Sam Chang: Hello, my name is Sam Chang. I'm a Urologist at Vanderbilt University in Nashville, Tennessee, and we really have an honor and privilege today to have Professor Alison Birtle. Professor Birtle obviously needs no introduction in the world of upper tract urothelial carcinoma for actually any GU Oncology. She is the Professor and actually a Consulting Oncologist in Lancashire, England. And she is here to actually give us the updated final results of the POUT trial, which I remember first hearing her actually abstract presentation at the plenary session at ASCO GU in 2018. She deserved and received great recognition for actually completing a randomized clinical trial in upper tract urothelial carcinoma, so we really have a great honor and privilege today, and thank you so much for spending some time with us.

Alison Birtle: Oh, Sam, I mean, what can I say after such an introduction? That was wonderful, and I'm delighted to be able to come and share the final results of POUT today. And of course, the first thing is that we would never have completed this study at all without the 75 centers across the UK who contributed at least one center in the real uro-oncology community who got behind the study together with our funders at Cancer Research UK, but also the patients, their families who so generously gave of their time, and our two patient representatives on the study who were Chris Harris, who was with me from the day we started conceiving the study when we had the first idea about POUT until the day that he died. And then Andrew Winterbottom, who was also a patient representative on the group who was again with the trial until he died.

And it's important that we mention those two extraordinary gentlemen every time I talk about POUT. So I'm delighted to share some of the slides with you today. So these are the final results that were published in the JCO just a month or so ago. And I'm delighted to tell you that for anybody who really wants to be up-to-date, we did have a letter that was submitted about some of the statistics with this paper. And we have a response to that, that's going to press right as we speak at the moment. So that's hot off the press. So this is the final data from POUT. And of course, POUT was originally set up because of the unmet need in this patient group in UTUC because we know this disease entity is completely different from bladder cancer. It's a bit like a non-identical twin in that respect, in that it has some similarities, but very different outcomes, and very different molecular characteristics.

And so this was an area of unmet need and it was an adjuvant study because we did a survey beforehand throughout the UK of service users. So we put together two groups of patients and focus groups. We also put together urologists and oncologists across the UK asking what did they currently do with patients with high-risk UTUC and was there enthusiasm for a study and should that study be neoadjuvant or adjuvant? And there was a unanimous decision from our urologists and oncologists that this should be an adjuvant study. And that was around the difficulty in diagnostics being certain beforehand that patients truly have a locally advanced UTUC.

And so this was an adjuvant study and the primary endpoint was three-year disease-free survival. And that was chosen because it seemed to be that patients, particularly with T3 or T4 tumors would relapse within that time period, so an important endpoint. And we chose this as an endpoint rather than overall survival because in a study with a rare incident tumor, you need to do two things. You need to get the design right, which is why we went to clinicians across the UK and to patients. But also, you need to make certain that you can deliver that study from a numbers viewpoint. And doing the primary endpoint of OS would just have made the trial far too big, remembering that this was the trial that people said could it be done because it was a rare incident tumor.

So the study was very pragmatic. There were no sexy drugs involved, it was standard chemotherapy. And the patients who were suitable had to have completely resected T2 to T4 disease. They could be node positive. But remembering within the study that we did not mandate a lymph node dissection, and that was because again, our surgical subgroup did a survey across the whole of the UK. And at that point, and indeed to date, an extended lymph node dissection or any formal lymph node dissection was not part of standard of care. So if there were any visible nodes on the scan, it was resected, but otherwise, there was not a formal lymph node dissection. And patients were randomized on a one-to-one basis to either surveillance or four cycles of adjuvant chemotherapy. That chemotherapy was either Gemcis or Gemcarbo. And the only reason to choose Gemcarbo was because of suboptimal renal function. And patients with a GFR of between 30 and 49 were randomized to Gemcarbo rather than to Gemcis.

And that had to be stipulated by centers at the outset. Follow-up was very pragmatic with standard imaging, standard cystoscopic assessments, and quality of life data embedded. And we also did a qualitative sub-study, which is looking at the language that we used in consultations to start off with, so we could then give top tips to people who recruited to the study.

So as you've already alluded to Sam, we presented this data many years ago now, the initial data at ASCO GU in 2018, and that was because we met the primary endpoint of three-year disease-free survival early. We met it at two years and we had at that point, a median follow-up of 30 months. We then continued with survival follow-up, which is what we're presenting today. We also presented some of the pre-planned analysis, which was triggered after 88 deaths at ASCO GU 2021.

