DS8201-a-U105 Trial of Trastuzumab Deruxtecan With Nivolumab in Patients With Urothelial Carcinoma – Matt Galsky
February 24, 2022
Matthew Galsky, MD, Director of Genitourinary Medical Oncology, Tisch Cancer Institute, Professor of Medicine, Mount Sinai
Alicia Morgans, MD, MPH, Genitourinary Medical Oncologist, Medical Director of Survivorship Program at Dana-Farber Cancer Institute, Boston, Massachusetts
ASCO GU 2022: Primary Analysis From DS8201-a-U105: A Phase 1b, 2-Part, Open-Label Study of Trastuzumab Deruxtecan (T-DXd) With Nivolumab in Patients With HER2-Expressing Urothelial Carcinoma
Alicia Morgans: Hi, my name is Alicia Morgans and I'm a GU medical oncologist at Dana-Farber Cancer Institute. I'm so excited to have here with me today, Dr. Matt Galsky, who's a professor of medicine and a GU medical oncologist at Mount Sinai. Thank you so much for being here with me today.
Matthew Galsky: Thank you.
Alicia Morgans: Wonderful. I wanted to talk with you a little bit about a presentation that you gave at GU ASCO 2022. You were able to present some data on a Phase I B, two-part open-label study of trastuzumab deruxtecan with nivolumab in patients who have HER2 expressing urothelial carcinoma. Which is a really exciting avenue, I think, for development in urothelial carcinoma. Can you tell us a little bit about the background, and then, what you were investigating?
Matthew Galsky: Absolutely. So, as you noted, this is a Phase I B study, lots of excitement around the combinations of antibody-drug conjugates, and immune checkpoint blockade in urothelial cancer. This study was actually started quite some time ago before we had some of that data, and it's taking a slightly different approach, than some of the contemporary data sets, with combinations in that the antigen that the antibody-drug conjugate is focused on is HER2.
We know that HER2 is overexpressed in urothelial cancer. That's been known for quite some time. Many drugs have been tried, focused on HER2 in urothelial cancer, with not much success in the clinic to date. But it's definitely overexpressed and potentially, represents a good vehicle for targeted delivery of chemotherapy. So, that's what this antibody-drug conjugate is. It's trastuzumab with a topoisomerase inhibitor as a payload.
This drug was given in combination with nivolumab in this Phase I B study in four different cohorts. There were two cohorts of patients with breast cancer, which we won't talk about. And two cohorts of patients with urothelial cancer. The patients with urothelial cancer had already received platinum-based chemotherapy and had progressed, but had not received any immune checkpoint blockade. And the two cohorts were patients with HER2 expression by immunohistochemistry at the two to three-plus level, and then at the zero and one plus level, for the other cohort.
Alicia Morgans: So that's really important and interesting, I think. So, just to make sure that I clarify for everybody, it sounds like they're really getting at least standard of care therapy, which is nivolumab. Obviously, they have not had a checkpoint inhibitor, so this is a reasonable next-line therapy for that. And then, you're adding on this additional agent targeting HER2. So really, I think, such a smart design, and really attractive to patients, because obviously, they want to try to have something that they think will be effective. So I just really, I commend you and the team on that novel approach, ensuring that patients have access to something that is at least is standard of care in this setting. So tell me, is there the thought that there would be synergy between the ADC and nivolumab?
Matthew Galsky: There is some thought that there'd be synergy. Certainly, these drugs might work just by independent drug action. They might be non-cross-resistant. But what we've seen, of course, with a series of antibody-drug conjugates in combination with immune checkpoint blockades so far, is that the combination seems to be maybe a little bit more than you would expect, based on the sum of their parts. Now, we don't have randomized datasets yet, but based on the Phase IIs, they seem to be performing a little bit better than you would expect with the individual components. So I think that there is something immunomodulatory going on there, and what that is, and why it seems to be consistent across ADCs, I think that's something that we need to figure out.
Alicia Morgans: Absolutely. I think there's always something to learn, and that, in particular, is a really interesting question about that potential synergy. So can you tell us a little bit about how the two cohorts did in terms of this Phase I B?
Matthew Galsky: Yes. So cohort three were patients with urothelial cancer who had HER2 expression at the two-plus or three-plus level. And I guess I would say anecdotally, the prevalence of HER2 overexpression in urothelial cancer, since we've been testing for a series of clinical trials, seems to be higher, in my mind, than I would've thought. And seems to be a little bit higher than what's been published in the past. And of course, it depends on how you score HER2 expression, but this is not uncommon in urothelial cancer, that's for sure.
So cohort three enrolled 30 patients. They got the combination treatment. And the objective response rate in those 30 patients was 36%, including a complete response rate of 13%. The waterfall plots, I think, tell maybe an even more nuanced story, as we've seen with some waterfall plots with ADCs plus immune checkpoint blockade, in that you really see the majority of patients having some regression of the tumor. And so this combination seems to be added to the list of ADC plus IO combinations that are showing fairly robust activity.
Alicia Morgans: That's great. And can you tell us a little bit about the tolerability and the side effect profile?
Matthew Galsky: Yes. There is a side effect that is somewhat unique with this particular antibody-drug conjugate, and that's interstitial pneumonitis. So it can cause pulmonary toxicity. Of course, nivolumab could also cause pneumonitis. And so that's something that was paid very close attention to during the development of this molecule, in addition to within this clinical trial.
Of the patients who developed pneumonitis in this study, the eight patients in that cohort, in six patients, it was a grade two or less. So typically, manageable holding drug, stopping the drug. But that is a side effect that is seen with this ADC that hasn't been seen with some of other ADCs, as you might expect, based on the mechanism of action of the payload. However, we don't see some other toxicities that we see with other ADCs, like neuropathy.
Alicia Morgans: And that's important, especially as we think about moving some of these agents forward, and potentially, even combining ADCs, or using them sequentially, we don't want to have toxicities that are going to be so overlapping. So as you think about this study, and you think about the two cohorts, any differences that you want to mention?
Matthew Galsky: The other thing I wanted to clarify about cohort four. Cohort four enrolled patients with HER2 one-plus tumors, and only four patients were enrolled, so that cohort was closed. That data is not reported because it's such a small cohort.
Alicia Morgans: Okay. Very important to mention. Thank you. So what would your take-home message be to folks who want to think more about this potential treatment option in the future, and future studies that might lead to its use in urothelial carcinoma?
Matthew Galsky: So this ADC directed against HER2 has activity in urothelial cancer in combination with immune checkpoint blockade. It's being studied now as a single agent, to further explore the activity in urothelial cancer, in a basket study. And so I think, we're going to see more with trastuzumab deruxtecan in urothelial cancer.
Alicia Morgans: Well, that is exciting news. Thank you so much for sharing this, for presenting it at GU ASCO 2022. And we look forward to hearing more from you in the future. We appreciate your time, Dr. Galsky.
Matthew Galsky: Thank you.