Sam Chang: Hello everyone. My name is Sam Chang. I'm a urologist in Nashville, Tennessee. And I am quite privileged today to have Sima Porten join us. Sima's presenting at the AUA 2022 session, that the SUO puts on every year in conjunction with the AUA. And she's actually going to be speaking on upper tract disease. So I want to ask Dr. Porten first, tell us perhaps, three key highlight points from your discussion that you're giving in the plenary discussion for the SUO.

Sima Porten: Sure. Thanks for having me here today. I think, the three main takeaway points of the talk are, number one, as urologists, we are the gatekeepers for the management of upper tract urothelial carcinoma. We perform the majority of the surgeries. We discuss pathology with patients. And because of that, it's really important for us to be aware of the systemic therapy options for patients. And that leads to the second point, in that, because we are the primary source of referral, that two large bodies of work, or data, have been presented, showing the importance of adjuvant therapy after upper tract urothelial cancer surgery, for patients with high-risk disease.

Sam Chang: We'll talk about those two, but yeah. Tell me your third highlight. What do you think?

Sima Porten: The third highlight is, the future looks bright. And in particular, there are clinical trials now that are biomarker based, primarily with FGFR3, examining adjuvant treatment for high-risk patients with specific genomic changes. And I think, that's going to be a really important progress in the future.

Sam Chang: Well, let's start with your first point regarding the gatekeeper and the urologist, in terms of the valuation and that type of thing. How good are we, as urologists, in terms of risk stratification, trying to figure out what's actually going on? Because that really helps dictate what we do next. Are there any kind of updates regarding what we're doing with risk stratification? Any insights?

Sima Porten: Yeah. So in terms of risk stratification, as urologists, I think we're really good at risk stratification of prostate cancer. It's sort of burned in our brains from training, and as we go into practice. For upper track disease, we're not as robust or methodical about using nomograms to help us assess risk. Right? And primarily, it's because we're a little limited with upper tract disease. Our biopsies are difficult. It's really hard to stage upper tract tumors. And so, some tips are, using the information that we have. Right? So you can use readily available nomograms. There's ones by Dr. Shariat, and some of our colleagues in Europe, that are great, and that can be found on various nomogram websites. Right?

Sam Chang: Sure.

Sima Porten: But there's also some key clinical features.

Sam Chang: Okay.

Sima Porten: Of course.

Sam Chang: What are those for you?

Sima Porten: Yeah.

Sam Chang: Yeah.

Sima Porten: So of course, obvious T3 disease on imaging. When you see something infiltrative in a renal pelvis tumor, into the kidney parenchyma. High grade cytology actually, is a pretty important predictor. There's some folks who talk about large tumor size, along with a high grade cytology, or a high grade biopsy, being upstaged. And so, those are a couple of the more robust clinical predictors that you can keep at the top of your mind. So if you see a relatively larger tumor, with a high grade cytology, and if you have it, a high grade biopsy, but it's really hard-

Sam Chang: Right.

Sima Porten: ... to get more than just high grade in there. Right?

Sam Chang:Right. Right.

Sima Porten: And then, pair that with imaging features, you can kind of put that in the top of your mind. Like, "Oh, I'm really worried that this person's cancer is worse than I thought."

Sam Chang: So let's take that high-risk patient, that now we get to 0.2, regarding the adjuvant setting now. I think, we're starting to get more familiar with the POUT data. And so, if you could briefly summarize that. And then, tell us about the more recent adjuvant data, looking at immunotherapy options.

Sima Porten: Yeah. The POUT data was a randomized control trial of about 300 patients. And patients were either put in the surveillance group, where you do your standard cystos and imaging. Or, they were given chemotherapy with gemcitabine and cisplatin, if your GFR was capable of tolerating that, or carboplatin, if it wasn't. And I think, the really important thing that this trial showed is that, in patients who got adjuvant chemotherapy, event free survival, and that's a big composite endpoint. But it went from being something like in the mid 50s, for patients who didn't get it, to 71% in patients who did. And so, it really made an impactful difference. When you look at disease free survival, the absolute difference between the two groups at three years, estimated, was about 25%. And that's pretty, that can be fairly powerful in terms of a patient's longevity.

Sam Chang: And then, so tell us now about the immunotherapy option that we now have in the adjuvant setting.

