Neuro-Oncology Neuro-Oncology 16(4), 469 –470, 2014 doi:10.1093/neuonc/nou036
“We will know it when we see it;” bevacizumab and glioblastoma Michael D. Prados, MD University of California San Francisco, Department of Neurological Surgery, Neuro-Oncology Service, 400 Parnassus, Room A-808, San Francisco, CA 94143-0372 ( [email protected]).
(PFS) and overall survival (OS). For the RTOG 0825 trial, the study was 80% powered to jointly detect a 25% reduction in hazard of death (2-sided P ¼ .046) and a 30% reduction in hazard of failure (2-sided P ¼ .004). For the AVAglio study, the study was 80% powered to detect a hazard ratio (HR) for progression of 0.77 (2 sided alpha of 1%), and a hazard ratio for overall survival of 0.80 (2 sided with overall alpha of 4%). In essence, the asymmetrically split significance in both studies was weighted towards overall survival, a traditional endpoint for phase-3 trials. Each trial had several secondary and exploratory endpoints, and imaging was assessed by investigators and in AVAglio, by central review. Neither study achieved an overall survival benefit. For the RTOG 0825 trial, median OS was 15.7 months versus 16.1 months comparing bevacizumab to placebo (P ¼ .21; HR 1.13). Median OS in the AVAglio trial was 16.8 months versus 16.7 months comparing bevacizumab to placebo (P ¼ .10; HR 0.88). Progression free survival was improved with bevacizumab in both studies. In AVAglio, median PFS was 10.6 months in the group receiving bevacizumab versus 6.2 months in the control group (P , .001; HR 0.64). In RTOG 0825, median PFS was improved with bevacizumab treatment (10.7 months versus 7.3 months in the control group; P ¼ .007; HR 0.79), but did not meet the pre-specified PFS endpoint and was not considered a “positive result”. In both trials, patients did “cross-over” to bevacizumab treatment at the time of progression. Within RTOG 0825, the crossover was pre-specified to bevacizumab alone or in combination with either temozolomide or irinotecan. Within the placebo group, protocol-related salvage occurred in 40.7% of patients, while in the bevacizumab arm only 20.9% received the regimens. Non-protocol therapy or no therapy also occurred in both arms. In AVAglio, additional treatment at the time of progression also occurred at the discretion of the treating physician. Within the intent to treat population 31% of patients received subsequent bevacizumab and 35.6% received further temozolomide. Arguably, within both of these studies and without a control group in the BRAIN trial, or a design to assess a survival benefit, it may not be completely clear if bevacizumab can improve overall survival. However, given the lack of an overall survival benefit within the context of RTOG 0825 and AVAglio trials, and no proof of survival in the BRAIN study, one then needs to assess whether there was any other clinically meaningful benefit to patients. In both studies, the rates of serious adverse events were more common with bevacizumab but no new toxicities were seen with either
# The Author(s) 2014. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: [email protected].
469
Downloaded from http://neuro-oncology.oxfordjournals.org/ at Kokusai Hoken Keikakugaku (UNIV OF TOKYO) on May 16, 2015
At a recent joint meeting on January 30, 2014 between stakeholders in the Neuro-Oncology community (clinical scientists, imaging experts, representatives from pharmaceutical and biotechnology companies, and philanthropy) and the Food and Drug Administration (FDA), discussing endpoints for clinical trials in recurrent glioblastoma, this phrase (“we will know it when we see it”) was used on several occasions. Either in a sense of hope or perhaps frustration with the lack of new agents in this disease, the comment reflected a sense by some in the meeting that imaging surrogates of tumor burden remain problematic, objective response remains elusive, landmark time to progression endpoints not validated, and neither of these endpoints are proven (yet) to be a true measure of efficacy for new therapies. There was general agreement that a sustained, durable, objective response could serve as a surrogate for preliminary approval of new agents, even in the context of a single arm study. This agreement assumed reliable, consistent and reproducible measures of “response” were standardized and could be used effectively in multi-institutional settings. Bevacizumab was given accelerated approval