which gliomas can escape antiangiogenic therapy: increased invasion and migration capacities; activation and/or upregulation of alternative proangiogenic signaling pathways; exacerbation of underlying hypoxia; increased pericyte coverage; increase of macrophages; and myeloid cell infiltration. A question that arose after initial bevacizumab trials was whether this drug could significantly increase the risk of diffuse nonenhancing tumor progression (so-called ‘secondary gliomatosis’). Recent retrospective studies and the AVAglio trial have not confirmed this hypothesis. Another promising avenue of antiangiogenic therapy has been targeting integrins aVb3 and aVb5 that are expressed on GBM cells and tumor vasculature. Some activity of a specific inhibitor of these integrins, cilengitide, was suggested across Phase II trials on recurrent GBMs. Moreover, a presumed more pronounced benefit in tumors with a methylated MGMT promoter has been hypothized: thus, a multicenter randomized Phase III trial (CENTRIC) has been performed to compare in newly diagnosed MGMT methylated GBMs, the association of cilengitide with radiotherapy and temozolomide with radiotherapy and temozolomide alone. The study results have been negative, as both OS and PFS have not been improved by cilengitide [11]. Ongoing trials are investigating either the combination of anti-VEGF and antiinvasion agents or novel drugs targeting different angiogenesis pathways. Financial & competing interests disclosure
R Soffietti has received grants, bursaries and served on the advisory board for Roche. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.
Expert Rev. Neurother. 14(1), (2014)
What have we learned from trials on antiangiogenic agents in glioblastoma?
the efficacy of cediranib as monotherapy, and in combination with lomustine, versus lomustine alone in patients with recurrent glioblastoma. J Clin Oncol 2013;31(26): 3212-18
References
Expert Review of Neurotherapeutics Downloaded from informahealthcare.com by Michigan State University on 03/01/15 For personal use only.
1.
Weller M, Cloughesy T, Perry JR, Wick W. Standards of care for treatment of recurrent glioblastoma – are we there yet? Neuro Oncol 2013;15(1):4-27
2.
Jain RK. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 2005; 307(5706):58-62
3.
Friedman HS, Prados MD, Wen PY, et al. Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol 2009;27(28):4733-40
4.
5.
Taal W, Oosterkamp HM, Walenkamp AME, et al. A randomized phase II study of bevacizumab versus bevacizumab plus lomustine versus lomustine single agent in recurrent glioblastoma: the Dutch BELOB study. J Clin Oncol 2013;31(15S):2001 Batchelor TT, Mulholland P, Neyns B, et al. Phase III randomized trial comparing
www.expert-reviews.com
6.
Chinot O, Cloughesy T, Henriksson R, et al. Efficacy and safety of bevacizumab (Bv) plus standard combination temozolomide (T) and radioterapy (RT) in newly diagnosed glioblastoma: final results froma AVAglio. Eur J Cancer 2013; 49(suppl 2):S774-5
7.
Gilbert MR, Dignam J, Won M, et al. RTOG 0825: Phase III double-blind placebo-controlled trial evaluating bevacizumab (Bev) in patients (Pts) with newly diagnosed glioblastoma (GBM). J Clin Oncol 2013;31(18S):1
8.
Cao L, Jiao X, Zuzga DS, et al. VEGF links hippocampal activity with neurogenesis, learning and memory. Nat Genet 2004;36(8):827-35
Editorial
9.
Nghiemphu PL, Liu W, Lee Y, et al. Bevacizumab and chemotherapy for recurrent glioblastoma: a single-institution experience. Neurology 2009;72(14):1217-22
10.
Herrlinger U, Schafer N, Steinbach JP, et al. Bevacizumab, irinotecan and radiotherapy versus standard temozolomide and radiotherapy in newly diagnosed, MGMT – non methylated glioblastoma patients: updated results from the randomized multicenter GLARIUS Trial. Eur J Cancer 2013;49(suppl 2):S774
11.
