This article is more than 5 years old. Information may no longer be current.
Failure of lomustine, bevacizumab for progressive glioblastoma likely to cause paradigm shift
Click Here to Manage Email Alerts
The addition of lomustine to bevacizumab failed to confer a survival advantage for the treatment of progressive glioblastoma in a phase 3 EORTC clinical trial, a finding that is likely to change research priorities for this disease.
“Wolfgang Wick, MD, and colleagues successfully answered a question that has plagued the neuro-oncology community for years,” Ashley L. Sumrall, MD, FACP, medical oncologist and section chief of neuro-oncology at Levine Cancer Institute of Carolinas HealthCare System and a HemOnc Today Editorial Board Member, who was not involved in the study, told HemOnc Today. “In this pivotal EORTC trial, the addition of bevacizumab [Avastin, Genentech] to lomustine [Gleostine, Corden] did not prolong survival for patients with progressive glioblastoma. This is the first phase 3 randomized controlled trial to demonstrate this finding.
“As enthusiasm for using bevacizumab to treat patients with glioblastoma has waned over the last few years, this may be the proverbial ‘nail in the coffin’ of this expensive therapy’s role in palliation,” Sumrall added.
Prior phase 2 trials demonstrated conflicting evidence regarding bevacizumab’s glucocorticoid-sparing effects, Sumrall said.
“For example, the BRAIN trial by Friedman and colleagues demonstrated a trend of decreased glucocorticoid usage among patients managed with bevacizumab,” she said. “This trial evaluated only 167 patients and noted that glucocorticoid-dependent patients required stable or lower doses while on bevacizumab. In EORTC 26101, researchers found no statistically significant benefit between use of glucocorticoids between the two arms.”
Results of the previous phase 2 BELOB trial suggested the combination of bevacizumab and lomustine improved survival for patients with progressive glioblastoma.
“The BELOB trial provided a noticeable survival signal, which prompted the EORTC 26101 phase 2 trial to be transformed into a full phase 3 study,” Wick, medical director of the department of neuro-oncology at Heidelberg University Hospital, told HemOnc Today. “BELOB demonstrated improved OS at 9 and 12 months for combined therapies using bevacizumab and lomustine vs. therapies based on either substance alone.”
©Philip Benjamin 2016
The EORTC trial expanded to a phase 3 trial to determine the safety and efficacy of the combination among a larger number of patients.
“Numerous questions arose after the release of the phase 2 trial data,” Sumrall said. “When the BELOB trial showed a trend of improved survival, researchers configured the EORTC trial into a phase 3 trial. The neuro-oncology community was excited again, thinking we almost had the answer to the elusive question of what constitutes optimal treatment for recurrent glioblastoma.”
Wick and colleagues randomly assigned 437 patients to a median of six treatment cycles with 10 mg/kg bevacizumab every 2 weeks plus 90 mg/m2 lomustine every 6 weeks (n = 288), or 110 mg/m2 lomustine alone every 6 weeks (n = 149).
If no adverse events higher than grade 1 occurred among the combination group in the first treatment cycle, lomustine dose increased to 110 mg/m2.
OS served as the primary endpoint. Secondary endpoints included PFS, landmark analyses for PFS and OS, toxicity, response rates according to the Response Assessment in Neuro-Oncology (RANO) criteria, clinical or neurologic deterioration-free survival, glucocorticoid use, and health-related quality of life of both patients and health care proxies, among others.
Researchers reported 329 (75.3%) OS events.
Locally assessed PFS was 2.7 months longer for patients in the combination group than for the monotherapy-treated group (4.2 months vs. 1.5 months; HR for progression or death = 0.49; 95% CI, 0.39-0.61).
Despite this, median OS was 9.1 months in the combination group and 8.6 months in the monotherapy group, an indication that the combination regimen did not provide an OS advantage over lomustine alone (HR for death = 0.95; 95% CI, 0.74-1.21).
Further, the combination regimen yielded no significant effects on health-related quality of life or neurocognitive function, the researchers noted.
In the combination group, 63.6% experienced grade 3 to grade 5 adverse events compared with 38.1% in the monotherapy group.
“We expected improved survival in this bevacizumab-based doublet but were incorrect in our assumptions,” Sumrall said. “The treatment conferred no improvement in neurocognitive functioning, amount of glucocorticoid requirement or OS.”
Bevacizumab may still be relevant for prolonging symptom-free survival, Wick said.
“In the United States, the 2009 approval [of bevacizumab] has led to the wide use of the compound at first progression,” he said. “In the European Union, bevacizumab is more commonly used in a palliative setting, rather than mainly with the intent to promote survival.