using an objective response measure, based upon a single, uncontrolled clinical trial (the BRAIN study), supported by results from a second independent study (1, 2). Confirmed and independently reviewed imaging responses, taking into account enhancing and T-2 /FLAIR sequences and steroid use, were seen in both studies at a much higher rate than historical controls. In full disclosure, I advocated for this indication at the FDA Oncology Drug Advisory Committee meeting, based upon the trial evidence, our own experience and that of others, and feeling that I really “knew it when I saw it.” Full approval by the FDA required confirmation in a larger randomized study. Two large, independent, well conducted and designed prospectively randomized, placebo controlled trials have now been reported testing whether the use of bevacizumab, when used in the up-front setting of newly diagnosed glioblastoma, has clinically meaningful benefit. The Avastin in Glioblastoma (AVAglio) study was sponsored by F. Hoffmann-La Roche, and randomized 921 patients from 120 sites in 23 countries (3). The Radiation Therapy Oncology Group (RTOG), with collaboration from the North Central Cancer Therapy Group (NCCTG) and the Eastern Cooperative Oncology Group (ECOG), randomized 637 patients from a total of 978 screened patients over a two year period in the United States and is designated as RTOG 0825 (4). Although there are differences in the actual design of the two studies, the co-primary endpoints in both studies included both progression free survival
Editorial
470
choose a progression free and objective response criteria, or consider toxicity and lack of survival benefit in making a choice. Rather than focus on the lack of survival in this patient population (we clearly are not there yet), one might actually focus harder on the fact that the use of this strategy can help some patients. The current list of the other FDA approved agents (carmustine, lomustine, temozolomide) offer little benefit, either progression free or overall survival in the majority of our patients. We clearly need more guidance on how to measure tumor burden, how to select patients, and how to rationally use any agent that seems to be, at least preliminarily, a biologically active agent, however one defines that term within Neuro-Oncology. We also need to be convinced that the process of selection of agents for future randomized trials, based upon single arm studies using objective response or progression-free outcome is the best path forward. Small sample size, early phase trials have merit, particularly in defining critical endpoints such as pharmacokinetic and pharmacodynamic endpoints. How to proceed to the next step, prior to a large randomized phase-3 trial may need some creative thought. Most of us feel that combinatory therapy will have a greater likelihood of success. How to move agents more quickly towards those types of studies need thoughtful discussion. Should different studies have been done prior to the decision to embark on these two large clinical trials? There has been considerable debate about these issues, and whether we are using our time, effort and increasingly scarce resources wisely. We need to spare patients treatments using potentially toxic agents that have a high likelihood of futility. It is gratifying that additional studies are ongoing, hopefully with more biologically-driven investigations that could support combination strategies within a more “precisely” chosen patient group. The need for effective therapies in glioblastoma, an incurable malignancy, is an unmet need. The Neuro-Oncology community needs to reach consensus about a strategic vision for all of the elements of clinical research, imaging, biomarkers, trial design, and prioritization. One hopes, with additional research, “we will know it when we see it”. Our patients deserve no less.
References 1.
Friedman HS, Prados MD, Wen PY, et al. Bevacizumab along and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol 2009; 27: 4733– 4740.
2.
Kreisl TN, Kim L, Moore K, et al. Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. J Clin Oncol 2009; 27: 740–745.
3.
Chinot OL, Wick W, Mason W, et al. Bevacizumab plus Radiotherapy-Temozolomide for Newly Diagnosed Glioblastoma. N Engl J Med 2014; 370: 709– 722.
4.
Gilbert MR, Dignam JJ, Armstrong TS, et al. A randomized trial of bevacizumab for newly diagnosed glioblasoma. N Engl J Med 2014; 370: 699–708.
