The absence of any effective combinatorial therapy in patients progressing on bevacizumab and evidence supporting both continuation and discontinuation of bevacizumab in this setting remain important areas for additional clinical trial evaluation in order to better guide our therapeutic decision making in the clinic.
The review by Weathers and de Groot in this issue of ONCOLOGY provides a comprehensive overview of the development of antiangiogenic strategies targeting the vascular endothelial growth factor (VEGF) receptor and pathway in patients with glioblastoma, an almost uniformly fatal disease and a malignancy recognized to be among the most highly angiogenic solid tumors. The authors describe the reported clinical experience with VEGF blockade using bevacizumab, a recombinant humanized monoclonal antibody, and a subsequent generation of promiscuous small-molecule tyrosine kinase inhibitors that typically target multiple cellular pathways in addition to the VEGF-mediated angiogenic cascade. These include cediranib and cilengitide, which were the subject of negative phase III trials in patients with recurrent and newly diagnosed glioblastoma, respectively. Despite early optimism, targeting VEGF and angiogenesis in glioblastoma has not yielded the revolutionary outcomes expected when dramatic imaging improvement was observed following bevacizumab treatment in initial cohorts of patients with recurrent glioblastoma. However, the development of bevacizumab in patients with malignant brain tumors provides an opportunity to review some of the defining principles of drug development, particularly in this challenging group of tumors characterized by limited drug accessibility, variable imaging appearance, and changing clinical symptomatology based on the status of the blood-brain barrier.
The first lesson to be learned from the past decade of clinical trials with bevacizumab in glioblastoma is that empiric evidence is just that, and requires careful clinical trial validation with mechanistic correlatives to understand the reasons why a specific anticancer agent does or does not produce responses in defined subsets of patients. Dr. Stark-Vance’s seminal observation that the active combination of bevacizumab and irinotecan (emerging as an effective therapy for her patients with colorectal cancer) could produce dramatic and immediate symptom and imaging improvement in refractory glioblastoma patients initiated a cascade of clinical trials evaluating this combination in larger groups of patients with recurrent glioblastoma. Unfortunately, ample evidence at the time suggested that irinotecan and its active metabolites had limited blood-brain barrier penetration and minimal, if any, single-agent activity, and were also responsible for the frequent and often moderately severe gastrointestinal toxicity seen in treated patients.[5,6] Despite these data, and largely because of the accelerated approval of bevacizumab based on the results of a phase II study in which one non-comparative arm combined irinotecan and bevacizumab, irinotecan remains a recommended option in the National Comprehensive Cancer Network guidelines and is still frequently used in first-line combination with bevacizumab, likely yielding excessive toxicity and no additional benefit in already symptomatic patients with recurrent glioblastoma. Although countless patients have been significantly, and at least transiently, helped by having access to bevacizumab following its expedited approval and availability, the absence of a well-designed phase III trial and the statistically forbidden yet commonplace comparison of efficacy between arms of a non-comparative phase II study has slowed our recognition of the true benefits and limitations of bevacizumab in this patient population.
A second reality in the development of novel agents in oncology-and perhaps in life in general-is that if a result seems too good to be true, it often is. The dramatic clinical improvement over hours to days seen in selected patients treated with bevacizumab, eerily reminiscent of the outcomes typically seen following initiation of glucocorticoid therapy in symptomatic glioblastoma patients with intracranial edema and mass effect, could not have represented an immediate antitumor response similar to those seen in highly aggressive malignancies like small-cell lung cancer and Burkitt lymphoma. Not until the elegant correlative imaging and biomarker work of Batchelor and colleagues in their phase II study of cediranib (in which they clearly described the rapid vascular normalization effects of VEGF receptor pathway blockade) did we truly understand the mechanism of the early beneficial effects of bevacizumab and get hints about the potentially limited antitumor activity of this agent. Again, this steroid-like improvement of the disrupted blood-brain barrier and reduction in peritumoral edema and mass effect is a clinically important effect of bevacizumab, justifying its availability for selected highly symptomatic patients and/or those with large, contrast-enhancing tumors. It is critical, however, to distinguish these effects from true cytotoxic or cytostatic effects on tumor cells themselves as we seek to optimize single-agent and combinatorial strategies with bevacizumab.
Finally, in the absence of randomized clinical trial data, the effectiveness of a novel therapy in a specific subset of patients with cancer, such as recurrent glioblastoma, does not imply that those results can be generalized to the entire population of patients with that disease regardless of where they are in their disease trajectory. The rapid and vociferous declaration that the activity of bevacizumab in the recurrent setting justified, and even mandated, its widespread use in newly diagnosed patients in the absence of convincing clinical trial data resulted in wasted resources and potentially exposed patients to toxicity without providing benefit. Not until the publication of the rigorously conducted, prospective randomized Radiation Therapy Oncology Group (RTOG) 0825 and AVAglio trials of bevacizumab in newly diagnosed patients with glioblastoma did we appropriately understand that bevacizumab has clear but modest effects on progression-free survival in these patients, a result largely expected based on the drug’s transient vascular normalization resulting in imaging and symptom improvement. In addition, it had no effect on overall survival and controversial effects on quality of life and neurocognitive functioning.
Despite its limited effectiveness, evaluation of bevacizumab in neuro-oncology has resulted in dramatic improvements in imaging interpretation and left us with many new and important questions to address. The difficulty in interpreting the status of tumor in the face of the imaging changes induced by active VEGF agents has directly led to the development of the Response Assessment in Neuro-Oncology (RANO) criteria, an important standardization of our imaging analysis in clinical practice and in clinical trials of patients with malignant brain tumors. The observation of potential synergistic effects of bevacizumab on immunosuppression when combined with immune-based therapies is exciting and provides a rationale for investigation of combinatorial opportunities with the new immune modulators and checkpoint inhibitors entering the clinic. Of concern is the controversial data that suggest certain glioblastomas develop a more invasive phenotype following bevacizumab therapy, as well as the implications this could have on outcomes, treatment options, and symptomatology. Finally, the absence of any effective combinatorial therapy in patients progressing on bevacizumab and evidence supporting both continuation and discontinuation of bevacizumab in this setting remain important areas for additional clinical trial evaluation in order to better guide our therapeutic decision making in the clinic.
Financial Disclosure:The author has no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.
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