NEWS & VIEWS TARGETED THERAPIES
Further delineating bevacizumab’s response spectrum David A. Reardon and Patrick Y. Wen
The use of antiangiogenic drugs, such as bevacizumab, represents an appealing intervention against cancer. However, not all malignancies are equally responsive to such treatment. Recent trials demonstrate the efficacy of this drug for advanced-stage cervical cancer and, despite limitations, bevacizumab provides an important clinical respite for most patients with progressive glioblastoma. Reardon, D. A. & Wen, P. Y. Nat. Rev. Clin. Oncol. 11, 243–244 (2014); published online 8 April 2014; doi:10.1038/nrclinonc.2014.61
the AVAglio nor the RTOG 0825 trials were able to identify any subgroup of patients who were more likely to benefit from treatment with bevacizumab based on prospectively evaluated clinical and molecul ar biomarkers (including me thylguanine methyltransferase status).2,3
‘‘
…why are some tumours less dependent on VEGF signalling?
’’
Imp or t ant ly, b ot h studies e va luated quality of life (QOL). Intriguingly, although similar validated tools including the EORTC QLQ30 and BN20 surveys were used, discrepant findings were reported. Some patients assigned to the bevacizumab group in the RTOG 0825 trial noted worsened QOL scores compared with patients in the placebo arm; by contrast, patients assigned to receive bevacizumab in the AVAglio trial showed consistently improved QOL scores over the course of treatment compared to placebo recipients. The reason for such divergent outcome remains to be defined, but it might
be related to a less-sensitive approach for the detection of patients with disease progression in the RTOG 0825 trial as a result of assessing progression based solely on enhancing tumour. Neurocognitive testing, which was assessed in most patients in the RTOG 0825 trial, revealed some diminished cognitive function among those who received bevacizumab.3 However, further investigation on the impact of bevacizumab on QOL and cognition for this indication is required before any final conclusions can be drawn. At the same time that the results of the RTOG 0825 and AVAglio trials failed to report an improvement in overall survival for the addition of bevacizumab to the standard treatment regimen for glioblastoma, the results of the GOG 240 randomi zed phase III trial for advanced-stage cervical cancer were published. This trial reported a 3.7 month improvement in both overall survival and PFS for the addition of bevacizumab to chemotherapy (paclitaxel plus either cisplatin or topotecan) compared with chemot herapy alone. 4 In the GOG 240 trial, comparable QOL for both
piyagoon/iStock/Thinkstock
Single-agent bevacizumab—a humanized monoclonal antibody that targets VEGF to inhibit angiogenesis—received accelerated approval by the US FDA in 2009 for recurrent glioblastoma, based on results from two phase II studies reporting durable responses.1 AVAglio2 and RTOG 0825,3 two separate placebo-controlled, randomized, phase III studies, further evaluating the activity of bevacizumab for the treatment of glioblastoma in newly diagnosed patients, have recently been published. 2,3 These two studies shared significant similarities, including the use of standard temozolomide chemoradiotherapy and statistical designs powered for detecting significant differences for both overall survival and progression-free survival (PFS). However, the studies also had important differences. The RTOG 0825 trial excluded patients with a poor prognosis investigated by biopsy only, determined treatment response by assessment of enhancing tumour only (Macdonald criteria), and included a predefined cross-over at disease progression, so that patients informed on their cohort-assignment could decide to start or continue bevacizumab.3 By contrast, the AVAglio trial allowed biopsy-only patients to be enrolled, assessed both enhancing as well as non-enhancing tumours for response, and did not include a planned cross-over (although 30% of patients assigned to receive placebo ultimately received bevacizumab at disease progression).2 Nonetheless, both studies demonstrated remarkably similar results, including a 3–4 month improvement in PFS, but no overall survival benefit.2,3 Of note, neither NATURE REVIEWS | CLINICAL ONCOLOGY
VOLUME 11 | MAY 2014 | 243 © 2014 Macmillan Publishers Limited. All rights reserved
NEWS & VIEWS treatment arms and a non-statistical trend of fewer neurotoxic symptoms among bevacizumab recipients were noted. Overall, the results of these three hallmark studies align along a continuum of therapeutic benefit associated with bevacizumab across the cancer spectrum. On the basis of the GOG 240 trial, cervical cancer is comparable to colorectal cancer in terms of representing the more responsive end of the spectrum with robust increments in both PFS and overall survival. Such benefit indicates, most probably, a more critical dependence of these tumours on VEGF signalling. For cervical cancer, a direct link between the causative agent, human papillomavirus, and VEGF activation has been described.5 In addition, the GOG 240 trial also supports a possible vascul ar normalization role of bevaciz umab that may augment chemotherapy delivery.6
