Advanced Clear Cell RCC: Role of Site of Metastases in Selecting First-Line Therapy


Shared insight on the importance of sites of metastases and how they may impact first-line treatment selection in advanced clear cell RCC.

Thomas Powles, MD:
Ben, I want to ask you a different question altogether. Let’s get our dirty linen out in public and put it on the table. What’s going on in the good-risk patients? Do we need to be giving those patients combination therapy, or is sunitinib hard to beat?

Benjamin Maughan, MD: That’s a really interesting question. The CheckMate 214 study included good-risk patients, but not in the primary end point. They did carve them out in their analysis, and ipilimumab-nivolumab didn’t seem to improve on the performance of sunitinib in that population. It gets a little more difficult with these other TKI [tyrosine kinase inhibitor]–I/O [immuno-oncology] studies because they lumped all the IMDC [International Metastatic Renal Cell Carcinoma Database Consortium] risk patients together—the good, intermediate, and poor-risk patients—in primary and secondary end points. They did some subsequent analysis of the favorable good-risk patients. There, the results that are so good in the total population are more muted or diminished in the favorable-risk group.

For instance, to my knowledge, with all of the TKI–I/O combinations, if you look at overall survival with whichever combination vs sunitinib, there’s no statistically significant improvement in terms of overall survival. There are improvements in PFS [progression-free survival]. For instance, there are improvements with response rates but not in terms of that important end point of overall survival. These patients clearly do well. We also get a feel or an understanding about how well they do because buried within this favorable-risk group are patients who have oligometastatic disease that we sometimes do surveillance for or that you can do metastasis-directed therapy for. This population clearly does well with a variety of approaches; therefore, it gets challenging.

Thomas Powles, MD: I have to disagree strongly with Ben.

Ulka Nitin Vaishampayan, MD: Yes.

Rana McKay, MD: No.

Thomas Powles, MD: Yes, talk about it. Great.

Benjamin Maughan, MD: It’s always risky to disagree with Ulka.

Ulka Nitin Vaishampayan, MD: This is a place where we need better biomarkers. Ideally, within the favorable-risk group, I’d like to tease out the population that needs the combination treatment. Right now, the only way to do that is with clinical parameters.

Thomas Powles, MD: I’m going to push you a little, Ulka, if I may?

Ulka Nitin Vaishampayan, MD: Yes.

Thomas Powles, MD: We don’t have good biomarkers. PD-L1 as a biomarker has performed. I’ll come back to that in a minute. I hear a lot about patient selection beyond the IMDC classification in broad terms. I agree with what you said. Let’s go beyond there, because sometimes people say, “Cabozantinib is for patients with bone metastases, those with liver metastases should get lenvatinib-pembrolizumab and, and for brain metastases, this 1 is a bit better.” How do you select? Is there any patient selection, or is it, “We’re fishing for stuff because we haven’t got other things to talk about”?

Ulka Nitin Vaishampayan, MD: I think there is.

Thomas Powles, MD: Tell me about that.

Ulka Nitin Vaishampayan, MD: The sites of metastases is a big 1. That’s not incorporated in any of our IMDC or MSKCC [Memorial Sloan Kettering Cancer Center] prognostic criteria. Bone metastases, liver metastases—clearly, if somebody is favorable risk by all other criteria but has liver involvement, in my mind, they’re poor risk. They need that combination immune-based regimen. On the other hand, there are lung metastases that are distals and slowly progressing. Sometimes you don’t have that timeline, so you have to create it. But those patients are on surveillance. To me, the favorable-risk group is a huge mixed bag. The liver and bone metastases make it clinically easy to determine that we need to do aggressive therapy.

Thomas Powles, MD: What you’re saying is you can pick between VEGF TKI–I/O and I/O–I/O–based on the presence and absence of metastases, which I don’t disagree with. For bone metastases and liver metastases, you’re giving VEGF TKI–I/O combinations.

Ulka Nitin Vaishampayan, MD: I’d go to at least a combination regimen.

Thomas Powles, MD: This is still in the good-risk patients?

Ulka Nitin Vaishampayan, MD: Yes, favorable risk.

Thomas Powles, MD: In the good-risk patients, you’re trying to distinguish between good risk based on the signs of the disease. That seems fair. Let’s go broader, and let’s just go around the table a little and talk about the intermediate- and poor-risk population. Let’s talk about bone metastases, liver, metastases, brain metastases, and sarcomatoid features. Do you want to start with bone, Eric? How do you look at bone metastases? Is there a specific regimen that you use?

Eric Jonasch, MD: If I had to, I’d choose between I/O–I/O vs I/O–TKI.

Thomas Powles, MD: You wouldn’t be differentiating between the different I/O–TKIs. You see them all essentially as interchangeable. Or is there a specific regimen for bone metastases?

Eric Jonasch, MD: Cabozantinib has a reputation of being good in bone, but whether this has been validated is unclear.

Thomas Powles, MD: I agree.

Eric Jonasch, MD: Based on my clinical experience, as well as the data out there, the cabozantinib-nivolumab combination for an individual who has bone metastases is a good regimen. I wouldn’t choose axitinib-pembrolizumab.

Ulka Nitin Vaishampayan, MD: Hmm.

Eric Jonasch, MD: At that very targeted VEGF inhibition, this seems not quite as good. With lenvatinib-pembrolizumab, we have updated data presented by Bob Motzer at KCA [International Kidney Cancer Symposium] last year, showing that from subset analysis, lenvatinib-pembrolizumab is probably good for these hard-to-treat areas like bone and liver. Cabozantinib-nivolumab and lenvatinib-pembrolizumab would be my go-to regimens for those difficult-to-treat areas.

Thomas Powles, MD: Let’s go to the liver. Does it worry you that 1 of the regimens is essentially more transaminitis? Are you picking any regimens with liver metastases or, are they all the same?

Rana McKay, MD: With liver, there isn’t necessarily anyone that’s more active. I come back to this: are you in visceral crisis and in need of a short-term response right away? Or do I have the luxury of the primary PD [progressive disease] rate, which with CheckMate 214 is around 20%, 17%? Can I risk that? That’s my barrier. If somebody has 1 liver metastasis and that’s all that they have, or maybe they’ve got disease elsewhere, then I’m not worried. Even if it grows a little, I’m not going to hurt that individual. I tend to favor I/O–I/O. I want to give the option of long-term disease, durability, and long-term disease control. If I’m worried about visceral crisis, if I’m worried about multiple hepatic metastases, I’m going to run into trouble. I have to get that disease in check first. Then I lean toward an I/O of VEGF combination. Generally, I like the nivolumab-cabozantinib regimen because the lower dose of the cabozantinib is easy to tolerate. Patients do well and feel better on it. I like that regimen, but I don’t think there’s a specific differentiator for the liver.

Transcript edited for clarity.

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