A recent study with the controversial drug bevacizumab (Avastin, Genentech/Roche), provides evidence that this drug therapy increases survival in patients with glioblastoma (brain tumor). Bevacizumab is an angiogenesis inhibitor meaning it slows down the growth of new blood vessels. The study comprised of a population-based analysis found that patients with glioblastoma who died in 2010 had survived significantly longer that those who died in 2008 with glioblastoma. The U.S. Food and Drug Administration (FDA) approved bevacizumab for administration to glioblastoma patients prior to 2010.
Researchers report that the median survival was 8 months for patients who died in 2006, 7 months in 2008, and 9 months in 2010. Additionally, the difference in survival was highly significant between 2008 (pre-bevacizumab) and 2010 (post-bevacizumab). They also report that the survival difference was unlikely due to improvements in supportive care because there was no significant difference between those who died in 2006 versus patients who succumbed 2 years later in 2008 (P = .4440).
According to Derek Johnson, MD, lead author and neuro-oncologist at the Mayo Clinic Cancer Center, Rochester, Minnesota, “The controversy is not so much whether Avastin works, although there is fundamentally some question about that, but it has been very difficult to prove.”
The FDA granted accelerated approval for bevacizumab in May 2009 for use in patients with glioblastoma that had progressed despite previous therapy. This drug is also approved in Japan, but not in Europe, except for Switzerland and Rumania. According to Dr. Johnson, the clinical trials that led to bevacizumab’s approval did not include head-to-head comparisons with other drugs. “By definition, in that single arm design — without something to compare it to, we don’t know for a fact if we are extending life.”
Johnson and colleagues determined whether bevacizumab had an effect on survival in glioblastoma in the U.S. using the Surveillance, Epidemiology and End Results (SEER) Program, following the FDA approval for this indication. The researchers were able to identify 5607 glioblastoma patients in the SEER database who qualified for inclusion in survival analysis. The analysis came back with 1715 patients (30.6 percent) died in 2006, 1924 patients (34.3 percent) died in 2008 and 1968 patients (35.1 percent) died in 2010. The researchers report that there was no significant improvement in survival between 2006 and 2008 in any age subgroup. A significant difference in survival was observed between 2008 and 2010 in every age subgroup, except for patients aged 18 to 39 years. Furthermore, in this subgroup, the longest-lived 25 percent of these patients were alive 32 months or longer before dying in 2008.
In 2010, the longest-lived 25 percent were alive 41 months or longer before death. A log-rank test was used to find survival difference (P=.0342) which was statistically significant.
According to Johnson, “Admittedly, it is indirect proof that bevacizumab increased survival. We found that patients who died after the FDA approval of bevacizumab lived significantly longer than those who died before the FDA approval. It’s tough to quantify the exact improvement in survival because we are talking about large groups of people. But overall, our study found that at the population level, treatment strategies involving bevacizumab prolonged survival in patients with progressive glioblastoma”.
Johnson points out that there are certain subpopulations that accrued a good deal of benefit and there may be some populations that didn’t change survival much at all. This study does not pinpoint the group most likely to benefit from the drug. It does provide a broader level of support that life expectancy is improving.
Bevacizumab has also been investigated as a first-line therapy in patients with newly diagnosed glioblastoma, however, the results are not convincing. Two studies were discussed at this year’s annual meeting of the American Society of Clinical Oncology — The Radiation Therapy Oncology Group (RTOG) 0825 study and AVAglio. The results from both trials were not clear that bevacizumab prolonged survival.
Mark Gilbert, MD, principal investigator of the RTOG 0825 study and a professor of neuro-oncology at the University of Texas MD Anderson Cancer Center, Houston, remarks that the recent study suggesting a survival benefit is “interesting and compelling. The paper is absolutely in line with what many of us feel and what I have already suggested, in that bevacizumab is a useful agent for patients with glioblastoma. What they claim is the reason for improved survival was the approval of bevacizumab for second-line or salvage treatment.”
Gilbert points out the crossover design of the RTOG 0825 study made it unclear as to whether there was a benefit up front, or back end, or both. However, the results of the current study would argue that it is probably both. Gilbert goes on further to say, “However, given the extra toxicity, there is very little reason to use it as a first-line therapy”. Gilbert reports that in his own study, the RTOG 0825, there was no survival difference in the 2 arms of the study. “If there’s extra toxicity and there’s no difference if you use it earlier rather than later, then why not delay the toxicity until later — unless we can define a patient subpopulation either on the basis of a clinical or biomarker that would tell us if this is a group who would benefit from front-line therapy.” Gilbert also notes that when research is drawn from a database, “you see real-world experience” with an agent. A database includes patients who might have been excluded from a clinical trial because of their performance status. “But these patients are in the database, and they probably didn’t get bevacizumab,” Dr. Gilbert said. “So if you just imagine the subpopulation in the SEER database who did get bevacizumab, and even with all of the dilution of the impact, there still is a survival effect, and that makes it even more compelling — there is something therapeutic about it.”
According to Martin van den Bent, MD, PhD, professor of neuro-oncology at the Daniel Den Hoed Cancer Center, Erasmus University, in Rotterdam, the Netherlands, it is difficult to draw conclusions from these findings. “The SEER data, unfortunately, lack data on treatment, which is a major shortcoming of this manuscript. In general, even for treatments in which an overall survival benefit has been demonstrated, once introduced in everyday clinical practice, the benefit is often smaller.” He also notes that bevacizumab was not used in all patients in the database. The most likely recipients were those with recurrent disease. “So despite the probability that many patients were not exposed to bevacizumab, an overall survival benefit is suggested. This means that the overall survival benefit in those patients that were receiving bevacizumab must have been even larger. How does that fit in with the randomized trials that completely failed to observe an overall survival benefit?”
Bent comments that “for me, that is really hard to understand. Not even the BRAIN trial provided compelling evidence of an overall survival benefit”. The Brain trial (AVF3708) was one of the 2 trials which the FDA based its accelerated approval for recurrent glioblastoma. It is reported that although results demonstrated radiographically defined tumor response, they weren’t able to definitively show that the use of bevacizumab had positively affected patient survival. Bent added that there is crossover in randomized trials, which may have affected the overall survival analysis. “But in the absence of treatment data in the SEER database, this does not provide real evidence.”