Sima Porten: So we don't have a trial dedicated to upper tract, in terms of immunotherapy. Our adjuvant trials have been in InVigor, which did not meet its endpoint, that allowed upper tract patients there. And then more recently, a CheckMate trial, which looked at nivolumab in the adjuvant setting, for patients with high-risk urothelial. And upper tract patients were allowed in there, but capped at 20%. So it was primarily, a cohort of muscle invasive patients. However, lower track disease patients, but some upper track disease patients were incorporated. And again, there, patients who got nivolumab had an improved disease free survival endpoint, compared to those who didn't. It was a pretty large trial, over 700 patients.

What's interesting there is, that this improvement led to the FDA approval of all patients with high-risk urothelial cancer, whether upper or lower tract. However, when subgroup analyses were done, and it comes with all the caveats of not-

Sam Chang: Sure.

Sima Porten:... doing that, the upper tract group didn't seem to benefit as much as those with bladder cancer, traditional bladder cancer. And so, that gives people a little bit of a pause, and is a little bit hypothesis generating. But if you take it in aggregate, it is an FDA approved therapy for patients with high-risk disease.

Sam Chang: We always struggle with the balance between neoadjuvant therapy versus adjuvant therapy. And then, although clearly, there's not the neoadjuvant level one data, there has been a tendency, even at our institution, to consider renal function, overall status, that if we can perhaps be able to successfully give neoadjuvant platinum based therapy before surgery, where we might not be able to do it after surgery, that we tend to give neoadjuvant platinum therapy. Now we've got options afterwards, adjuvant nivo, as well as adjuvant carbo plus gemcitabine. As you refer patients to your oncologist, how do they make the decision on which way to go? Let's stick with still, the high-risk patient, the one with the T3 disease on imaging and the positive cytology. For those patients, are patients at UCSF still getting neoadjuvant? Are they all waiting to get adjuvant? Tell me what your medical oncologists are thinking about.

Sima Porten: For someone who's got that clinical T3 on imaging, I would say that, their preference is, if they're right on the border, particularly of platinum eligibility, that those patients, we still utilize neoadjuvant-

Sam Chang: We do, as well.

Sima Porten:... cisplatinum based chemotherapy.

Sam Chang: We do, as well.

Sima Porten: The harder one is, what if you have a high grade T1 patient? And you're trying to figure out, should I give this person based on clinical staging, right, on the nomograms, they're high-risk, they have a high-risk cytology, but do I really think that they have T3 or node positive disease? Which is one of the inclusion criteria for getting adjuvant chemo. Or T2 is allowed for patients who have not been pre-

Sam Chang: Pretreated.

Sima Porten: Pretreated-

Sam Chang: Okay.

Sima Porten:... as well too, for adjuvant immunotherapy. And so, that's the harder struggle. Right? You have a borderline renal function.

Sam Chang: Right.

Sima Porten: You've got T1 disease, and you know your clinical staging has limitations. So are you over-treating the patient with the cisplatin, or are you being safe, because you know you're going to lose a renal unit and have some decline. And I think, that's the harder nuanced decision.

Sam Chang: Yeah.

Sima Porten: Right? And so, I would say, that's how... And we go back and forth on patients, and we end up talking to patients about this kind of yin and yang. It was a little more difficult when there were not these adjuvant options. Right?

Sam Chang: Exactly. Exactly. Exactly.

Sima Porten:  And I would say, now that there are, we do end up having this conversation a lot more for these borderline patients. And sometimes, it ends up being something like, a patient's having bleeding.

Sam Chang: Yes.

Sima Porten:  And they're on the border. Well, bleeding, in pain, we're going to go with the surgery first-

Sam Chang: We're going to treat with the surgery, sure.

Sima Porten: ... and see what the pathologic stage is, and then, decide on adjuvant therapy. And if kidney function is not great to support any kind of chemo, or there's other contraindications, there's the ability to use adjuvant nivolumab.

Sam Chang:Adjuvant immunotherapy. I think, it's not too dissimilar from... I think we actually now, with more options, which are great, because we have more options for both lower tract and upper tract. It means our patients have more options, but it can sometimes put us in more diagnostic and therapeutic quandaries. I think of the small localized T2 bladder cancer that, oh, neoadjuvant, neoadjuvant chemotherapy. But in 50, 60% of the time, absolutely unnecessary. T2, perhaps even higher. But now, we actually have options for adjuvant therapy, if that patient ends up having more aggressive disease. And so, it's always difficult. It's becoming more difficult, which is actually I think, beneficial to the patient, in terms of having options. And just like, as you said, explaining the pros and cons, I think, will be really important.

