Evolution of the NCCN Guidelines for Kidney Cancer -Tian Zhang

(Length of Discussion: 12 min)

Tian Zhang and Charles Ryan highlight recent updates in the NCCN treatment guidelines for kidney cancer resulting from data leading to changes in treatment options. Incorporation of initial diagnosis, disease biology, risk category, and clinical factors assist with selecting the most appropriate therapy for these patients.


Tian Zhang, MD, Assistant Professor of Medicine in the Division of Medical Oncology and the Department of Medicine and a member of the Duke Cancer Institute

Charles J. Ryan, MD

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Chuck Ryan: Hello. We're at ESMO 2018, and I'm delighted today to be joined by Tian Zhang from Duke, who's an Assistant Professor of Medicine at the Duke Cancer Institute. While Dr. Zhang does a variety of clinical work in a variety of contexts, today, we're going to focus on kidney cancer. We're going to focus on the NCCN Guidelines and how they're evolving actually very rapidly. Fill us in on what's going on.

Tian Zhang: Absolutely. So, as you know, the treatment landscape for renal cell carcinoma has really changed even in the last year. We've had two new approvals in the first-line setting for metastatic renal cell carcinoma, and so in that light, the NCCN Guidelines have changed as well. They really have changed from a long list of drugs with various categories of recommendation to really thinking about prognostic scores for patients as they start on therapy. So, when they're diagnosed with their metastatic disease, where do they fall in terms of prognostic risk? So, we've used the IMDC criteria, the Heng criteria for a number of years now, separating outpatients based on favorable, intermediate or poor risk.

You know, and I will just highlight for our audience, that we really look at a variety of clinical as well as laboratory factors, including time from the initial diagnosis to systemic therapy, Karnofsky performance status less than 70, and then a variety of laboratory features like neutrophilia and thrombocytosis, anemia, hypercalcemia. So, if patients have zero at these of these criteria, they're in the favorable-risk, and if they have one to two, they're in the intermediate-risk, and then more than three, they're in the poor-risk category. This really predicts, these clinical factors really predict quite very well for prognosis and survival on treatment.

So, many of our first-line metastatic trials now are done while risk stratifying patients into these categories, and so the NCCN Guidelines really have changed to reflect that. So, they've shown favorable-risk and the different treatments that are available. So, the category one recommendations are still for sunitinib and pazopanib, but then, in the category 2B, recommended categories, cabozantinib has a feature and then as well as ipilimumab, nivolumab. Then, if you will look at the intermediate poor-risk disease category one really is ipilimumab, nivolumab, immunotherapy combination, as well as cabozantinib based on the CABOSUN trial.

Many patients and providers will question why the separation and what's really the possibilities of treatment here and the implications. So, what we wanted to highlight was in the intermediate poor-risk, these are the patients who were enrolled to the CABOSUN trial, the first-line cabozantinib versus sunitinib trial. So, in that setting, cabozantinib showed about a three-month improvement in median progression-free survival, which was the primary endpoint of the study. So, cabozantinib is probably the first VEGF plus MET and AXL TKI to show an improvement over sunitinib in this first-line setting, but based on that data, really, it limited enrollment to intermediate poor-risk patients. So, that's why it has that category one designation in the intermediate poor-risk. As well in that setting, we know that the CheckMate 214 study really highlighted in the intermediate poor-risk patients who were randomized to ipilimumab, nivolumab versus sunitinib that these patients had improved overall survival as well as progression-free survival and response rates.

So, we have two new treatment options for intermediate poor-risk patients, but in the favorable-risk setting, I think these really reflect that we're learning more about renal cell biology because specifically in the CheckMate 214 study, we see that the favorable-risk patients, and there were about 249 of these patients, they actually did better with sunitinib when they were randomized to either ipilimumab, nivolumab versus sunitinib. These patients actually had better response rates, better progression-free survival with sunitinib. So, I think in this favorable-risk category, we're starting to understand that there's a dependence on the VEGF and angiogenesis pathway that maybe we didn't know before. So, that's why sunitinib and pazopanib still hold category one designation in favorable-risk disease but then also suggested are considerations of ipilimumab, nivolumab as well as cabozantinib.

There's a designation on cabozantinib in that favorable-risk as category 2B, which shows that there was some consensus for recommending cabozantinib in that setting, but it was not uniform across the panel, and so that just really means that for CABOSUN, the trial that randomized cabozantinib versus sunitinib, it was only for intermediate poor-risk disease. So, if you extrapolate that into favorable-risk disease, that's why they came up with-

Chuck Ryan: Let's focus on this biology question for a second-

Tian Zhang: Yeah, sure. Yes.

