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Dr. Brian Rini:
Welcome to The ASCO Post Roundtable Series on Treatment Considerations in Renal Cell Carcinoma. I'm Dr. Brian Rini. I'm the Chief of Clinical Trials at Vanderbilt Ingram Cancer Center. And joining me today are two of my colleagues and I'll let them introduce themselves. Katy, if you want to start.
Dr. Katy Beckermann:
Hi everyone. It's great to be here. My name is Katy Beckermannn. I'm an Assistant Professor at Vanderbilt, also focused on GU medical oncology.
Dr. Pedro Barata:
Hi there. I'm Pedro Barata. I'm also a GU oncologist and Associate Professor of Medicine at Case West University at University Hospital Seidman Cancer Center in Cleveland, Ohio.
Great. Thanks for joining to both of you. Today. We're going to discuss recent updates in the treatment of advanced kidney cancer and how to integrate these new developments into three patient case studies. And our first case study will focus on adjuvant therapy.
So this is a 68 year old African-American female who presented with left flank pain in one episode of gross hematuria. She underwent CT scan imaging, which revealed a large left renal mass with a renal vein thrombus. You can see on the images on the right side of the slide, a very classic hypervascular renal mass that looks like clear cell kidney cancer, kidney cancer, of course, one of those diseases you can almost diagnose radiographically. Fortunately she did not have distant metastases, maybe even before we get to the rest of her treatment, Pedro, let me ask you first, would you routinely biopsy this patient? Let's assume she's eligible for nephrectomy. Do you routinely biopsy patients before you take them to nephrectomy?
No, unless I have a protocol when I'm thinking to consider neoadjuvant approach of some sort. I mean, as we know, surgery can offer us both a diagnostic opportunity as well as the therapeutic opportunity. And so in general, I don't consider biopsy standard of care.
Yeah, I think that's right. I mean, I think unless there's some doubt about the diagnosis, is this transitional cell, is it something else? But as I said, this is pretty classically radiographically kidney cancer. This patient undergoes a left radical nephrectomy and it indeed shows about an 11 centimeter clear cell kidney cancer grade III, pathologic stage T3aN0. There's no noted sarcomatoid changes or necrosis. Past medical history I should mention is arthritis, sort of an unclear history. The patient has taken low-dose steroids forever but doesn't really know much more about it. Has hypertension controlled on two medications, obesity, and also controlled hypothyroidism.
So Katy, let's start with you. When we're, we see a lot of these patients in clinic and they're coming back for their urology follow-up. They often have a medical oncology visit the same day to talk about risk of recurrence and adjuvant therapy. What are the tools you use to estimate risk of recurrence in this patient or in any patient?
Yeah, I think there's some really great nomograms, coming from many different institutions. Memorial Sloan Kettering has one, Fox Chase has one. And really I'll sit down with the patient and walk through the features of their pathologic diagnosis and really diving into the details there. So I'll look at tumor size, discussing T stage, discuss with them what it means to have a grade 1 through a grade 4 Fuhrman grade, how that indicates aggressive biology or not. And then specifically here where the path commented on sarcomatoid features, how we know that that may portend a more aggressive biology or feature.
Pedro, how do you do it? What are the tools you use? I mean, patients want to know, Hey doc, what's the chance of this coming back? How do you estimate and quantify that?
Yeah, now we have computers in the room and so I tend to use more the UCLA, it’s another nomogram. I agree, Katy, we can use any, I think that's the one I tend to use more probably because the calculator is easily accessible and kind of patients to see using those key zone factors. So they see it's kind of personalized. So I just go through what it is and how the numbers came out of that. And then depending on the nomogram, you might have a line, survival line, along with it or just numbers and just, we spend a little bit of time going through what those numbers represent to them. In general, we're talking about recurrence and overall survival.
And then we can talk about what to do not only in terms of surveillance, but also whether or not there's an opportunity for treatment, right? So for instance, some of the scores take into consideration the histology, some don't. So of course I don't consider adjuvant therapy, which I think we're going to talk a bit beyond clear cell these days, but it's all, so I go through the histology as well as other factors and why the numbers can look better or worse in the future for that particular patient.
And we have a slide here. I took a screenshot of the Fox Chase nomogram, which I tend to use in clinic. As you both mentioned, there's a number of nomograms. Many of them are, the initial publications are 20 years old, but we're still using them. I mean UISS was in the early 2000s, well before I think either of you were doing this. So it's good and bad. These are very established nomograms. The Fox Chase uses data from the ASSURE study, the adjuvant TKI study that ECOG did. So it's the most updated, so to speak, the most recent dataset. But yet the factors that go into it are still the same that we've been using for over two decades; size of the tumor, stage and grade, predominantly; some of the risk groups/risk schema use necrosis, some use sarcomatoid. UISS, I think, uses symptoms or performance status.
