ASCO 2013: GBM Trials Bring Frustrating Answers and New Questions
By Anette Breindl
CHICAGO ‑ From a scientific perspective, at least, the RTOG 0825 and AVAglio studies were a terrific success: they suggested plenty of avenues for future research.
Clinicians, however, may be left scratching their heads about what the data mean for their patients. And so, in time, may the FDA.
Both RTOG 0825 and AVAglio are Phase III randomized controlled trials looking at the effects of Avastin, (bevacizumab, Genentech/ Roche) in patients with newly diagnosed glioblastoma multiforme. Both reported results at the annual meeting of the American Society for Clinical Oncology over the weekend.
In the big picture, RTOG 0825 and AVAglio had similar results. Neither study showed an effect on overall survival (OS) when Avastin was added to the standard of care. The RTOG 0825 study did identify a gene signature that appears to correlate with response to the drug, though its validity will have to be confirmed in an independent study.
The AVAglio study showed a statistically significant effect on progression-free survival (PFS). In the RTOG 0825 study, relapse was also delayed, but the data failed to reach the trial’s strict prespecified values for statistical significance.
A Sunday session put both studies into context with each other, as well as with other clinical and preclinical studies looking at antiangiogenesis therapy in brain cancer.
At that session, David Reardon from the Dana-Farber Cancer Institute pointed out that in a worst-case scenario, the data could jeopardize the access of glioblastoma patients to Avastin. Avastin received accelerated approval in glioblastoma in 2009 on the basis of imaging data.
The question now hinges on whether the increases in PFS, as well as other available data on softer endpoints such as quality of life, meet the bar for showing significant clinical benefit. Overall, the data seem to allow for possibilities from full approval to reversal of the accelerated approval.
In the case of metastatic breast cancer, the FDA revoked its accelerated approval due to lack of a survival benefit ‑ a decision that now has some clinicians worried that the same fate could befall the drug in glioblastoma.
When asked whether it was a realistic possibility that the FDA might yank Avastin’s approval in recurrent glioblastoma, John de Groot of MD Anderson Cancer Center was succinct. “I sure hope not,” he told BioWorld Today.
The situation for recurrent glioblastoma differs from that for metastatic breast cancer in important ways. Breast cancer patients, even those with metastatic disease, have more options than those with glioblastoma.
PFS also has a greater impact on brain cancer than breast cancer patients, because of the cramped quarters of the brain, progressive disease almost always has immediate effects on cognitive and motor functions. Other studies have shown that patients receiving Avastin are more likely to be able to live independently, and have less need for corticosteroid drugs.
Panel participant David Reardon highlighted the reduced need for steroid in his Sunday presentation. “My patients tell me they hate their steroids as much as they hate their disease,” he told the audience. A reduced need for corticosteroids alone “should have an important effect on the quality of life.”
The waters are further muddied by the fact that although RTOG 0825 and AVAglio agreed in their survival data, they were in striking disagreement about whether from a quality of life perspective, patients are better off receiving Avastin – or worse.
While the AVAglio study found that patients receiving Avastin had a better quality of life, the RTOG 0825 study found worse neurocognitive performance in patients receiving the drug than in those receiving placebo.
Several possibilities could account for the discrepancies. The simplest is that they are a statistical fluke.
But the two studies also used different methods to collect and analyze their quality of life or net clinical benefit data. And Reardon said that fact alone points to the need for the oncology community to reach consensus on the appropriate way to collect and analyze quality-of-life data.
“These [data] are too critical,” he said, “for us to not be able to analyze them effectively.”
See Tuesday's BioWorld Today for More on This Story.
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