‘‘
…these … studies align along a continuum of therapeutic benefit associated with bevacizumab across the cancer spectrum
’’
The RTOG 0825 and AVAglio trials sugg est that glioblastoma has an inter mediate responsiveness to bevacizumab, hallmarked by a disproportionate improvement in PFS relative to overall survival. Therefore, glioblastoma aligns with nonsmall-cell lung, breast, renal, pancreatic, prostate and ovarian cancers in terms of its responsiveness to this drug. Such results raise several important considerations. First, could an actual improvement in overall survival be mitigated by a crossover effect? In the case of glioblastoma this possibility seems unlikely as overall survival in the patients assigned to receive placebo in the RTOG 0825 trial—who were allowed to cross-over to bevacizu mab on disease recurrence—was at most 1.5 months longer than the overall survival observed in patients treated with temozolomide chemoradiotherapy before bevacizumab availability.7 Second, could the PFS benefit simply be a ‘smoke and mirror’ effect due to vascular permeability changes that result in misleading imaging response assessment? On the basis of this concern, the RANO criteria were implemented to improve response assessment. 8 Importantly, even after incorporating these more stringent criteria, bevacizumab was 244 | MAY 2014 | VOLUME 11
associated with an unprecedented PFS‑6 rate among patients with recurrent glioblastoma.1 In addition, many patients also noted improved neurological deficits as well as diminished dependence on chronic corticosteroid use, all of which support an important beneficial effect of bevacizu mab that cannot otherwise be currently attained for these patients and cannot be overlooked, despite the failure of this agent to improve overall survival. Third, why are some tumours less dependent on VEGF signalling? Angiogenesis, driven by markedly elevated VEGF levels, is striking among glioblastomas. In fact, vascular proliferation is a histopathological requisite to diagnose glioblastoma. Nonetheless, glioblastoma exhibits several features that portend adaptation to VEGF inhibition. Glioblastoma is a markedly complex malignancy with multiple dysregulated cell signalling pathways activated within any given tumour.9 Blockade of one key pathway might simply be bypassed by the activation of another pathway. Glio blastomas also express a myriad of proangiogenic growth factors, many of which can be upregulated following VEGF blockade. 10 Furthermore, unlike nearly every other aggressive cancer, glioblastoma does not metastasize systemically and the explanation for this atypical behaviour remains a mystery. Instead, glioblastomas are inherently infiltrative and invasive, which may permit proliferation and growth, despite a blunted vascular supply as a consequence of VEGF inhibition. Glioblastoma is also known to thrive in hostile microenvironments characterized by hypoxia and ana erobic metabolism. These aggregate features of glioblastomas predict adaptive capabilities that could lead to resumed and possibly enhanced tumour growth following VEGF inhibition. Finally, a concern unique to brain cancers is whether tumour vasculature normalization might restore or tighten the existing blood–brain barrier and, therefore, further impede the delivery of potentially beneficial antitumour therapeutics. For patients with malignancies that position at either the responsive or insensitive ends of the benefit spectrum, the role of bevacizumab is clear, and it either appropriately integrates into standard therapy or is disregarded. Thus, bevacizumab seems likely to become an accepted therapy for patients with advanced cervical cancer. However, for tumours that align at an intermediate position on the responsiveness
spectrum, the role of bevacizumab is less clear and more challenging to establish. For patients with glioblastoma, a dearth of treatment options exist and innovative treatment strategies are desperately needed. Bevacizumab, despite its limitations, offers glioblastoma patients with progressive disease a reprieve, albeit not durable, from the unrelenting onslaught of neurological decline that characterizes this disease. Department of Medical Oncology, Center for Neuro-Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA (D.A.R., P. Y.W.). Correspondence to: D.A.R. [email protected] Competing interests D.A.R. has served as a consultant and receives honouraria from Amgen, Apogenix, EMD Serono, Genentech–Roche, Merck/Schering–Plough, Momenta Pharmaceuticals, Novartis and Stemline Therapeutics. P.Y.W. has served as a consultant and receives honouraria from Celldex, Genetech– Roche, Momenta Pharmaceuticals, Novartis and Sigma–Tau. 1.