Downloaded from http://neuro-oncology.oxfordjournals.org/ at Kokusai Hoken Keikakugaku (UNIV OF TOKYO) on May 16, 2015
temozolomide or bevacizumab. Both studies were careful to assess some measures of health related quality of life, and to some extent neurological function. In contrast to an increase in treatment-related toxicity in the AVAglio study, patients treated with bevacizumab achieved a significantly longer “deteriorationfree survival” as measured by 5 pre-specified measures (global health status, physical functioning, social functioning, motor dysfunction, and communication deficits). In addition, those patients had longer periods of time off steroids and longer period of time with a Karnofsky performance score of 70 or greater. In sharp distinction, the RTOG 0825 trial, using longitudinal measures of patient reported outcomes (MDASI-BT, EORTC QLQ30/BN20) and neurocognitive functioning found that patients treated with bevacizumab had significant worsening of these measures over time compared to placebo. Multiple subgroup analyses were performed without a clear message whether predictive biomarkers exist to aid clinicians in deciding whether to use this agent in the setting of newly diagnosed disease. In both studies the MGMT status, surgical status, KPS, age and RTOG recursive partitioning analysis class were not predictive of a benefit of bevacizumab for PFS or OS. The RTOG 0825 trial assessed a molecular signature using an expanded set of genes from previously published mesenchymal profiles which showed a potential relationship of that profile with OS for patients treated with bevacizumab compared to placebo. This is a preliminary correlative observation and needs prospective validation. So, we have studies showing what appears to be an increase in objective response rates that appears unique when bevacizumab is used in the relapse setting, but without proof of a survival benefit (which was not tested). The current studies appear to show a convincing and clear lack of a survival benefit in newly-diagnosed disease (albeit with the confounding of cross-over), but what appears to be a longer interval of progression-free survival, with less need for steroids. The trade-off is more toxicity, and there are conflicting results in terms of quality of life measures between the two trials. Neither study provides any evidence that a subgroup might benefit from the use of bevacizumab more than another. One wonders whether we really do “know what we are seeing.” Most of us in our daily practice use bevacizumab for our patients. Most of us have seen, in at least some patients, a dramatic reduction in both enhancement and T-2/FLAIR and a reduction in the need for steroids (a significant quality of life benefit). These patients appear to have a progression-free survival benefit that “may” be clinically meaningful. This experience is supported by the results of the BRAIN study in relapsed disease (1). “We know it when we see it.” Yet, there are other cases where this drug has minimal if any benefit, and has potential risks, some severe and long lasting. In addition, there is no proven evidence of a survival benefit, supported by the results of the currently reported trials. The discussion of risk/benefit ratio with our patients is clearly of issue; whether to use this agent at time of relapse or at the time of initial diagnosis, or not at all. Does one
“We will know it when we see it;” bevacizumab and glioblastoma Michael D. Prados, MD University of California San Francisco, Department of Neurological Surgery, Neuro-Oncology Service, 400 Parnassus, Room A-808, San Francisco, CA 94143-0372 ( [email protected]).
(PFS) and overall survival (OS). For the RTOG 0825 trial, the study was 80% powered to jointly detect a 25% reduction in hazard of death (2-sided P ¼ .046) and a 30% reduction in hazard of failure (2-sided P ¼ .004). For the AVAglio study, the study was 80% powered to detect a hazard ratio (HR) for progression of 0.77 (2 sided alpha of 1%), and a hazard ratio for overall survival of 0.80 (2 sided with overall alpha of 4%). In essence, the asymmetrically split significance in both studies was weighted towards overall survival, a traditional endpoint for phase-3 trials. Each trial had several secondary and exploratory endpoints, and imaging was assessed by investigators and in AVAglio, by central review. Neither study achieved an overall survival benefit. For the RTOG 0825 trial, median OS was 15.7 months versus 16.1 months comparing bevacizumab to placebo (P ¼ .21; HR 1.13). Median OS in the AVAglio trial was 16.8 months versus 16.7 months comparing bevacizumab to placebo (P ¼ .10; HR 0.88). Progression free survival was improved with bevacizumab in both studies. In AVAglio, median PFS was 10.6 months in the group receiving bevacizumab versus 6.2 months in the control group (P , .001; HR 0.64). In RTOG 0825, median PFS was improved with bevacizumab treatment (10.7 months versus 7.3 months in the control group; P ¼ .007; HR 0.79), but did not meet the pre-specified PFS endpoint and was not considered a “positive result”. In both trials, patients did “cross-over” to bevacizumab treatment at the time of progression. Within RTOG 0825, the crossover was pre-specified to bevacizumab alone or in combination with either temozolomide or irinotecan. Within the placebo group, protocol-related salvage occurred in 40.7% of patients, while in the bevacizumab arm only 20.9% received the regimens. Non-protocol therapy or no therapy also occurred in both arms. In AVAglio, additional treatment at the time of progression also occurred at the discretion of the treating physician. Within the intent to treat population 31% of patients received subsequent bevacizumab and 35.6% received further temozolomide. Arguably, within both of these studies and without a control group in the BRAIN trial, or a design to assess a survival benefit, it may not be completely clear if bevacizumab can improve overall survival. However, given the lack of an overall survival benefit within the context of RTOG 0825 and AVAglio trials, and no proof of survival in the BRAIN study, one then needs to assess whether there was any other clinically meaningful benefit to patients. In both studies, the rates of serious adverse events were more common with bevacizumab but no new toxicities were seen with either
