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Ashish Kamat: Hello everybody, and welcome to UroToday's Bladder Cancer Center of Excellence. I'm Ashish Kamat, professor of Urologic Oncology at MD Anderson Cancer Center, and it's a distinct pleasure to welcome to the forum a dear friend and a bladder cancer expert, Professor Shilpa Gupta.

Shilpa is joining us today in a dual role as an expert who's going to present to us the best of ASCO in advanced bladder cancer, but also this is sort of like an inaugural kickoff for you, Shilpa, because you're joining the UroToday Center of Excellence as the editor-in-chief for the Advanced Bladder Cancer section. So in your dual role today, Shilpa, welcome and thanks for taking the time and the stage is yours.

Shilpa Gupta: Thank you, Ashish. I would like to thank you and UroToday for this opportunity. I am happy to discuss the best of ASCO in Advanced Bladder Cancer and look forward to working with you and the team as the editor moving forward.

So for the best of ASCO 2024, I chose these three abstracts, which I'll briefly go over. One is the abstract 4509, where characterization of complete responders to Nivo GemCis versus GemCis alone in patients with lymph node-only metastatic urothelial cancer from the CheckMate-901 trial was presented by Dr. Galsky. The second abstract is the patient-reported outcomes from the phase three trial of EV Pembro versus platinum chemotherapy from the EV-302 trial, which I had the honor to present. And the third abstract is an interesting correlative aspect of circulating tumor DNA assessment in patients in advanced urothelial cancer treated with Pembrolizumab or platinum-based chemotherapy from the KEYNOTE-361 trial.

Starting with our first abstract, I just want to refresh the audience with the study design of CheckMate-901. In question here are the patients who are cisplatin eligible who were randomized to Nivolumab and GemCis. So chemotherapy up to six cycles and Nivolumab for a total of two years versus up to six cycles of chemotherapy only. The majority of these patients did not get maintenance immunotherapy in the chemotherapy arm. The study previously met the primary endpoint of overall survival and progression-free survival improvement. As we can see here, overall survival with the immunotherapy chemo doublet was 21.7 months versus 18.9 months with chemo alone. And in this ASCO meeting, they looked at the complete responders, specifically, and how the patients with lymph node metastasis did with the Nivolumab GemCis.

So if we look at the two groups, Nivo GemCis and GemCis alone, about 18% of patients had lymph node-positive disease. And in that, we can see the baseline characteristics here. The majority had bladder cancer, and as expected, the majority had an ECOG performance status of 2. Also, we know that lymph node-only metastasis is a good prognostic sign. No matter what patients get, they will do well. And in this, we see that when patients got Nivo GemCis, the twelve-month CR rate was 70% compared to GemCis alone, which was 32%. And the CR rates were 34% with Nivo GemCis versus 19% with GemCis alone.

So here, as you can see, the maximum benefit seen was in the pelvic lymph nodes and also the distant lymph nodes, but not the retro-peritoneal lymph nodes as much. But overall, this was encouraging to see. The progression-free survival in patients with lymph node-only disease here was 30.5 months with Nivo GemCis versus 8.8 months with GemCis. And the overall survival, the median OS, was 46.3 months versus 24.9 months with chemo.

So in summary, this exploratory analysis with lymph node-only disease patients from the CheckMate-901 trial shows that Nivo GemCis induced durable disease control and clinically meaningful improvements in overall survival and progression-free survival with a fixed duration of GemCis and up to two years of Nivo. We know that EV-Pembro is also the new standard of care and the preferred standard of care. So in patients where we are not using EV-Pembro, this is certainly a reasonable option, especially given the limited duration of treatment.

The next abstract was the patient-reported outcomes from the EV-302 trial, and this is the study design. Previously untreated advanced urethral cancer patients were treated with EV and Pembro versus platinum-based chemotherapy. And the point to be noted here is that platinum chemo was for up to six cycles. EV-Pembro, in this study, Pembrolizumab was up to two years maximum duration and there was no end duration for EV, so it continued until patients had loss of benefit or adverse events they couldn't tolerate further.

