Safety and Efficacy of CDX-014, an Antibody-drug Conjugate Directed Against T cell Immunoglobulin Mucin-1 in Advanced Renal Cell Carcinoma - Bradley McGregor
Bradley McGregor, MD, Clinical Director, Senior Physician, Instructor in Medicine, Lank Center for Genitourinary Oncology, Harvard Medical School, Dana-Farber Cancer Institute
Alicia Morgans, MD, MPH Associate Professor of Medicine in the Division of Hematology/Oncology at the Northwestern University Feinberg School of Medicine in Chicago, Illinois.
Alicia Morgans: Hi, this is Alicia Morgans, GU medical oncologist and Associate Professor of Medicine at Northwestern University. I'm so excited to talk today with a friend and colleague, Dr. Brad McGregor, who is the Clinical Director of the Lank Center for GU Oncology at the Dana-Farber Cancer Institute and someone who's been really pushing boundaries in clinical trials for kidney cancer, as well as some rare GU tumors. Thank you so much for being here today, Brad.
Bradley McGregor: Thanks for having me.
Alicia Morgans: Wonderful. I wanted to talk with you a little bit about some work that you've recently presented thinking about using new antibody-drug conjugates in places other than urothelial cancer, where we know we have an approved agent. You really investigated this antibody-drug conjugate in the kidney cancer space. Can you tell us a little bit about that?
Bradley McGregor: Yeah. With renal cell carcinoma, there's really been an avalanche of new therapies in the past couple years moving into the frontline. Now, we have IO combinations, IO and VEGF TKIs. But unfortunately, as we take all these agents that are highly active in later lines and move into the frontline, we're really left with not everyone responds. We really need to find new, novel targets, novel ways to treat these patients who unfortunately don't respond to those therapies.
So with that in mind, we looked at using the antibody-drug conjugate. And so KIM-1, or TIM-1, is something that's expressed on renal cell carcinoma, not actually expressed on healthy kidney tissue, although it is overexpressed in the settings of acute kidney injury. So given that there's this unique target, this was a Phase I study to look at escalating doses and dosing frequencies of an antibody-drug conjugate against KIM-1 that was linked to MMAE, which is the same as high toxic chemotherapy used in enfortumab vedotin.
Alicia Morgans: That's so interesting. Like you said, just to emphasize, it's so important when we are looking for targets, if at all possible, to choose a target that's going to be expressed pretty heavily on cancer cells and less so on normal cells. That's not always possible, but it sounds like this was, at least theoretically, going to be a really good option. We know MMAE can work in other tumor types. So a really exciting combination. Tell us a little bit about what you saw.
Bradley McGregor: Yeah, so we were, again, looking for that unmet need of those patients who are progressing on the existing therapies. These were heavily-treated patients. Most of them had progressed on immunotherapy and VEGF therapies, and they were in a dose-escalation scheme. We ended up enrolling 16 patients into the protocol at increasing doses.
What we found in initial dosing schema, at every three weeks, there were dose-limiting toxicities, where actually we had one unfortunate multisystem organ failure. We reevaluated, and we actually adjusted the dosing schema and to go to every two weeks. But as that was happening and we started re-enrolling, given issues with the company, we actually decided to halt the trial a total of 16 patients.
What we saw in the 16 patients was we did have one patient with an actual clinical response. It was actually quite durable and went on for a long time. It was actually at the second-lowest dose in the trial. We also had some other patients who had some pretty good shrinkage, though did not meet the criteria for response. And it is a proof of concept on those patients who seem to have the greatest benefit had strong TIM-1 expression.
Alicia Morgans: That's really interesting, and I'm glad that you were able to do the correlative work to really look to see the association between TIM-1 expression and responses. So very, very exciting. Also, nice to hear that although at some of the doses you did have some really significant toxicities, that the one patient who had the more robust response was at one of the lower doses. It sounds like this drug though is not ultimately going to be moving forward for several reasons. Is that correct?
Bradley McGregor: At this time, correct. It's not moving forward. There seems to be some sort of activity there. Unfortunately, just having TIM-1 expressed in the tumor didn't quite respond. So those who responded had TIM-1, but if you had TIM-1, you didn't necessarily respond.
