Alicia Morgans: Hi, I'm so happy to be here with Dr. Petros Grivas, who's a professor of medicine and the clinical director of the Genitourinary Cancer Program at the University of Washington and at the Fred Hutchinson Cancer Center in Seattle. Thank you so much for being here with me today, Professor Grivas.

Petros Grivas: Thank you so much, Dr. Morgans. It's always a pleasure. Great to see you and learn from you, as always.

Alicia Morgans: Well, always a wonderful thing to learn from you too, and today we're really going to be learning about the TROPHY-U-01 cohort 3 data that was up updated at GU ASCO 2023. Can you tell me a little bit about it, please?

Petros Grivas: Absolutely. Alicia, thank you for asking and highlighting this important study. This is a phase II trial looking at the combination of pembrolizumab, anti-PD-1, plus sacituzumab govitecan, let's call it SG, an antibody-drug conjugate against Trop-2, carrying a payload with the SN-38, the metabolite of irinotecan, topoisomerase I inhibitor. That combination was evaluated in 41 patients who had early progression resistance to platinum-based chemotherapy as a second-line therapy.

We evaluated this population because we know that patients who have early progression on platinum-based chemotherapy usually do not do that well. We recently published a manuscript, Alicia, with a number of great mentees and we looked at the time to progression on chemotherapy, and the shorter the time, the earlier resistance for progression platinum-based chemotherapy, the worse the outcomes were with single-agent sequel inhibitor second line. So, definitely we need combinations in that particular setting.

We looked at this combination, SG plus Pembro. As I mentioned, 41 patients in the second line setting after platinum refractory disease. About half of the patients had received platinum-based chemotherapy in the neoadjuvant or adjuvant setting and the other half in first-line treatment of metastatic disease. Interestingly, the response rate to platinum-based chemo was low, was much lower than expected, again, with a short time to progression. In that phase II study, the primary endpoint was overall response rate based on independent blinded central review. We want to see at least 17 responses out 41 patients to carry this as a positive trial and move it forward to, potentially, phase III. We used the RECIST 1.1 criteria and we have, of course, secondary endpoints of clinical benefit rate, PFS, OS, toxicity, and safety.

Briefly, I can tell you, Alicia, that for out of 41 patients, 34 were male and most of patients had equal P0 to 1. About, I would say, 80% or so had visceral metastasis, and approximately 30% had liver metastasis, with three-quarters of the patients had at least one valuable risk factor. So definitely a prognostically challenged group with usually adverse prognostic factors and challenging prognosis.

Jumping to the results, we actually show that the overall response rate was 17 out of 41 patients, exactly what the target was, translating to a 41% overall response rate based on independent blinded scan review, and about half of those responses, 20%, was a complete response, which I think is pretty remarkable for this patient population. The other interesting finding was the median duration of response was more than 11 months, which I think is relevant and gives you a sense that pembrolizumab may add value in that case by deepening the response, increasing the response rate, and producing some more durable responses similar to what we have seen with other ADC/IO combinations.

In the waterfall plot, we see that about 3 out of 4 patients, 72%, had reduction in the tumor size, which I think was a very relevant finding. The median PFS and OS were very promising. I think median PFS was about 5.3 months and median OS was more than a year, approaching 13 months. So I think, overall, very promising signal. Most responses were rapid at the time of the first scan.

Toxicity was as expected with each agent by itself, with diarrhea being a prominent side effect. About 70% of patients had diarrhea, mostly was grade 1, grade 2 and usually managed by education, hydration, and anti-diarrhea medications. Nausea and bone marrow suppression was also noted. There was a 10% febrile neutropenia, which is exactly what you see with SG alone. So, overall, I would say we use growth factor in those patients. Even off-trial we do much better and have much less chance of febrile neutropenia, so I have incorporated using growth factor in my practice for those patients.

Overall, the combination was feasible and toxicity profile was, overall, manageable, with what we expect to see from either agent alone. I think we had about 39% of patients had dose reduction of SG and about 15% discontinuation. We're excited about the data and there was no treatment-related death on the study. And I think the question is, where we go from here? In my humble opinion, the signal is strong enough to consider a phase III trial, and that's what we're discussing right now with the investigator team.

Alicia Morgans: Well, I think that that really is exciting and especially let's focus in on the 20% of patients with a complete response, which seems to be a change in what was initially reported. You did have a preliminary report of data describing this combination, and with further follow up, it seems that more patients seem to have achieved that complete response status. Can you tell me a little bit about that?

Petros Grivas: Yeah, I think, as you said, Alicia, it's very interesting, because if we look at the historical data with pembrolizumab alone, we've seen about 20% of overall response rate in these patients. And we saw the double with the combination here. As you said, 8 out of 17 responses were complete responders. Median duration of response, 11 months. That's very meaningful. We're going to actively, actually, look at the breakdown of those complete responders, and we have a nice spider plot and manuscripts is under review. So, hopefully, we can show some more granularity of those patients in the manuscript.

