 “Advanced Renal Cell Carcinoma: Putting Advances Into Practice.”I'm Dr Dan George, from the Duke Cancer Institute in Durham, North Carolina. Joining me today in this discussion are my colleagues, Dr Neeraj Agarwal, from the Huntsman Cancer Institute at the University of Utah, in Salt Lake City; Dr. Rana McKay from UCSD [The University of California San Diego] in San Diego, California; and Dr Sumanta Pal, from the City of Hope Comprehensive Cancer Center in Duarte, California.

Today, we're going to discuss a number of topics pertaining to the use of systemic therapy for advanced metastatic clear cell renal cell carcinoma [RCC]. We’ll discuss the latest research in the field, and the impact of recent clinical trials on making decisions around treatment selection. Let's get started with our first subject.

Let me start first with Rana, and we must start thinking about this in terms of frontline clinical trial data in advanced renal cell carcinoma. Before we make a treatment decision on a patient in the frontline setting, we usually start with some kind of risk assessment. Now, Rana, there have been a number of risk stratification models out in metastatic renal cell carcinoma; how relevant are they in your everyday practice for patients, how do you use them, and what do you use?

The risk stratification models are significant in this day and age, particularly the IMDC [International Metastatic RCC Database Consortium] risk factors that integrate laboratory values, performance status, and time to systemic therapy from diagnosis, so they're highly relevant. The model has been integrated into our frontline trials: KEYNOTE-426, CheckMate 214, to help us risk stratify patients to understand outcomes for different subsets of patients. The IMDC were initially validated in the context of the VEGF targeted therapy era. Predating that were the Motzer criteria, the Memorial Sloan-Kettering Cancer Center [MSKCC] criteria, that were validated in the cytokine era. Now in the context of these risk stratification rules being integrated into our frontline trials, they are helpful in deciding how to select therapy for any given patient.

There's been some elegant work that’s been conducted by David McDermott, MD, and his team from the IMmotion studies, speaking to the biology of each in the different risk groupings. The favorable-risk patients seem to have a more angiogenesis-high signature, and that seemed to have panned out in the frontline IO [immune-oncology]/VEGF trials, where there seems to be a signal that those patients may benefit from VEGF inhibition. Whereas, those who have intermediate- and poor-risk disease seem to have a more upregulated immune signature. The application of these risk stratifications is important. They’re critically important in not just determining systemic therapy but also in thinking about the role of cytoreductive nephrectomy in the context of people who have advanced RCC. Given the number of risk factors that any one individual may have, deciding for up-front nephrectomy or delayed nephrectomy may be important, so these are critically important in this day and age.

 Good, I agree. Monty, expand on it a little bit for me. We use IMDC probably more than some other models, but do you use that in every patient? How do you use it? Are there certain variables within IMDC that you look for, particularly to help you think about if there is an underlying biology to this? What are your thoughts on these models in your practice?

That’s a great question, Dan. When we talk with our colleagues in the community, they sometimes suggest that they might be using a gestalt impression of whether a patient is good risk, intermediate risk, or poor risk. As time goes on, Rana spoke to this beautifully: now that we understand the biological underpinnings of what good, intermediate, and poor is, I am sticking to the criteria more directly. I have to say, it's been a long time since I've not staged a patient with IMDC risk characteristics. I tend to be a bit of a purist there nowadays.

 That’s great. Neeraj, can you comment on this as well? When I see a patient who has a good performance status, I tend to think of them as a good-risk patient. However, when you start to look at some of the laboratory test results, and you start to look at the burden of disease and some of the timing of that metastasis from diagnosis, you start to add up these criteria. You can quickly realize that this patient may be a bit higher risk than you originally thought. Getting past this visual assessment and being more quantitative in this is extremely helpful. I've been burned by being fooled. The patient looks pretty good in the exam room, but then when you get the labs back the next day, you’re saying, “Wow, there's more going on here than I thought.”

Neeraj, what's your take on IMDC, and how do you think of this in terms of individual factors? Is there any one factor in IMDC that weighs more heavily on you than another?

Like Rana, you, and Monty said, I use it for pretty much all my patients. It’s a standard as a part of my initial visit now that IMDC will be mentioned, and without that, my note is incomplete. We are looking at all these factors in all patients. I’ve been surprised to see how patients can be categorized into poor-risk versus favorable-risk once we start counting the factors.

Which factor sways me the most: time from original localized kidney cancer to time of nephrectomy to onset of metastatic disease. That’s one factor I take into account and keep in mind. If a patient is developing a metastatic disease within 4 months or 5 months from nephrectomy, that’s a bad sign. If I see someone who is coming to me 8 years after original nephrectomy, it's a different disease.

 That’s a great point. It’s the only factor that speaks to the natural history of the disease; everything else is pretty immediate or static, and it's the one that is undeniably cancer. For anemia, there are a lot of factors that affect anemia. Or even hypercalcemia, it could be due to dietary things or sedentary factors or whatnot. Performance status is definitely affected by a lot of factors in the patient. That natural history of disease is so specific and relevant in kidney cancer, particularly in our good-risk patients, almost to the very good-risk patients. 

I want to get back to something that Rana brought up. She brought up the angiogenic profile that’s been looked at and correlated to some of our better-risk patients. It’s fascinating because we’ve known from the beginning that the loss of VHL [Von Hippel-Lindau disease] is a common biologic, angiogenic alteration that accompanies clear cell carcinoma frequently early on in this disease, and it drives that angiogenic profile. Everything else is secondary to that. Those inflammatory factors and other things get piled on and built onto that as the tumor burden increases and the genetic complexity diversifies, but it starts as an angiogenic biology. The tumors that retain that are pretty dominant on that. They tend to be the good-risk patients, but there are probably some of our intermediate- and poor-risk patients who still have an angiogenic profile; they just have other factors with it as well. We’re going to think about this now as we start asking questions about combination therapy.

Rana R. McKay, MD, University of California San Diego Medical Center

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