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Pedro Barata: Hi, I have the pleasure of being joined today by Dr. Bradley McGregor. Dr. McGregor is a friend, colleague, he's a kidney cancer expert and the director of the Clinical Research GU Group at Dana-Farber. Brad, thank you so much for taking the time to be here with us today.

Bradley McGregor: Thanks so much for having me.

Pedro Barata: Absolutely. So congratulations, great presentation, at ASCO GU. Great meeting, by the way, and great job presenting the results of this COSMIC study, which is this trial for non-clear-cell, renal cell carcinoma looking at a combination of cabozantinib with atezolizumab, right? Very interesting. Maybe should we start by reminding us what the design of the study really was?

Bradley McGregor: Yeah, so I mean, non-clear-cell, renal cell carcinoma or the variant histology renal cell carcinoma is really an unmet need for our patients. I mean, we know we extrapolate a lot of the data from clear-cell and use the same in these variant histologies, but we really need to have data to help guide therapy. So COSMIC-021 was actually a really large multi-arm phase 1 trial looking at the combination of cabozantinib dose of 40 milligrams with atezolizumab every three weeks. And they had multiple different cohorts in GU and non-GU malignancies including clear-cell. This was specifically a cohort that focused on those patients with those varying-histology, renal cell carcinomas in which all patients received the combination of the two drugs and were treated until unacceptable toxicities or clinical progression. And actually, patients could actually continue beyond radiographic progression if they're deriving a clinical benefit.

Pedro Barata: So very important, very interesting design, right? Because you're really looking, seeking for efficacy signal in these different cohorts of patients, if you will. So let's focus specifically on your cohort, right, the non-clear cell, renal cell cohort, and can you share with us the main findings as far as your efficacy and safety for that cohort of patients?

Bradley McGregor: Yeah, so we actually were fortunate to be able to present this data now a couple years ago with just over a year of follow-up. And at that point, what we showed is there was activity for the combination of cabozantinib and atezolizumab across these 32 patients with variant-histology renal cell carcinoma over which half of them were papillary and then the rest were smattering of unclassified and chromophobe. And so we showed there was certainly clinical activity in that population with no new toxicity signals and that data is what led to, in the ongoing CONTACT-03, looking at the role of cabo and atezo versus cabo after immunotherapy, this data actually led to the inclusion of papillary renal cell carcinoma in that ongoing trial. But that was very short follow-up. So this was actually with over three years of follow-up to see, "Hey, where are things at this point in time?"

And I think what's quite remarkable is that with the extended follow-up, as to be expected, the response rate didn't change with the extended follow-up, the PFS didn't change per se, but what we saw is that there are patients at three years still deriving clinical benefit. And actually, at the datalog, five patients continue on therapy at that point in time. And if you look at the figure, there's actually a lot of those patients who actually had progression continue beyond progression and actually developed a response with continued therapy. So really quite remarkable in showing that this combination of TKI and IO certainly has some long-term responses independent of the objective response rates that we always think about overall. But with continued follow-up, we're really seeing some prolonged durable responses in some of these patients.

Pedro Barata: Well, I mean, I'm hearing what you're sharing and I think it's so important for so many reasons, right? When I look at the data for non-clear cell, right, we went from not having a lot of data with TKI monotherapy and we established sunitinib and then we got important study, another important study, in PubMed that can established cabozantinib at least for papillary RCC. And now, more recently, we have studies like yours, right, highlighting the potential use and role of an IO plus TKI with the same TKI by the way, cabozantinib, as a combo, suggesting that a lot of patients might actually benefit from the combo compared to TKI monotherapy. So that's so important, in my opinion. And now, again, studies like yours where you actually going beyond papillary histologies, right, and providing data with these combination regiments, right?

So I guess we have an emergence on IO-based combos. Yes, we see that in clear cell, but we are now seeing this in unclear cell as well. So I guess I have to ask you this because it is becoming a crowded area of different IO-based combos, right, including cabozantinib as a backbone, we have different checkpoint inhibitors being combined with cabozantinib. I guess my question to you is do you see any clear winner compared to the others? What are the next steps for us as we address patients who have these rare forms of RCC papillary, but again, chromophobe, translocation, unclassified, et cetera, right? What are your views about that and can you share a little bit, 'cause I know you're very involved with research from that perspective, what the next steps might look like for us?

Bradley McGregor: Absolutely. So I'm actually going to have to take everything about non-clear cell and compress it into 10-minute, and I'll try to take that 10-minute talk that I'm giving and give that in 1 minute. But I think, without a doubt, treatment for these variant histologies is emerging. I think ultimately, we love to see a histology-directed approach where we treat papillary different from translocation different from chromophobe, and I think we're actually slowly getting there in trials like that are possible. What we have now though, as you point out, we have a lot of trials looking at different combinations of TKI and IO. We have data for cabo-nivo, len-pembro, and now we have our data for cabo-tezo. Where the cabo-tezo brings to the table right now is the extended follow-up, three years of follow-up. We don't have that with any of the other trials.

And what it gives us hope for is that those durable responses that were seen in clear cell, they can happen in these varying histologies as well. And so that's the hope is that this is going to be a factor going forward. So which one is the winner? I think cabo-nivo, len-pembro, cabo-tezo, close to 50% objective response rates in those papillary unclassified, which is fantastic. I think we'll hope to see more durability overall. What we do know overall is chromophobe, unfortunately, even though those sarcomatoid features, which are such a poor prognostic factor, that chromophobe sarcomatoid doesn't seem to respond to IO the way clear cell sarcomatoid does, and it is really an unmet need. The question is can we do more, right? So cabo-nivo, len-pembro look great, can we get more response? Can we get more durability? And so we actually have an investigation trial looking at the combination of cabozantinib with nivolumab and ipilimumab in these variant histology immuno cell carcinomas.

We enrolled 40 patients in the first cohort starting with a dose of 40. We look forward to seeing those results soon. Given what we saw with COSMIC with a toxicity profile, we're actually enrolling another 20 patients starting with a little bit lower dose of cabo to see if by lowering the dose of cabo upfront with that nivo-ipi, can we actually improve the dose density intensity of the nivo-ipi and then increase the cabo later on? And so I think that will be an important additional study. And of course, all these studies can be really important to sort of take a step back, look, do that science, work with our partners to see other markers' response, and how do these variant histologies respond to these different combinations?

Pedro Barata: Right. I mean, you raise such important points. I mean, one of them is definitely dosing with triple therapy, right? When we saw COSMIC-313, and we're looking about how many patients actually end up getting three or four cycles of ipi, we had that discussion for a long time and so forth. And so the fact that you guys are looking at dosing in a careful manner, right, and trying to find out where's really the sweet spot for this cocktail of these three therapies, right as far as dosing, I think is really, really smart.

And so I'm really happy to hear that actually, your concept is actually moving forward in a very nice way. And yeah, we're probably going to be here talking about the results of that particular trial. Brad, this is great, great conversation. Congratulations again. The long-term follow-up is really important. I think you really touched on very important points, right, for unclear cell, RCC patients, right, go beyond papillary. You do highlight the difference between chromophobe and other histologies perhaps as far as efficacy with this combo, right? So again, congratulations for the great job you did. I'm looking forward to see that work published soon, and I'm sure we're going to be here sharing soon again.

Bradley McGregor: Thank you so much.