The key here was the efficacy and safety endpoints were previously shown to be really remarkable, setting this as the new standard. It met the PFS and OS endpoints. But the highlight of this presentation was the patient-reported outcome endpoints, which we had as a key secondary endpoint of time to pain progression changed from baseline in the brief pain inventory versus pain at week 26. And this actually, the time to pain progression, had its alpha allocated, so it was a predefined endpoint. And there were other pre-specified endpoints which were descriptive with no adjustment for multiplicity.

So these were the data we have seen previously at ESMO. It nearly doubled the median progression-free survival and overall survival with EV-Pembro compared to chemo. Really impressive hazard ratios and P-values.

And the overall safety summary, we have also seen it was generally manageable with EV-Pembro consistent with previous studies. But the nature of toxicities was very different from chemo. For example, peripheral neuropathy, rash, and diarrhea were key toxicities patients had with EV-Pembro compared to myelosuppression with chemo.

I want to highlight here that the PRO collection occurred at baseline, then weekly for 12 weeks, and then every three weeks beyond the end of treatment and progression through survival follow-up, which is really a unique aspect because all of the PRO studies stopped when the treatment stops. But in this, patients filled the surveys even when they were progressing through treatment and were on subsequent treatments, which is really capturing the entire journey of a patient.

The two questionnaires we used were the EORTC QLQ-C30, which consisted of cancer-related symptoms, function, quality of life, global health status, and the brief pain inventory. The time to pain progression and mean change from baseline and worst pain was the pre-specified endpoint, like I mentioned earlier.

The PRO compliance remained over 70% through week 17 in the chemo arm and week 29 in the EV-Pembro arm. And again, this is also due to the fact that the chemo ended at six cycles, so patients had less contact with the study team, and if they progressed, they were really less motivated to fill the surveys. And with EV-Pembro, because they were coming to the clinic a lot as EV never really stopped, it's expected to see these changes. Time to pain progression was not statistically significant with EV-Pembro compared to chemo. But then a lot of patients don't have that much pain at baseline. When we look at the change in worst pain, although predefined clinically meaningful thresholds were not met in either treatment arm, we saw that EV-Pembro treated patients reported improved pain compared to baseline. As we can see here, the green arrow going downwards is improvement, the red arrow going upwards is worsening, and larger improvements were seen with EV-Pembro.

When we focused on patients who had moderate to severe pain at baseline from the disease, which is about a third of patients, we saw that both groups had clinically meaningful improvements in the worst pain, but there were larger improvements with EV-Pembro.

And change in the quality of life and the global health status, we see that patients in the chemotherapy arm had a transient worsening from week one to week 17, and patients in EV-Pembro had a transient worsening at week three, returning to baseline at week four. Improvement is designated as going up, and we do see that there were not clinically meaningful differences between the two groups.

And this is, I think we see some striking changes here, in this slide. When we look at patients with moderate to severe pain at baseline, the patients treated with EV-Pembro had a clinically meaningful improvement in the quality of life scores, where a ten-point change is considered clinically meaningful. As we can see here in the chemo arm, patients really don't reach that clinically meaningful threshold. And across cisplatin-eligible and cisplatin-ineligible subgroups, we see that in the cisplatin-eligible subgroups, patients with EV-Pembro fared a little better than those who are cisplatin ineligible. And also, this slide shows the differences in the chemo arm. We know that cisplatin is a little harder to give than carboplatin and patients have more comorbidities, but EV-Pembro performs consistently across both arms.

And in this, we see that across all the functioning domains, EV-Pembro was favored over chemotherapy in terms of all the functioning across physical, social, cognitive, and emotional.