Stupp R, Hegi ME, Gorlia T, et al. Standard chemoradiotherapy ± cilengitide in newly diagnosed glioblastoma (GBM): updated results and subgroup analyses of the international randomized phase III CENTRIC Trial (EORTC trial 2607122072/Canadian Brain tumor Consortium). Eur J Cancer 2013;49(suppl 2):S775
3
What have we learned from trials on antiangiogenic agents in glioblastoma? Expert Review of Neurotherapeutics Downloaded from informahealthcare.com by Michigan State University on 03/01/15 For personal use only.
Expert Rev. Neurother. 14(1), 1–3 (2014)
Riccardo Soffietti Author for correspondence: Department of Neuro-Oncology, University and City of Health and Science Hospital of Turin, Turin, Italy [email protected]
Elisa Trevisan Department of Neuro-Oncology, University and City of Health and Science Hospital of Turin, Turin, Italy
Roberta Ruda` Department of Neuro-Oncology, University and City of Health and Science Hospital of Turin, Turin, Italy
Trials on recurrent glioblastoma have shown that bevacizumab alone is able to increase response rate on MRI, median and 6-month progression-free survival (PFS), and modestly overall survival, allowing an improvement of neurological function and a reduction of steroids. Any drug combination was not superior over bevacizumab alone. A synergistic effect of CCNU has been suggested when added to bevacizumab (BELOB trial), but excluded when added to cediranib (REGAL trial). Phase III trials on bevacizumab in newly diagnosed glioblastoma have shown an improvement of PFS of 3–4 months, but failed to prolong overall survival. The AVAglio trial has reported an improvement of quality of life, while the RTOG 0825 did not, and suggested a negative impact on neurocognitive functions. The GLARIUS trial, focusing on newly diagnosed glioblastoma without MGMT methylation, suggested an advantage for bevacizumab plus irinotecan. The Phase III CENTRIC trial has excluded any role for cilengitide in addiction to standard treatment in newly diagnosed glioblastoma.
The standard management of newly diagnosed glioblastoma multiforme (GBM; Grade IV WHO) involves maximal safe surgical resection, followed by radiotherapy with concomitant and adjuvant temozolomide and treatment options at relapse are limited [1]. GBM has the highest degree of vascular proliferation among solid tumors, and angiogenesis is a crucial step in the development and progression. VEGF is a key growth factor in promoting angiogenesis in gliomas: endothelial cells express and upregulate VEGF and its receptors, resulting in both paracrine and autocrine loops that drive endothelial cells permeability, proliferation and invasion. The main mechanism of action of anti-VEGF agents, such as bevacizumab (monoclonal antibody against VEGF) or cediranib (oral pan VEGF inhibitor), consists in a transient normalization of the abnormal tumor vasculature, leading to a reduction of the vasogenic edema [2]. The normalization of tumor vessels may theoretically improve the efficacy of chemotherapy by increasing the exposure of tumor cells to cytotoxic drugs and the
efficacy of radiotherapy by reducing tumor hypoxia. However, this vascular normalization is time-limited, as the restoration of blood–brain barrier integrity could lead to ischemia and hypoxia thereafter. In a multi-institutional randomized noncomparative Phase II trial for recurrent GBM (BRAIN Study), 167 patients were assigned either bevacizumab or bevacizumab combined with irinotecan [3]. For those patients on bevacizumab alone, 6-month progression-free survival (PFS) was 43%, objective response rate 28% and median overall survival (OS) 9 months. For those patients on bevacizumab and irinotecan, 6-month PFS was 50%, objective response rate 38% and median OS 8.7 months. Overall, when comparing the results of available Phase II trials on bevacizumab, alone or in combination with irinotecan, with those of standard cytotoxic chemotherapy (i.e., temozolomide, nitrosoureas) in the setting of recurrence, several findings are clear: bevacizumab alone has activity and clearly increases response rate on MRI, PFS at 6 months and median PFS; conversely, the impact of bevacizumab on OS is less clear. The improved
KEYWORDS: bevacizumab • cediranib • cilengitide • glioblastoma • VEGF
www.expert-reviews.com
10.1586/14737175.2014.873277
2014 Informa UK Ltd
ISSN 1473-7175
1
Expert Review of Neurotherapeutics Downloaded from informahealthcare.com by Michigan State University on 03/01/15 For personal use only.