So they're all variations around the theme. And I don't think we're here to say that one is right and the other's wrong, but I do find that quantifying something that I put in my note. And it's also, I think, useful for the patient. I find myself saying to patients for this patient, the Fox Chase nomogram would predict about a 50% risk of recurrence at 5 years and probably more towards 60% at 10 years. So pretty high risk. I find those numbers tend to resonate with patients, but then I also tell them in the same breath that their risk of recurrence is either 100% or zero. They're either destined to recur or not. And unfortunately, we don't have good tools, be it ctDNA or functional imaging or something to tell us around about an individual's risk of recurrence. We're merely estimating it based on these features.
So I think it's important to do. I think it helps patients understand quite obviously the risk of recurrence. And then we're about to talk about adjuvant therapy. And so for me, and I think for the patient's risk of recurrence, very much plays into the decision about adjuvant therapy.
So let's turn our attention to that data set now. So the KEYNOTE study, which was first reported maybe a couple years ago, most recently updated about a year ago at ASCO GU in a Lancet Oncology publication, randomized high-risk resected kidney cancer to a year of adjuvant pembrolizumab or a year of placebo, and showed a disease-free survival advantage hazard ratio of 0.63 in the most updated publication and presentation. This was with about 2 1/2 years of follow-up, which isn't very much since the median time of recurrence is about 5 years for these patients.
So relatively limited follow-up, but curves that split and stay split. So Katy, let's start with you. Let's take our hypothetical patient. Let's say the risk of recurrence is approximately 50%. She's sitting before you in clinic. She's 6, 8 weeks out for nephrectomy. Everything's recovered, wounds are healed, all that good stuff. And patient says, doc, should I get therapy or not? And of course we're going to talk to the patient, but you're the expert, so she's going to rely on you for decision making. What's your take of these data and how would you approach this patient?
Yeah, so I think it is a very individualized treatment decision, and I certainly make the recommendation, but I do so in the context of what the patient, her goals, age, medical comorbidities, all that in context of the data as well. So not hearing that this patient has any other outstanding autoimmune issues that would be a terrible contraindication to immune therapy, I think I would discuss the use of adjuvant therapy for this patient with a fairly high risk of recurrence at 5 years. But it would be in the context again, of having a very thoughtful conversation about the permanent side effects that can also come from checkpoint inhibition in a patient who might already otherwise be cured of disease from their surgery.
Is that, is the fact that patients on a little bit of prednisone for some really undefined arthritis scare you, would send them to rheumatology or not? How'd you handle that?
Yeah, and we've done some work. I have a colleague, Dr. Doug Johnson has done some work at this, but even for patients who have a controlled autoimmune problem, while certainly there can be exacerbations on checkpoint inhibition that generally it's felt to be safe. And so that particular low-dose prednisone doesn't necessarily make me want to refer to rheum for this patient. If it were someone, again, here who was on multi immunosuppressives or having flares requiring hospitalizations, then again, all in the context of what's going on that individual patient and I would probably reconsider whether adjuvant were a benefit.
And then one last question for you and then Pedro, I'm going to ask you basically the same questions. We would agree 50, 60% is a pretty high risk of recurrence in our world. Node positives, probably 70 or 80%, but it doesn't get much higher than this patient. Is there a minimum percent risk of recurrence that a patient has to have for you to more strongly recommend adjuvant pembro? I mean, in the study, I believe T2 high grade was the lowest risk that could have gotten in. And so call that 30%. This patient's 50%. So is there a number in your head where you say, boy, if they're above this number, I'm really going to lean towards adjuvant therapy.
Again, I think it's all, I know I'm walking the line here, but I do think it's all in the context of what's going on in their comorbidities and everything else. We've seen the subgroup analysis where M1 disease seemingly had a better separation of the curves essentially compared to high-risk T3 grade 3 and grade 4 sarcoma. So we know if we break down this data that yes, I feel like the more concerning features, sarcomatoid features, grade 4, M1, lymph node involvement, It'll have me pressing to start somebody on adjuvant.
So higher risk, you're more likely to start, but you've also, you dodged my question. Is there a minimum number. The patient has just, let's say just 30% risk of recurrence, so there's a two-thirds chance this patient won't have cancer, it’s never going to recur. Is that too low for you?
