CHICAGO -- Progression-free survival may not be a good surrogate endpoint in metastatic breast cancer, FDA researchers warned.
At best, progression-free survival appeared to be a weak predictor of overall survival, reported Patricia Cortazar, MD, of the FDA's Division of Drug Oncology Products in Silverspring, Md., and colleagues, at the American Society of Clinical Oncology meeting.
Pooled analysis of 14 trials submitted to support drug approvals in metastatic breast cancer turned up no significant association between the two endpoints overall.
The softer progression-free survival explained just 6.7% of the effect on overall survival, which Cortazar called "problematic" in an interview with MedPage Today.
"This is not new," she noted. "We've been telling people to power their trials for overall survival."
The disconnect between progression-free survival and overall survival may have been one reason why bevacizumab (Avastin) obtained, and then lost, its indication for metastatic breast cancer.
The FDA initially granted the drug special, fast-track approval in metastatic breast cancer, based on results from a trial that showed a doubling in progression-free survival for bevacizumab plus paclitaxel (Taxol) versus paclitaxel alone.
But none of the subsequent trials could show an overall survival benefit, and the progression-free survival benefits were no better than modest either. The FDA moved to revoke the indication in late 2010.
Although drugmaker Genentech has appealed the FDA's decision, the latter was seen as a signal that the agency will increasingly expect overall survival results in the drug approval process.
Cortazar had no comment on the matter of bevacizumab. She also noted that any future decision by the agency regarding acceptance of progression-free survival data to support new drug approval would have to be made internally.
But leading breast cancer specialist Edith Perez, MD, of the Mayo Clinic in Jacksonville, Fla., suggested that bevacizumab may actually have tripped up the analysis.
The AVADO and RIBBON1 and RIBBON2 trials with bevacizumab in metastatic breast cancer showed modest gains in progression-free survival of one to two months.
Those "absolute changes in progression-free survival may have been so small that they would not have been expected to lead to an improvement in overall survival," Perez warned in an interview with MedPage Today.
Another problem was that many of the patients received one or more other therapies after the study drug that may have impacted survival, she noted.
An analysis limited to studies that showed at least a four-month improvement in progression-free survival over the control group may have had a better shot at showing a difference if there were one, Perez suggested.
However, Perez cautioned that it is too early to give up on progression-free survival as an endpoint. Rather, the message is that a statistically significant progression-free survival advantage is not necessarily a clinically meaningful one, she said.
Cortazar's analysis included only metastatic breast cancer trials that led to new drug approvals, or that were presented to an FDA advisory committee or at another public meeting.
Among the 9,819 patients in the 14 trials, none of the subgroup analyses by hormone receptor, HER2 status, and number of prior lines of therapy showed a significant link between progression-free survival and overall survival.
The only such association was among patients with triple-negative tumors without estrogen, progesterone, or HER2 overexpression, a group for whom progression-free survival appeared to explain 39.9% of the variance in overall survival (R2=0.399, 95% confidence interval 0.132 to 0.666).
"This finding will be further evaluated," Cortazar's group noted in the overall survival presentation.
At best, progression-free survival appeared to be a weak predictor of overall survival, reported Patricia Cortazar, MD, of the FDA's Division of Drug Oncology Products in Silverspring, Md., and colleagues, at the American Society of Clinical Oncology meeting.
Pooled analysis of 14 trials submitted to support drug approvals in metastatic breast cancer turned up no significant association between the two endpoints overall.
The softer progression-free survival explained just 6.7% of the effect on overall survival, which Cortazar called "problematic" in an interview with MedPage Today.
"This is not new," she noted. "We've been telling people to power their trials for overall survival."
The disconnect between progression-free survival and overall survival may have been one reason why bevacizumab (Avastin) obtained, and then lost, its indication for metastatic breast cancer.
The FDA initially granted the drug special, fast-track approval in metastatic breast cancer, based on results from a trial that showed a doubling in progression-free survival for bevacizumab plus paclitaxel (Taxol) versus paclitaxel alone.
But none of the subsequent trials could show an overall survival benefit, and the progression-free survival benefits were no better than modest either. The FDA moved to revoke the indication in late 2010.
Although drugmaker Genentech has appealed the FDA's decision, the latter was seen as a signal that the agency will increasingly expect overall survival results in the drug approval process.
Cortazar had no comment on the matter of bevacizumab. She also noted that any future decision by the agency regarding acceptance of progression-free survival data to support new drug approval would have to be made internally.
But leading breast cancer specialist Edith Perez, MD, of the Mayo Clinic in Jacksonville, Fla., suggested that bevacizumab may actually have tripped up the analysis.
The AVADO and RIBBON1 and RIBBON2 trials with bevacizumab in metastatic breast cancer showed modest gains in progression-free survival of one to two months.
Those "absolute changes in progression-free survival may have been so small that they would not have been expected to lead to an improvement in overall survival," Perez warned in an interview with MedPage Today.
Another problem was that many of the patients received one or more other therapies after the study drug that may have impacted survival, she noted.
An analysis limited to studies that showed at least a four-month improvement in progression-free survival over the control group may have had a better shot at showing a difference if there were one, Perez suggested.
However, Perez cautioned that it is too early to give up on progression-free survival as an endpoint. Rather, the message is that a statistically significant progression-free survival advantage is not necessarily a clinically meaningful one, she said.
Cortazar's analysis included only metastatic breast cancer trials that led to new drug approvals, or that were presented to an FDA advisory committee or at another public meeting.
Among the 9,819 patients in the 14 trials, none of the subgroup analyses by hormone receptor, HER2 status, and number of prior lines of therapy showed a significant link between progression-free survival and overall survival.
The only such association was among patients with triple-negative tumors without estrogen, progesterone, or HER2 overexpression, a group for whom progression-free survival appeared to explain 39.9% of the variance in overall survival (R2=0.399, 95% confidence interval 0.132 to 0.666).
"This finding will be further evaluated," Cortazar's group noted in the overall survival presentation.
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