So in summary, EV-Pembro significantly improved progression-free survival and overall survival in frontline advanced urothelial cancer patients compared to chemo without detriment to the global health status, quality of life, pain, or functioning, especially in patients with moderate to severe pain at baseline where there were clinically meaningful improvements. And data collection across the entire journey was a notable approach, and this can help us inform future trials.

The third abstract is from the KEYNOTE-361 trial, which was a negative trial, but this abstract looked at circulating tumor DNA assessment in patients treated with Pembro or platinum-based chemo and was presented by Dr. Tom Powles, who was the lead author of the KEYNOTE-361 trial. For the purposes of putting things into perspective, this was the original study KEYNOTE-361 where newly diagnosed patients were randomized to Pembrolizumab or Pembrolizumab and chemotherapy or chemotherapy alone. And patients who were randomized to Pembrolizumab alone were those who were cisplatin ineligible.

In the ctDNA sub-study, the authors looked at the serial testing of ctDNA at baseline and for cycle two, but not beyond that. So these results are merely hypothesis generating and the first results we are seeing in a metastatic setting. So I'll say here that it was interesting to see that the association between baseline ctDNA level and the clinical treatment outcomes differed a bit and favored Pembrolizumab. If, let's say, patients had higher ctDNA at baseline, they did better with Pembro, but they had higher clearance at cycle two with chemotherapy, as we can see here, 41% versus 11%. And when we look at the TMB status and PD-L1 high status against all exploratory, it seems like the patients who had high TMB and high PD-L1 seemed to do better with Pembro.

So as a conclusion of this abstract, I'll say that ctDNA levels at baseline appear prognostic for Pembro, and reductions during cycle one were associated with the outcomes. And the patterns were different between Pembro and chemo, and early dynamics did not really offer additional benefit in predicting outcomes. And the limitation of this study was that there were no serial collections beyond cycle two. So that really does not tell us what happened to these patients later on.

Ashish Kamat: Thank you so much, Shilpa, for that succinct presentation. I know it must have been really hard for you with so many exciting things happening at ASCO for you to just drill down on three, but I think those are the three ones that most people need to know about, right? You presented everything really well. So I'll just ask you one question for the benefit of our audience and the audience is a global audience. So with that in mind, what can our audience and oncologists today take away from what was presented, and the three abstracts that you presented, and use to implement in their practice right now?

Shilpa Gupta: I think these presentations merely consolidated what we have already known. So EV Pembro, as you know, is just the preferred front-line treatment for NCCN guidelines and also now in the ESMO guidelines, although they don't have access to it yet. So I'd say that EV Pembro, the clinical benefit seen is unprecedented, and with the PRO outcomes, seeing that it did not deteriorate their quality of life or pain is reassuring. So if people can use it, that just reassures them that this will not lead to a worsening in quality of life.

With GemCis Nivo, that is also an approved regimen and category one, but not the preferred option. But we know that not everybody can get EV Pembro or may not have access to it. So if patients are getting GemCis Nivo, especially if they have only lymph node disease, they will really outperform chemo. And we've also seen in the past that those patients really do well just with chemo, also, followed by immunotherapy. So I think whatever people choose to do in the frontline setting, I think the options that we have now are all well-tolerated and manageable, so this was reassuring.

Ashish Kamat: No, I was just going to say regarding the ctDNA, of course.

Shilpa Gupta: Yeah, I was saying that it's not ready for prime time, but this was good hypothesis generating data, I think.

Ashish Kamat: Right. Everybody seems to be jumping on the ctDNA bandwagon, which I think is great enthusiasm, but we need to remember, we need to study it, it needs to be validated. It's still, at this point, something that is a research tool, but I expect it'll be something we use in clinical practice, but it's not ready yet.

And I really like the way you summarized the whole chemo EV Pembro aspect because clearly, we have a major improvement in response and survival, but we do have to keep in mind the potential financial toxicity that our patients across the globe have to face. And access is an important thing as well.

Shilpa, once again, thank you for taking the time. This was great. Great to have you on board.

Shilpa Gupta: Thank you, Ashish.