The researchers found that bevacizumab did not improve overall survival. “Progression-free survival was prolonged but did not reach the prespecified improvement target,” the authors of that study wrote. Moreover, the researchers identified higher rates of neurocognitive decline, greater symptom severity, and declined health-related quality of life among patients who received bevacizumab compared with the placebo group.

In the last of the bevacizumab trials listed as reversals in the new analysis, 485 patients with supratentorial glioblastoma received intravenous bevacizumab and 463 patients received placebo every 2 weeks for 6 weeks, plus radiotherapy and oral temozolomide for 6 weeks.6 After a 4-week break, patients received maintenance bevacizumab or placebo for six 4-week cycles plus temozolomide for the first 5 days of each cycle, followed by bevacizumab monotherapy or placebo until the cancer progressed or unacceptable toxicity occurred.

The coprimary end points of that study were progression-free survival and overall survival. The results showed that bevacizumab improved progression-free survival but did not improve overall survival. Moreover, a greater proportion of patients in the bevacizumab group (66.8%) experienced grade 3 or higher adverse events compared with the placebo group (51.3%).

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But Michael Schulder, MD, vice chair of neurosurgery at North Shore University Hospital in Manhasset, New York and Long Island Jewish Medical Center in New Hyde Park, New York, who was not involved in any of the studies, does not think that the authors of the new analysis should have classified any of the above 3 trials as reversals, because bevacizumab in glioblastoma “never got remotely close to being a standard of care.”

For example, the new analysis “claims that the AVAglio study constituted a ‘reversal’ of treating patients with newly diagnosed glioblastoma using bevacizumab,” Dr Schulder said. “This statement is not quite correct, as such use of bevacizumab had never been considered part of the standard of care, nor was it routinely used. That study did in fact show some biological effect, in that time to progression was prolonged in the bevacizumab group.”

Dr Schulder noted that some neurooncologists choose to use bevacizumab in specific cases of glioblastoma. One example would be “a patient with a newly diagnosed glioblastoma who cannot have the majority of the tumor removed and who has symptoms from the large mass,” Dr Schulder said. In progressive glioblastoma, bevacizumab is usually used as the last line of treatment, he said.

The issue of bevacizumab approval for glioblastoma was recently mentioned in an invited commentary published in JAMA Internal Medicine.7 The authors of the commentary pointed to no improvement in overall survival and some other end points, as well as the significant differences in toxic effects between the 2 arms found in the confirmatory EORTC-26101 trial. “Nevertheless, the FDA approved bevacizumab for progressive glioblastoma,” the authors of the commentary wrote.7

References

  1. Herrera-Perez D, Haslam A, Crain T, et al. Meta-research: a comprehensive review of randomized clinical trials in three medical journals reveals 396 medical reversals. eLife. 2019;8:e45183.
  2. Genentech. FDA grants accelerated approval of Avastin for brain cancer (glioblastoma) that has progressed following prior therapy [press release]. Published May 5, 2009. Accessed June 25, 2019.
  3. Roche. FDA grants Genentech’s Avastin full approval for most aggressive form of brain cancer. Published December 6, 2017. Accessed June 25, 2019.
  4. Wick W, Gorlia T, Bendszus M, et al. Lomustine and bevacizumab in progressive glioblastoma. N Engl J Med. 2017; 377:1954-1963.
  5. Gilbert MR, Dignam JJ, Armstrong TS, et al. A randomized trial of bevacizumab for newly diagnosed glioblastoma. N Engl J Med. 2014;370:699-708.
  6. Chinot O, Wick W, Mason W, et al. Bevacizumab plus radiotherapy–temozolomide for newly diagnosed glioblastoma. N Engl J Med. 2014;370:709-722.
  7. DiMagno SSP, Glickman A, Emanuel EJ. Accelerated approval of cancer drugs—righting the ship of the US Food and Drug Administration [published online May 28, 2019]. JAMA Intern Med. doi: 10.1001/jamainternmed.2019.0584

Topics:

Brain Cancer Glioblastoma Head and Neck Cancer