There's not a number. Yeah, right. I don't tend to start people with T2 grade 3, grade 4. Again, if the patient came in and they were educated and really pushing for it, we'd really have to have a conversation about what the risk is.
Sure. Pedro, same questions to you. How would you approach this patient? Maybe just anything to add, to what Katy said.
Right. Just a piggyback on this, actually, I just got a patient I saw 3, 4 weeks ago, 3 weeks ago I believe. And risk of recurrence for him was about 25% or so. And all of a sudden, there's no magic number. We were going through the data. I wasn't thrilled about it. I offered the option and he definitely wanted to do it. So it was almost like us giving, we're going through the tolerability of the agent. He was a young guy in his 40’s. We went through the tolerability of a year of immunotherapy, the potentially immune-related adverse events that could come out of it. The lack of survival that we don't know if we're able to cure or delay, that remains to be seen. He is a very educated person, but just to say, we ended up doing it.
So we actually started adjuvant pembro. So I think there's definitely not a magic number. I agree that we look at the breakdown, although the trial was not designed to answer the question by intermediate-high vs high vs post-M1. But I think it's a fair statement to say, as we see those other ratios dropping significantly as we move from intermediate-high risk all the way to post metastasectomy, as we answer to the question when and not if recurrence, when the answer seems to be more when I think all of us are going to be far more comfortable doing it. And so we ask same question on Twitter, and a lot of providers feel more comfortable doing the high-risk and the post-metastasectomy compared to intermediate-high risk, if you will. And so that tends to be my practice. I usually share a lot of patients asking what would you do if you were in my shoes?
And I try to answer that question knowing that it's different if I'm 40 vs if I'm 80. And number of other factors, right? The arthritis, I agree with you, Katy. I don't think that's a formal contraindication; it’s something to bring up through our conversation. There's a chance there might be an exacerbation of that disease with the need for probably more immunosuppression down the line, but we don't know that unless we go through it. And the way I look at these data, some people, actually, one patient did ask me something that we don't talk a lot, but we know is a statistical calculation, which is the number needed to treat.
So I had one or two patients ask me, okay, doc, so how many of patients need to get this to benefit me? Which is basically, well tell me the number needed to treat. So I actually had to go and divide the one by the delta, which is 10 or so percent or 9%, which I believe is around 10 or 11 patients. So sometimes I bring that number up to look at the delta, the absolute difference of 10%, 9%. So there's a way to go around that. But I agree in general with all Katy's thoughts were, and I just share a little bit of what sometimes happens in clinic when we go around pembro.
Okay, that's helpful. And I think we'll sort of wrap up this adjuvant discussion. We have a slide on toxicity also, and I think we'd all agree, single agent immune therapy, single agent pembro is pretty well tolerated, but I think there's an 8% incidence of high dose steroids in this trial. So if you're in that 1 out of 10 or maybe 2 out of 10 patients who have either high grade and/or lifelong toxicity such as endocrinopathies, it can be pretty significant. So while most people will sail right through it, again, if you're in that rare subset, more rare subset, there could be issues. And then maybe the last thought, and I'll ask you each just to agree or disagree, I have a pretty low threshold to stop therapy. So if I see a little creatinine bump, if I see, I don't know, something immune and it just makes me nervous and I'm on dose whatever, 2, 3, 4, 5, my threshold to stop is pretty low. Do you, Pedro? You agree?
Yeah, I agree with that approach. Yeah, that's a very reasonable thing to do.
Yeah, I agree.
Yeah. And I tend to treat sort of the upper half of KEYNOTE risk. And as you know, we can all influence patients by recommending it strongly or saying, eh, I'm not sure I'd do it. We all understand that. So I tend to recommend it more strongly in the upper half of risk with a low threshold to stop.
So just the key clinical takeaways from this, that estimating risk of recurrence in kidney cancer does allow some quantification of recurrence and therefore can calculate the absolute benefit of adjuvant therapy, adjuvant pembrolizumab, in this case. Adjuvant pembro does reduce risk of recurrence with small, but real, risk of significant or even permanent toxicity. And notably, we don't have time to talk about this, but other adjuvant studies, there were three other adjuvant studies presented at ESMO last year, that did not demonstrate benefit of adjuvant immune therapy. And that's a whole separate discussion. There's probably reasons for each of them, but I do mention that to patients to put it into context.
This brings us to the end of this case. Please see the other segments for further discussion about the latest data in renal cell carcinoma, or visit ASCO post.com.