Jamie DePolo: Hello. Thanks for listening. I’m podcasting at the 2022 San Antonio Breast Cancer Symposium. My guest is Dr. Sara Hurvitz, professor of medicine at the David Geffen School of Medicine at UCLA and the Jonsson Comprehensive Cancer Center. At the conference this morning, Dr. Hurvitz presented overall survival results from the DESTINY-Breast03 study, comparing Enhertu to Kadcyla as a second-line treatment for HER2-positive metastatic breast cancer. Earlier results from this study showed that Enhertu offered better progression-free survival than Kadcyla, but overall survival results were not ready at that first interim analysis. Dr. Hurvitz, welcome to the podcast.
Dr. Sara Hurvitz: Thank you so much for having me.
Jamie DePolo: So, could you just briefly summarize the study for us? What were you looking to find?
Dr. Sara Hurvitz: Absolutely. We evaluated, in a large phase III clinical trial, the activity, the clinical activity and safety of T-DXd compared to T-DM1. Prior to doing this trial, T-DM1 was the standard of care to give to a patient if their disease had grown after trastuzumab and a taxane, and we wanted to see if this new drug, T-DXd, was better than T-DM1. Our primary aim of this study was to look at whether we could extend how long patients could live with their disease under control, the progression-free survival, but a key secondary endpoint was looking at the overall survival, and as you mentioned, when we first looked at progression-free survival data and showed that stunning result where there was a real difference in favor of T-DXd, the overall survival data was not yet mature enough for us to call it a difference.
Jamie DePolo: Okay. Thank you, and now, based on these previous results on Enhertu or T-DXd, as it’s known by oncologists, that’s pretty much now the preferred second-line treatment for metastatic HER2-positive breast cancer, based on these results, correct?
Dr. Sara Hurvitz: Exactly. The progression-free survival benefits that were reported in September of 2021 were almost immediately practice-changing in regions of the world where Enhertu is available, there such a strong a benefit seen. Even though the overall survival was not met, the oncologists began immediately giving T-DXd to patients if their disease, or after their disease, had grown on a taxane and trastuzumab.
Jamie DePolo: Okay, and now, could you tell us about the latest results? I believe progression-free survival benefits continued, but you also have now the overall survival results?
Dr. Sara Hurvitz: Absolutely. The overall survival, at this first analysis, the first formal analysis, was significantly better in the patients treated with Enhertu. Now, we talk about medians. Median survival is when half the patients remain alive and half the patients do not. The median was not yet met in either treatment arms We don’t have a month number for patients in either arm.
However, when we look at the difference between the two survival curves, there is a 36% improvement in terms of survival associated with Enhertu. So, that’s statistically significant. There was a p-value that tested this, and yes, it does look like it’s actually very statistically significant. Moreover, the progression-free survival data were updated this time around, and the median progression-free survival for T-DXd, or Enhertu, was 28.8 months, compared to 6.8 months for T-DM1. That’s roughly four times better progression-free survival with T-DXd.
Jamie DePolo: Okay. Well, that all sounds really great, and I do want to ask about side effects, though, because quality of life is so important for people living with metastatic disease. So, I know that interstitial lung disease and pneumonia, they can be severe side effects of Enhertu, and in your presentation, you showed that the rate at your interim analysis, it was 10% for these type of lung problems. Now it’s up to 15%. I guess I have two questions. Do you think that’s going to get higher the longer...you know, as you get more data? And also, how do you kind of reassure people that, you know, may get this drug that it’s okay?
Dr. Sara Hurvitz: Great questions. Absolutely. It’s not a homerun for patients if patients are having significant toxicities or not feeling well on a therapy. Interstitial lung disease is the one life-threatening side effect that we’ve been monitoring really closely on all studies with Enhertu. In this particular trial, you’re right, we saw an increased rate of all levels of severity of ILD. Went from 10.5 up to 15.2% at this recording. However, no patients died from interstitial lung disease. There were no severe cases of interstitial lung disease, known as grade 4. There are no additional cases of grade 3, which is moderately severe. All of the additional cases were mild and reversible. And so, why are we seeing sort of better data than reported in other trials relating to Enhertu in terms of this side effect profile?
It may be that we, as investigators, have gotten much better at picking it up and managing it quickly. So, I tell my patients, you know, call me immediately if you have shortness of breath, cough, difficulty breathing at all, so that I can evaluate you. Because we would hold T-DXd out and actually completely discontinue it if ILD were found and a patient was symptomatic.
So, as a clinician, we continue to monitor the CAT scans, the CT scans of the lungs, fairly frequently for patients who are on T-DXd, because, often, the first sign of ILD is in somebody who has no symptoms whatsoever. We just see little infiltrates or shadow in the lungs of patients being treated with it, and if you withhold the therapy at that point, before symptoms develop, it will usually resolve. So, I think we’re getting better at managing it. It’s not a super common side effect, but it’s something that is very notable, because we don’t want it to get to the point where it’s severe or life threatening.
Jamie DePolo: Okay, and one last question. If you do catch the lung problems early like that, withhold Enhertu, can the person then restart on the medicine once those things have resolved, and is it likely to come back? Like, does it keep coming back each time?
Dr. Sara Hurvitz: If a patient has all the imaging findings of ILD, but no symptoms and their O2 [saturation] is normal, you can hold therapy and repeat the scan. Maybe give some steroids, and if the ILD findings on imaging go away, you can resume Enhertu. If the patient has any level of symptoms or findings on their clinical examination, like a low O2 [saturation], they should discontinue it permanently, and we do not re-challenge patients with it. There are clinical trials addressing whether we can safely re-challenge it, but I would never do that to a patient outside of the confines and careful monitoring of the trial setting.
Jamie DePolo: Okay. Dr. Hurvitz, thank you so much.
Dr. Sara Hurvitz: Thank you so much.
