This transcript has been edited for clarity.
Eric Jonasch, MD: Hi. I'm Dr Eric Jonasch. I'm a medical oncologist at MD Anderson Cancer Center. I'm joined by Dr Katy Beckermann, who's a medical oncologist at Vanderbilt. Our topic today is patients with favorable-risk advanced renal cell carcinoma. How should we treat these individuals in the frontline setting? It's a topic that I think is somewhat controversial.
We're going to try to round out some of this in terms of why it is, what we do, and future directions. Katie, just as a summary, the NCCN [National Comprehensive Cancer Network] guidelines do have some differences between the favorable- and the intermediate- and poor-risk patients in terms of treatment options. Why don't you go through those quickly?
Katy Beckermann, MD, PhD: Over the past couple of years, one of the changes that we've seen in the guidelines has certainly been acknowledging the way our trials have been designed and how we're interpreting the data from those trials, and, strikingly, that in the frontline setting, an immunotherapy (IO)-based doublet is now standard of care for all patients with renal cell carcinoma.
But if we look across IMDC [International Metastatic Renal Cell Carcinoma Database Consortium] subgroups, we recognize that the biology of the subgroups is different, and the NCCN guidelines have changed to reflect that. We certainly have a recommendation of an IO/tyrosine kinase inhibitor (TKI) as the category 1 level–based evidence in patients who have favorable-risk disease.
Jonasch: It's pretty interesting when we look at the data on the "why," right? One of the things that I'm always struck by is that when we look at the favorable-risk subgroups, should we be looking at subgroups in studies that are not powered for these subgroups? That's probably dangerous. But when you then start seeing a pattern across multiple studies, it starts giving you a little bit of confidence that this is a real thing.
One of the things that's always struck me was that the axitinib/pembrolizumab study, the nivolumab/cabozantinib study, as well as the pembrolizumab/lenvatinib studies against sunitinib all show great objective response rates and overall survival and progression-free survival advantages. But with the favorable-risk group, the overall survival does not seem to be better for any of these regimens compared with sunitinib.
This is true also for ipilimumab and nivolumab. In your practice, how do you use this knowledge? And how do you treat patients differently?
Beckermann: I first take a step back and think about how we created these wonderful guidelines based on IMDC criteria that were developed during a time when patients were undergoing frontline treatment with TKI. That really helped us discern some of the biologic underpinnings that would predict whether a patient would have an excellent response to TKI, and it probably said something about the biology of their disease — that the biology in the majority of those patients was angiogenically driven.
When I have a patient who's coming to me and has favorable risk, maybe slower-growing disease, the first thing I think about is how a good-risk patient maybe doesn't necessarily need systemic therapy right away. Part of my practice — and I don't know if this is the same for you.
But we recognize from prospective studies that Dr Brian Rini has led that we can, in some instances, just monitor and, again, discuss with the patient. We can acknowledge that favorable risk likely means slow-growing disease, and that in delaying systemic therapy, there's no loss of ability to still gain control of that cancer when, ultimately, we do eventually have to start systemic therapy.
Often, I'm looking at the patient and asking, do I even need to start systemic therapy? Can I perhaps monitor and delay the side effects that we recognize come, unfortunately, from systemic therapy? The second thing I think about is that perhaps if it's a favorable-risk patient, if this is an oligometastatic patient, is there any opportunity here, again, to avoid side effects that can come from treatment by, perhaps, local stereotactic body radiation therapy to the region? Eric, is that something that you all see and do?
Jonasch: Absolutely. In oligoprogression, or oligometastatic disease or paucity of disease and/or very slow growth of disease with excellent performance status, I'm absolutely going to suggest to a patient that they could consider a treatment-free observation period. And those are really interesting studies that Dr Rini has published. I think we're seeing this in real life.
But the thing is, we still have these guidelines that say that the IO/TKIs are the preferred regimens. The single-agent TKIs are "other recommended." When you're seeing these individuals, when you do initiate systemic therapy, how often are you giving single-agent TKI?
