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Pedro Barata: Hi, my name is Pedro Barata. I'm a GU Medical Oncologist and Associate Professor of Medicine at University Hospital Seidman Cancer Center in Cleveland, Ohio. I'm very happy today to be joined by Dr. Benjamin Berger and Dr. Matthew Labriola. So from our opportunity to chat, Dr. Berger is a stellar Internal Medicine Resident at Duke. He has been learning and working quite a bit and quite successfully with the Duke team, the Duke GU team, and the senior person behind the scenes has been Dr. Matthew Labriola, who has been able to work with Dr. Berger on a project we'll be chatting today. But first, welcome both, thank you for taking the time to chat.

Matthew Labriola: Thanks, Dr. Barata, I appreciate it.

Benjamin Berger: Thanks for having us.

Pedro Barata: Thank you both. So first, congrats, I think you wrote a very nice piece, titled Treatment of Recurrent Metastatic RCC After Adjuvant Immunotherapy, and what a hot topic that is. A lot has happened in a relatively short period of time. We thought we were set up for sunitinib, and then we got KEYNOTE-564 and all the other trials who read out recently. Before we do a deep dive on your paper that came out recently at the Kidney Cancer Journal, which I welcome everybody to read it, maybe I'll ask with, first with Dr. Berger, can you tell us, remind us all, what are your thoughts, what's available as far as adjuvant therapy for patients in a high risk for recurrence?

Benjamin Berger: Sure, yeah. It's interesting because there has been so much going on in the past one or two years, but really the history of trials for adjuvant therapy for RCC goes back almost 30 years, back to the Interferon era. But there have been five big trials of VEGF-TKIs that have been largely negative. I know you mentioned sunitinib and the STRAC trial, which had a positive signal but was contradicted by the ASSURE trial. And KEYNOTE-564 that you mentioned is the first trial of immunotherapy for patients with RCC who are at high risk of recurrence.

And just to summarize, that was just published in 2021, and patients were randomized to pembro versus placebo, and that they were given pembro for a year after their surgery, and there was a statistically significant difference in disease-free survival in that group. And then, interestingly enough, three other trials of adjuvant and also neoadjuvant immunotherapy at least had their results presented last year, and those were all negative. The emotion trial with otelixizumab and Checkmate-914 with NIVO IPI, and then the Prosper trial, also with nivolumab, all have been negative. And so right now, as it stands, pembro has been FDA approved for adjuvant therapy, and is the only immunotherapy, and probably the best adjuvant therapy, for RCC.

Pedro Barata: Right, so that's a beautiful summary. Thank you for that. You walked us through, I guess, the last 20 or 30 years, to your point, as far as exploring therapies in the adjuvant setting. Dr. Labriola, I've actually asked this question on Twitter, and it's quite interesting because if we were to ask ten different GU experts, I guess, whether it's urologists or Med-Oncs, I have the sense that a number of them are indeed offering adjuvant pembrolizumab, for a year, to patients at high risk of recurrence. Some folks are offering for those at a higher risk for recurrence, just a reminder, I think the study, the KEYSTONE-564, enrolled intermediate high risk, high risk in post metastasectomy. And there are some folks who actually were waiting to see what happens as far as survival curves to make that decision. Wondering, what are your thoughts about that, where you stand, and if you're offering a patient with adjuvant pembrolizumab, what's your thought process if the patient ends up progressing?

Matthew Labriola: Yeah, absolutely. Yeah, it's a great question, and a good one that we're still trying to answer. What I do when I see patients is that I explain the data. I tell them, "Hey, we have this data from KEYNOTE-564 with adjuvant pembrolizumab showing a DFS benefit. We have an OS signal, but that data's not yet mature." And explain to them that there are three other trials that have not shown benefit so that they understand the landscape. You have to explain that in a way that the patient will understand.

But really, who am I treating with adjuvant pembrolizumab? It's the higher risk patients in that study. So, those who had M1, NED, no evidence of disease, those with higher grade tumors. And although we don't really have a lot of this data in real time, those who did happen to have PDL1 scores that are higher did do better in that trial.

I explain to them that there is a DFS benefit and that there's an OS signal, but I also need to explain to them the risks, in KEYNOTE-564, about, I think it was 30% or so patients ended up having grade three or higher AEs, and that's significant. They need to know what they're up against and the potential for toxicity here.

So anyway, I do offer the therapy to those higher risk patients, and some take it, some don't. But for those who want to be aggressive, who have high risk disease, especially younger patients are typically accepting therapy and I try to treat them for the full year if I can.

So that's into your first question, and I think the question from there, and the crux of this paper is, what do we do when they recur? The idea behind this paper is driven by real life, these patients that we see in clinic and they recur, and the question is, do you continue IO? Do use single agent TKI? There's so many different factors that are going to be playing in here. The ones that we highlighted in our paper are a lot of the things that we think about when we're treating metastatic RCC in the frontline. What is the burden of disease? Or how rapidly progressive is the disease? Is there an impending visceral crisis that we need a rapid response? What are the patient specific factors that we are worried about, including comorbid conditions, any contraindication to one of the particular therapeutic classes? What is their IMDC risk score? All these things that we are taking into account.

And then what we really tried to focus on in this paper is, what is the timeframe to recurrence? And how does that help us decide on therapy? There's a nice schema in the paper, if you guys want to take a look at it. And I know that we all love schemas, so if you take a look at the algorithm, what we really did is we broke up the patients into three main groups, and the middle group we sub-categorized.