Editorial
` Soffietti, Trevisan & Ruda
objective response and PFS at 6 months rates observed in the BRAIN study resulted in May 2009 in the accelerated approval by US FDA of single-agent bevacizumab for patients with recurrent GBM after standard treatment, while EMA rejected the approval in the EU due to the lack of an OS advantage resulting from Phase III comparative studies: thus, bevacizumab in the EU is still an off-label drug. The use of bevacizumab has been shown to quickly decrease peritumoral edema, thereby reducing the requirement for chronic corticosteroid use in up to 70% of patients and allowing a reduction of side effects. None of the drug combinations employed so far have demonstrated superiority over bevacizumab alone. This is true for irinotecan, carboplatin, etoposide, dose-intense temozolomide, cetuximab or erlotinib. A possible synergistic effect, in terms of OS, when adding CCNU to bevacizumab, has been recently reported in Dutch randomized Phase II study (BELOB study) [4]: a Phase III EORTC trial has been launched to confirm this finding. On the other hand, a randomized Phase III trial (REGAL) on recurrent GBM has not found any advantage for the addition of CCNU to cediranib [5]. Two Phase III trials on newly diagnosed glioblastoma, evaluating the role of bevacizumab added to standard radiotherapy and temozolomide, have just been completed. The AVAglio trial (registration trial mainly conducted in Europe) has shown a significant advantage for bevacizumab-treated patients in terms of PFS (6.2 vs 10.6 months) and quality of life maintenance [6], but has failed to demonstrate an advantage in terms of OS (16.8 vs 16.7 months). Confirmed pseudoprogression has been found in 2.2 versus 9.3% for bevacizumab-treated versus nonbevacizumab-treated patients. The results of RTOG 0825 (USA) [7] in terms of PFS and OS are similar to those of AVAglio; conversely, the US trial has reported that quality of life, symptom burden and cognitive functions worsened during PFS in bevacizumab-treated patients. These differences could be at least in part due to some differences in the selection criteria of the two trials: AVAglio included a large proportion of patients with a residual tumor burden after biopsy or incomplete resection, while RTOG 0825 excluded patients with a biopsy only and had a greater number of large resections. Cognitive tests were performed in a minority of patients only and were analyzed longitudinally up to 46 weeks only. As it stands, the OS data from both trials do not support the routine use of bevacizumab in the upfront treatment setting in all patients. The risk of a cognitive impairment after bevacizumab, as suggested by the RTOG trial, must be carefully evaluated in future studies, especially within the best prognostic subgroups of patients; for example, newly diagnosed GBMs after extensive resection and with methylguanine methyltransferase [MGMT] promoter methylation. In this regard, one must pay attention that there are experimental studies suggesting an important role of VEGF in maintaining neurogenesis and cognition [8].