I think the toxicity profile is something that would be explored with higher numbers. I think one of the concerns that TIM-1 is overexpressed on kidney injury, so in a patient who has acute kidney injury from conscious nephropathy, there's potential that you may actually have a revved-up system in which the normal kidney gets attacked and can lead to more issues. It's theorized that that's maybe what happened to the one patient who had the multisystem organ failure.
I think overall though, the data reinforces that kidney cancer, unfortunately, doesn't seem to respond to cytotoxic chemotherapy. Within the multiple studies, aside from maybe those with sarcomatoid renal cell or some of the baring histology, really renal cell carcinoma has been relatively resistant to cytotoxic chemotherapy. And this sort of continues to show that despite an enhanced delivery of the chemotherapy, we didn't see activity.
Alicia Morgans: Well, that is definitely unfortunate, but it is helpful to know that with an MMAE antibody-drug conjugate, you were able to suss out some additional safety signals that might help us?
Bradley McGregor: It definitely draws some activity. I think it's interesting, this trial was done concurrently as the EV trials were being done, and we actually had several patients with grade 3 hyperglycemia on this protocol, which when we think about what we've seen with EV, one of the sort of rare, but concerning toxicities, is this risk for hyperglycemia, which really suggests there may be something with MMAE as a cause of this hyperglycemia. So it supports what's wrong. Unfortunately, don't know the mechanism by which that is happening, but it does seem to be a recurring theme when we look at these antibiotic conjugates with MMAE.
Alicia Morgans: That is really interesting. And antibody-drug conjugates, unfortunately, not at least in this case successful in renal cell carcinoma, but have been really successful in multiple settings of urothelial cancer, multiple drugs. Let us know what your thoughts are on using antibody-drug conjugates in other GU malignancies?
Bradley McGregor: Yeah, I would agree, to date, the story for ADCs in renal cell carcinoma has been underwhelming, although we await the results of a Phase II trial of another antibody-drug conjugate against ENPP3, and those patients with clear cell compared to axitinib, which we should hear results on that soon. But I would agree that in urothelial carcinoma, antibody-drug conjugates have certainly revolutionized therapy. When we look at enfortumab vedotin, and these are patients in the EV trial one that had been heavily treated with platinum and immunotherapy, we saw a 44% response rate. When we think of taxanes in that setting, the response rates are less than 15% in most studies.
What's really notable is that there were some very deep responses, some CRs in that study, and it seemed to be durable. So that's exciting, and now we await the results of the Phase II trial versus chemotherapy. There's also other antibody-drug conjugates coming along. I think one that's furthest along, is sacituzumab govitecan, which is being studied at this point in time, but there's also antibody-drug conjugates against part two that are in development as well. So I think this is really going to be an important step in the treatment of patients with urothelial carcinoma.
Alicia Morgans: Absolutely. And it's so exciting too to see the combinations with PD-L1 or checkpoint inhibitor approaches too, that we may ultimately see combinations coming down the line in urothelial cancer that may even have a synergistic approach.
Bradley McGregor: When you look at that data with EV plus pembro with a 70% response rate in those patients that were not [inaudible 00:08:02] cisplatin, that's unheard of. And you see those responses and you wonder, can we move that earlier into the disease course, maybe in the neoadjuvant space or the adjuvant space and prevent these patients from needing this therapy in the metastatic setting? So I think there's really a lot of excitement about how these drugs are going to change the treatment for urothelial carcinoma.
Alicia Morgans: Absolutely. Well, I so appreciate your time and hearing your insights on antibody-drug conjugates, both in terms of your Phase I in renal cell carcinoma, but also more broadly in GU tumors and urothelial cancer, more specifically. So if you had to sum up what we talked about today and your thoughts on antibody-drug conjugates in GU cancers, what would your message be to listeners?
Bradley McGregor: So I think the antibody drug conjugates are going to be a mainstay of therapy for urothelial carcinoma. And their role is going to probably move earlier into the disease course, as we learn more about different combinations and different approaches to that. Unfortunately in renal cell carcinoma, which tends to be relatively resistant to cytotoxic chemotherapy, while we did see some efficacy in our study, it was pretty low. And I think there needs to be work that still needs to be done to advance that field board in renal cell carcinoma.
Alicia Morgans: Great. Well, we look forward to hearing more from you and I certainly look forward to hearing more about the studies that you've mentioned and the work that you do. And I so appreciate your time and your contribution today. Thank you so much.
Bradley McGregor: Thank you.