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 who will introduce themselves.
Dr. Katy Beckermann:
Hi, everyone. It's wonderful to be here. My name is Katy Beckermann. I'm an Assistant Professor and also focus on GU Medical Oncology at Vanderbilt University Medical Center.
Dr. Pedro Barata:
Hey there. Thank you also for having me on this great panel. I'm Pedro Barata. I'm a GU oncologist, Associate Professor of Medicine at Case West University at University Hospital Seidman Cancer Center in Cleveland, Ohio.
Dr. Rini:
Great. Thank you both for joining. Today, we're going to discuss recent updates in the treatment of renal cell carcinoma. We're going to try and integrate these new developments into patient case studies. Our second installment is going to focus on the frontline treatment of advanced kidney cancer.
So first the case. This is a 63-year-old male who has multifocal pulmonary mets. These are biopsy proven recurrent clear cell kidney cancer. He had a nephrectomy, at that time, localized, clear cell kidney cancer, 4 years prior. So now after a number of years has these small pulmonary nodules, biopsy proven, IMDC favorable risk and the patients otherwise asymptomatic with normal labs and presents to your clinic to talk about the next step. So Katy, let's start with you. We have a number of options on the slide as the next step, but it's open, whatever you think. How would you approach this patient?
Dr. Beckermann:
Yeah, I think that this is a patient who by IMDC criteria, the biology is favorable risk suggesting a slow-growing disease and low volume of disease here. So I would talk to this patient about their comfort in monitoring and observing where the disease is at, doesn't sound like they're having any symptoms in their labs are normal. So I think that would be very reasonable.
Dr. Rini:
And on the scans, they showed you three lung nodules, let's say that's all there is for the sake of argument. When do you employ SBRT? When do you employ local therapy to metastatic disease?
Dr. Beckermann:
Yeah, I mean I think, certainly, it would not be unreasonable if the only disease were these three locations and/or again, this would put them out of favorable risk. But I certainly think about SBRT, and any patient with metastatic disease who's symptomatic, an oligo met or something like this.
Dr. Rini:
Pedro, what do you think? We have a low volume, pretty slow growing a couple years and we all see these patients that have a scan with a couple nodules, you're not sure. And then 6 months later, maybe there's another one or maybe it's gone from 2 to 3 millimeters and then eventually things sort of blossom and, in this case, biopsy proven. How do you approach these patients?
Dr. Barata:
So I think the first part is to answer, in my mind the question you just answer, which is how, what's the pace of growth? I think that's very relevant. And so I don't jump to do SBRT right away just to answer the question about local therapy. Why? Because if 3 months later instead of three lesions, I have 10, then I got the answer. I don't think local therapy would help that patient. So I waited a little bit to understand how the biology of the disease. And then we also know that some of our friends from radiation, I mean they don't like to zap lesions are 3 or 4 millimeters. They wait a little bit longer, they grow a bit further. So at that point also the pace of growth of the different lesions, are they all growing at the same time? Are you having new lesions or it's one dominant and it's growing more than everything else? And I think that will dictate to some extent how I would bring local therapy on table.
And in addition to that, am I going to do that with a goal of delaying times to systemic therapy or the goal would be to see in a low volume patient, a low tumor burden, is can I offer him durable remission, potentially cure, which will get us into the IO based approach. So that's how I think of when I see a patient with oligo metastatic disease.
Dr. Rini:
Is there a number of lesions above which you'd say, "Boy, I wouldn't do SBRT." Let's say you watch this patient 3, 6, 9 months, there aren't new lesions and they're all slowly growing. Is it 3, 5, 10? What's your number where you say, "Okay, that's too many."
Dr. Barata:
I don't think there's a magic number. I don't think there's a difference between 4 and 5 or 3 and 6. I would argue the more, if you go beyond 5, definitely 10. I think a lot of us are not going to be offering that. In general, I'm thinking oligo metastatic disease, probably up to 3 to 5 lesions or so. And also in places where you can actually do something about, right? Because sometimes the location matters. We're assuming it for this case it's easy because it's in the lung, we're assuming there's not going to be a lot of toxicity along with it and it's safe to do so. But in general, up to 5, although it's no different than 4 or 6 in my mind.