Cohen, M. H. et al. FDA drug approval summary: bevacizumab (Avastin) as treatment of recurrent glioblastoma multiforme. Oncologist 14, 1131–1138 (2009). 2. Chinot, O. L. et al. Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma. N. Engl. J. Med. 370, 709–722 (2014). 3. Gilbert, M. R. et al. A randomized trial of bevacizumab for newly diagnosed glioblastoma. N. Engl. J. Med. 370, 699–708 (2014). 4. Tewari, K. S. et al. Improved survival with bevacizumab in advanced cervical cancer. N. Engl. J. Med. 370, 734–743 (2014). 5. Clere, N. et al. The human papillomavirus type 18 E6 oncoprotein induces vascular endothelial growth factor 121 (VEGF121) transcription from the promoter through a p53independent mechanism. Exp. Cell. Res. 313, 3239–3250 (2007). 6. Jain, R. K. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 307, 58–62 (2005). 7. Stupp, R. et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol. 10, 459–466 (2009). 8. Wen, P. Y. et al. Updated response assessment criteria for high-grade gliomas: response assessment in neuro-oncology working group. J. Clin. Oncol. 28, 1963–1972 (2010). 9. Cancer Genome Atlas Research Network. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455, 1061–1068 (2008). 10. Batchelor, T. T. et al. AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell 11, 83–95 (2007).
www.nature.com/nrclinonc © 2014 Macmillan Publishers Limited. All rights reserved
Further delineating bevacizumab’s response spectrum David A. Reardon and Patrick Y. Wen
The use of antiangiogenic drugs, such as bevacizumab, represents an appealing intervention against cancer. However, not all malignancies are equally responsive to such treatment. Recent trials demonstrate the efficacy of this drug for advanced-stage cervical cancer and, despite limitations, bevacizumab provides an important clinical respite for most patients with progressive glioblastoma. Reardon, D. A. & Wen, P. Y. Nat. Rev. Clin. Oncol. 11, 243–244 (2014); published online 8 April 2014; doi:10.1038/nrclinonc.2014.61
the AVAglio nor the RTOG 0825 trials were able to identify any subgroup of patients who were more likely to benefit from treatment with bevacizumab based on prospectively evaluated clinical and molecul ar biomarkers (including me thylguanine methyltransferase status).2,3
‘‘
…why are some tumours less dependent on VEGF signalling?
