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Pedro Barata: Hi there, and welcome. My name is Pedro Barata. I'm a GU medical oncologist at Case Western University, at the University Hospital's Seidman Cancer Center.

Today, it is my true pleasure to be joined by Ben Maughan. Ben is a friend and colleague. He's also the assistant professor and the medical director of the Investigational Drug pharmacy at Huntsman Cancer Institute in Salt Lake. Welcome, Ben.

Ben Maughan: Thanks, Pedro. It's fantastic to be here visiting with you today. I always look forward to visiting with you. Anyways, it's so nice to be here.

Pedro Barata: No, thank you for joining. I'm really excited by our conversation today, because you really highlight the work that you and others have been doing in non-clear renal cell carcinoma. For the folks who are listening to this today, we're going to be talking a little bit about RCC, particularly papillary RCC, and we'll be highlighting a couple of studies that are relevant.

Maybe Ben, because I know you are heavily involved with work that was done with PAPMET, Right? PAPMET was published not that long ago, that really asked the question about the role of cabozantinib versus sunitinib, even though the original design wasn't like that. So as I said, you were heavily involved. We worked with Monty Pal and others on that design. Successful trial data out there, that helps us to treat people with MET papillary renal cell carcinoma. So perhaps we'll start there. Can you highlight for the audience, perhaps less familiar with that study, what were the take home message from PAPMET?

Ben Maughan: Yeah. The whole reason that SWOG 1500 or PAPMET came about is that, we know papillary kidney cancer is a distinct histology with distinct molecular drivers, a distinct prognosis. It's different than the other non-clear cell histologies. It's certainly different than the most common kidney cancer histology, which is clear cell. Despite that, a lot of the regulatory bodies have approved all of the treatments that we have for kidney cancer, regardless of histology. It's just a blanket approval for kidney cancer. And so, that just really lends towards this concept or idea that all the physicians are really, we're lumping them together. We're just treating them as one, despite their different molecular characteristics and prognosis.

SWOG has this storied history of leading trials in papillary kidney cancer, to try and identify uniquely effective therapies for this space. The most recent, as you mentioned, was led by Dr. Monty Pal, SWOG 1500, or PAPMET. In this clinical trial, it was really an effort to identify and create a standard of care for this specific histology.

One of the molecular features that's quite common for many patients with papillary kidney cancer is alterations to MET. So in this clinical trial, so in PAPMET, or as I call it now, PAPMET 1, but in PAPMET, the idea was to compare four different therapies. So the defacto standard of care was sunitinib, because there was some retrospective studies, more retrospective studies, regarding that disease, demonstrating some efficacy. So then it was, these other three arms were individually compared to sunitinib.

During the interim analysis, it turns out that two of them dropped out, because they were not as effective as sunitinib. So crizotinib and savolitinib were both found to be less effective than sunitinib. So those arms were terminated early. So it really ended up this head-to-head comparison between cabozantinib and sunitinib. Cabozantinib significantly improved progression-free survival. And so, that has created cabozantinib as the standard of care for the first-line therapy for the treatment of papillary renal cell carcinoma.

Pedro Barata: Thank you, Ben. That's actually a fantastic summary. And to your point, I like when you call it PAPMET 1, because it really is and-

Ben Maughan: Now it is. Now it is.

Pedro Barata: Right. And yeah, I will get to that in a sec. When we look at the options out there, a lot of us kind of felt that we needed a head-to-head study to establish between different TKIs, if you will. And this is perhaps the first to do that, successfully favoring cabozantinib. And at least in my practice, cabozantinib became the standard of care following the data from PAPMET.

Now, we also know that the management of advanced RCC is changing, particularly in clear cell subtypes, with emergence of multiple IO based combos. So we have ipi/nivo, we have axi/pembro len/pem, cabo/nivo, axi/avelumab, et cetera. And a lot of those combos actually improve outcomes for patients with clear cell, and really, the standard of care, and are being offered to patients worldwide. And the question really is, while that is very, very important, the management change quite a bit, we still don't have a lot of data beyond clear cell component RCC, if you will. And of course in non-clear cell includes papillary, as you said, and also other tumor types, chromosome translocations, or in others if you will, collecting DUB, medullary.

So the question is, I know you sit down and you brainstorm with a lot of smart people, to come up with the next level of trial for papillary RCC leveraging on PAPMET 1, and you came up with PAPMET 2. And so, instead of me summarizing the trial, I'd really like you, if you may, to tell us exactly how you come up with that design, and how we can actually think that's, or how you think that's actually going to provide additional information that are going to be helpful for us treating physicians out there, when we have a patient with papillary RCC.

Ben Maughan: Yeah, that's a really good question. The issue is that, now in clear cell disease, we have definitive absolute concrete proof, the combination therapy using an immune therapy backbone, whether that's ipi/nivo using an IO/IO combination, or some TKI based combination is, as you highlight, is far superior than starting off with a single agent TKI, at least as far as measured by sunitinib. So now, combination therapy is and should be, the standard of care first-line treatment for patients with metastatic clear cell kidney cancer.

