Alicia Morgans:Hi, my name is Alicia Morgans and I'm a GU Medical Oncologist at Dana-Farber Cancer Institute. I am 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 and the Fred Hutchinson Cancer Center. Thank you so much for being here with me today, Dr. Grivas.

Petros Grivas: Thank you so much Alicia for inviting me. Always a great pleasure discussing with you.

Alicia Morgans: Always a pleasure to talk to you too, Dr. Grivas. Now, we are here to talk today about the presentation you made at GU ASCO 2022 with the TROPHY-U-0-1 data looking at patients who had had progression of metastatic disease. And this patient population had been exposed to Platinum in the past and now is going to receive Sacituzumab govitecan in combination with a PD1 approach, or a PDL-1 approach. Can you please let us know really the rationale for that and what you and the co-investigators looked into.

Petros Grivas:Thank you so much Alicia, that's a great question. And I would like to start by saying that the TROPHY user one trial is a multi cohort study, phase 2 study, that asks different questions. Cohort 1 was the one that led to the accelerated approval by the FDA of Sacituzumab govitecan, let's call it SG, in the approved line of therapy. So, patients after progression platinum-based chemotherapy and sickle inhibition, SG has approval by the FDA based on a response rate, 27% and tolerability in terms of multiple toxicity profiles in prior treated patients. So, the question that has come up was how about trying to go a little bit earlier before checkpoint inhibition and combining SG with anti-PD-1 pembrolizumab in patients with platinum refractory advanced urothelial cancer in the second line setting. And there has been a lot of rationale and discussions why antibody drug conjugates could be, or should be combined with immune checkpoint inhibitors.

And there has been a study published about four years ago, looking at the Topoisomerase I inhibitor, Irinotecan, that has been shown to upregulate MHC class I and PDL-1 expression and depleting T-regs. So, this is relevant because if you look at Sacituzumab govitecan, SG, it's made of a anti-trop-2 antibody linked with an SN-38. So, there is a strong rationale there to combine. And hopefully the goal is to induce immunogenic cell death that can stimulate the immune system. So, strong rationale for the study also in the context of the impressive pembro EV data that have seen. But the pembro EV data was in a different line. It was in the frontline setting. Cisplatin, eligible patients. This is different. This is second line platinum with refractory patients. And that's also relevant because Alicia, when we look at the makeup of the population in the cohort three of the TROPHY user one that we're discussing today, this is a very difficult population.

If you look at the demographics, for example, about 30% of patients had liver meds. And if you look at the Belmont risk factors about... I would say a quarter of the patients had two Belmont risk score of two factors. About half of the patients had received platinum-based chemotherapy for metastatic disease in the frontline and about half had neoadjuvant or adjuvant platinum-based chemotherapy and had progression. And the response rate, the best response to prior systemic chemo in metastatic disease in this half of the patient cohort had baseline chemo, the responder was low. Was about 14%. So, very lower, much lower than what we expect with platinum-based chemo. So, a very difficult population, platinum progressors, poor actors. And if you look at the median time between the last prior chemo dose and the start of the screening of the trial was about 1.5 months. So, a very, very aggressive, difficult to treat population of patients.

Alicia Morgans: And I think I would just emphasize that it's actually important for us to do clinical trials in this type of a population because these are some of the patients that we see in our clinical practice. And these are the patients where we want to be able to really know what to do because we have very little time to do something effective before the performance status of the patient drops off and the disease really gets the upper hand on us. So, can you tell us a little bit about the data? What did you find when you combined these two approaches?

Petros Grivas: Absolutely, Alicia. So, with this caveat in mind, and then this selection bias in a single arm phase two study and the lack of randomization, we have to keep these baseline factors in mind how we interpret the data. So, we had 41 patients in this study and we wanted to see at least 13 responses to reject the null hypothesis that the response rate was at 20% or less. So, with that in mind, we actually had 14 responses out of 41 patients. So, it's a 34% objective response rate. And about 11 additional patients had stable disease as best response. So, we talk about a clinical benefit rate of 61% and about two thirds of the patients had some degree of reduction in the tumor size. So, overall significant activity, 63% had tumor shrink cut on scans. The median time to response was two months and the median duration of response and median overall survival were not reached yet with a median follow up of 5.8 months. The median PFS was 5.5 months. That's a key summary of the efficacy and points.

Alicia Morgans: So, as you think about this data and you try to pull it apart, I think one of the most important questions is how much the pembrolizumab might be adding to the SG. The response rates that you've discussed are clearly higher than we would expect, or that I would expect at least from pembrolizumab as a single agent. So, really then I would think, what is this adding to the SG which I also would expect to have a reasonable response rate? What are your thoughts there?