Chuck Ryan: ... because it's really interesting what you just brought up. So, what you're suggesting, and the NCCN Guidelines reflect this a little bit, is that perhaps in good risk disease, VEGF biology is driving, but are you suggesting or do the guidelines suggest that those may be tumors that are slightly more resistant somehow to immunotherapy or let's turn it around and say, do we have evidence biologically to say that immunotherapy is more favorably deployed in intermediate and poor-risk because of some underlying biological fact? Then, the third part of that question is where does the MET targeting fit in here? Is MET not target in good risk disease whereas it is in poor-risk disease? How do you parse that out in your mind?

Tian Zhang: Yeah, I don't think we have all the data to tell us, right, but we may have some coming out here at ESMO from  Dr. Rini who is presenting the biologic signatures of patients who do well with atezolizumab, sunitinib, the angiogenesis signature versus the inflammatory signature. The clinical models that we have for favorable, intermediate and poor-risk are all very clinical factors, right? They're not DNA-based, and they're not RNA-based. They're all things that we can tell about a patient when they walk into clinic.

I think the factors that we highlighted, they reflect inflammatory disease, right? So, neutrophilia and thrombocytosis are all very much reflecting inflammation. We know that in those patients, potentially, they have more immune-driven disease, right, and so favorable-risk disease really doesn't have any of those criteria. So, I think they are, by nature of how we define the criteria to be less inflammatory, maybe more VEGF-driven.

Chuck Ryan: Do you think there is an issue around the site of metastasis and inflammatory status that clinicians should be mindful of? If they're seeing a patient with predominant bone disease, predominant liver disease, does that affect treatment?

Tian Zhang: Yes, so this ties into your earlier question also about MET and that we didn't actually discuss, but MET is the receptor for hepatocyte growth factor, and we see in patients with renal cell carcinomas that have metastasis in the bone or liver that these patients have more MET staining when we do immunohistochemistry on the frozen sections. So, in that case, I do think that MET has more of a role to play in patients who have more bone or liver METs. I've seen in my clinical practice that inhibiting MET with cabozantinib in patients with bone METs, for example, has more disease control capabilities than VEGF alone.

Chuck Ryan: Great. So, for the clinicians out there around the world who have most or all of these drugs at their disposal, what I think I heard you say is think about risk group, VEGF-targeted therapy in the good, immunotherapy is an option in the intermediate and poor as is cabozantinib.

Tian Zhang: That's right.

Chuck Ryan: Just focus on that decision right there, immunotherapy versus cabozantinib in the intermediate and poor-risk disease. Where do the guidelines take us on that, and what's your experience?

Tian Zhang: Yeah, so the NCCN Guidelines say category one for ipilimumab, nivolumab. It definitely has the FDA approval in the intermediate poor-risk disease.

Chuck Ryan: Category one, just for the viewers, based on a randomized controlled trial showing survival benefits.

Tian Zhang: Overall survival benefits, absolutely and also, it shows cabozantinib in the same category of ... It's not designated as category one because it's still based on CABOSUN, which was a Phase II trial that was powered around progression-free survival, but it had a trend toward overall survival benefit. The hazard ratio there was like 0.8, and so in that setting, and I think cabozantinib still does have a role. This is a very good question about how do you choose between ipilimumab, nivolumab combination versus cabozantinib? It's been a question that we also struggle within clinic because it's hard to tell who will respond when they walk in the door.

I tend to use more patient tumor burden as well as the site of metastasis as my decision making, in the process of decision making. So, patients who have disease in very particular areas that are prone to complications if they have inflammatory responses, so that's patients who have disease in vertebral bodies with epidural extension that may progress into cord compression if we have some inflammatory responses in the tumor microenvironment. It's patients who have retroperitoneal lymphadenopathy that have some hydronephrosis and that may obstruct their kidneys if they have some inflammatory responses to immunotherapy. So, those patients, I tend to choose cabozantinib over ipilimumab, nivolumab.

I think there will be more actually at ESMO this weekend where we will hear more biomarkers of responses from the CheckMate 214 study. I'm excited to hear that data to see who will respond better to immunotherapy versus VEGF-targeted therapies, but we really don't have head-to-head comparisons of ipilimumab, nivolumab versus cabozantinib. So, it's hard to choose. Certainly, in the setting of the newer data coming out with VEGF I-O combination strategies, it will be really interesting to see where the field integrates all of this data into their practice.

Chuck Ryan: Right. It'll be really interesting to see if ultimately we end up sequencing patients' tumors and putting them into a VEGF-targeted therapy bucket based on that, based on biology.

Tian Zhang: Biologic signatures.

Chuck Ryan: It just sounds like that signal is kind of there, and we'll be eager to hear more about that.

Tian Zhang: Absolutely.

Chuck Ryan: So, it's really enlightening, and it's amazing to hear about the changes in the guidelines so rapidly evolving as we get this new therapy. I mean, really the cabozantinib data and the ipi-nivo data are now only a couple years old and then ipi-nivo is published this year. It's already changing the standard of care, so a really great opportunity to watch biology unfold and clinical care. So, thank you very much for enlightening us, and congratulations on your work.

Tian Zhang: Absolutely. Thanks for having me.