Dr. Rini:
And then 5 sort of become the number for oligo mets and some other diseases, prostate, which we all see. I'm not sure where that number came from, but it probably seems reasonable. But to your point, its location, it's pace, it's new lesions, it's health of the patient. But I think the message is that observation and local approaches are still part of the management of kidney cancer. They've always been since I've been doing it and I think they continue to be.
Dr. Barata:
And Brian, just to highlight the importance of, we're talking about high dose of radiation, radiosurgery, right? And not conventional dose of radiation. So for those who are listening, thinking about kidney cancer being not known as a radioresistant tumor, we're talking about a higher, the ability to deliver higher dose of radiation to a specific location known as radiosurgery SBRT.
Dr. Rini:
Yeah, correct. This first was developed through lung cancer. It's now pursued in many cancers and the local control with SBRT and kidney cancer is about 90%. So 90%, probably even more than that. So it is very effective when given in high doses, to your point. Let's move on with the case.
This patient was actually observed for a couple years, at year-end did have growth of just one of the nodules with the others being stable. So SBRT was pursued for that nodule as we've discussed. And then the patient was observed further. But unfortunately, at that 2-year mark, developed mild back pain and gets imaging and now has sort of a paraspinal metastases as you see on the screen; sort of this hypervascular left paraspinal met, which is unusual, but if you take care of enough kidney cancer, you'll sometimes see these very hypervascular muscle metastases. A biopsy is pursued, and it is clear cell kidney cancer. And at this point now has multiple lung nodules that are growing. So I think we'd agree that this patient now is entering the need for systemic therapy.
So it's a pretty good performance status, it’s symptomatic. So as a performance status of 1, but normal labs. So Katy, let's start with you. We know IO based doublets are the standard of care. We've had a number of updates of all the data, including a couple recently at ASCO. How would you approach this patient?
Dr. Beckermann:
Yeah, so I think your point is that the standard option here, this is a patient with favorable risk, and I would definitely offer them a combination therapy. Several of these trials are approved for favorable risk disease and IO/TKI would be one of the standard of care options that I would specifically think about in this patient. And the reason I'm thinking that is now this patient has a met that's causing pain, causing symptoms. And I think given the biology of their disease, it's likely angiogenically driven and this patient, I think hopefully going to respond to a TKI. But I would also definitely want to do that in combination with a PD-1 inhibitor because I think that's the only thing that gives them an option for durable benefit. So I would think about IO/TKI. I'll say with the caveat that if this patient had only had lung only disease and those were the things that were growing, well, not approved for good risk biology, I think that IO/IO does also have some benefit and a nice high CR rate with the subset of lung only disease patients responding quite well to checkpoint inhibition.
Dr. Rini:
Probably IO/TKI and that's really driven by the sort of symptomatic progression. Which one are you choosing and why?
Dr. Beckermann:
I'm trying to remember this. I don't remember any other specific contraindications.
Dr. Brian Rini:
No contraindications, healthy, reasonably young.
Dr. Beckermann:
Yeah. So I feel pretty comfortable using any of the IO/TKIs and sometimes I'll choose one of the TKIs based on a medical comorbidity. For example, more resistant hypertension or something that I'm going to be tweaking. So for this patient, I think really any of them would be reasonable.
Dr. Rini:
You have to choose one.
Dr. Beckermann:
Sure. Okay. Maybe pembrolizumab and lenvatinib.
Dr. Rini:
Based on the highest response rates and albeit likely with the most toxicity. Pedro, what do you think?
Dr. Barata:
Yeah, so two approaches. I was actually thinking what I would do from the medical management and also from that lesion that's symptomatic, right? I'm debating back and forth whether or not I would offer actually radiation with palliative intent because it's not touching the bone at this point that I can see on the scan, I would monitor that closely. And I think we all get a little bit nervous when we're starting seeing bone involvement by RCC than to not do well. It's almost like a different beast. So if I suspect there's bone involvement, I would probably have a low hanging fruit to offer local control of that particular lesion in addition to medical management. I agree with Katy. Definitely, not a TKI monotherapy. I would do an IO-based approach. Probably cabo/nivo would be my choice here. Because I think patients do, I think there's a good balance between tolerability and efficacy. This patient is good risk. If I control that met, I think these patients going to do great. The outcomes for patients with favorable risk are the best with an IO and TKI, it's possible that being a good risk, it might be an angiogenic profile in this tumor, but it's also possible it might be an immunogenic, right? There's still some, less common but still possible. So I do consider an IO-based approach to TKI in general for patients with favorable risk disease.
