Temozolomide in combination with radiation for newly diagnosed glioblastoma was approved by the U.S. Food and Drug Administration in 2005—almost 10 years ago—but we have unfortunately made little progress in improving survival for this incurable brain tumor. Despite recent completion of three large, randomized phase III trials, management of newly diagnosed glioblastoma remains a therapeutic challenge. Two of these recent trials, Radiation Therapy Oncology Group (RTOG) 0825 and AVAglio, randomly assigned patients with newly diagnosed glioblastoma to chemoradiation plus bevacizumab (Avastin) or placebo.1,2 Both studies failed to show improvement in overall survival in the bevacizumab-treated arm although AVAglio did show modest improvement in progression-free survival with bevacizumab.
The Need for ‘Smart’ Clinical Trials
The CENTRIC study, reported by Stupp and colleagues in The Lancet Oncology and reviewed in this issue of The ASCO Post, adds to the list of trials failing to impact overall survival.3 The therapeutic challenge that has emerged in the past 10 years is that the underlying heterogeneous biology of these tumors (eg, MGMT methylation status, IDH mutation status, and other unknown molecular markers) largely dictates individual tumor behavior and our current drugs are doing little to affect this biology.
In an effort to more narrowly define the molecular characteristics of glioblastoma, CENTRIC was performed in patients with MGMT methylation, a marker thought to be both prognostic and predictive of response to temozolomide. The study confirmed the prognostic significance of this marker: Patients experienced a median overall survival of 23.6 months, which was similar to the 21.7 months of the MGMT-methylated cohort in the original European Organization for Research and Treatment of Cancer (EORTC)/National Cancer Institute of Canada (NCIC) trial of radiation and temozolomide (and better than the 14.6 months reported in the unselected patients).4
Unfortunately, though, the results of CENTRIC, RTOG 0825, and AVAglio suggest we have done little to deflect the survival curve of specific tumor subtypes by adding additional drugs. As our knowledge of the heterogeneity of tumor molecular make-up increases, we will be increasingly challenged to design “smart” clinical trials that more selectively target specific tumor subtypes—the elusive holy grail of personalized medicine.
What Can We Learn From CENTRIC?
Perhaps the most useful lesson learned from CENTRIC was the feasibility of timely central tumor tissue analysis. The authors were able to assess an impressive 3,060 tumor samples from 146 study sites in 25 countries without significant delay in starting chemoradiation after surgery. This ability to rapidly collect and process tissue suggests that we may be able to design those smart, targeted-agent clinic trials in a multicenter setting. Given the likelihood of increasingly smaller samples sizes as we hone down tumor subtypes, multicenter collaborative trials will be critically important. CENTRIC demonstrated that this process is feasible, but what we need now are better drugs and a better understanding of why drugs did or did not work in individual patients so we can move the field beyond radiation and temozolomide.
Disappointingly, there appeared to be strong biologic rationale for adding cilengitide, an αvβ3 and αvβ5 integrin inhibitor, to chemoradiation in this setting. Preclinical models showed that αvβ3 and αvβ5 integrins were expressed on glioma and endothelial cells and that integrins were important in multiple cell survival processes: proliferation, migration, angiogenesis—all key cancer targets.5-7 There was even evidence of possible synergy between cilengitide and radiation.8 Phase I and II trials had suggested improvement in survival compared to historical controls.9,10 Nevertheless, despite these promising early results, CENTRIC failed to improve survival.
Similar strong biologic rationale and promising early clinical trial data preceded the failed RTOG 0825 and AVAglio trials, raising the question of how can we improve the likelihood of success. One proposal has been randomized phase II trials, but these can be unpalatable to patients facing an incurable disease when there is a placebo or control arm.
Thus, more innovative work needs to be done to clarify the biologic impact of tumor molecular subtypes and making sure the drug matches the molecular subtype. Increasingly, phase I and II trials are focusing on highly selected tumor populations, which may help address this issue. In addition, to the extent possible, correlative studies of tissue, blood markers, or imaging markers of response that help elucidate the biological mechanism of tumor response to treatment are needed. If patients are going to participate in a trial, we should hopefully learn as much as possible from their commitment. Of course, all of this comes with additional cost.
In summary, there have been several recent disappointments for patients and health-care providers caring for glioblastoma patients. Nevertheless, with each failure, we hopefully can still take a half step forward. For example, can the 3,060 glioblastoma samples collected in CENTRIC become a tissue repository to help clarify tumor heterogeneity and associated response to therapy or survival? Ultimately, we need better drugs and this will require a better understanding of the complexity of glioblastoma pathophysiology. ■
Disclosure: Dr. Gerstner reported no potential conflicts of interest.
References
1. Gilbert MR, Sulman EP, Mehta MP: Bevacizumab for newly diagnosed glioblastoma. N Engl J Med 370:2048-2049, 2014.
2. Chinot OL, Wick W, Mason W, et al: Bevacizumab plus radiotherapy–temozolomide for newly diagnosed glioblastoma. N Engl J Med 370:709-722, 2014.
3. Stupp R, Hegi ME, Gorlia T, et al: Cilengitide combined with standard treatment for patients with newly diagnosed glioblastoma with methylated MGMT promoter (CENTRIC EORTC 26071-22072 study): A multicentre, randomised, open-label, phase 3 trial. Lancet Oncol 15:1100-1108, 2014.
4. Hegi ME, Diserens AC, Gorlia T, et al: MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 352:997-1003, 2005.
5. Bello L, Francolini M, Marthyn P, et al: Alpha(v)beta3 and alpha(v)beta5 integrin expression in glioma periphery. Neurosurgery 49:380-389, 2001.
6. Roth P, Silginer M, Goodman SL, et al: Integrin control of the transforming growth factor-beta pathway in glioblastoma. Brain 136:564-576, 2013.
7. Schnell O, Krebs B, Wagner E, et al: Expression of integrin alphavbeta3 in gliomas correlates with tumor grade and is not restricted to tumor vasculature. Brain Pathol 18:378-386, 2008.
8. Mikkelsen T, Brodie C, Finniss S, et al: Radiation sensitization of glioblastoma by cilengitide has unanticipated schedule-dependency. Int J Cancer 124:2719-2727, 2009.
9. Stupp R, Hegi ME, Neyns B, et al: Phase I/IIa study of cilengitide and temozolomide with concomitant radiotherapy followed by cilengitide and temozolomide maintenance therapy in patients with newly diagnosed glioblastoma. J Clin Oncol 2010;28:2712-2718.
10. Nabors LB, Mikkelsen T, Hegi ME, et al: A safety run-in and randomized phase 2 study of cilengitide combined with chemoradiation for newly diagnosed glioblastoma (NABTT 0306). Cancer 118:5601-5607, 2012.
Dr. Gerstner is a member of the Department of Neurology, Massachusetts General Hospital Cancer Center, Boston.