The other thing I would say is that we are all discussing about the concept of therapy de-escalation and I think we have to start somewhere. And I think, for now sacituzumab govitecan, is given to progression or toxicity. Of course, with dose reduction it's something we can try to maintain the patient on. But eventually, even in the broader context of ADCs and IO combinations, it will be ideal if we can have a fine-tuned benefit risk ratio, and maybe we go to a maintenance strategy down the road with maybe one of the drugs. Overall, I think that 20% complete response rate in the second-line setting is something we do not see that often, even with chemotherapy with historical data. And, of course, we saw a 20% complete response rate within enfortumab second line after second inhibition in EV-201 cohort two. But, definitely raises enthusiasm.

Alicia Morgans: Well, it is very interesting. Now, one thing that can be, I think, potentially challenging for people who have less experience with SG than you do is the diarrhea, and especially when we combine with pembrolizumab, which also could be associated with an ICI-associated colitis, it is absolutely something that clinicians will need to be able to understand and differentiate so that they can best deal with the underlying cause and then fix that for their patient. Do you have any guidance or any words of wisdom on that? And also, did you see a higher rate of diarrhea in this combination study than you did in studies that really were just assessing the single agent of sacituzumab govitecan?

Petros Grivas: Alicia, great question. Diarrhea, to your point, can be potentially caused by either checkpoint inhibition or sacituzumab. I think the majority of the events in that combination are probably because of the sacituzumab govitecan. It's usually situational around the administration of the drug and usually managed with anti-diarrhea medications. I think from the practical standpoint, I think if someone has the type of diarrhea you would expect based on the timing, temporarily just happening a few days after sacituzumab administration with just loose stool, not voluminous diarrhea, no other symptoms, I think it's reasonable to try some anti-diarrhea medications. And that usually results to improve many of the symptoms and can give you a satisfaction that is most probably with managing this, and also give you some sense that this is probably related to saci.

If, of course, it continues, it's probably good to rule out infection as what may happen in those patients, but also keep in mind the immune-related colitis, which is not common, it can happen in a small proportion of patients, but if the diarrhea is loose stool and the pattern of the diarrhea, voluminous, high-volume, and unrelated temporarily with such administration and not improved with anti-diarrhea medication in the absence of infection, I think we should have definitely low threshold evaluating for colitis. There's strong collaborations with GI teams to do these stool analyses, potential starting steroids, and do colonoscopies in patients with immunotherapy. But at least in our study, we did not see higher proportion of colitis compared to what you would expect with Pembro alone, and the proportion of patients who received systemic steroids was exactly in line with what we have seen with checkpoint inhibitor monotherapies.

Alicia Morgans: Great. Well, thank you for that. I think you are one of the most knowledgeable on this combination and I think it's great for clinicians to have that guidance as they try to consider this combination, potentially, moving forward, especially as it goes out into a phase III trial. Hopefully, fingers crossed. If you had to sum up this presentation and the data on the combination of sacituzumab govitecan and pembrolizumab, what would your summary be?

Petros Grivas: Alicia, I would say I'm very enthusiastic about the signal. These data are not practice changing. I'm not recommending doing this combination in clinical practice right now, but I'm definitely supporting and I'm trying to get the consensus needed for a phase III trial. To your point, I think the efficacy signal in combination with a manageable overall safety profile makes the case. I think the next step is also to look at potential biomarkers. For example, Trop-2 protein expression, UGT1A1, gene polymorphisms and associations with efficacy and toxicity, and potentially other biomarkers are something we're looking down the road.

I think, overall, the future is brighter with the concept of ADCs plus immunotherapy combinations. We have to figure out the right sequences. People are asking me what I think about the Pembro EV vs Pembro SG. It's a reasonable question. The problem is we have different treatment settings and therapy lines where these combos have been tested, so it's hard to compare apples and oranges. Obviously, Pembro EV response rates look much higher, but I think its chemotherapy naive patients in the first line is different than platinum refractory and early platinum progression. So, it's good to have options and at least good to evaluate them at clinical trials, Alicia.

Alicia Morgans: Yes, I completely agree. And although this is not ready for prime-time in the clinic yet, we do look forward to seeing this move hopefully into a phase III. Clinicians, be on the lookout. If it moves into a phase III and you have eligible patients, we will definitely encourage you to send them to the centers that have the study open so that they could potentially help support further learning and hopefully have an active drug combination in their treatment paradigm. So, thank you so much for your time and your expertise tonight, Dr. Grivas.

Petros Grivas: Thank you so much, Dr. Morgans. Always a pleasure to talk to you and looking forward for further research down the road. Appreciate you.

Alicia Morgans: Appreciate you. Thank you.