So this was the original efficacy data from 2018. The study recruited from 2012 until 2017 and we stopped short of the number of patients we needed to make this a robust study for overall survival as our secondary endpoint. And that was because we'd met the primary endpoint of disease-free survival and metastasis-free survival early. And so the IDMC met and said, "Look, we can't carry on recruiting to the study because it would be unethical because you've met your primary endpoint, and we could discuss whether that was the right or wrong thing to do because the overall survival data is obviously underpowered." But nevertheless, I think from a patient viewpoint, it would've been very difficult to have continued recruiting.

So this was the original data; you can see at three and five years. There was a strong signal in favor of treatment effect from chemotherapy for both disease-free survival and metastasis-free survival. And these were across all of our pre-planned subgroups for chemotherapy type, margin status, and nodal status. This was the overall survival data at the time; it was immature, but just to remind you, this wasn't powered for overall survival because we had shut early. We shut at 261 patients rather than the number we originally wanted, which was 345.

So these are the updated analyses, and you can see we still have that magic difference in DFS and metastasis-free survival in favor of chemotherapy. And what this shows is that at five years, we still have a strong treatment effect with a very strong hazard ratio in both disease-free survival and metastasis-free survival. We can also see that you do have a separation of the curves in terms of overall survival. And what the new paper shows is that it did meet the criteria for improvement in OS on univariate analysis, and on multivariate analysis, there was a strong trend towards an overall survival benefit. And that survival benefit was seen most in years three and four. We also saw no new safety signals with longer follow-up. We've given this chemotherapy for years in urothelial cancer, we know what side effects to expect, and there was nothing different with the extended follow-up.

We could also see that the quality of life was maintained. If we look at the Forest Plot, what you can see here is that this really strengthens some of the questions originally that were around the carboplatin data, but you can see that the carboplatin data remains robust. The only reason to use carboplatin was because of poor GFR, and where the wider confidence intervals are, this is because, in particular with the nodal status patients, since there wasn't a formal node dissection mandated, then you had fewer patients. But there is still no reason to suspect that the treatment effect would be less in these groups of patients. In fact, that would be a rather foolish thing to assume.

So that's the end of my slides. What POUT showed was that we have strengthened the data around carboplatin. We've strengthened the data in terms of the five-year disease-free survival benefit. There is a strong trend on multivariate analysis towards an overall survival benefit of 12%. There is a statistically significant benefit on univariate analysis. And we also presented, which I haven't shown on these slides, that there is no impact on bladder cancer recurrence by giving chemotherapy. There was no difference between the two.

Sam Chang: You stole my question here already.

Alison Birtle: Sorry.

Sam Chang: That was actually a question I had. As I see all this, I had not heard yet what happens to the bladder and/or the contralateral upper tract. So at this point at least, it seems from what you just said, systemic chemotherapy did not impact the recurrence rate within the bladder. How about the contralateral upper tract? Did you see any difference there?

Alison Birtle: No. And interestingly, when we looked at the bladder recurrence, I think that just probably emphasizes the fact that lower and upper tract are different beasts, really. So it would be interesting, we are analyzing at the moment the samples that we collected in POUT, looking at things like FGFR receptor status. And I think that's going to be very interesting when we look at future targets in this disease setting.

Sam Chang: No, that's a great point. And obviously, looking at, as you say, if you look along the molecular level, obviously, there are some similarities, but within the same patient, there clearly seem to be differences in the upper tract versus the lower tract. And it will be, as you gather more information and look at the tissue, to be able to see if you can tease out those differences. But it's a message that I think from a urologist standpoint, we need to continue to emphasize: we need to continue to monitor these patients in their lower tract and to make sure that they continue to get cystoscopies.

Honestly, I think that's often kind of forgotten, at least in the US. We have the advantages of multidisciplinary care. But at times, I think the urologists forget, to be honest, that you've got to keep an eye on this lower tract. So with this data over the past few years, it clearly has changed the landscape. It has set a new standard of care, honestly, when we have these patients. As you counsel these patients both before and after surgery, what really drives the decision? You think it's higher risk disease, the health of the patient? What really comes into play as you have the discussions with the patients regarding the decision on whether or not to receive adjuvant therapy?

Alison Birtle: So I think what we learned from the qualitative sub-study of POUT, which we don't often talk too much about, but these were taped recordings. The patients consented separately so that we could gather information and analyze it about the language that we use when we talk to patients. And then from that, we brought out top tips, which we did separate versions for urologists, oncologists, clinical nurse specialists, research nurses, et cetera. And what was really obvious was that if you come back for your histology visit to your urologist and your urologist says, "I've got it all out," you immediately close the door on any discussion around adjuvant treatment because that patient hears, "I've got it all out." And so they interpret that as, I need no extra treatment unless you say, well, look, we need to wait until your pathology comes back, and this is beforehand, we need to wait until the results come back because you may need some extra treatment depending on what we find, which is a discussion we have in breast cancer.

