Frontline Clear Cell Kidney Cancer: Treatment Selection and Patient Considerations

By Brian Rini, MD, FASCO, Tian Zhang, MD, David F. McDermott, MD, Hans Hammers, MD, PhD - Last Updated: November 13, 2023

A roundtable discussion, moderated by Brian Rini, MD, addressed considerations for clear versus nonclear cell kidney cancer, as well as recent data from ESMO 2023. Dr. Rini was joined by Tian Zhang, MD; David McDermott, MD; and Hans Hammers, MD.

In the first segment of the roundtable series, the panel shared their approach to treatment selection for clear cell kidney cancer.

Watch the next segment in this series.

Dr. Rini: We’re going to talk about a lot of different areas of kidney cancer. The first area we’re going to focus on is frontline clear cell kidney cancer. We’re going to talk about non-clear cell next. Let’s just start with your general approach to the typical patient. Advanced clear cell patient; let’s say they’ve already had a nephrectomy, let’s take that out of the equation. One IMDC [International mRCC Database Consortium] risk factor, no contraindications of medications, etc. Your run-of-the-mill, typical RCC patient. Tian, why don’t you start and just give us, what are you thinking about? What leans you one way or the other? What are the considerations?

Dr. Zhang: The immunotherapy doublets have obviously been our standard so when I approach that patient in clinic, it’s often their symptom burden and also the amount of disease burden. Even in one IMDC risk, we have variations of that. SThe people who are not so symptomatic and have minimal burden of disease, I’m really thinking ipilimumab/nivolumab IO/IO [immunotherapy] doublets at this point. If they have more symptomatic disease, need an earlier disease control, I’m thinking some of the VEGF/IO combinations.

Dr. Rini: We talk about symptomatic high-volume disease; how do you define that? I know it’s the eye of the beholder.

Dr. Zhang: I agree. If they have particularly rapidly growing disease that’s causing a lot of pain or maybe it’s next to a critical structure and next to a nerve ending in the spine or next to porta hepatis nodes pressing on the bile duct or something like that. Those types of things I’ll think about.

Dr. Rini: What percent of patients in your clinic do you think fall into that symptomatic enough for category?

Dr. Zhang: Early disease control?

Dr. Rini:  Yeah, where that’s important.

Dr. Zhang: Of all of the kidney cancer patients I see, probably 20%/30%.

Dr. Rini: Okay. It’s a pretty good amount.

Dr. Zhang: Yeah.

Dr. Rini: But otherwise, you default to ipilimumab/nivolumab ?

Dr. Zhang: Right.

Dr. Rini: Okay. David?

Dr. McDermott: I agree with much of Tian’s approach, not surprisingly. In our clinic, we generally don’t use IMDC criteria to pick therapy. It’s certainly very helpful for prognostication and talking to patients about how serious their situation is. Certainly [has] been helpful to us to get a sense of what the real-world experience is. But I think what most of the trials we’ve seen have showed is as a predictive tool, it’s not great particularly at long-term outcomes. I agree with Tian’s approach, unless people are in dire straits, we are offering them PD-1 or PD-1 CTLA-4 as a first-line approach based on their risk tolerance, meaning we have a frank conversation with them about how adding CTLA-4 doubles the risk of toxicity, particularly severe toxicity. If they’re okay with that, taking that risk, we do the combination of ipilimumab/nivolumab.

Dr. Rini: You have the same approach of a bulky symptomatic patient or critical organs, you might give IO/TKI [tyrosine kinase inhibitor]. Is that fair to say?

Dr. McDermott: Yeah.

Dr. Rini: Same questions. How do you define that and what percent is that?

Dr. McDermott: Well, it’s not firmly defined. I think if someone’s in the hospital for example presenting, they’ll get a TKI usually in the hospital and then outpatient IO therapy. If you get a sense that they might not be well enough to be treated in 2 or 3 months, they get an IO/TKI. My percentages are maybe slightly lower than Tian’s, but they’re pretty low. Most people get PD-1 first knowing that they can get TKI as salvage and many of them will need it. I think one of the problems we face as a field early on, particularly when developing ipilimumab/nivolumab is we didn’t transition quickly enough to TKI. If you look at CheckMate 214, there are a lot of early deaths in that trial, which are worrisome, so we need to change our approach to be more aggressive about adding a TKI if you don’t see an early response.

Dr. Rini: Do you think maybe that was because it was of the pseudo-progression and let’s wait and maybe they’ll respond and really they were just progressing and now we know a little better?

Dr. McDermott: I think it’s part of it and one of my biggest mistakes of my career was being partly responsible for that whole pseudo-progression concept. I think it happens; we see that sometimes in melanoma. I don’t think we see it in other diseases, and particularly with patients with symptomatic worsening, you almost absolutely have to be changing right away and we need to drill that into our…

Dr. Rini: Yeah, I agree. I think sometimes some mediastinal nodes will increase, but true pseudo-progression and then response, I’m not sure. I’ve seen it maybe once or twice at most though.

Dr. McDermott: Right. That’s partly why that trial did what it did. I think also some toxicity issues with the combination, some people not transitioning over to nivolumab maintenance if they didn’t get all 4 doses. That’s one of the things that has interested me about the COSMIC-313 experience is there they gave the ipilimumab/nivolumab more like we give it in clinic and the results are better.

Dr. Rini: Pretty good. Yeah.

Dr. McDermott: So that’s good.

Dr. Rini: Hans, how do you approach patients?

Dr. Hammers: Yeah, actually very similar to David. I don’t actually really care about the risk status. I actually just asked the question, “Does the patient need a TKI right now or not?” That percentage in my clinic is less than 10%. It’s really symptomatic patients worried about critical structures. Even if a patient has a pain somewhere we can radiate that, we can do other things. Pain per se, if there’s not a critical structure associated with it, I really don’t care about. But then there are patients in the hospital. I just had a patient last week, I ran lenvatinib across in the hospital because she was on high levels of oxygen for example.

Then coming back to what David was saying, I think is absolutely correct. There were constraints on CheckMate 214 and that was the first immunotherapy. Patients wanted to stay on it. You didn’t want to pull them off too early, etc. These days, if I get worried about some early progression or for some time that the patient needs to actually have the immune system get control of the cancer, I may fly in a TKI early. In fact, I had just add it to the doublet if I have to. Nowadays we can be much more selective in how we actually approach this problem. I think most patients don’t need a TKI, the vast majority, I focus on IO/IO.

Dr. Rini: Just for balance, I tend to be more of an IO/TKI user, so I believe in ipilimumab/nivolumab. Certainly for sarcomatoid, I think the data is great. All the regimens have sarcomatoid data, but ipilimumab/nivolumab’s is the most mature by far. Also central pathology review, I just think it’s better data. Young healthy patients, I tend to be an IO-TKI user. I tend to use lenvatinib/pembrolizumab, but lenvatinib is troubling in terms of toxicity as you all well know, certainly at 20 mg. Then I tend to use axitinib/pembrolizumab if I’m worried about patients’ frailty. I think to answer my own question about how many patients have bulky symptomatic disease, I think it’s probably 10% or less, I think somewhere in there. Again, it’s very gray. We would all probably define it differently. You know it when you see it. It’s one of those things, but we all define it differently.

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