Petros Grivas:It's a great question, Alicia, and it's always hard to discern and compare across different lines of setting. First line, second line, third line, especially with the confounding factor and selection bias of the patient population that make up your study. I would say yeah, if you want to talk about additive or logistic effects, you probably may want to see a higher number of responses. But again, it's hard to compare apples and oranges. I think that my personal bias here is that we take into account the very poor prognostic factors in this patient population. A response rate of 34%, the second line setting is promising and definitely supports in my opinion, further investigation of this combination. The question is, where do you go next? Do you do a second line trial? Do you go further and you go to frontline? Do you do a IO plus Sacituzumab govitecan in the frontline setting? I think it's probably reasonable to consider that.

Again, in the frontline setting, you have a different makeup of patients so you make up much higher benefits. So, I think it's interesting in the cohort four and five of this study who are evaluating Sacituzumab in combination with cisplatin in the cohort four followed by maintenance avelumab plus Sacituzumab which is an interesting cohort we don't have data yet. And cohort five are going to look at the triplets. Will be cisplatin plus Sacituzumab plus avelumab, and then maintenance therapy. So, will be interesting to see how this plays out but I think based on what we discussed, this combination looks promising and merits further investigation.

Alicia Morgans: That is a perfect answer for an impossible question. So, thank you for humoring me on that. And I agree. I do look forward to seeing where this goes and certainly shifting the population a little bit will be interesting. And in a larger study where you can compare against SG alone or pembro alone, whichever is the design of the study, you will be able to answer that question more fully. But as we wrap up, I'd love to hear how did the toxicity profile come out for this study? Because certainly we would think that these do not have overlapping toxicities necessarily, although there's always at least in my mind, the question of whether something that releases a lot of neoantigens in the setting of a checkpoint inhibitor may lead to some higher rates of immune related toxicity. So, what did you see?

Petros Grivas: Great question, Alicia. And always the efficacy data should be taken into the context of safety toxicity data. If you look at the treatment related adverse events and focus our discussion on that, we saw about 70% diarrhea of any grade. If you look more in detail, 20% of patients, one out of five had grade three or four diarrhea. Usually these patients can be managed as an outpatient with only few needing hospitalization. Hydration and diarrhea medications, education of patients are important. Overall, I would say, if you look at the grade three, four adverse event rate treatment related was 59%. And in specifically 39% of patients had some reduction of the Sacituzumab dose because of toxicity. There was no treatment related deaths. And if you look at the patients who had immune related adverse events, I would say a quarter of the patients, 10 out of 41 had some degree of steroid exposure. But about half of them were topical.

So, only 10% of patients, four out of 41, required systemic steroids. Two for diarrhea, one for pruritus, one for rash. So, what you see there is that the requirement for oral steroids is very similar to what you see with pembro alone. There was no increase there. And the last point I will make Alicia is the neutropenia. This is a classical side effect of Sacituzumab. The rate of febrile neutropenia was 10%. So, four patients out of 41. And none of those four patients had previously received growth factor. And growth factor support was given in only 29% in this patient population. So, growth factor could potentially help in terms of addressing neutropenia.

Alicia Morgans: That's all very, very helpful. And we'll have to talk at another time about how you tease apart diarrhea related to SG versus an immune related colitis. So, I feel like we will have to have a whole sort of discussion around how we kind of tease out those side effects. But for now, I'd love to hear your summary of this data and congratulations again on your work.

Petros Grivas: Alicia, thank you. In summary, I would say in a platinum refractory, I would say population with many negative prognostic factors based on the platinum refractory setting, [Belmory 00:10:49] score, based on the low response to prior platinum chemotherapy and the short time that the labs between prior chemo and a screening for this cohort, the data of Sacituzumab govitecan plus pembro showed an encouraging anti-tumor activity. Overall response rate, 34% in the 10 to three population meeting our primary objective. We want to see at least 13 responses. We saw 14. Clinical benefit rates 61%. Median PFS, 5.5 months. Median duration of response, median OS not yet. Toxicity profile, it's what probably you would expect from individual agents. It was, I would say overall manageable. Diarrhea needs some further attention of course, as we discussed. And there was no increase in systemic response required a newly adverse event rate.

This was reassuring that it's manageable and no other new safety signals. So, I think the data support further evaluation of this combination, either in the second line or even in the frontline setting, I would argue. And obviously, there's a lot of ongoing work on biomarkers and the other cohorts of the TROPHY user one study. Cohort four and five are still running and cohort two. And of course, a phase III TROPiCS-04 trial that looks at Sacituzumab govitecan monotherapy versus taxane. And this is in third or fourth line setting. So, we're very excited about the program and hopefully to be able to show you more data in the future.

Alicia Morgans: Fantastic. Thank you so much for your efforts. Thank you to all the patients of course, and we really appreciate your time and expertise.

Petros Grivas: Thanks to all the patients who are the reason for what we do. Thank you for having me, Alicia.