# The Author(s) 2014. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: [email protected].
469
Downloaded from http://neuro-oncology.oxfordjournals.org/ at Kokusai Hoken Keikakugaku (UNIV OF TOKYO) on May 16, 2015
At a recent joint meeting on January 30, 2014 between stakeholders in the Neuro-Oncology community (clinical scientists, imaging experts, representatives from pharmaceutical and biotechnology companies, and philanthropy) and the Food and Drug Administration (FDA), discussing endpoints for clinical trials in recurrent glioblastoma, this phrase (“we will know it when we see it”) was used on several occasions. Either in a sense of hope or perhaps frustration with the lack of new agents in this disease, the comment reflected a sense by some in the meeting that imaging surrogates of tumor burden remain problematic, objective response remains elusive, landmark time to progression endpoints not validated, and neither of these endpoints are proven (yet) to be a true measure of efficacy for new therapies. There was general agreement that a sustained, durable, objective response could serve as a surrogate for preliminary approval of new agents, even in the context of a single arm study. This agreement assumed reliable, consistent and reproducible measures of “response” were standardized and could be used effectively in multi-institutional settings. Bevacizumab was given accelerated approval using an objective response measure, based upon a single, uncontrolled clinical trial (the BRAIN study), supported by results from a second independent study (1, 2). Confirmed and independently reviewed imaging responses, taking into account enhancing and T-2 /FLAIR sequences and steroid use, were seen in both studies at a much higher rate than historical controls. In full disclosure, I advocated for this indication at the FDA Oncology Drug Advisory Committee meeting, based upon the trial evidence, our own experience and that of others, and feeling that I really “knew it when I saw it.” Full approval by the FDA required confirmation in a larger randomized study. Two large, independent, well conducted and designed prospectively randomized, placebo controlled trials have now been reported testing whether the use of bevacizumab, when used in the up-front setting of newly diagnosed glioblastoma, has clinically meaningful benefit. The Avastin in Glioblastoma (AVAglio) study was sponsored by F. Hoffmann-La Roche, and randomized 921 patients from 120 sites in 23 countries (3). The Radiation Therapy Oncology Group (RTOG), with collaboration from the North Central Cancer Therapy Group (NCCTG) and the Eastern Cooperative Oncology Group (ECOG), randomized 637 patients from a total of 978 screened patients over a two year period in the United States and is designated as RTOG 0825 (4). Although there are differences in the actual design of the two studies, the co-primary endpoints in both studies included both progression free survival
Editorial
470
choose a progression free and objective response criteria, or consider toxicity and lack of survival benefit in making a choice. Rather than focus on the lack of survival in this patient population (we clearly are not there yet), one might actually focus harder on the fact that the use of this strategy can help some patients. The current list of the other FDA approved agents (carmustine, lomustine, temozolomide) offer little benefit, either progression free or overall survival in the majority of our patients. We clearly need more guidance on how to measure tumor burden, how to select patients, and how to rationally use any agent that seems to be, at least preliminarily, a biologically active agent, however one defines that term within Neuro-Oncology. We also need to be convinced that the process of selection of agents for future randomized trials, based upon single arm studies using objective response or progression-free outcome is the best path forward. Small sample size, early phase trials have merit, particularly in defining critical endpoints such as pharmacokinetic and pharmacodynamic endpoints. How to proceed to the next step, prior to a large randomized phase-3 trial may need some creative thought. Most of us feel that combinatory therapy will have a greater likelihood of success. How to move agents more quickly towards those types of studies need thoughtful discussion. Should different studies have been done prior to the decision to embark on these two large clinical trials? There has been considerable debate about these issues, and whether we are using our time, effort and increasingly scarce resources wisely. We need to spare patients treatments using potentially toxic agents that have a high likelihood of futility. It is gratifying that additional studies are ongoing, hopefully with more biologically-driven investigations that could support combination strategies within a more “precisely” chosen patient group. The need for effective therapies in glioblastoma, an incurable malignancy, is an unmet need. The Neuro-Oncology community needs to reach consensus about a strategic vision for all of the elements of clinical research, imaging, biomarkers, trial design, and prioritization. One hopes, with additional research, “we will know it when we see it”. Our patients deserve no less.
