Ashish Kamat: It gives me great pleasure to welcome you here, Alison.

Alison Birtle: Thank you.

Ashish Kamat: Alison Birtle is a Consultant Oncologist and Senior Lecturer at Rosemere Cancer Center. Thank you so much for taking time off today from a busy GU ASCO schedule.

Alison Birtle: You're very welcome.

Ashish Kamat: So for those of you that don't know Alison, she sort of set the world of upper tract disease on fire recently with a successful completion of a very positive study. And I'd love for you to go over the study in a little bit of detail for our audience, and then the results, and where you think it is taking the field forward.

Alison Birtle: I'd be delighted to. So we all know that there's a real unmet need in upper tract urothelial carcinoma because it's, obviously, less common than bladder cancer. But if you look at it stage for stage, the actual outcome of these patients is much poorer. And there was a real dearth of evidence, we had retrospective case series that were all very small, but there was from one of them, of 43 patients, there was a tantalizing hint of a treatment effect in terms of survival by giving adjuvant chemotherapy. And we know that upper tract urothelial carcinoma shares a lot of similarities with bladder cancer where we know that systemic therapy works. And so we set out to look ... it was a very simple question, there were no exciting new drugs, but the basic question was, does adjuvant chemotherapy reduce the risk of relapse for patients who've had a potentially "curative," in inverted commas, nephroureterectomy?

And I say potentially curative because the population was patients who were T2 to T4 disease who could be node-positive as long as any visible nodes were resected at the time of surgery. And they then had a negative post-operative scan. But these patients, obviously, have a tendency to relapse within the first two to three years post-surgery. So we had a very simple study surveillance compared with four cycles of adjuvant chemotherapy that had to be initiated within 90 days of their surgery. And one of the reasons why, say, the previous studies that Cora Sternberg did in bladder cancer struggled to recruit was because of the morbidity of a cystectomy. Whereas nephroureterectomy is much less of a morbid operation.

So we set out to look for a 15% difference between the two arms and that was powered to look for a survival advantage at three years in terms of disease-free survival. And all patients had to fit the criteria. And the chemotherapy we used was two different regimens that both included gemcitabine on day one and day eight. And then, the second drug was either cisplatin or carboplatin. And the only reason to use carboplatin was GFR. So we know, in real-life, that people use cisplatin down to a GFR of 50. Although, a lot of the trials look at a GFR of 60. Real-life, we all use GFRs of 50. So if your GFR was 50 or above, then you got gemcitabine/cisplatin, if it was between 30 to 49 you got gemcitabine/carboplatin.

Now, if you had a patient who was not fit for cisplatin they weren't allowed to have carboplatin so we didn't want a whole lot of frail patients into the study. And what the study showed was that it was very deliverable. So 75% of patients who got chemotherapy had all four cycles of chemotherapy. We showed that the side effect profile was exactly what you would expect with those drugs, which of course we will use every day in normal practice. And it was also a positive study because what happened was the independent data monitoring committee met and found that there was an improvement in favor of adjuvant chemotherapy at two years rather than three. And rather than a 15% difference, there was a 17% difference. So the hazard ratio is 0.45 and this was across all of the subgroups that we had.

So it's very important to understand that the subgroups were preplanned. None of these were ad hoc added on at the end. So the subgroups we're looking at nodal status, margin status, and type of chemotherapy. And all of those were positive. Although the confidence intervals are wider because of there being fewer numbers in some of those subgroups. So we have, for the first time, a randomized control trial in upper tract urothelial carcinoma of adjuvant therapy that's shown an improvement in disease-free survival with very manageable and expected toxicity. And that should really, now, be the standard of care for these patients.

We also have the first step of quality of life data because, again, it's a niche study, no previous data at all. And what you get is a fall in the overall global quality of life, peaking at around cycle three of chemotherapy. And that seems to be linked to a bit of nausea and vomiting. Interestingly more in the carboplatin group, probably because we don't give as much of the potent antiemetics in that group. And then returning to normal within about a month of finishing chemotherapy. So that's the first quality of life data that we have as well.

Ashish Kamat: That's excellent. And, again, I want to congratulate you on leading the successful completion of a trial in the adjuvant arena. A few critics have often stood up, and I'm sure they've asked you as they've asked others, why not do this in the neoadjuvant setting?