Beckermann: I pretty firmly believe that the IO component of these doublet combinations is what is allowing for a durable chance, and many of us hope even a cure, in some patients. So I only consider single-agent TKI if a patient really has an absolute contraindication to getting IO therapy.
For example, we are at a transplant center. I have had a few patients who can't get IO because of their transplant. Or perhaps they have a severe autoimmune problem where an IO agent is, in discussion with the patient, probably contraindicated. Otherwise, I really heavily favor a combination approach when I'm starting a patient on systemic therapy.
Jonasch: I guess the dilemma here is that there isn't an overall survival advantage, but there's clearly a progression-free survival advantage, clearly an objective response rate advantage. In my discussions with patients and with some of our colleagues, the benefit that having sustained response provides to a patient, in terms of their aggregate quality of life, is something that we really do need to consider.
I think this is a reasonably strong argument for giving the doublet therapy as opposed to monotherapy. Obviously, from a health economics perspective, one is considerably more expensive than the other. And I agree with you — there's a subset of individuals to whom we don't want to give IO therapy. For those individuals, I guess the dilemma is a little simpler. Do you ever give IO monotherapy in the frontline setting for these patients?
Beckermann: I have in the past. It's a little less common, recognizing that doublet therapy does tend to have a higher objective response rate. But in this good-risk population, as you mentioned earlier, maybe the volume of disease is lower. Perhaps it's a more frail individual. And we're trying to avoid the toxicity of a TKI and see if we can get away with a single agent. But the majority of the time, I tend to start — based on the guidelines and the data — the combination approach. What about you?
Jonasch: Very rarely. I think the data are there. We have the KEYNOTE-427 data. We do see that the objective response rates for IO monotherapy — pembrolizumab, in this situation —is in the low 30% range. But the flipside to that is that the PD [progressive disease rate] as best response for IO monotherapy is also in the 30% range, which means that close to a third of patients will have progression as their primary response to that approach, which is somewhat risky. So it makes me a little hesitant to do it. And I do, as you say, typically give the IO/TKI.
Your group really has been at the forefront of looking at these molecular subtypes, like the paper that Bob Motzer and Brian Rini published, looking at these seven subcategories. And there's a study that's currently underway that's trying to use this to allocate treatment. Why don't you tell us about that?
Beckermann: Again, we recognize that these IMDC criteria were really created in an era when TKI was the major player. We're trying to step back and say that we now have these combination treatments using IO doublet or IO with a TKI. Are there additional metrics that we should be looking at? Can we base our decision of frontline therapy on the biology of a patient's own tumor?
We know, as you mentioned, from prior study using VEGF blockade and IO, that there are different gene-expression categories: an angiogenically driven gene expression category, a T-effector category, and then a couple of other categories that we're really trying to understand a little bit better. What we're doing in this clinical trial is taking a patient's own tumor and perform RNA sequencing to understand what is the biology driving an individual's cancer.
Does it show that angiogenically driven tumor, in which case they are getting assigned treatment with an IO/TKI agent? Or do they have an immune effector T-cell–type signature, which we think perhaps enriches that immunoresponsiveness? And then they're getting assigned a PD-1/CTLA-4 regimen. And if they're in one of these other clusters, where we need to understand the biology differently, they're going on a physician choice. And we're following to see how response happens for those groups.
It's very exciting. I hope that this will further our understanding across disease types. But we recognize in the favorable-risk group that while maybe the majority of those patients have angiogenically driven tumors, we still think that there's a subtype whose tumors are driven by a T effector. They might be a minority and might be less so than we see in the poor and intermediate IMDC categories. But this is what we're hoping will help add to the IMDC knowledge that we have.
Jonasch: I'm glad that we are actually applying some science to our empiricism with this trial. Hopefully, what we've talked about is helpful for the audience in regard to the general approach to this challenging subcategory. It was great chatting with you.
Beckermann: Same here.
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Cite this: Treatment of Patients With Favorable-Risk Advanced Renal Cell Carcinoma - Medscape - Nov 16, 2023.