Dr. Rini:
So you'd give cabo/nivo. So for both of you, in the two questions, the subsets in the phase III’s of about 20% or 30% of favorable risk have failed to demonstrate a survival advantage. Hazard ratios bounce around, but let's call them all 1.0 with overlapping curves. I think that's fair. So why not give TKI monotherapy? Pedro, you first.
Dr. Barata:
So first of all, the trials that we have, were not powered to answer the question specific for good risk. So we can look but the size of the data as much as-
Dr. Rini:
But even if they were 10 times the size, those curves would've still overlapped.
Dr. Barata:
Well, maybe. That might be the case. Yeah. If we were-
Dr. Rini:
Let's assume so.
Dr. Barata:
Sure. But we have a lot of reasons for not doing that. So first of all, favorable risk patients tend to do well, right? With anything we do. But I would argue for a 63-year-old man, which I believe is his case, survival, to your point about OS, it's going to be probably still impacted by his metastatic RCC. I don't like to save good options for later. And I do see a superiority of other endpoints that matter to me. Time to the next subsequent therapy, response rate, including CR rate, a number of PD rate, they all favored IO/TKI compared with TKI monotherapy. There might be the chance that this is tumor is monogenic in nature, which we have no idea from what the phase III trials we've done. I'm offering an IO upfront, which I believe we're going to help that patient, vs holding tight until he progresses and get, I'm guessing nivolumab based on CheckMate 25.
So I don't see a reason not to, if I find the right balance between the efficacy, which is way better with an IO/TKI and tolerability, which I believe there's a good balance with cabo at lower dose at 40 along with nivolumab. So I think is the other way around. I wouldn't go just by OS. That's a good sign that patients are doing well regardless. But actually, we can all make that claim from a statistical perspective at least. That is definitely true, if we take a thousand people with good risk and get them on sunitinib, they do going to do exactly the same way as patients on IO/TKI.
Dr. Rini:
So it's really driven by the non-survival endpoints. This is what you're saying.
Dr. Barata:
Based on the numbers we know today or based on the data we have available. Yes.
Dr. Rini:
Yeah. Okay. Katy, what do you think? Why not TKI monotherapy? Because that's being done, but there's a good chance of patients still getting TKI monotherapy even for non-favorable risks. But how about this patient?
Dr. Beckermann:
Yeah, back to what I said before, I think there's just such a low CR rate. I think Dena Battle gave a great ASCO presentation, patients want to be cured, and I just don't feel great about telling them that they're ever going to get cured with TKI monotherapy. So I think the chance for cure is with an IO-based doublet, take your pick cabo/nivo is great, pembro/lenva, pembro/axi.
Dr. Rini:
I mean, I think there's non-survival advantages. I think the good news is also you're not adding a whole lot of toxicity to IO/TKI vs TKI. Even putting aside some of the quality-of-life data, which I find complicated to interpret. I mean just we've all given these regimens, we've all given TKIs in clinic and the toxicity of these regimens is largely driven by the TKI, which is common to both regimens. And yes, there are IO toxicities, but I think in the IO/TKI, they're relatively minimal and manageable. And then what we touched on is there's clearly a subset of favorable risk, even though largely angiogenic driven that are immune responsive and probably really responsive to ipi/nivo. And we don't yet have the tools to identify those patients, but I think that's a challenge for the field moving forward is to identify patients based on those biologic features. Other thoughts about the case?
I think we'll just wrap up with the takeaways from this case is that observation and local approaches, historically, metastasectomy; more recently, SBRT are viable in low volume into an RCC and really, really can prolong the time to systemic therapy. And patients love not being on therapy. I can tell you they love it when they don't need therapy and can have their freedom and freedom from toxicity. And so we shouldn't forget that in the management of patients. And there's probably a good 10%, 15%, maybe 20% of patients where that might be applicable. Standard initial therapy and advanced kidney cancer is an IO based doublet, a PD-1 inhibitor based doublet, whether it's combined with ipilimumab largely in intermediate and poor risk patients, or one of the TKIs as we discussed. And there are advantages and disadvantages to each regimen, we didn't have time to sort of go down into the weeds. But familiarity with the regimen and expertise in knowing how to give it, knowing when to hold drugs, knowing when to dose reduce, I think is the most critical thing.
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 ascopost.com.
