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Alicia Morgans: Hi, my name is Alicia Morgans. I'm a GU medical oncologist and associate professor of medicine at Northwestern University. I'm so excited to have here with me today, a good friend and colleague Dr. Petros Grivas who's an associate professor of medicine and a GU medical oncologist at the University of Washington. Thank you so much for being here with me today, Dr. Grivas.

Petros Grivas: Thank you so much, Alicia, for having me. It's exciting times indeed.

Alicia Morgans: Yes it is. And it's really exciting to think about some of the presentations that you participated in at ESMO 2020, a really impactful virtual meeting, particularly in urothelial cancer, where you and colleagues presented the TROPHY-U-01 data. And I think there was actually a presentation in Cohort 1 as well as the trials and progress for Cohort 3. Can you tell us a little bit about that?

Petros Grivas:  Absolutely. Thank you, Alicia, for bringing this up. We're very excited about antibody-drug conjugates in general in the metastatic urothelial cancer. And I know you and me have talked about it. We can never be satisfied enough in urothelial cancer in terms of having treatments. So far we have a great repertoire of options, but we'll never be satisfied, we need more options and we all welcome more options. And this idea is very important and is driving the conduction of more clinical trials in this disease because we cannot have enough treatment options for our patients. So with that context, I would say that in terms of antibody-drug conjugates, there are many that are being evaluated in this disease. And then enfortumab vedotin has the majority of the data points and datasets and enfortumab vedotin is approved by the FDA for patients who have already had progression on platinum-based chemotherapy and checkpoint inhibitor in this third-line space, and accelerated approval came from the EV-201 single-arm Phase two study, that was already published in JCO by Dr. Rosenberg, Dr. Petrylak and other colleagues.

And also we had a recent press release last week from the EV-301 trial that saw that there was an overall survival benefit with enfortumab vedotin versus salvage chemotherapy with the hazard ratio of 0.70, which is interesting. And we have not seen the data yet, but we look forward to see that data. So we have this context of datasets of enfortumab vedotin. And as I mentioned before, we can never stop. We need more options in those patients. And in that context, we have now very promising and encouraging data from a different antibody-drug conjugate called sacituzumab govitecan, or IMMU-132. In contrast with enfortumab vedotin, sacituzumab govitecan has a different target and enfortumab vedotin is targeting Nectin-4, sacituzumab is targeting Trop-2. Different target, but significantly expressed, I would say ubiquitously, in urothelial cancer cells.

And it's linked with a toxin payload called SN-38, which is a metabolite of irinotecan, a Topo1 inhibitor. So sacituzumab govitecan had very promising data from the Phase 1 study. And Dr. Tagawa showed some very promising data from the 35 first patients that are all in Cohort 1 in this TROPHY-U-01 trial, at ESMO from last year. Now Dr. Loriot presented very nicely, the full dataset of Cohort 1 with single-agent sacituzumab govitecan in Cohort 1 of the TROPHY-U-01 trial. These are patients who are after prior-chemotherapy and immunotherapy. So third-line and beyond. Patients may have received multiple prior therapies. The median number of prior therapist was three and their edge was between one and eight. So definitely heavily predicted population of patients. And 88% of patients had at least one Bellmunt risk factor, so definitely a negative prognostic factor group. Despite these challenges, and 28% of patients had liver metastasis, despite this adverse prognostic features, the overall response rate with single-agent sacituzumab govitecan was 27% with a 5% CR rate and 22% PR rate.

So definitely very important data and encouraging and probably half of that overall response rate was seen with docetaxel in prior historical controlled trials. So the overall responses of 27% appears about approximal double of what we have seen with historical chemo data. The median duration of response was 5.9 months, and the median PFS 5.4 months with a median overall survival was 10.5. Obviously, the PFS and OS data have to be interpreted with caution in this single-arm Phase 2 study with possible selection biases, but definitely are very promising numbers. And in context of a relatively manageable toxicity profile, set the stage for potential accelerated approval of this agent in this heavily pre-treated population. In terms of toxicity, we show definitely neutropenia and about 10% of patients had febrile neutropenia, but only 30% of the population of Cohort 1 utilize growth factor.