But as I mentioned a few minutes ago, the approvals are blanket wide across all histologies. So we have access to use those combinations as first-line therapy for our patients with metastatic papillary kidney cancer. And in addition to that, we have some single arm, sometimes multi-institution, sometimes single institution, prospective studies, demonstrating that there is an immune therapy effect in papillary kidney cancer.

So this was, I think, first well done with KEYNOTE-427. Cohort B was monotherapy with pembrolizumab in all non-clear histologies, that the majority of those patients that were enrolled had, in cohort B, had papillary kidney cancer. And there was a respectable response rate to single agent pembrolizumab. And then this has subsequently also been demonstrated with certain combinations. Again, to really all just in single arm fashion. So the COSMIC study was the first to show that cabo/atezo had some activity in papillary disease. There's been some others now with cabo/nivo demonstrating some activity. Most recently at ESMO this year, Laurence Albiges presented their prospective study of lenvatinib and pembrolizumab, and all of these are demonstrating reasonable response rates in patients with metastatic papillary kidney cancer.

So all of this, I think, really just highlights the value of doing a prospective clinical trial, looking at combination therapy really, versus single agent and defacto sequential therapy. Because we know that anytime you do combination treatments, you're increasing the toxicity to the patients. But whether you're truly improving their long-term outcomes, over say, sequential therapies, is difficult to answer. And it's impossible to answer that question in the context of the trials that have been done, because none of them are randomized studies.
And so, I think that highlights the particular value of PAPMET 2. And in PAPMET 2, we are randomizing patients to the standard of care today, which is cabozantinib. I should say, the standard of care for metastatic papillary kidney cancer. We're randomizing them to cabozantinib, or to cabozantinib plus atezolizumab. Really testing, is combination therapy effective?

At the time we designed this study, because these cooperative group studies take a little while to develop, the best data we had for a combination checkpoint inhibitor therapy in papillary kidney cancer was with cabo/atezo from the COSMIC trial. Since then, there's a couple of other combinations, again, as I mentioned before, that have demonstrated activity. But anyway, that's why this particular combination came about, because we were trying to get moving on this as quickly as possible, and that's the data we had at the time.

Pedro Barata: No, I appreciate that, Ben. And by the way, congrats, it's a fantastic design. Do you mind reminding us, how many patients you're looking for, and what's the endpoint of the study? I think it's PFS, but just confirm that for me. And then, what is the plan, as far as how many sites you can get up and going, and help with those efforts? They are really important efforts.

Ben Maughan: Yeah, great question. So in terms of the other details of the design of the study, you're right. The primary endpoint is progression-free survival. We feel that based on the published data so far, progression-free survival appears to be a robust sort of surrogate of overall survival. So the primary endpoint is progression-free survival. And in a rare disease like this, where accruals take more time than if we were to do a first-line clear cell kidney cancer trial, trying to get the results as quickly as possible, it is important. And so, choosing progression-free survival as the primary endpoint, is one way to try and help achieve that.

Overall survival is a important secondary endpoint. Again, because part of the other intention that I have with developing this particular study, is to try and answer, as best we can in a rare disease, if combination therapy is more effective than sequential single agent therapy for these patients. And so, we're collecting a lot of longer term information on these patients, what therapies they're receiving afterwards. Again, we're collecting overall survival data. It's not the perfect design to answer the sequential question, but it will give us a lot of insight, to try and better understand if we really should be mimicking, at least as far as today, that the strategies we're learning in clear cell, is that really what we should be doing for papillary? Or do we really need to start creating a whole new pathway, or direction, of how we think about treating them?

In terms of the total number of patients, it's approximately 200 that we're planning to enroll. A little bit less than, but roughly about 200. Because this is a rare disease, it's really going to require help broadly across the range. If we look at the enrollment numbers for, again, PAPMET 1, this was open at a lot of centers. And most centers enrolled between one and three patients, which is what you would expect for a rare disease like this. Many of us don't see, many oncologists in the country don't see papillary disease very often, so they're not going to enroll that many patients. So we're really trying to get the word out, and try and do as much as we can to facilitate people opening this trial, both here in the United States and in Canada.

Pedro Barata: Got it. Ben, this is fantastic. Maybe I'll just take this opportunity for sites out there, for those colleagues listening to this, who have access to the NCI cooperative groups mechanism, to actually encourage them to open the study, have it available at their sites, and help these efforts. They are really important as you probably, the goal is to see if you can establish an IO based approach. In this case, cabo/atezo, based on previous data as you mentioned, as well, if we can actually provide data to basically support our decisions in clinical practice.

So Ben, it was so great to have you here today. Thank you for being generous, and allowing you to sit down with us today, and talk a little bit about your work. It's been great. I mean, you've been doing fantastic work in the RCC space. And I just hope this trial goes well, the enrollment goes well. It's just up and going, as you said, and I'm just hoping you'll be here probably in two years or so, and talking about the results of these trials. So congratulations again, and thank you for taking the time.

Ben Maughan: Thank you, Pedro. It was so wonderful to visit with you, and to talk about this study. I know we've had multiple conversations, just personally, you and I, about this. And I really appreciate your input, and your perspective that you've had throughout the year. So thank you so much.

Pedro Barata: Thanks.