Alison Birtle: So the reason we didn't do this in the neoadjuvant setting were two things. If we go back to when we initiated the study, we go back to 2010 when we were first thinking about it. And we did a survey across the UK looking at what the standard of care was, which was surveillance with chemotherapy given on a case by case basis. And we posed a very simple question, would you want to do a neoadjuvant or an adjuvant study? And there was a lot of concern based on potentially over-treating patients who had T1 disease because no matter how good your diagnostics are you can't be 100% certain before surgery that you're dealing with a T2 tumor, and the majority of these patients were T2. And so there was a worry about over-treating PT1 disease or indeed treating patients who didn't have cancer.

So if we look at, there were two publications, one by Shatar et al, which showed that in patients who were thought to have an obvious upper tract tumor that was invasive on their preoperative CT urograms, about 12% of those patients didn't have cancer at all. And if you look at the mit C study, which is Tim O'Brien's study of giving single shot mitomycin after nephroureterectomy, about 9% of that patient group didn't have either TCC, they didn't have cancer, or it was an adenocarcinoma or a squam. So we were worried about over-treating patients and the oncology community and the urology community in the UK, which is our target population at the time, were much more in favor of an adjuvant study. However, what really clinched it was we did two patient focus groups and we posed the same questions to the patients, and I spent two days with these patients, and they were, again, because of that issue of diagnostic uncertainty they were much keen on having an adjuvant study.

Ashish Kamat: That's interesting. So the patient focus groups were actually factored into the study design, which is critical, and I think we need to do that in the design of more studies going forward. Speaking of going forward, where are you with the study design for the next phase of the POUT? Which, I understand, is called POUT 2, is that correct?

Alison Birtle: We were very innovative and why rock a winning formula? So it is going to be called POUT 2. And, obviously, the standard of care will be chemotherapy using a similar population in terms of eligibility. Although, I think we would look at including some more patients into the carboplatin arm. So we'd look at people who are cisplatin-ineligible not because of frailty, but because of things like tinnitus, or peripheral neuropathy. So it's a little bit more real-life from that viewpoint.

At the moment, obviously, there's some debate about the efficacy of IO in the adjuvant setting, which would be the obvious way to go. However, urothelial cancer is very different, I think, in the upper tract than compared to the lower tract. You've got a higher rate of microsatellite instability, so it may be that you get differences with an IO for upper tract disease than for lower tract disease. And, obviously, the adjuvant studies at the moment with an IO post-cystectomy had an ad hoc amendment to allow no more than 10% of upper tract patients to go into those studies, but that was not a pre-planned subgroup. That was a just add it on at the end because we're not recruiting that well.

But, obviously, there are other agents that have come through in the last few years. We've got quite a lot of interest in the FGFR receptor inhibitors, and EV as well is sort of exploding onto the scene. So I guess it's a work in progress and the design is an understandably being influenced by some of the data that's come through in the last sort of six months or so. The primary publication for POUT, we've all waited for it. That should be out, hopefully, before the end of February 2020 and that will be in the Lancet.

Ashish Kamat: Well, congratulations once again.

Alison Birtle: Thank you.

Ashish Kamat: This has been great. Any closing thoughts for our audience as we wrap up?

Alison Birtle: I think POUT succeeded for a number of reasons. Everybody said it wouldn't, but it succeeded because we had patients involved in every step. So before we went for funding, patients were involved in the design, they were involved in the patient information sheets, and all steps of that. And we had patients on the trial management group. So Andrew Winterbottom, who was the founder of the UK based advocacy group, Fight Bladder Cancer, was instrumental in helping us to get the trial design right.

And I think quite often we forget about that. So we have a really exciting idea for a study, but then the patients don't want to go in it. So you wasted all the money and the effort to get that trial open, and it fails to recruit. And we need to be much more mindful of that now because, at the end of the day, the patients have to want to go into that trial, and have to know it's of benefit to them.

Ashish Kamat: I think that's a great point that you made and a wonderful way to and our conversation. Thank you again so much for taking the time. It's always a pleasure.

Alison Birtle: Thank you. I've really enjoyed it.