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Following the annual meeting of the American Society of Clinical Oncology (ASCO) CancerNetwork speaks with Dr. Kimberly Blackwell, professor of medicine and assistant professor of radiation oncology at Duke Cancer Institute at Duke University in Durham, North Carolina. Dr. Blackwell is involved in studying the angiogenesis process, and hormonal and neoadjuvant therapy for breast cancer, among other research topics, and is heavily involved in early- to late-stage clinical trials for breast cancer.
CancerNetwork: A lot of the excitement at ASCO this year was due to the data you presented of the results of the EMILIA trial showing that the antibody-drug conjugate trastuzumab(Drug information on trastuzumab) entansine (T-DM1) extended progression-free survival compared to standard of care in HER2-positive women previously treated for their metastatic breast cancer. Could you put these results in context for us? What does this mean for HER2-positive breast cancer patients?
Dr. Blackwell: First of all, thanks for letting me join you to discuss the EMILIA study and some of the other interesting things that happened at ASCO this year. I was lucky enough to be able to present the EMILIA study, which was a study of over 980 patients—a prospective, registration-intense phase III study of T-DM1 vs standard lapatinib and capecitabine(Drug information on capecitabine). These were patients that in the most practical terms were first-, second-, or third-line metastatic breast cancer patients, and all of the patients were required to have had a taxane as well as trastuzumab. A little over half the patients had seen over a year of trastuzumab, and the majority of the patients were receiving the treatment on study as a second- or third-line metastatic treatment. It was a global study with 213 centers, and between the two arms of the study the characteristics of both the patients and the disease were well matched. And as you alluded to, the primary endpoint of progression-free survival was met and the absolute improvement in median progression-free survival was about 3.2 months. Now that in itself is always very exciting. We also saw a not statistically significant improvement in overall survival. The hazard ratio was 0.62 with a P value of .0005. But because the survival analysis was an interim analysis, the P value had to be less than .0003 to reach statistical significance. And the absolute difference which was a planned analysis at 2 years was actually 18% absolute difference between those patients who received T-DM1, the new antibody-drug conjugate, vs the control arm, which was lapatinib and capecitabine.
So I think anytime we see a treatment option that improves outcome, people’s ears perk up and we all start thinking about when the drug becomes available, how we are going to use it. Probably the second most exciting finding in the EMILIA study was that the drug, which is a traditional cytotoxic known as DM1 and bound to trastuzumab, has very little toxicity associated with impact on quality of life and other measures such as grade 3 or greater adverse events. And this is a real proof-of-principle study in that it showed that if you can link a cytotoxin to an antibody and deliver it directly to the cancer cell, then the side effect profile will be quite favorable. We saw an 18% absolute difference in treatment discontinuation due to adverse events. It was higher in the control arm compared to the T-DM1 arm. If you look at the side effect profile of T-DM1, it is primarily lab-based abnormalities. We saw about 4% incidence of elevation in AST and ALT compared to 2% in the control arm and we saw about a 12% incidence of grade 3/4, thrombocytopenia. It is unclear what causes the thrombocytopenia, although a lot of people are looking at it. So in total we saw very mild liver toxicity, very mild thrombocytopenia. Compared to the known toxicities of lapatinib and capecitabine it was a very well-tolerated regimen. People are excited, even if they don’t take care of a lot of breast cancer patients, because of the proof of concept that maybe we could lessen the toxicity of chemotherapy by binding it to a tumor-directed antibody.
CancerNetwork: Sure, and as you said, both the safety and efficacy results of EMILIA were really exciting. When can we expect final overall survival data?
Dr. Blackwell: So, that is subject to much discussion and as was highlighted to me multiple times during the national meeting, it really goes back to, How positive does a trial have to be in order to get a drug approved in the United States and throughout the world? The planned overall survival analysis is meant to occur when 500 deaths have occurred but the median overall survival for the T-DM1 arm has actually not been reached compared to 23.3 months for the control arm. So if the event rate continues to parallel where the survival curves have gone it would not be until early 2014, although I think many people are very anxious to have this drug available to their patients, and so I wouldn’t be surprised if there were a lot of discussion about having additional survival analysis, but that remains to be seen.