We have it in bowel cancer, we have it in every setting where there's adjuvant treatment given, but we weren't doing it at all in upper tract disease. And so we were closing the door, and that was the biggest thing that we found, that discussion with the urologist is vitally important. So if we just say to patients ahead of time, "Look, we just need to see what is the difference, what's the pathology when you come back for your first visit? And then we'll make a final decision about whether you need anything to reduce your risk of recurrence." Because the other thing we realized is patients weren't being told about the risk of recurrence. So they were being told that actually you've had all that you need. And the impression that patients were being given was that it would never come back. And obviously, that's not the case when we've got something which is bladder cancer itself is a systemic illness, and UTUC has a higher recurrence rate than bladder cancer.

So we just need to be open about patients. And when we've got something where we can say, "Look, this is going to reduce your chance of recurrence, there's a 17% difference." If this was breast cancer, they like things like 5% improvement. So we've had drugs that cost lots of money reimbursed on a tiny amount, and this is cheap as chips chemotherapy, and its 17% difference in DFS with a strong trend of 9% to OS.

So this is really important data. And I think the other thing is that we might've expected because of the molecular makeup of UTUC, that checkpoint inhibitors would be really exciting in this space. And it's been an utter disappointment because the adjuvant studies that we've had looking at checkpoint inhibitors are resoundingly negative in UTUC. And you can have all the caveats, you want to say they're smaller numbers, but of course, they're always going to be smaller numbers because it's a rare cancer, but it's been resoundingly negative, whichever way you cut it, whichever checkpoint inhibitor you look at, whether it's atezo, it's pembro, whether it's nevo, they've all been negative. And we've sort of answered that question already, how many more times do we need to look at it? It's done.

Sam Chang: I think those two points are under, at least in the US for sure, underappreciated, the continued need for evaluating the bladder. But the point that you raised regarding it's up to the surgeon at the time or honestly prior to the surgery to mention and to counsel to make sure that they understand that as part of this whole process, is that we need to consider systemic therapy depending upon just as you said, what the pathology shows. And I found quite telling when you said, when the urologists or the surgeons basically say it's all out, that that door has shut. That quotation, I think really carries a lot of weight because from a patient standpoint, it does really then decrease kind of the impact of any other possible therapy in their mind, as you say. So Alison, has that been published anywhere? I know you all have videos and you presented that, but has that been published anywhere? Because I would love to make sure that we know that more in the US.

Alison Birtle: Yeah, I mean I think we talked about it, but I don't think we directly published it. And obviously, there are a number of other things that we're looking at publishing, not least sort of things from the surgical subgroup. But that is a very good point, and I'm going to write myself a note to email the trials team about it because it is the whole qualitative aspect that I think some of it has been less well documented. I mean, I always talk about it because I think that people often don't realize the amount. This was an academic study. It was funded by Cancer Research UK, but it was an academic study and in a rare cancer group with very different randomizations, with clinical equipoise, there were lots of reasons why we should never have been able to do this study, but it did require a huge amount of input from everybody that was involved from the trials team.

But also, if you lead that sort of a study, you have to invest such a lot of your own time into that when it's an academic study. And I think that's the only way that studies with rare cancers can actually work. So as CI, you have to reach out to sites individually, you have to discuss problems, you have to discuss patients that might be challenging in terms of recruitment. I mean, I had to stand by my own protocol when I had an overweight, hypertensive, 76-year-old diabetic whose GFR was 75. So I had to stand by my protocol and say, right, I will give you cisplatin, not carboplatin, because the only reason to get carboplatin would be if your renal function was poor. And to be honest, he got through three cycles before we had any form of an issue at all. And then he had a minor cardiac event, which meant we had to dose reduce the final cycle. But you have to make sense. You stand by your protocol and you commit to it, particularly in these hard-to-randomize, difficult clinical equipoise cancers. And I think I've learned a lot from it.

Sam Chang: We have all learned a lot from all your efforts. And so I want to end this by making sure that you understand the gratitude of not only the academic community but patients with this cancer. Now the focus and the attention for this less common cancer have really increased exponentially, I have to say in large part due to the efforts that you've made to bring this to a multidisciplinary group and to be able to actually now offer these to patients, to counsel patients more wisely. We really are indebted to you and your team and your patients and all your efforts. So I wanted to end this by saying thank you so much, and we look forward to seeing more information coming out from this very, very important study.

Alison Birtle: Thank you ever so much. Very kind.