And I think with dose reductions, if needed, and growth factor support, we can get the patients through the neutropenia relatively well. The diarrhea was another issue. About two-thirds of the patients had diarrhea, but the grade three was only about 10% or so. And this usually well-managed with proper education of patients, loperamide, diphenoxylate, [inaudible 00:05:28] medications, and it's usually situational around the administration date of the drug. So overall I would argue that toxicity profile needs attention, but overall seems manageable. And in the context of the very promising activity, set the stage for two things. Number one for potential consideration by regulatory agencies of this agent for accelerated approval. And secondly, for a Phase 3 trial, that TROPICS-04, that will compare definitively sacituzumab govitecan compared to salvage chemotherapy, single-agent vaccine in US and different in Europe to see whether this drug can improve overall survival compared to the salvage chemotherapy in the future.

Alicia Morgans: I think that's really exciting, and I certainly am looking forward to these future trials. You know, there was also recently reported data on Cohort 2, which is patients who had progressed after chemotherapy, I think. Can you give us a little recap of that data, which was presented I believe at GU ASCO or maybe at ASCO earlier this year?

Petros Grivas: Thank you, Alicia. Another important question. Cohort 2 was focused on patients who had prior checkpoint inhibitor in advanced disease. These are patients who could not have received chemotherapy with platinum in advanced disease settings. So these are the patients who may be unfit for any platinum or they have opted to get checkpoint inhibitor frontline and second-line they couldn't receive platinum therapy and they could have gone to this Cohort 2. And prior therapies are allowed, as long as you didn't have received platinum-based chemotherapy for advanced disease. The signal from this interim analysis was very promising. Dr. Petrylak presented this data, the interim data from Cohort 2, at the ASCO virtual meeting and very encouraging overall response rates that was consistent with what we saw with Cohort 1. So definitely setting the stages, as I mentioned, for review of the totality of the data sets by regulatory agencies.

I think the important message is that this agent seems to be well-tolerated even in those who did not receive chemotherapy and those who received chemotherapy. Again, a significant intensity has to be noted in the toxicity profile, but it has different toxicity profile than in enfortumab vedotin. And those, I can personally think that both of those agents may have space in advanced urothelial cancer, obviously, enfortumab verdotin has more data. Depending on a different toxicity profile, you can potentially see a sequence of those agents and because of the different mechanisms of action, I do not perceive any reason to see cross-resistant mechanisms. They are different drugs, different target, different link here, different toxin. So I can potentially see a sequence of those agents in clinical practice down the road, if both of those agents become available in the future.

Alicia Morgans: Absolutely. And importantly, as you corrected, Cohort 2 was in patients who had received immunotherapy, checkpoint inhibitor therapy. They were not eligible to receive chemotherapy in the metastatic setting. And this is really important, that we have more therapies that even in this population that may be a little more frail or may have some neuropathy or other limiting factors, renal dysfunction, for example, that may not allow them to get chemotherapy. They are able to get this antibody-drug conjugate tolerated, and then still benefit. And as you said, we do need all of the treatments that we can get for this patient population, because there are many patients that you treat and that I treat, I think, that end up getting all of the treatments available, progressing on those treatments. The treatments failed them, but they are still actually pretty fit and really could get another therapy or perhaps even another after that.

So having options for multiple antibody-drug conjugates, will give those patients options in the long run. And I really do look forward to the day when this is available to us. So you have a trial in progress that was also presented at ESMO. This was Cohort 3 from TROPHY-U-01. Can you tell us a little bit about that and how that will continue to move the needle?

Petros Grivas: Thank you, Alicia. Again, a very important critical question. So Cohort 3 is a combination of pembrolizumab, an anti-PD-1 agent plus this antibody-drug conjugate, sacituzumab govitecan. And the impetus of this Cohort 3 was a very promising and exciting data from the Phase 1 BEV-103 trial, that Dr. Hahn presented and Dr. Rosenberg presented in the future, in the frontline setting that showed very encouraging signals of 71% of a response rate and 93% disease control rate with EV and pembro. And the question we had is, is that specific for EV? Or it's a class-effect that if you release neo-antigens by immunogenic cell death using an antibody-drug conjugate like sacituzumab govitecan, can you reproduce these exciting results with sacituzumab govitecan plus pembrolizumab?