“In countries without approval, the drug is administered to improve symptoms and reduce steroid use,” he added. “Bevacizumab may still have uses in glioblastoma, but not as a means of prolonging OS.”
Still, almost two-thirds of patients on the combination therapy experienced grade 3 to grade 5 adverse events, Sumrall said.
“For a palliative-intent therapy, this therapy seems to cause more harm than good,” she said. “A paradigm shift is likely to follow.” – by Melinda Stevens
References:
Friedman HS, et al. J Clin Oncol. 2009;doi:10.1200/JCO.2008.19.8721.
Taal W, et al. Lancet Oncol. 2014;doi:10.1016/S1470-2045(14)70314-6.
Wick W, et al. J Clin Oncol. 2016;doi:10.1200/JCO.2016.34.15_suppl.2019.
Wick W, et al. N Engl J Med. 2017;doi:10.1056/NEJMoa1707358.
For more information:
Ashley L. Sumrall, MD, FACP, can be reached at Levine Cancer Institute, 1021 Morehead Medical Drive, Charlotte, NC 28204; email: ashley.sumrall@carolinashealthcare.org.
Wolfgang Wick, MD, can be reached at Neurology Clinic and National Center for Tumor Disease, University of Heidelberg and German Cancer Research Center, Im Neuenheimer Feld 400, D-69120 Heidelberg, Germany; email: wolfgang.wick@med.uni-heidelberg.de.
Disclosures: Sumrall reports financial relationships with AbbVie, Amgen and Novocure. Wick reports consultant roles with Bristol-Myers Squibb, Celldex Therapeutics and Merck Sharp & Dohme; lecture fees from Bristol-Myers Squibb; and grant support and drugs for the EORTC trial provided by Boehringer Ingelheim and Roche. Please see the full study for all other authors’ relevant financial disclosures.
Perspective
Back to Top
Stephanie E. Weiss, MD
There is no gold-standard treatment for recurrent glioblastoma. This trial compares outcomes for patients with recurrent glioblastoma who received a combination of commonly used second-line systemic agents lomustine and bevacizumab, against single-agent lomustine.
Lomustine is an alkylating chemotherapy. Bevacizumab — an antibody against vascular endothelial growth factor — is mechanistically distinct and works by pruning and renormalizing tumor-related neovasculature. The FDA approved bevacizumab for use in recurrent glioblastoma in 2009 based, in part, on findings from the BRAIN trial, in which bevacizumab appeared to be a relatively safe drug that produced responses resulting in a meaningful decrease in steroid use, and prolonged PFS. Despite great enthusiasm to study bevacizumab in newly diagnosed patients with glioblastoma, the results were disappointing.
The current trial looks at the safety and effectiveness of adding bevacizumab to lomustine. Importantly, the authors used RANO criteria to assess progression on imaging. Researchers also administered a battery of tests related to cognitive and functional well-being.
In spite of improved PFS with combined therapy, there was no survival difference between the study arms. This uncoupling of progression-free benefit from a survival benefit has been previously observed in an earlier trial of bevacizumab in newly diagnosed glioblastoma (RTOG 0825). However, in that study, researchers assessed response to therapy — and progression — with older and less nuanced imaging criteria that would miss increasing tumor infiltration even while the main mass appeared controlled. This also would explain the worse cognitive outcomes in the experimental arm despite the appearance of tumor control. This study used the more appropriate RANO criteria, designed to identify the nonenhancing, infiltrative progression more commonly seen among patients actively on bevacizumab. It is then particularly interesting that no neurocognitive benefit occurred with the use of bevacizumab, as the authors effectively assessed superior PFS — including infiltrating PFS — in that group.
Bevacizumab failed to demonstrate steroid-sparing effects, contrary to prior observations. Given the drug’s ability to restore the blood-brain barrier and suppress mass effect, it is frequently used among patients with glioblastoma and subtotal resection to facilitate a steroid taper and avoid their oft-debilitating side effects This is an important observation because severe — probably drug-specific — side effects were more common among the combined-therapy group.
Finally, the authors observed that their findings were contrary to those of the BELOB trial in which bevacizumab resulted in an OS benefit when added to lomustine. However, unlike the BELOB trial — where bevacizumab was not available off study and thus crossover to the drug was virtually unheard of in the control group — in the EORTC trial, more than 35% of patients on single-arm therapy went on to receive bevacizumab at progression. Thus, the lack of survival benefit may be due to effective salvage.
Reference:
Gilbert MR, et al. N Engl J Med. 2014;doi:10.1056/NEJMoa1308573.
Click Here to Manage Email Alerts