Risk Stratification in Metastatic Renal Cell Carcinoma - Episode 3

Role of TKIs in Intermediate or Poor-Risk mRCC


Sumanta Kumar Pal, MD: We’re going to move to another controversial topic, which is not on the topic of good-risk disease but intermediate- and poor-risk disease. And the question I have for you here is—and I may start with you, Tian—is there a role for TKIs [tyrosine kinase inhibitors] in this setting alone, as monotherapy? Are there certain patients you might choose for that purpose?

Tian Zhang, MD: In this setting, I really do debate about ipilimumab-nivolumab combinations versus, say, cabozantinib in the frontline setting based on cabosun [cabozantinib-sunitinib]. And the patients I generally try to choose for cabozantinib or VEGF-TKI would be patients who have critical metastases at specific sights of disease. Say they have a metastasis in the spinal column that might have some epidural extension, and I’m afraid that any local inflammation might tip them over toward cord compression. Or they have a lymph node in the retroperitoneal that’s pushing on a ureter and causing some mild hydronephrosis, if there’s any inflammation there that may get worse and the kidney function may worsen. Many of these patients, as you know, have only a single kidney, so their renal function is pretty tenuous. So for anything like that, where a structure can become inflamed and cause some obstruction and cause further clinical problems and symptoms, I’m leaning toward using a more directed therapy for early disease control and a faster response.

Sumanta Kumar Pal, MD: Well, it sounds like a brilliant approach. Neeraj, what do you think?

Neeraj Agarwal, MD: I think I’m very intrigued by this approach. I think this is very similar to what I have in my mind when I’m seeing these patients. But I just want to build upon what you said. So yes, we are looking for those patients who do not have the time to wait for the responses or progression-free survival benefit. They need immediate benefit. And we know that there’s a large number of patients who may not achieve a progression-free survival benefit with ipilimumab-nivolumab. Yes, we are really excited about the complete responses. But on the other side, there are going to be maybe 30% or 40% of patients who may not see immediate benefit. So when I see high-volume, rapidly progressive disease, especially with bone metastasis, liver metastasis, and as you said, impending cord compression, I tend to use cabozantinib first, followed by nivolumab or ipilimumab-nivolumab.

Sumanta Kumar Pal, MD: I think that makes a lot of sense. That tends to be my algorithm too for high-risk, rapidly progressing disease and bone metastases. I think cabozantinib is a very sensible strategy. Also, I’ll just throw in there that if I see patients—and I’m sure you guys do as well—who travel quite a distance to the tertiary center, where they may not have appropriate follow-up for autoimmune-related adverse effects, those are also patients for whom I think about using a TKI up front.

Neeraj Agarwal, MD: That’s a great point, yes. We always have those who are elderly patients, frail, living 100 miles away, and commuting 3 hours to come to the cancer center. How good will they be in responding? How responsive will they be to our directions—of calling us with 5 episodes of diarrhea, right? So I think for those patients who are already vulnerable and who may not be as communicative, I think those are the patients I really worry about with the ipilimumab-nivolumab combination.

Tian Zhang, MD: Absolutely. I think sometimes, in that very frail population, those patients are not the patients who are going on clinical trials, right? The people who come in on a wheelchair and are really quite frail and have really large disease burden. Disease burden is something that we see on scans and it doesn’t quite make it into our risk stratification. But I think it’s something very real that we all take into our clinical impressions when we’re thinking about these patients. And so when people have very high-disease burden, they need a quicker time to respond. These are the opportunities when I think of TKIs. And we’ll get into TKI-plus-immunotherapy combination strategies in the up-front setting, which can get them to an earlier response.

Sumanta Kumar Pal, MD: Makes sense, makes sense. I saw some great data at ASCO [the American Society of Clinical Oncology Annual Meeting] not long ago from the Dana-Farber Cancer Institute group. And Brad, I think you were part of this abstract looking at autoimmune disease and immune therapy. Can you give us a sense of what to do for that population? I think we all see it, right?

Bradley McGregor, MD: Right. I think this was a study that was retrospective, looking at patients who had a history of autoimmune disease and were treated with immunotherapy, and it seemed it was safe. It required monitoring, but it was done. When done appropriately with appropriate follow-up, despite a history of autoimmune disease, it seemed safe. Granted, these were not things that were active, such as Crohn disease, colitis, or something along those lines. These are histories of autoimmune diseases. Often it was something like rheumatoid arthritis or something that would not be life-threatening should it get out of control quickly. But it certainly seems as if a history of autoimmune disease, especially if it is quiescent, should not be an absolute contraindication immunotherapy. Though on all the clinical trials, that is certainly the case.

Tian Zhang, MD: And those patients were excluded on the trials, right? And so your data really help put in a perspective of what we do in clinical practice and try to manage these patients. They’ve had this long history, but they’re on very low steroid doses or nothing at all, or some NSAID [nonsteroidal anti-inflammatory drug] doses, and while we’re treating them with immunotherapy checkpoint inhibitors, we’re also watching their symptoms very carefully.

Sumanta Kumar Pal, MD: Now, do you have a line in the sand for this? If a patient, for instance, comes in on Remicade, is that a patient you might consider for nivolumab and ipilimumab?

Neeraj Agarwal, MD: I won’t.

Sumanta Kumar Pal, MD: No. What do you think, Tian?

Tian Zhang, MD: No.

Neeraj Agarwal, MD: I think when you talk about looking at patients with autoimmune diseases, there’s a whole spectrum, as you said. Autoimmune hypothyroidism is different from Crohn disease or ulcerative colitis. So yes, there is a spectrum, and yes, I think milder forms of autoimmune diseases must be fine. It should be OK; we see them all the time. But for anybody who has any clinically meaningful autoimmune disease requiring active treatment, I will not think about checkpoint inhibitors in those patients.

Sumanta Kumar Pal, MD: That makes sense.

Tian Zhang, MD: I think with a steroid dose, the prednisone equivalent of 10 mg or less a day, those are the patients I would consider. I agree, absolutely, that anybody who has a true disease-modifying agent like Remicade or Humira, those patients are at high risk for flare-ups, especially if we’re activating their immune systems, and I absolutely would hold off on checkpoint inhibitors in all patients.

Neeraj Agarwal, MD: And if they’re already on so many immunosuppressive medications, I worry about the efficacy of immune checkpoint inhibitors in those patients.

Transcript Edited for Clarity