2
An open issue is whether any subgroup of patients could benefit most from bevacizumab. This did not emerge from a subgroup analysis of AVAglio trial; on the other hand, a retrospective review on recurrent GBM reported that patients aged ‡55 years had an improved PFS when treated with bevacizumab, and this was related to a higher VEGF expression in tumor specimens [9]. A randomized Phase II trial (ARTE Trial) is being conducted in Switzerland on newly diagnosed GBM patients aged >65 years. Interestingly, a randomized Phase II trial restricted to newly diagnosed GBM patients without MGMT promoter methylation (Glarius trial) has shown a significant increase in both PFS and OS when adding bevacizumab plus irinotecan to standard radiotherapy and temozolomide [10]. GBMs invariably relapse after initial response to anti-VEGF therapy. There are different mechanisms by which gliomas can escape antiangiogenic therapy: increased invasion and migration capacities; activation and/or upregulation of alternative proangiogenic signaling pathways; exacerbation of underlying hypoxia; increased pericyte coverage; increase of macrophages; and myeloid cell infiltration. A question that arose after initial bevacizumab trials was whether this drug could significantly increase the risk of diffuse nonenhancing tumor progression (so-called ‘secondary gliomatosis’). Recent retrospective studies and the AVAglio trial have not confirmed this hypothesis. Another promising avenue of antiangiogenic therapy has been targeting integrins aVb3 and aVb5 that are expressed on GBM cells and tumor vasculature. Some activity of a specific inhibitor of these integrins, cilengitide, was suggested across Phase II trials on recurrent GBMs. Moreover, a presumed more pronounced benefit in tumors with a methylated MGMT promoter has been hypothized: thus, a multicenter randomized Phase III trial (CENTRIC) has been performed to compare in newly diagnosed MGMT methylated GBMs, the association of cilengitide with radiotherapy and temozolomide with radiotherapy and temozolomide alone. The study results have been negative, as both OS and PFS have not been improved by cilengitide [11]. Ongoing trials are investigating either the combination of anti-VEGF and antiinvasion agents or novel drugs targeting different angiogenesis pathways. Financial & competing interests disclosure
R Soffietti has received grants, bursaries and served on the advisory board for Roche. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.
Expert Rev. Neurother. 14(1), (2014)
What have we learned from trials on antiangiogenic agents in glioblastoma?
the efficacy of cediranib as monotherapy, and in combination with lomustine, versus lomustine alone in patients with recurrent glioblastoma. J Clin Oncol 2013;31(26): 3212-18
References
Expert Review of Neurotherapeutics Downloaded from informahealthcare.com by Michigan State University on 03/01/15 For personal use only.
1.
Weller M, Cloughesy T, Perry JR, Wick W. Standards of care for treatment of recurrent glioblastoma – are we there yet? Neuro Oncol 2013;15(1):4-27
2.
Jain RK. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 2005; 307(5706):58-62
3.
Friedman HS, Prados MD, Wen PY, et al. Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol 2009;27(28):4733-40
4.
5.
Taal W, Oosterkamp HM, Walenkamp AME, et al. A randomized phase II study of bevacizumab versus bevacizumab plus lomustine versus lomustine single agent in recurrent glioblastoma: the Dutch BELOB study. J Clin Oncol 2013;31(15S):2001 Batchelor TT, Mulholland P, Neyns B, et al. Phase III randomized trial comparing
www.expert-reviews.com
6.
Chinot O, Cloughesy T, Henriksson R, et al. Efficacy and safety of bevacizumab (Bv) plus standard combination temozolomide (T) and radioterapy (RT) in newly diagnosed glioblastoma: final results froma AVAglio. Eur J Cancer 2013; 49(suppl 2):S774-5
7.
Gilbert MR, Dignam J, Won M, et al. RTOG 0825: Phase III double-blind placebo-controlled trial evaluating bevacizumab (Bev) in patients (Pts) with newly diagnosed glioblastoma (GBM). J Clin Oncol 2013;31(18S):1
8.
Cao L, Jiao X, Zuzga DS, et al. VEGF links hippocampal activity with neurogenesis, learning and memory. Nat Genet 2004;36(8):827-35
Editorial
9.
Nghiemphu PL, Liu W, Lee Y, et al. Bevacizumab and chemotherapy for recurrent glioblastoma: a single-institution experience. Neurology 2009;72(14):1217-22
10.
Herrlinger U, Schafer N, Steinbach JP, et al. Bevacizumab, irinotecan and radiotherapy versus standard temozolomide and radiotherapy in newly diagnosed, MGMT – non methylated glioblastoma patients: updated results from the randomized multicenter GLARIUS Trial. Eur J Cancer 2013;49(suppl 2):S774
11.
Stupp R, Hegi ME, Gorlia T, et al. Standard chemoradiotherapy ± cilengitide in newly diagnosed glioblastoma (GBM): updated results and subgroup analyses of the international randomized phase III CENTRIC Trial (EORTC trial 2607122072/Canadian Brain tumor Consortium). Eur J Cancer 2013;49(suppl 2):S775
3
