Ian Krop, MD, PhD: Hello, I'm Ian Krop. I'm a medical oncologist and the Chief of Clinical Cancer Research at Yale Cancer Center.
Interviewer: Can you briefly summarize the results of DESTINY-BREAST02 that you’re presenting here at San Antonio?
Dr. Krop: The DESTINY-BreastO2 trial was designed as a confirmatory study of the previous DESTINY-Breast01 trial. So that was a study that showed that trastuzumab deruxtecan, which is an antibody drug conjugate against HER2, is very active in patients who had HER2-positive metastatic breast cancer that previously had progressed on T-DM1. That was a small phase two trial and so as a confirmatory trial, the DESTINY-Breast02 trial looked at the same patient population, HER2-positive patients with metastatic breast cancer that previously had been treated with T-DM1, and randomized them to either trastuzumab deruxtecan as a single agent or treatment of physicians' choice, which is in this trial was capecitabine with trastuzumab or capecitabine with lapatinib. And there were 400 patients enrolled on the TDX-d arm and 200 patients on the TPC arm. And the primary endpoint of the study was progression-free survival, but we also looked at overall survival as an important secondary endpoint.
Interviewer: How will these results, along with the results from DESTINY-Breast03 being presented in the same session, impact the use of trastuzumab deruxtecan in the clinic?
Dr. Krop: The results of the DESTINY-Breast02 trial, which we're presenting at San Antonio this year, show very clearly that trastuzumab deruxtecan, or TDX-d, is superior to the treatment of physicians’ choice regimens in terms of progression-free survival, which again was the primary endpoint. So there was a 64% reduction in the risk of progression or death with TDX-d compared to TPC. The median PFS was about 18 months with TDX-d versus seven months with TPC, and this benefit was seen across all of the usual subgroups, it was highly statistically significant. Overall survival also was statistically significantly improved with TDX-d. So about a 36% reduction... I'm sorry, 34% reduction in the risk of death with TDX-d. And that translated to a median improvement in survival of about 13 months with TDX-d compared to the control arm of chemotherapy, with HER2-directed therapy.
Things like response rate, clinical benefit rate also were highly improved with TDX-d compared to treatment of physicians’ choice. And the safety profile of TDX-d in this study, it was very similar to what we've seen in other studies. There were no new safety signals, nausea and vomiting were the most common adverse events, they tended to be low grade and manageable. But we do see, as with all TDX-d studies, the potential risk of interstitial lung disease or pneumonitis, and that was about 10% of patients in this trial in keeping with what we've seen in other studies, if not actually a little lower in this trial. Most of those were low grade events, but there were two patients, or 0.5%, who unfortunately did have fatal ILD felt to be related to the drug. So as with any TDX-d study, ILD remains an important potential risk and needs to be monitored when using this drug. So in terms of how these results factor in, especially in conjunction with the DESTINY-Breast03 results.
So again, the DESTINY-Breast02 study confirms the TDX-d is very active in patients who previously had T-DM1, so that's third or later line of treatment, but the DESTINY-Breast03 trial, which was presented last year and will be updated again this year at San Antonio, showed that TDX-d is actually far superior to T-DM1 in the second-line setting, and given the really dramatic improvements with TDX-d, very long progression-free survival and we'll have updated overall survival at this study... at this meeting, I think TDX-d remains the standard of care in the second line, and really for the vast majority of patients should be used in that second-line.
So the updated results of... or the results of the DESTINY-Breast02 trial, the third and later line trial, really don't impact clinical practice very much given that TDX-d should be used in the second-line for most patients. In the rare situation where we have a patient who's already received T-DM1 and hasn't received TDX-d, then the results from our study clearly show that TDX-d is active in that population. But again, that's going to be a small fraction of our HER2-positive metastatic patients, and in general, we should be using TDX-d in the second-line.
Interviewer: What’s next for TDX-d in HER2-positive disease? Are there future trial results that you’re looking forward to?
Dr. Krop: So given the efficacy of TDX-d and the third-line with the D-B02 trial and in the second line in the D-B03 trial, it's clear that this is a very active drug in HER2-positive breast cancer, and that's led to interest in expanding our exploration of the drug in other time points in a patient's journey with this disease. So there are trials going on in the first-line metastatic setting and I think most interestingly in early disease, there's a trial looking at TDX-d in patients who have residual disease after neoadjuvant therapy, we know that's a population who is at increased risk for recurrence. So that trial is randomizing patients to either TDX-d or T-DM1 to see if TDX-d is able to further reduce the risk of recurrence compared to T-DM1, and there are trials going on in the neoadjuvant setting as well. So I think we will soon, in the next few years, have really a bigger data set of TDX-d across really the whole spectrum of HER2-positive disease.