’’
Imp or t ant ly, b ot h studies e va luated quality of life (QOL). Intriguingly, although similar validated tools including the EORTC QLQ30 and BN20 surveys were used, discrepant findings were reported. Some patients assigned to the bevacizumab group in the RTOG 0825 trial noted worsened QOL scores compared with patients in the placebo arm; by contrast, patients assigned to receive bevacizumab in the AVAglio trial showed consistently improved QOL scores over the course of treatment compared to placebo recipients. The reason for such divergent outcome remains to be defined, but it might
be related to a less-sensitive approach for the detection of patients with disease progression in the RTOG 0825 trial as a result of assessing progression based solely on enhancing tumour. Neurocognitive testing, which was assessed in most patients in the RTOG 0825 trial, revealed some diminished cognitive function among those who received bevacizumab.3 However, further investigation on the impact of bevacizumab on QOL and cognition for this indication is required before any final conclusions can be drawn. At the same time that the results of the RTOG 0825 and AVAglio trials failed to report an improvement in overall survival for the addition of bevacizumab to the standard treatment regimen for glioblastoma, the results of the GOG 240 randomi zed phase III trial for advanced-stage cervical cancer were published. This trial reported a 3.7 month improvement in both overall survival and PFS for the addition of bevacizumab to chemotherapy (paclitaxel plus either cisplatin or topotecan) compared with chemot herapy alone. 4 In the GOG 240 trial, comparable QOL for both
piyagoon/iStock/Thinkstock
Single-agent bevacizumab—a humanized monoclonal antibody that targets VEGF to inhibit angiogenesis—received accelerated approval by the US FDA in 2009 for recurrent glioblastoma, based on results from two phase II studies reporting durable responses.1 AVAglio2 and RTOG 0825,3 two separate placebo-controlled, randomized, phase III studies, further evaluating the activity of bevacizumab for the treatment of glioblastoma in newly diagnosed patients, have recently been published. 2,3 These two studies shared significant similarities, including the use of standard temozolomide chemoradiotherapy and statistical designs powered for detecting significant differences for both overall survival and progression-free survival (PFS). However, the studies also had important differences. The RTOG 0825 trial excluded patients with a poor prognosis investigated by biopsy only, determined treatment response by assessment of enhancing tumour only (Macdonald criteria), and included a predefined cross-over at disease progression, so that patients informed on their cohort-assignment could decide to start or continue bevacizumab.3 By contrast, the AVAglio trial allowed biopsy-only patients to be enrolled, assessed both enhancing as well as non-enhancing tumours for response, and did not include a planned cross-over (although 30% of patients assigned to receive placebo ultimately received bevacizumab at disease progression).2 Nonetheless, both studies demonstrated remarkably similar results, including a 3–4 month improvement in PFS, but no overall survival benefit.2,3 Of note, neither NATURE REVIEWS | CLINICAL ONCOLOGY
VOLUME 11 | MAY 2014 | 243 © 2014 Macmillan Publishers Limited. All rights reserved
NEWS & VIEWS treatment arms and a non-statistical trend of fewer neurotoxic symptoms among bevacizumab recipients were noted. Overall, the results of these three hallmark studies align along a continuum of therapeutic benefit associated with bevacizumab across the cancer spectrum. On the basis of the GOG 240 trial, cervical cancer is comparable to colorectal cancer in terms of representing the more responsive end of the spectrum with robust increments in both PFS and overall survival. Such benefit indicates, most probably, a more critical dependence of these tumours on VEGF signalling. For cervical cancer, a direct link between the causative agent, human papillomavirus, and VEGF activation has been described.5 In addition, the GOG 240 trial also supports a possible vascul ar normalization role of bevaciz umab that may augment chemotherapy delivery.6
‘‘
…these … studies align along a continuum of therapeutic benefit associated with bevacizumab across the cancer spectrum
’’
The RTOG 0825 and AVAglio trials sugg est that glioblastoma has an inter mediate responsiveness to bevacizumab, hallmarked by a disproportionate improvement in PFS relative to overall survival. Therefore, glioblastoma aligns with nonsmall-cell lung, breast, renal, pancreatic, prostate and ovarian cancers in terms of its responsiveness to this drug. Such results raise several important considerations. First, could an actual improvement in overall survival be mitigated by a crossover effect? In the case of glioblastoma this possibility seems unlikely as overall survival in the patients assigned to receive placebo in the RTOG 0825 trial—who were allowed to cross-over to bevacizu mab on disease recurrence—was at most 1.5 months longer than the overall survival observed in patients treated with temozolomide chemoradiotherapy before bevacizumab availability.7 Second, could the PFS benefit simply be a ‘smoke and mirror’ effect due to vascular permeability changes that result in misleading imaging response assessment? On the basis of this concern, the RANO criteria were implemented to improve response assessment. 8 Importantly, even after incorporating these more stringent criteria, bevacizumab was 244 | MAY 2014 | VOLUME 11
