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Alicia Morgans: Hi, I am so excited to be here today with Dr. Guru Sonpavde, who is a professor at the University of Central Florida, as well as being a GU medical oncologist at Advent Health Cancer Institute. And Dr. Brad McGregor, who is a friend and colleague at Dana-Farber Cancer Institute with me, also a GU medical oncologist. Thank you both so much for being here today.

Guru Sonpavde: Thank you, Alicia.

Bradley McGregor: Thanks for having us.

Alicia Morgans: Wonderful. So both of you really had a wonderful abstract, and Dr. McGregor, you had a wonderful presentation at ESMO 2023, and this was on the DAD trial. Really exciting, somewhat stressful. I remember when I first learned about it, this combination of enfortumab vedotin and sacituzumab govitecan.

And so Guru, can you tell me, set the stage. Why was this trial necessary? And tell me how the two of you really thought outside the box in designing it.

Guru Sonpavde: Yeah. Thank you, Alicia. The rationale is really quite simple. We used to combine chemotherapy agents with different mechanisms of activity, different toxicities, many years ago. And so, this really is no different than that. These are essentially smart targeted chemotherapy drugs, enfortumab vedotin and sacituzumab govitecan. In this case, for advanced urothelial carcinoma. And of course, we got lucky, because these two ADCs, approved in urothelial carcinoma, target different surface membrane targets. Of course, Nectin-4, in the case of enfortumab vedotin. TROP2 in the case of sacituzumab govitecan. And of course, the payloads are also different. MMAE, the tourmaline toxin in the case of EV. And SN-38, that's an irinotecan metabolite, a Topo-I inhibitor. And of course, the toxicities are mostly non-overlapping. As we know with EV, you get neuropathy, the rash, and the hyperglycemia. And of course with the sacituzumab govitecan, we see myelosuppression, we see diarrhea.

So really, there's a little bit of overlap of myelosuppression with these two drugs, but largely non-overlapping toxicity. So this made sense, that we could potentially combine these two drugs and get additive or synergistic activity. We also know that sacituzumab govitecan, in the Phase II trial, there was activity in a small subset of patients who had progressed after enfortumab vedotin. So really, we thought that these two drugs could be non-cross resistant. They have these non-overlapping toxicities, different payloads, different surface targets. So really, resistance to one could be overcome by activity with the other agents. So that's what led us to combine these two drugs. We called it the Dual Antibody Drug Conjugate trial or DAD trial, a catchy name.

And really, so the eligibility in this case, we picked a population where we had approval of enfortumab vedotin, which was in the third-line setting. And later, we amended it to allow the second-line cisplatin ineligible setting. As it turned out, most patients were post both chemo and immune checkpoint inhibition. We needed predominant urothelial carcinoma, of course, the adequate organ function, no small cell carcinoma, no active CNS metastasis, and no uncontrolled diabetes.

And Gilead, of course, funded this trial. They gave us the sacituzumab govitecan supply, and funded this trial.

So the design, very simply, is a Phase I design using the BOIN design, the Bayesian Optimal Internal design. And we were starting with lower doses of both sacituzumab and enfortumab, at eight milligram per kilo sacituzumab, day one, day eight, every three weeks. And the EV was one milligram per kilo day one and day eight, every three weeks. So three week cycles. And then we had dose escalations going up to full single agent doses of the 10 milligram per kilo and the 1.25 milligram per kilo for sacituzumab and enfortumab vedotin, respectively.

So that's the simple design. Now, I think that I'll let Brad talk about what happened on the trial. We later had to amend the study, to allow prophylactic GCSF, according to ASCO guidelines. And I guess, we can get to the results of the efficacy and toxicities, if Brad wants to go there.

Alicia Morgans: That's great. And I just want to say, I love the way that you thought of it, thinking about the combination of chemotherapy. That we've used this in the past, obviously, with non-overlapping toxicities. But this was the first study where two antibody drug conjugates were used in combination. Is that true? So I'll ask Brad that, and certainly tell us the results of the study as well.

Bradley McGregor: Yeah. It was really exciting. So to my knowledge, I think this is the first trial that combines two ADCs in any malignancy, not just bladder cancer. So really, really exciting data to be a part of it.

And so, as Guru alluded to, right, this was a Phase I BOIN design, where the primary objective was really to assess the safety and feasibility of combining EV with SG, by determining the maximum tolerated dose through the BOIN design.

So we enrolled 24 patients, of which 22 patients actually started cycle one day one of therapy. So after the first six patients enrolled, the two DLTs were both neutropenic fever. And these were in patients that were both over the age of 75 with comorbidities. Really, patients that giving SG monotherapy, I would've probably wanted to give prophylactic GCSF with cycle one.

So at that point, we actually amended the protocol to allow GCSF with cycle one, per investigator discretion. And what we subsequently saw is, of the next 17 patients who wanted to get therapy, 16 and 17 did receive prophylactic GCSF with cycle one. So that sort of overlays the data.