The first group of patients that we wanted to focus on are those who had recurrence during immunotherapy. During that year of pembrolizumab, if you're getting an interval scan and you see progression, what do we do for those patients? And I think of kidney cancer as having two different drivers. There's the more immune driven RCC, and then there's some of this more angiogenic driven RCC. And if a patient is progressing while on immunotherapy, in my mind they need a change in class to see a response. So in these patients, definitely want to switch to VEGF-TKI. And the question then becomes, and the question that we don't know yet, is what is the actual benefit of continuing the IO in these patients who are getting VEGF-TKI? And those questions are going to be answered in a bunch of currently ongoing trials, CONTACT 0-3, PEDIGREE, TENEVO I mean, these are all trials that are hopefully going to answer these questions for us.

But in general, I would recommend, if progressing on adjuvant pembrolizumab, that you would just switch to single agent TKI until we have data from those trials.

Pedro Barata: So let me stop you there because, thank you, great summary by the way. I agree the schema looks really good, and I would argue that group of patients who unfortunately will progress while on IO is perhaps the one that more people would come up and agree with what to do next, right?

Matthew Labriola: Yeah.

Pedro Barata: Well, we're at least saying, we really need to bring a new mechanism of action. We do have target therapies available, we're going to use one of them. But the question, to your point, we hear that quite a bit. Should I keep pembro, and just bring Axi on board and lenvatinib on board, for example. Lenvatinib and since they're approved then, I mean, I'm right there with you when you're saying that studies like Contact Three and Tenevo would probably help us make that decision be better.

But let me get to the difficult piece of the schema or thought process, which I think is, what if a patient completes one year regimen pembro, and then recurs six months later, versus 12 months later, or versus two years later. Tell me, what are your thoughts about that? Are they the same patient? Are you going to do the same thing? How do you break it down?

Benjamin Berger: Yeah, this is the hardest question, and as clinicians, and we are seeing a patient in the clinic, this is where we're really scratching our heads. So what we really focused on in this paper, and I think the best thing we have to go on, is the data we have in the pharmacokinetic space about how the receptor occupancy of our immunotherapies and how long we're seeing an effect. There was a paper in the JCO that we highlighted in this review that showed, and I do want to clarify, it's nivolumab that was studied in this JCO paper, we don't have data for pembrolizumab. But with nivolumab, at least, at two months after getting at least three doses of nivolumab, 70% of T-cell PD1 receptors were still being activated. And then at nine months, it was still 40%, and then at one year there was no further occupancy.

That's why we broke it down, so if you're past a year, we're thinking we're probably not having much activity at this point, so that's when a full fledged go ahead and continue the IO VEGF combination. If we're less than six months based on this receptor occupancy data, I feel like the immunotherapy is still working, so if they're progressing despite that, probably not as much of a benefit for continuing IO.

It's that six to 12 month period that's really, really hard, because based on this data, maybe there's some activation still happening, but how much? And these are the patients that typically recommend doing both, just since we don't know the answer yet and would rather have both mechanisms on board as long as the patient can tolerate it and they haven't had any immune related adverse events.

Pedro Barata: Yeah, great answer. I really love the fact that you go back to the pharmacokinetics, it's so important, and I think it beautifully supports the decision making that we have to do in real life. I love that. I love the conversation. Perhaps one more question before I let you guys go. What are your thoughts? I mean, we've seen some movement. I mean, whether or not we see the data in a more positive tone, or a less positive tone, as far as looking at the absolute difference in terms of disease for survival around 10 or 11% at two years. The reality is, it is standard of care, and patients are getting it.

And a lot of the ongoing studies, or studies being designed as we speak, are using pembrolizumab as the control arm, and not observation, for instance. You've seen, there's a couple of designs with different approaches including IO based combinations, you are probably aware of one being explored with belzutifan, for example, and HIF inhibitor. There are other combinations out there being explored. I guess the question is, Dr. Labriola, do you think we're able, with treatment intensification management setting, to cure more people? Because ultimately that's the goal, the goal is, you don't have to discuss your paper because patients don't progress, right?

What exactly are your thoughts on that? Where do you spend with that? What do you think the field might be moving?

Matthew Labriola: Yeah, great question, Dr. Barata. Yeah, I hope that this paper becomes obsolete in the future because that's really the hope. We want to cure as many patients as possible. And yeah, I think the most exciting trial that's ongoing is the one that you just mentioned with belzutifan, so that's Light Spark-022, that's looking at pembrolizumab plus belzutifan versus pembrolizumab alone in the adjuvant setting. I think Dr. Chuari presented that data at ASCO 2022, and it has a similar population of patients as we saw in the adjuvant pembro data with KEYNOTE.

I think that's really exciting, the HIF2 alpha inhibitor. Mechanistically, I think it's an exciting class of drugs. We've seen it work in Von Hippel Lindau associated RCC, so definitely has a basis to work here in this setting as well. I do have some concern, I mean, one of the main side effects that we see with that drug is hypoxia. We'll see when you're mixing it with pembrolizumab and you already have a risk of immune related pneumonitis, we're going to be having a tough time teasing those two out. But I'm hopeful with that mechanism added to pembrolizumab, and hopefully more down the line, that we can move the needle and cure more patients.

Pedro Barata: Wonderful. That's a great answer. Thank you both for joining us today. What a thoughtful conversation and thought process that you guys provided. I think it was really helpful. Again, congrats on your paper, very helpful, very informative. I think treating physicians out there are going to use it as how to navigate as we are getting more and more patients being treated with adjuvant immunotherapy for high risk renal cell carcinoma. So with that, congratulations, thank you, and I'm looking forward to chatting with you both soon again. Thank you.

Matthew Labriola: Absolutely. All the kudos to Dr. Berger who led this initiative.

Benjamin Berger: Oh, thanks so much.

Matthew Labriola: Yeah.

Benjamin Berger: And thanks for having us, Dr. Barata. It's a great conversation.