associated with an unprecedented PFS‑6 rate among patients with recurrent glioblastoma.1 In addition, many patients also noted improved neurological deficits as well as diminished dependence on chronic corticosteroid use, all of which support an important beneficial effect of bevacizu mab that cannot otherwise be currently attained for these patients and cannot be overlooked, despite the failure of this agent to improve overall survival. Third, why are some tumours less dependent on VEGF signalling? Angiogenesis, driven by markedly elevated VEGF levels, is striking among glioblastomas. In fact, vascular proliferation is a histopathological requisite to diagnose glioblastoma. Nonetheless, glioblastoma exhibits several features that portend adaptation to VEGF inhibition. Glioblastoma is a markedly complex malignancy with multiple dysregulated cell signalling pathways activated within any given tumour.9 Blockade of one key pathway might simply be bypassed by the activation of another pathway. Glio blastomas also express a myriad of proangiogenic growth factors, many of which can be upregulated following VEGF blockade. 10 Furthermore, unlike nearly every other aggressive cancer, glioblastoma does not metastasize systemically and the explanation for this atypical behaviour remains a mystery. Instead, glioblastomas are inherently infiltrative and invasive, which may permit proliferation and growth, despite a blunted vascular supply as a consequence of VEGF inhibition. Glioblastoma is also known to thrive in hostile microenvironments characterized by hypoxia and ana erobic metabolism. These aggregate features of glioblastomas predict adaptive capabilities that could lead to resumed and possibly enhanced tumour growth following VEGF inhibition. Finally, a concern unique to brain cancers is whether tumour vasculature normalization might restore or tighten the existing blood–brain barrier and, therefore, further impede the delivery of potentially beneficial antitumour therapeutics. For patients with malignancies that position at either the responsive or insensitive ends of the benefit spectrum, the role of bevacizumab is clear, and it either appropriately integrates into standard therapy or is disregarded. Thus, bevacizumab seems likely to become an accepted therapy for patients with advanced cervical cancer. However, for tumours that align at an intermediate position on the responsiveness
spectrum, the role of bevacizumab is less clear and more challenging to establish. For patients with glioblastoma, a dearth of treatment options exist and innovative treatment strategies are desperately needed. Bevacizumab, despite its limitations, offers glioblastoma patients with progressive disease a reprieve, albeit not durable, from the unrelenting onslaught of neurological decline that characterizes this disease. Department of Medical Oncology, Center for Neuro-Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA (D.A.R., P. Y.W.). Correspondence to: D.A.R. [email protected] Competing interests D.A.R. has served as a consultant and receives honouraria from Amgen, Apogenix, EMD Serono, Genentech–Roche, Merck/Schering–Plough, Momenta Pharmaceuticals, Novartis and Stemline Therapeutics. P.Y.W. has served as a consultant and receives honouraria from Celldex, Genetech– Roche, Momenta Pharmaceuticals, Novartis and Sigma–Tau. 1.
Cohen, M. H. et al. FDA drug approval summary: bevacizumab (Avastin) as treatment of recurrent glioblastoma multiforme. Oncologist 14, 1131–1138 (2009). 2. Chinot, O. L. et al. Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma. N. Engl. J. Med. 370, 709–722 (2014). 3. Gilbert, M. R. et al. A randomized trial of bevacizumab for newly diagnosed glioblastoma. N. Engl. J. Med. 370, 699–708 (2014). 4. Tewari, K. S. et al. Improved survival with bevacizumab in advanced cervical cancer. N. Engl. J. Med. 370, 734–743 (2014). 5. Clere, N. et al. The human papillomavirus type 18 E6 oncoprotein induces vascular endothelial growth factor 121 (VEGF121) transcription from the promoter through a p53independent mechanism. Exp. Cell. Res. 313, 3239–3250 (2007). 6. Jain, R. K. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 307, 58–62 (2005). 7. Stupp, R. et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol. 10, 459–466 (2009). 8. Wen, P. Y. et al. Updated response assessment criteria for high-grade gliomas: response assessment in neuro-oncology working group. J. Clin. Oncol. 28, 1963–1972 (2010). 9. Cancer Genome Atlas Research Network. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455, 1061–1068 (2008). 10. Batchelor, T. T. et al. AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell 11, 83–95 (2007).
www.nature.com/nrclinonc © 2014 Macmillan Publishers Limited. All rights reserved
![[Response predictive biomarkers to targeted therapies in oncology].](/assets/img/hold.png)
