Andrew D. Seidman, MD: Aditya, given Mark’s comment in the post-KATHERINE era, and maybe you can speak to those trial data, when you have a patient who has had trastuzumab emtansine [T-DM1], and hopefully you haven’t had too many of them yet, but undoubtedly, they will relapse. Does that make you think differently about first-line therapy? Do you think about variables like time to relapse? How do other trials like HER2CLIMB and DESTINY now make you revisit CLEOPATRA almost a decade later?

Aditya Bardia, MD, MPH: A good question. This is about a patient who’s had disease recurrence on adjuvant T-DM1?

Andrew D. Seidman, MD: Or 6 or 18 months later.

Aditya Bardia, MD, MPH: It’s different. In a patient who has had disease recurrence within 6 months of adjuvant T-DM1, I must see when the patient received THP [docetaxel, trastuzumab, pertuzumab]. Most likely the patient received neoadjuvant THPand then had residual disease and then got T-DM1. If it’s a year to 2 years after the neoadjuvant THP, you could recycle THP again, like the CLEOPATRA regimen. But if the disease-free interval is shorter, I would be a bit more wary of using THPagain, especially because we have other drugs. Trastuzumab deruxtecan [T-DXd] would be a very reasonable choice in that setting. It also depends on the disease burden. If the patient has disease recurrence and it’s predominantly in the brain and just some evidence of disease elsewhere, I would use tucatinib, which has shown evidence of disease control in the brain, along with trastuzumab and capecitabine.

Andrew D. Seidman, MD: Aditya, can you speak to the DESTINY trial, the study that was recently presented at ESMO [European Society for Medical Oncology meeting] that informed us about how these 2 antibody-drug conjugates [ADCs] compared to one another?

Aditya Bardia, MD, MPH: The DESTINY data series, it’s a number of DESTINY trials. It started with DESTINY-Breast01, which looked at trastuzumab deruxtecan as a single agent in heavily pretreated patients, and we saw impressive response rate of waterfall plot like we’d never seen before. That resulted in FDA-accelerated approval of trastuzumab deruxtecan for patients with pretreated metastatic HER2-positivebreast cancer. At ESMO this year, we saw the results of DESTINY-Breast03. This was a traditional randomized phase 3 trial. More than 500 patients were randomized to receive T-DM1 versus trastuzumab deruxtecan. It was in the second-line setting similar to the EMILIA trial where T-DXd was the study therapy and T-DM1 was the control group. The study was positive, and the results were very impressive. The median progression-free survival with T-DM1 was about 6 months. Very similar to what we’re seeing in EMELIA, but the median progression-free survival with trastuzumab deruxtecan was not reached in the trial. As per investigator assessment, the median progression-free survival was 25.1 months. There was a more than 4-fold improvement in median progression-free survival. This corresponded to a hazard ratio of 0.28, something we’ve never seen before in this setting. There’s also a trend toward improvement in overall survival.

In terms of response rate, it was, again, higher with trastuzumab deruxtecan, 79.1%. That’s close to 80%. Out of every 5 patients who were enrolled, 4 of them had an objective response rate compared to 34.2% with T-DM1. There was clear evidence of activity that was much superior to T-DM1. In terms of adverse effects, an adverse effect that we were particularly nervous about was pneumonitis because in the original DESTINY-Breast01 study, there were treatment-related deaths because of pneumonitis with trastuzumab deruxtecan.

Andrew D. Seidman, MD: Aditya, I’m just going to ask Ruta to comment on that issue and the general issue about tolerability and safety and toxicity across this landscape. How much is this a driver of your decision-making in first and second-line therapy? Or how much are you driven by the Kaplan-Meier curves?

Ruta Rao, MD: To pick up where Aditya left off, we were particularly concerned about the risk of interstitial lung disease [ILD] in the DESTINY trial because of what we had seen in the earlier trial. But in the DESTINY-Breast03 trial, what they saw was that the percentage of ILD that occurred in the patients who received trastuzumab deruxtecan was 10.5%, and most of those, or 9.7%, were grade 1 and 2, and there were no deaths from ILD in this trial. This is compared to 1.9% of ILD seen in the patients who received T-DM1. From a toxicity standpoint, we can see that ILD was still there, but not concerning at the same level as we had seen in the previous trastuzumab deruxtecan trial.

Andrew D. Seidman, MD: I know we’re going to get to some of these in a more granular way as we go through some of the cases, and the audience will let us know how they feel, but any thoughts? Aditya maybe I can come back to you just before we get into another toxicity, which is potentially gastrointestinal. Maybe you can review the HER2CLIMB study design and results for us, and then I can bring it back to Ruta before we get to our first interactive case.

Aditya Bardia, MD, MPH: Absolutely. The other drug that merits discussion is tucatinib, and it was approved based on the results of HER2CLIMB. This was a randomized, double-blind placebo-controlled trial, about 600 patients with metastatic HER2+ breast cancer randomized to receive trastuzumab along with capecitabine or placebo versus trastuzumab, capecitabine, tucatinib, a HER2TKI [tyrosine kinase inhibitor]. The difference between tucatinib and other TKIs like neratinib is that it does not impact the other HER family like EGFR or HER3. The incidence of adverse effects like rash or severe diarrhea is much lower. The trial was positive. It was initially presented at a San Antonio Breast Cancer Symposium, and then there was an update earlier this year at ASCO [American Society of Clinical Oncology annual meeting]. Essentially the study showed that patients who received tucatinib had an improvement in progression-free survival, as well as overall survival. The updated results showed that the median overall survival in patients who received tucatinib was 24 months, about 2 years, as opposed to 19 months, a year and a half, in the placebo arm. There were clear improvements in progression-free survival and overall survival. What was also impressive about the HER2CLIMB trial was that it allowed patients who had stable or progressive brain metastasis. In that subgroup, you could clearly see an improvement in disease control in the brain, as well as extracranially, with tucatinib. This has led many of us to consider this drug, particularly in patients who have brain metastasis. In terms of adverse effects, diarrhea was the No. 1 adverse effect that was seen because they’re combining tucatinib plus capecitabine, being both agents that can cause diarrhea.

Andrew D. Seidman, MD: We don’t have direct head-to-head comparisons, and I’m not sure if we ever will, comparing the HER2CLIMB regimen to either ADC. Ruta, conceivably you might choose either in a certain circumstance. Does the toxicity profile and your ability to manage it become a factor? How do you parse the difference between using Cape [capecitabine], tucatinib, and trastuzumab versus trastuzumab deruxtecan, for example, or trastuzumab emtansine?

Ruta Rao, MD: The adverse effect profile becomes very important when we’re choosing our next regimen for our patients. Just as Aditya was saying, diarrhea was the most common adverse event in the HER2CLIMB trial, in both arms, but it was seen slightly higher in the patients who received the tucatinib-containing arm. In addition, in that trial, we did see patients with palmar-plantar erythrodysesthesia, or hand-foot syndrome, nausea, fatigue, and vomiting, and they also noticed some increase in the AST [aspartate aminotransferase], ALT [alanine aminotransferase], and fatigue. One of the important things is that in that trial, they did not use prophylaxis for diarrhea. One of the things we can do in our clinical practice is to obviously educate our patients about the risk of developing diarrhea, as well as using prophylaxis or being very early to start treatment once they develop diarrhea.

Transcript edited for clarity.