So who do we enroll? So patients, as Guru said, had to have one prior line of therapy ineligible for cisplatin, or two lines of therapy. 22 of the 23 actually progressed on at least two lines of therapy, and 40% progressed on three lines of therapy. So this was heavily pretreated. The median age was 70, and patients range up to the age 88, of which I treated. So this was patient that you would think of in the clinic, albeit the center of two academic centers, but these were not all 40 and 50-year-old patients.

So what do we find in terms of the maximum tolerated dose? So we look at this, nine patients were treated at dose level one, that's eight and one, SG and EV. And there's actually only two DLTs, both neutropenic fever. And so, we escalated to dose level two, of which eight patients were treated at dose level two, that's eight and 1.25. And there was actually only one DLT, and that was a delay in therapy, which it turns out, was actually for immune related colitis. So it wasn't even related to any of the therapy.

Then at dose level three, we enrolled six patients, of which five of the six were valid for DLT. One of the patients actually had a UTI and never got day eight a therapy. So it was not evaluable. What we saw was three dose limit toxicities in that group, a neutropenic fever, there was severe mucositis, and delay in toxicity, for a variety of toxicities.

So we look at that altogether. The maximum tolerated dose per the BOIN design is actually full dose EV and SG. So dose level of three. 10 mgs kg of SG. 1.25 mgs per kg of EV, day one and eight, a 21-day cycle. That's the maximum tolerated dose. That's because there's only one DLT in the next lower dose. That being said, that is not what we recommend for recommended Phase II dose. When we look at that dose level, the median number of cycles at that dose was only one. A majority of patients were dose reducing by cycle two. And there was a lot of toxicity.

So when we look at dose level two, one level down, still maintain that dose intensity and density of EV, but reducing that SG dose. The median cycles was four, and overall, much better tolerated longer term, looking at cumulative toxicities. So while the maximum tolerated dose is full dose, impressing they gave them together, that's not really what we recommend. And that really goes into efficacy. So across all dose levels, this is, again, this is pretreated patients, 40% had three lines or more. The objective response rate was 70%. Of 23 patients, we have three CRs, and there's likely to be more with extended follow-up.

And there's a large proportion of patients that stop therapy for toxicities. Because the way the product was designed, we, like probably everyone here, was worried that patients would get one dose of the doublet and then never get two drugs again. So we said we had to get both drugs on day one of each cycled to continue. So a lot of patients after eight to 11 cycles elected to stop therapy, just because of cumulative toxicities from EV. But a lot of those patients did stop, have been off treatment for a prolonged period of time. The first patient been treated, had been off over two years in ECR. Another patient's been off for 19 months, with liver met that continued to shrink off therapy. So really, really exciting efficacy.

And then, beyond the dose limiting toxicities and all that, what about toxicities? So as expected, there's toxicities with this regimen, with a caveat that most patients got prophylactic GCSF. With that caveat, the toxicities were very manageable, but the most common toxicities being diarrhea, anemia, neutropenia. So what we sort of expect to see with these agents. We didn't see any synergistic toxicity. So we had some marked increase in grade three neuropathy, or severe colitis, or anything along those lines. So it seemed to be quite manageable in the clinic, with what we sort of expect from both drugs on their own.

Alicia Morgans: So that's really important. No synergistic toxicities. You really saw additive toxicities, which sounds like what you would expect from these drugs alone. I have to say, my eyebrows raised a little bit when you said that patients are going to eight to 11 cycles. I think that's pretty phenomenal. And when we think about just single agent EV or single agent SG, that's a really long run for those drugs, given the toxicities that we know we manage, but can build up over time, and can be challenging for patients.

Guru, I know you, obviously, you had patients on this trial, you really know what it's like to take care of this population. We heard the data from Brad. Would love to hear, what did you have? In your clinic, how was it taking care of these patients?

Guru Sonpavde: Yeah. So we essentially saw toxicities that would be consistent with each of these single agents, EV and sacituzumab. Now, one of the things we heard from Brad was that the maximum tolerated dose was the full doses of each drug. However, as you know, the MTD is determined based on just cycle one. And what we were concerned when we saw this agent given repetitively, these agents given in combination repetitively, was that there was an accumulation of toxicities. And after cycle one, there were patients that were running into problems. And so, there were many patients at the highest dose that needed dose reductions. And also, patients that needed more than one dose reduction at the highest dose. And therefore, we felt that going forward, if you wanted to repeat the cycles and go a long time, the dose level two would be the right dose. Which is the maximum dose of enfortumab, 1.25, but the reduced dose of sacituzumab, at eight milligram per kilo. Again, both drugs given day one and day eight.