So the Cohort 3 is up and running. We are enrolling patients, and we're very excited about it. Obviously, this was a trial in progress at ESMO. So we do not have any data to report yet, but we're hoping that in the near future, we'll have an interesting dataset with pembro plus sacituzumab to report in this heavily pre-treated patients. These are actually patients who are platinum-refractory, so you can give pembro plus sacituzumab govitecan second-line or beyond. In this particular study, as long as the patients are I-O-naive, they haven't received immunotherapy for advanced disease. And I'm believing that this cohort will accrue very quickly because of the enthusiasm around both drugs. And we'll see whether the combination works or not.

Alicia Morgans: I completely agree. I think there was definitely a lot of enthusiasm. That was a response rate, if you include stable disease in particular, that was just phenomenal and really encouraging to all of us, that we might be able to do a lot more than we even actually expected was possible. So I look forward to seeing the interim and then the ultimate results of that trial. I wish you and the patients luck as you continue to enroll in that trial. And I'm very, very excited to see where that ultimately goes. So as you think about sacituzumab govitecan and where it will ultimately fit into this treatment landscape, what are your thoughts? What are your closing messages for those who are trying to learn a little bit more about this and antibody-drug conjugate, and think about where to place it in their treatment landscape?

Petros Grivas: Absolutely. This is important to keep in mind when we treat these patients, how we can fit new agents and novel therapies. Right now I think the most important thing is accrual in clinical trials. So I always welcome that. I always put that with flashing lights in my presentations, clinical trial accrual. So this is a message for the patients and the providers, even community oncologists. It's great to pick up the phone and call colleagues who have trials available and some of the trials are open community side. So that's a big message. If the Cohort 1 data gets reviewed favorably by the regulatory agencies, we don't know that yet, but if that's the case, sacituzumab govitecan could potentially get accelerated approval in these heavily pre-treated population. So it can be third- or fourth-line of therapy kind of thing. And if you think about right now, we'll have platinum chemotherapy, we'll have checkpoint inhibitor, we have enfortumab vedotin, and for selected patients, erdafitinib.

So that could potentially be a fifth agent that can be available. And then as I mentioned, it has less data and less level of evidence compared to enfortumab, but there are some toxicity differences and sacituzumab has significantly less neuropathy. And also, it does not appear to be an issue with hyperglycemia. So patients who are morbidly obese, they have uncontrolled diabetes or significant neuropathy could potentially receive this drug before enfortumab. That's an open question. However, as I mentioned, enfortumab vedotin has a higher level of evidence so far, especially with a Phase 3 trial showing overall survival benefit. So the sequence will be defined as we take all these factors into account, efficacy, toxicity, level of evidence.

But I'm very interested, personally, about the combinations, both EV-pembro and sacituzumab-pembro. If the data looks good, I can see those agents being moved earlier. EV-302 trial, and the frontline setting is an example of that. And potentially, who knows? If the data looks good, some of those combinations could be used in the neoadjuvant setting to see if we can cure more patients early on. So we'll have to wait and see the datasets, but I'm very excited about the emergence of new data and testing of new compounds that we discussed some of them today. There are others too, in urothelial cancer space.

Alicia Morgans:  Wonderful. And as we talked, even just before we started recording, there may be an opportunity to treat patients with chemotherapy, checkpoint, EV, and sacituzumab govitecan as well as some also receiving erdafitinib. It would be wonderful if we could get all of these treatments into some of our patients, because we ultimately want to give them every opportunity to have disease control. And when one drug fails them, it's a wonderful feeling to say, "You know what? I have something else and I think it can work for you." And I really applaud you on continuing to move these options forward, to give us those opportunities, to have the options for patients to try to control their disease. So thank you so much for your efforts. What a wonderful, wonderful set of presentations at ESMO this year. Congratulations on all of your work. And thank you so much for your time.

Petros Grivas:
Thank you so much, Alicia. I agree with you, it's exciting to be in the field and treating patients, do everything we can for the patients and do everything we can in clinical research and transitional research. Thank you so much for inviting me today, Alicia, and your great questions.

Alicia Morgans: Thank you.