Management of Papillary Metastatic nccRCC

In a roundtable focused on non-clear cell renal cell carcinoma, moderator Daniel Joyce, MD, of Vanderbilt University Medical Center, led panelists David McDermott, MD, of Beth Israel Deaconess Medical Center; Katy Beckermann, MD, PhD, of Vanderbilt University Medical Center; and Laurence Albiges, MD, PhD, of Institut Gustave Roussy in a discussion on the management of differing disease states, new approaches such as IO/TKI and PD-L1, novel trials, and adjuvant treatments.

In the first segment of this series, the panelists discuss the management of papillary metastatic nccRCC.

Watch the second part of this roundtable: IO/TKI and PD-L1 Approaches, Trials in nccRCC

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Dr. Joyce:
Hi, I am Dan Joyce. I’m a urologic oncologist at Vanderbilt University, and I’m thrilled to be joined by really an all-star cast of medical oncologists here. We have David McDermott, Katy Beckermann, and Laurence Albiges. We’re going to talk a little bit about non-clear cell renal cell carcinoma, and I want to start by talking mainly about papillary because that’s the most common type of that non-clear cell histology. And I’d like to start just by giving us a little bit of historical context. So take us back five, six years. How are you managing papillary renal cell carcinoma when it’s metastatic?

Dr. Albiges:
Sure. So the first thing we have to know is that non-clear cell as an entity has a dismal prognosis when compared to clear cell RCC, but for a long time was treated in the same way as we are doing with clear cell RCC because we didn’t have many trials. We had small phase two, prospective phase two, which started generating single agent activity such as sunitinib, but also everolimus, axitinib. And what we could see from those single arm study was a dismal prognosis with a response rate in the range of 20, 25%, and a median progression free survival of about six months. So really something that is not fantastic, and the overall survival was, for papillary, in the range of one year, depending on what we used to cluster as type one and non-type one, or type two papillary RCC.

Dr. Joyce:
So yeah, interesting. Sunitinib, maybe mTOR inhibitors, the standard of care back then, taking the lead from clear cell renal cell carcinoma. 2021, the PAPMET trial is published and really establishes, in a randomized control fashion, cabozantinib as superior to sunitinib. How did that change your practice now? Is everybody getting single agent TKI, or is there still some heterogeneity in how you’re managing those patients at that time?

Dr. Beckermann:
I think it’s been helpful data, and maybe we can talk a little bit about how it’s used worldwide when we think about sunitinib and cabozantinib, because I think it differs by country what’s available. But I think hopefully it gets a little bit at the biology that maybe cabozantinib, with its MET inhibition, is able to be more impactful on patients with papillary-driven where we think MET may be having some impact and driving that biology. I do think now, and we can talk about some of the newer trials that are showing combination agents, also where available, are having increased response rate and what we hope lead to more durable response.

Dr. Albiges:
Yeah, I think PAPMET was really a turning point given two things. First, it was a papillary-dedicated trial, and it was a randomized study on the rationale that MET could play a role. Because there’s about one-third of the patient that have papillary RCC that have what we call MET-driven tumors, this is an entity that has been built over time based on the fact that some of those patients have high expression of MET or also amplification of the receptor. So I think it’s important because biologically, it makes sense from it had a rationale, but also it was randomized. And I agree with you, cabozantinib really stood up there and was considered as a new standard of care in the guidelines worldwide for frontline papillary RCC.

Dr. Joyce:
So it’s interesting, this MET-driven therapy. What is it about cabozantinib in particular that showed a result when you have other trials, say the SAVIOR trial, which compare cabo versus savolitinib, no difference in progression-free survival. So both MET-directed TKIs. Why is cabo showing a response and others aren’t?

Dr. Albiges:
So that’s not an easy question. What we can say is that cabo is a very potent VEGF TKI. And the fact that cabo came out superior in PAPMET study, was it related to the potency of the TKI or to the MET inhibition part? That, we cannot really answer. What is important around the SAVIOR trial is that it’s a randomized study with a biomarker-selected patient population. And I think this is really another step forward for the non-clear cell papillary field because although it’s a rare entity, we were able to define a papillary-driven study.

Dr. Joyce:
And so not surprisingly, just like clear cell, we’ve had a whole slew of single-arm trials, albeit. Looking at combination therapies now, TKI IO, IO-IO, and more recently at ESMO, the SUNNIFORECAST data coming out looking at an IO-IO combination, Ipi-Nivo. How do you guys view that data? Does it inform what you’re doing now? Have you changed your practice based on any of these findings?

Dr. Albiges:
Maybe, David, you want to start with pembrolizumab single-arm study. I think this is very important piece of information, because for a long time, we thought that papillary and non-clear cell would not respond to immune checkpoint inhibitors. And really, with your study, you changed the game there.

Dr. McDermott:
Well, okay. Going back, you asked about the history of non-clear cell. So I was the oldest person by a lot on this panel, I can remember the pre-VEGF era for treating both clear cell and non-clear cell kidney cancer. And as Laurence is alluding to, in that era, we tried a lot of different things, chemotherapy, cytokine therapy. And because cytokine therapy was pretty inert in that group of patients, and we knew far less about that group than we do now, there was a general assumption, a conventional wisdom that non-clear cell kidney cancer was pretty unresponsive to immune therapy.

So that actually, in some ways, was wrong, as Laurence is alluding to. But it set the field back because then when we got more active PD-1 agents, non-clear cell patients were excluded from those trials, both in the metastatic setting and now in the adjuvant setting. So part of the reason we lack data on non-clear cell kidney cancer is because we were incorrectly excluding them based on the experience with cytokine therapy.

And Laurence is setting me up to talk about the trial that I was part of, which was KEYNOTE 427, which at the time was a single arm trial, the largest non-clear cell trial at that point. And it showed, surprising to all of us, activity in a fairly large group of patients, most of whom were papillary, and a response rate of 25% in that group, which is not that far off from what we see with single agent PD-1 in clear cell patients. And that trial has implications for what we’ve done since then, both moving PD-1 earlier into the adjuvant setting, but talking about combinations of PD-1 plus a variety of these other drugs, and is probably going to have impacts on both how we treat metastatic papillary kidney cancer, but hopefully how we treat these patients in the adjuvant setting as well.