And the prophylactic GCSF was allowed, as you heard, after the initial few patients, per ASCO guidelines. So it was not mandatory, but per ASCO guidelines, and as you did here, basically everybody from that point on did receive GCSF. Because as you know, urothelial carcinoma patients frequently fulfill the ASCO guidelines for prophylactic GCSF.

Alicia Morgans: Yes, they certainly do, especially the age range that you guys enrolled. And Brad, it sounded like you had some patients who had continued disease control, even with cessation of treatment. And I think we've all kind of seen and talked about this happening in settings where EV is used, and would love to hear your thoughts on, is this something that you did see among the patients that were treated in the DAD trial?

Bradley McGregor: Yeah. 100%. I think we had multiple patients that elected to stop for just the cumulative toxicities after a prolonged time. And a majority of the patients who stopped, are able to have continued benefit. At the time of analysis, nine of the 23 evaluated patients had responses that were ongoing. Of which a minority, those were actually still on active therapy. So I think there does seem to be something there. I mean, this is small numbers, but three CRs out of 23 evaluated patients with several more that are very close to a CR, it was really exciting. I have to tell you, it was really gratifying in the clinic to use this, and to give it to these patients, and just see their diseases respond so dramatically.

I think to your point, when can we stop? How long do we have to give this for? I think these are the questions we're going to ask, as we think about the next level. One of the things we're looking at is maybe even using ctDNA and monitoring that clearance. When can we stop it? But I can just tell you that, the patients on this trial overall, their quality of life was good. This was something that was manageable. And in many ways, I found it almost in some ways easier to give than sequential SG followed by EV, just because the patients were less beat up at the time, right? You start EV and SG together. They had been on EV for a prolonged period of time with the neuropathy and the cumulative myelosuppression.

So I did personally find it was well tolerated, and I really had no problem putting any patients who met eligibility criteria, which is why we had patients up to the age of 88. It was remarkably well tolerated and manageable, right? Toxicities are there, but there wasn't anything different. And I'm really, really excited to see, with a larger cohort, is that activity 70% response rate. Can we maintain that in a larger cohort? And I hope we can.

Alicia Morgans: Especially since these patients had had treatments before. So this is not first-line therapy.

So Guru, I'd love to hear your thoughts as we wrap this up. Where do you see this fitting into the larger landscape, which continues to change around us, in urothelial carcinoma?

Guru Sonpavde: Right. I think we heard transformative data at the ESMO meeting where the EV plus pembrolizumab combination was much better than the gemcitabine platinum combination for the first-line therapy. And this is across cisplatin ineligible or eligible disease. And the median survival with EV/pembro was, as you saw, 31.5 months, something we've never seen before.

So the obvious question now is, can we add sacituzumab to EV/pembro and make it have even better outcomes? So this is of interest. We need to see if this combination, the triplet, will be feasible and safe. So that, I think, is on our mind to do.
And I think that one of the problems in urothelial cancer, of course, is that you cannot get in multiple lines of therapy. Historically, as you know, only 50, 60%, sometimes less, go on to get second-line therapy. So really, you might get just one shot at this disease, and that's why a potent tolerable combination is something to look at. So that is on our mind to combine sacituzumab with EV/pembro.

Alicia Morgans: That's great. And Brad, future directions from your perspective. And give us a summary. What's the take home message from this work?

Bradley McGregor: Yeah. I think from my standpoint, this is the first trial in mUC that shows that two ADCs can be given safely. And remarkably the maximum tolerated dose, albeit based on DLTs during cycle one only was full dose of both drugs. So I think that alone hopefully represents a paradigm shift, how we think about ADCs and other cancers. And we can think about combining ADTs across plenty of diseases.

Looking specifically at bladder cancer, I think a 70% objective response rate, albeit in only 23 patients, is really exciting. And I think we need to validate that. So I think one of the things is, we're going to expand that, right? So we're going to do a multicenter expansion with over 40 patients. That's going to be opening in the next couple of months. That we're really trying to see, is this 70% real? And what is toxicity in a larger population, patients using that DL2.

And as Guru alluded to, beyond that, beyond DAD, as the space changes, where can we look at this elsewhere? So I think, there is the expansion to add SG to EV plus pembro, that's called the DAD IO or DAD-IO, which will be also opening soon.

And then, I mean, I love to think, can we think about this even beyond that space? If you have a same type response rate, can we use it in the neoadjuvant setting? And this is knowledgeable. I think there's so many different ways that we can think about it. But I think, it's really exciting so that EV and SG can be given safely, with a very manageable toxicity profile, with hints of really intriguing efficacy.

Alicia Morgans: Well, thank you so much, both of you, for sharing the data today. Congratulations on a really thought-provoking trial that will continue to change the landscape, even as it changes around you. Because you've already got DAD-IO in the works. And I love the names that you're using, they are encouraging. And certainly the data is even more so. So thank you both for your time and for your expertise.

Bradley McGregor: Thank you.

Guru Sonpavde: Thank you.