Welcome to The Breastcancer.org Podcast, the podcast that brings you the latest information on breast cancer research, treatments, side effects, and survivorship issues through expert interviews, as well as personal stories from people affected by breast cancer. Here’s your host, Breastcancer.org senior editor Jamie DePolo.
Jamie DePolo: Hello. Thanks for listening. I'm podcasting from the European Society for Medical Oncology 2023 Congress in Madrid, Spain. My guest is Dr. Aditya Bardia, associate professor of medicine at Harvard Medical School and attending physician at Massachusetts General Hospital. He also serves as the director of the Breast Cancer Research Program at Mass General.
At this conference, Dr. Bardia presented results from the TROPION-Breast01 trial, which is comparing a new antibody drug conjugate, datopotamab deruxtecan, called Dato-DXd for short, to doctor's choice of chemotherapy for inoperable or metastatic hormone receptor-positive, HER2-negative breast cancer that had grown while being treated with hormonal therapy, and also had been treated with chemotherapy. He's going to discuss the results with us. Dr. Bardia, welcome to the podcast.
Dr. Aditya Bardia: Thanks for having me. It's my pleasure to be here today.
Jamie DePolo: Great. So, Dato-DXd is an antibody drug conjugate. So, could you explain what an antibody drug conjugate is, just so everybody understands?
Dr. Aditya Bardia: Yeah. Absolutely. So, antibody drug conjugate, essentially, has two components. The first, it's an antibody that is linked with a payload via a linker, and the advantage with an antibody drug conjugate is you can deliver high doses of the payload to the cancer cells, while sparing the normal cells. So, it improves the efficacy of the agent while reducing the toxicity.
Jamie DePolo: And when you say payload, that's like the chemotherapy part of the drug? Is that right?
Dr. Aditya Bardia: That is exactly right. Often, it's like chemotherapy, including chemotherapy agents in the past that were discontinued because they were too toxic. But here, because the chemo is selectively delivered to cancer cells, it actually is better, because you can kill the cancer cells while reducing toxicity.
Jamie DePolo: Great. Now, I know Enhertu and Trodelvy are two other antibody drug conjugates that are used to treat breast cancer, and they've also been shown to be more effective than chemotherapy against certain types of metastatic breast cancer. So, is that kind of the way breast cancer treatment, or at least metastatic breast cancer treatment, is going? It seems like these antibody drug conjugates are...you know, there's becoming more of them, and they seem to be more effective than some of the chemotherapies we already have.
Dr. Aditya Bardia: That's exactly correct. So, we already have two antibody drug conjugates approved, and this is a third antibody drug conjugate that has shown good results, and it looks like that's the wave of the future, that these antibody drug conjugates will replace chemotherapy so we have a more effective and less toxic option.
Jamie DePolo: Okay. Could you summarize the study for us? What were you trying to see?
Dr. Aditya Bardia: The TROPION-Breast01 trial evaluated Dato-DXd for patients with endocrine-resistant metastatic breast cancer. So, usually, for patients with hormone receptor-positive, metastatic breast cancer, we use endocrine-based therapy first, but then, later on, patients have endocrine-resistant disease, and chemotherapy is widely used in this setting, but the concern with chemotherapy is that the effectiveness is not great.
And it can be associated with significant toxicity, like low [blood] counts, diarrhea. It can impact the nerves with painful neuropathy. So, there's a need for better agents in this setting. So, Dato-DXd was compared to standard chemotherapy of physician's choice for patients with endocrine-resistant metastatic breast cancer, and showed that there was an improvement in survival with Dato-DXd as well as reduced toxicity.
So, the progression-free survival, which essentially means that the duration that patients were able to remain on the drug without their disease increasing, was much better with Dato-DXd as compared to standard chemotherapy, and the rate of severe adverse events were about half with Dato-DXd as compared to standard chemotherapy. So, it was not only more effective, it was also less toxic, which is what we want with an antibody drug conjugate.
Jamie DePolo: Sure, and how long were the people in the study followed? I know this was a phase III trial. I'm just wondering how long the follow-up was.
Dr. Aditya Bardia: These are the first results that were presented. The follow-up, the median follow-up, was about 10 months. So, we need additional follow-up to look at overall survival, which will be presented in the future.
Jamie DePolo: Okay, and you mentioned the side effects were about half. What were the most common side effects caused by Dato-DXd?
Dr. Aditya Bardia: With Dato-DXd, the common side effects were mouth sores and dry eyes. With standard chemotherapy, the common side effects were decreases in the white cell count, which can then result in increased infection, and there was one death because of infection from standard chemotherapy.
Jamie DePolo: Okay. Well, that all sounds great, and I know Dato-DXd isn't approved yet, but it sounds like, with these results, that the company that makes it is going to apply for approval. That's what I would assume. So, going forward, how do doctors decide which of these three antibody drug conjugates to start with?
It's a two-part question.
And then what happens if someone does have the breast cancer grow, if they have progression, while they're on an antibody drug conjugate? Can they try another? I'm hoping you can put the results kind of in context for us for people who are diagnosed.
Dr. Aditya Bardia: Absolutely. So, to answer your first question, yes, the company plans to file for approval. These are the first results. When asked for their press release, they've officially announced that they plan to apply for approval for Dato-DXd for patients with endocrine-resistant, metastatic breast cancer, and if approved, you're exactly right. We'll have three agents in this setting, Trodelvy, Enhertu, and then Dato-DXd. So, it'll be a question of how do you select these agents? I think it'll boil down to both efficacy, but also toxicity profile.
Trodelvy is given day one, day eight, every 21 days. Side effects are low counts, diarrhea. Enhertu is given every three weeks. Common side effects are nausea, and sometimes can cause inflammation of the lungs, and Dato-DXd, the common side effects are mouth sores and dry eye, and it's given every three weeks. So, it'll be a factor of looking at convenience, a factor of the side effect profile, besides efficacy, that'll help physicians decide what to do.
To answer your second question, if a patient is on, say, Enhertu and then has disease progression, physicians, at this time, are already considering Trodelvy after that, because these antibody drug conjugates just appear to be better than chemo. So, if a patient has disease progression on Enhertu, I would rather use an antibody drug conjugate over standard chemotherapy in this setting. There are ongoing studies looking at these sequencing questions, but until we have results from those studies, I expect providers will just use ADC after ADC.
Jamie DePolo: Okay, and then one last question. I know you mentioned interstitial lung disease, and I know that can be a side effect of Enhertu. Is that also potentially a side effect of Dato-DXd, given that the payload or the deruxtecan is the same in both?
Dr. Aditya Bardia: The incidence was much lower, because drugs that target HER2, like Enhertu, tend to cause pneumonitis because there is HER2 expression in the lung tissue. The other drugs that target HER2, like T-DM1, have also been reported to cause pneumonitis. So, some of this is based on the expression of HER2 in the lung tissue, not necessarily because of the payload. In the TROPION-Breast01 trial, the incidence of pneumonitis was single digits, like 2%, 3%. So, it's not the same as what was seen with T-DXd. I think it's a combination of both the antibody and the payload.
Jamie DePolo: Okay. Dr. Bardia, thank you so much. This has been very helpful. I look forward to seeing what happens with Dato-DXd in the future.
Dr. Aditya Bardia: Yeah. Absolutely. No, thanks so much for having me. Good to discuss this with you, and it's exciting news for the field to have options for our patients with metastatic breast cancer.
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