Carlson, Robert H.
CHICAGO—The experimental microtubule inhibitor eribulin increased median overall survival by about two and a half months compared with standard single-agent treatments or radiation in women with advanced breast cancer, a statistically significant increase reported here at the ASCO Annual Meeting.
Researchers in the Phase III EMBRACE (Eisai Metastatic Breast Cancer Study Assessing Physician’s Choice Versus Eribulin E7389) trial said the results—overall survival of 13.12 months vs 10.65 months—were notable in that no other single chemotherapy agent has shown a survival advantage in many years.
But Eric Winer, MD, Director of the Breast Oncology Center at Dana-Farber Cancer Institute and Professor of Medicine at Harvard Medical School, told the trial’s lead researcher during a news conference that some might think the improvement “didn’t look like a good, long time.”
Asked by Dr. Winer for his response, Christopher Twelves, MD, Professor of Clinical Cancer Pharmacology and Oncology and Head of the Clinical Cancer Research Group at the University of Leeds, said, “The key point for me, in terms of benefit, is that it is a statistically significant benefit in a situation where, to put it bluntly, we very rarely see this sort of improvement.”
Dr. Twelves presented his data on the trial of 762 patients in an oral session and the study was also one of several highlighted in a news conference on advances in treatment of breast cancer.
Most similar studies have used progression-free survival and sometimes response rate to look for evidence of clinical benefit, he noted.
Researchers have come to believe there are better surrogates of outcome than overall survival, “but in this current study we see that it is possible with an active drug to prolong overall survival, and that was our primary endpoint.”
Dr. Twelves switched the viewpoint to that of individual patients: “If and when the drug becomes available and we discuss treatment options with these women, there are women with heavily pretreated disease who remain relatively fit and are interested to pursue other options. Currently we don’t have strong evidence of other treatments we can offer to suggest which—if any—routine treatment is appropriate.
CHRISTOPHER TWELVES,...Image Tools
“What this study gives us is robust data that for eribulin we at least have a defined survival benefit.”
He agreed that the benefit may seem modest for those who still have decades to live—”But many women will have a major event [planned for] later on in the year, be it the wedding of a child or the birth of a grandchild [and thus then would have the extra time needed],” he said.
He recalled seeing a patient just recently who wanted to see her daughter turn four years old. “She talked quite openly that this was the last birthday she would see, but was very keen on being there,” he said.
Dr. Twelves said, “We cannot tell the regulators what to do, and neither can we tell our patients what to do, but at least we can give patients the information and help them make those choices.”
From a Sea Sponge
In the news conference, Dr. Winer did say that eribulin provides a new option for women with advanced breast cancer and might be combined with other agents in the future
Eribulin is a non-taxane microtubule dynamics inhibitor, derived from the Halichondria okadai sea sponge.
The randomized, open-label Phase III study compared women with heavily pretreated locally recurrent or metastatic breast cancer receiving eribulin with women receiving a treatment of their physician’s choice—meaning any single-agent chemotherapy, hormonal treatment, or biological therapy approved for the treatment of cancer, or palliative radiotherapy administered according to local practice.
Comparing eribulin with regimens of choice, he said, “reflects a real-world setting where a variety of agents are used to treat patients with advanced breast cancer.”
Subjects in the trial had received at least two (but no more than five) prior chemotherapy regimens, including a taxane and an anthracycline.
Among the 762 women in the trial, those receiving eribulin (508 patients) survived a median of 2.47 months longer than those in the comparator arm (254 patients)—13.12 months versus 10.65 months, respectively.
A secondary endpoint, overall response, statistically significantly improved. There was no statistically significant improvement in progression-free survival.
“Until now there hasn’t been a standard treatment for women with advanced breast cancer, and for those who have already received all of the recognized treatments, these are promising results,” Dr. Twelves said.
The median age of the study subjects was 55; 16% had HER2-positive disease and 19% were negative for estrogen, progesterone, and HER2 (triple negative).
The Grade 3/4 adverse effects of eribulin were asthenia in 7.6% of patients, neutropenia in 44.0%, and peripheral neuropathy in 8.4%.
The rate of treatment-emergent serious adverse events was reported equally for the two study arms, at 25% each.
Balancing Benefit & Risk
Dr. Twelves said side effects with eribulin were no more severe than those associated with the commonly used chemotherapies for advanced breast cancer, and that there had been no difference in overall toxicity rates and no serious advents that called for dose adjustments.
The side effect profiles were different, though: “In terms of physician’s choice of drug, side effects were generally consequences of the characteristics of the chemotherapy patients were to receive,” he said.
“For example, there was more myelosuppression with eribulin but a lower rate of neutropenic infection and complications,” he said. On the other hand, there was a higher incidence of neuropathy, as is the case with other microtubule inhibitors, but a break in treatment would resolve the neuropathy.
As in Phase I trials, he said, fatigue was seen in equal rates in both arms.
Dr. Winer asked Dr. Twelves to speculate about FDA approval, but Dr. Twelves said he could not as those decisions are quite complex. He did say, though, that there is reasonable chance this drug will be approved because there aren’t many drugs that show a survival advantage in this setting.
And it is a positive trial, he said, with a notable difference in survival.
Dr. Twelves added that this is a single agent, whereas with previously approved drugs, such as trastuzumab, the major benefits were in seen combination therapies.
“In my recollection, the last drug to show a survival benefit in metastatic breast cancer as a single agent was docetaxel, approved more than 10 years ago, and that was in less pretreated disease,” he said.
Targeted Therapy, Not More Chemotherapy
Eric Winer, MD, was asked at the ASCO news conference to speculate on whether the eribulin trial data were sufficient for Food and Drug Administration approval. He said there is a “reasonable chance” from a positive study showing a survival benefit in a patient population where there is no clear choice of therapy.
But then he said he was not sure that there are going to be many more chemotherapy agents approved in this era of targeted therapy.
“Eribulin may be one of the last. I just don’t think there is going to be much development of new chemotherapy agents in this setting.”
In an e-mail exchange after the meeting, Dr. Winer added “I may be wrong, but I just don’t see too many chemotherapy agents coming online, and it is not clear that we need many more chemotherapy agents approved for women with breast cancer.
“This is the era of targeted therapy, not more chemotherapy,” Dr. Winer said. “We have a number [of agents already], and a number to combine with other agents, and this may be one of the last.”
© 2010 Lippincott Williams & Wilkins, Inc.