As you have a patient, that ends up having high-risk disease, that you've done the nephroureterectomy, did not get any treatment up front, ends up having borderline renal function, to me now, I think our medical oncologists are struggling a little bit now with, do we do chemotherapy based on a carboplatinum/gemcitabine combination, which may not be as effective, but clearly in the trial, as a kind of an aggregate, it was beneficial. Or do we go nivo again? Difficult questions. Do your medical oncologists, do they have an algorithm? Do they go case by case? How do they try to figure out what to do in that kind of situation?

Sima Porten: We generally go case by case, because what it is, is a battle of our subset analyses on both fronts. Right? The subset analyses, maybe carbo didn't really cross the threshold, and the significance.

Sam Chang: Right. Right.

Sima Porten: And maybe, upper tract with nivo, didn't really cross the threshold through significance. And even though, when you think about it from a statistical perspective, you're not supposed to-

Sam Chang: Right. Exactly.

Sima Porten: ... pay attention to it, sometimes it's very challenging when you're trying to make a decision, for that not to be running through your mind.

Sam Chang: Right.

Sima Porten: I would say. Just from a clinical practical perspective. Right?

Sam Chang: Sure. Sure.

Sima Porten: So what are some of the things that we factor in? We do get staining for PD-L1, PD-1, sometimes that's able to push folks-

Sam Chang: Sure, one way or the other. Absolutely.

Sima Porten: ... one way or another. I think, some of the really interesting work on CT DNA is, might be. It's very exciting in the treatment of muscle invasive bladder cancer.

Sam Chang: Yeah, absolutely.

Sima Porten: Maybe there's a role here. And this is where the FGFR3 targeted trials are really interesting too, in terms of, well, should we do that? And if they're cisplatinum ineligible-

Sam Chang: Right.

Sima Porten: ... could we do that?

Sam Chang: You could switch over. Yeah.

Sima Porten: And save the other treatments for down the line. I would say, it's a gray thing-

Sam Chang: Right.

Sima Porten:... that it's becoming more complex.

Sam Chang:  Exactly.

Sima Porten: But we are having these conversations just a lot more now. When before, there wasn't really much to talk about.

Sam Chang: Exactly. So then, to your third point, regarding better risk stratification with genetic signals, and those types of things, what would you predict, as the most impactful here, short term and long term?

Sima Porten: I think, it would be setting up a pathway, a little bit like some of our colorectal colleagues have done. Right? When a specimen is sent to pathology, all of these, many things right now, get interrogated. Right? They look for microsatellite instability, because they're looking for Lynch.

Sam Chang: Right.

Sima Porten: They have some different targeted therapies down the road as well, depending upon the center and what's available, it's all done automatically.

Sam Chang: Right.

Sima Porten: Right now, to have that done, I probably fill out about like four or five different paper forms, to get those types of assays sent.

Sam Chang: Right.

Sima Porten: Right?

Sam Chang: And you're at a major institution.

Sima Porten: Yes.

Sam Chang: The vast majority of what you're describing, we're not able to do. But you think that, as we become more and more familiar with these either impactful findings, or predictive findings, that hopefully, become more kind of standardized. Is that what you think?

Sima Porten: That is what I'm hoping for. Because I would say, that's the... If you just think about it practically, when you're sitting in front of a patient, and telling them, talking to them about their pathology, and you're like, "Now I have to send off these things to figure out what to do next." Right? Right now, trials are still being done to figure out which of those markers will be clinically useful.

Sam Chang: Right.

Sima Porten: But if you had that available right there, then you can have a lot more robust and clear discussion. So I think, as the field moves, and maybe if the trial ends up being positive for FGFR3 targeting, and maybe as the next generation of immunotherapy trials-

Sam Chang: Come through.

Sima Porten: ... come through, in particular, also looking at things like CT DNA, that there could be a very robust pathway, based on what is called on path, that starts right there.

Sam Chang: Right.

Sima Porten: So you're able to quickly make these decisions. Right? Adjuvant therapy has a time limit.

Sam Chang: Right.

Sima Porten: It's got to be started, in the 90 to 120 days.

Sam Chang: Exactly. Right, exactly. Or you're starting to look at salvage there, or something pops up. But the ability to, kind of again, that whole move to personalizing and individualizing medicine. I think, once we get that more standardized, just like you said, it becomes a process that is automatic, then our patients, more and more patients, are going to be able to gain benefit from it, and be able to then, tailor their own treatment. I always look forward to seeing what UCSF does, what you do personally, because you guys have really always been... Look at what's been done in prostate cancer from UCSF, in terms of nomograms, and predictions, and those types of things. I really look forward to future findings from you, and from your institution. And Sima, thank you, as always, for spending some time with us.

Sima Porten: Thank you for having me.