References 1.
Friedman HS, Prados MD, Wen PY, et al. Bevacizumab along and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol 2009; 27: 4733– 4740.
2.
Kreisl TN, Kim L, Moore K, et al. Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. J Clin Oncol 2009; 27: 740–745.
3.
Chinot OL, Wick W, Mason W, et al. Bevacizumab plus Radiotherapy-Temozolomide for Newly Diagnosed Glioblastoma. N Engl J Med 2014; 370: 709– 722.
4.
Gilbert MR, Dignam JJ, Armstrong TS, et al. A randomized trial of bevacizumab for newly diagnosed glioblasoma. N Engl J Med 2014; 370: 699–708.
Downloaded from http://neuro-oncology.oxfordjournals.org/ at Kokusai Hoken Keikakugaku (UNIV OF TOKYO) on May 16, 2015
temozolomide or bevacizumab. Both studies were careful to assess some measures of health related quality of life, and to some extent neurological function. In contrast to an increase in treatment-related toxicity in the AVAglio study, patients treated with bevacizumab achieved a significantly longer “deteriorationfree survival” as measured by 5 pre-specified measures (global health status, physical functioning, social functioning, motor dysfunction, and communication deficits). In addition, those patients had longer periods of time off steroids and longer period of time with a Karnofsky performance score of 70 or greater. In sharp distinction, the RTOG 0825 trial, using longitudinal measures of patient reported outcomes (MDASI-BT, EORTC QLQ30/BN20) and neurocognitive functioning found that patients treated with bevacizumab had significant worsening of these measures over time compared to placebo. Multiple subgroup analyses were performed without a clear message whether predictive biomarkers exist to aid clinicians in deciding whether to use this agent in the setting of newly diagnosed disease. In both studies the MGMT status, surgical status, KPS, age and RTOG recursive partitioning analysis class were not predictive of a benefit of bevacizumab for PFS or OS. The RTOG 0825 trial assessed a molecular signature using an expanded set of genes from previously published mesenchymal profiles which showed a potential relationship of that profile with OS for patients treated with bevacizumab compared to placebo. This is a preliminary correlative observation and needs prospective validation. So, we have studies showing what appears to be an increase in objective response rates that appears unique when bevacizumab is used in the relapse setting, but without proof of a survival benefit (which was not tested). The current studies appear to show a convincing and clear lack of a survival benefit in newly-diagnosed disease (albeit with the confounding of cross-over), but what appears to be a longer interval of progression-free survival, with less need for steroids. The trade-off is more toxicity, and there are conflicting results in terms of quality of life measures between the two trials. Neither study provides any evidence that a subgroup might benefit from the use of bevacizumab more than another. One wonders whether we really do “know what we are seeing.” Most of us in our daily practice use bevacizumab for our patients. Most of us have seen, in at least some patients, a dramatic reduction in both enhancement and T-2/FLAIR and a reduction in the need for steroids (a significant quality of life benefit). These patients appear to have a progression-free survival benefit that “may” be clinically meaningful. This experience is supported by the results of the BRAIN study in relapsed disease (1). “We know it when we see it.” Yet, there are other cases where this drug has minimal if any benefit, and has potential risks, some severe and long lasting. In addition, there is no proven evidence of a survival benefit, supported by the results of the currently reported trials. The discussion of risk/benefit ratio with our patients is clearly of issue; whether to use this agent at time of relapse or at the time of initial diagnosis, or not at all. Does one
