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Pedro Barata: Hi, and welcome. I'm Pedro Barata, a GU oncologist at University Hospital Seidman Cancer Center in Cleveland, Ohio. Very happy to have you. Dr. Braun is a friend and a renowned scientist and-

David Braun: I owe you money for that, I think.

Pedro Barata: That was good. You're a famous scientist and also clinician working out of Yale. You're doing a fantastic job in kidney cancer work. Really original data and very important data, particularly in the biomarker world. And it was wearing that hat that you actually gave a remarkable talk at this coming out of ASCO GU about, or around, biomarkers, and the importance of biomarkers in the clinical management of renal cell carcinoma.

So maybe we'll start there. David, can you summarize for us, and perhaps for those who didn't get the chance to watch it, what were kind of the top biomarkers? You spent time walking us through that?

David Braun: Absolutely. And thanks again so much for the opportunity to chat today.

I think a lot of my thought processes, there are so many things that are tried, and how can we have a framework for thinking about biomarkers? And so, that was a lot of the presentation, trying to put things into buckets. How can we think of things ranging from basic histology, the most conventional tool we have, looking under the microscope, to really looking at a little bit more complex things like immunofluorescence, and what are the types of cells that are present within the tumor? All the way up to newer technologies like genomics. How might things like tumor mutation burden play a role or not play a role? And to, I think, what is probably the most advanced within kidney cancer, at least recently, which is transcriptomics, RNA-Seq data, really trying to understand how the biology of these clear cell tumors are actually different between patients. And how we can think of different molecular subtypes, and how that might ultimately translate to different outcomes and different responses to therapies.

And so, I think that's one of the main focuses of really the work, is to think about how we can put this into a framework? And then to have a little bit of fun too, and talk about what does the future look like? What are the next generation of things? How do we integrate single-cell sequencing, and spatial transcriptomics, and functional modeling? And that's not ready for prime time yet, but something that I think in the coming years will play a role. So at least thinking about those in the back of our mind as well.

Pedro Barata: Right. So fantastic points and great summary. I love the way you organized them into buckets; that makes our life easier, I guess. So let's start there. Because obviously, there's an emergence of tumor sequencing and molecular characterization of tumors with whole exome, with whole transcriptome sequencing. You did mention whole transcriptome sequencing. On that note, what is coming out of that? Should we be thinking about signatures?

David Braun: Yeah.

Pedro Barata: Should we think about something else? Tell us a little bit more about that.

David Braun: Yeah. And I think the first step that the field certainly moved towards is DNA sequencing, is whole exome sequencing. And we had learned from other tumor types that either specific mutations, we look at lung cancer and think of EGFR mutations, or general measures of tumor mutation burden, that those might be important for a response. And that's just not the case in kidney cancer. We just don't see that in the same way, where total mutation burden really plays a big role in response to immunotherapy. And beyond some individual papers, and we've contributed to this as well, where maybe in very specific settings, PBR1 might be associated with favorable outcomes. None of those are really ready for prime time. None of those are something that are clinically actionable, where it should really impact patient decision.

Pedro Barata: Right.

David Braun: I think now with the introduction of transcriptomics, RNA sequencing, it's starting to change. And it's not that it's brand new. There's been work about trying to think about molecular subtypes for a while, angiogenic favored subtypes versus immune. But I think this really took off more substantially with the analysis of the IMmotion151 trial, though. The tumors there, work led by Brian Rini, Bob Motzer, the Genentech team, which really sought to discover, are there different molecular subtypes of kidney cancer that we can really glean from RNA-Seq data? And what they found was, what we might expect, angiogenic type tumors, what they called clusters one and two, more immune tumors like clusters four, but a whole range of biologies that we're really not addressing yet in kidney cancer.

Pedro Barata: Right.

David Braun: And so the question is, how do those impact therapies? And in that at least initial analysis in IMmotion151, it really did. If you were angiogenic, you did pretty well with sunitinib. That was a pretty good therapy. If you were more immune-focused or proliferative, clusters four and five, those are really the ones that benefited from an immune-based therapy.

And so, that leaves a whole host of questions open in the field. Are these clusters real? I think they are. Are they predictive of response across different types of therapy? I think that remains to be determined, and lots of people are looking into it, including our group. But ultimately, all of these need to be prospectively tested. And I think Brian, and Katy Beckermann, and Scott Hague are doing a remarkable job with Optic RCC. So this is actually possible, it's not a trivial thing to be able to have an RNA-Seq biomarker-driven trial, but they're really thinking about it. If we classify patients as those angiogenic, get an anti-angiogenic drug, nivo, cabo. If you're purely an immune-focused subtype, then get a pure immune therapy. And I think that's going to be a really informative trial, and a really good proof of concept.

Pedro Barata: What exactly would you say? Hey, you know what? Here's a 101 of the things that we do care and that actually helps me to decide if I go with the IO/IO, IO/TKI, or perhaps another option.

David Braun: It's really the key question right now. Which of these are ready for prime time?

Pedro Barata: Right.

David Braun: And again, we do a lot of spatial work, and single-cell sequencing, and all these sorts of things in the lab, but it's Monday morning. How does this impact clinical practice? And I would say of all these advanced technologies, the only thing that really, at this moment in time, is ready for prime time, is still looking under the microscope. It's that sarcomatoid and rhabdoid features; those are really important. And we know that those are ones that really benefit from immunotherapies. That those are ones historically that did, unfortunately, very poorly with targeted therapies. And now in the era of immune therapies, they're still very aggressive tumors but have remarkable responses, and sometimes really durable responses. And we can see this in a variety of domains.

And so, if we go to the CheckMate-214 analysis, led by Dr. Tannir, we saw that almost 60% of patients who had sarcomatoid features had responses, and nearly 20% had complete responses, which is just remarkable for an aggressive histology like sarcomatoid. Our group has looked at this as well in real-world cohorts, whether that's IMDC or patients seen in the Harvard system, and we found the exact same pattern that those with sarcomatoid or rhabdoid features really had far superior outcomes with immunotherapy, compared to targeted therapies or non-immunotherapy.

Pedro Barata: Right.

David Braun: And then most recently, this was work led by Chris Labaki, who was a fellow in my group and Toni Choueiri's group, and is now a resident. Where he looked really very intelligently at non-clear cell, really a huge gap, these variant histologies, and asked, is this phenomenon still true? And this was just presented at ASCO last year, but the same pattern holds up for these variant histologies, these non-clear cells with sarcomatoid or rhabdoid components. They do much better with immunotherapy-based approaches than non-ICI.

Pedro Barata: Right. This is so important, right?

David Braun: Yeah.

Pedro Barata: Because the non-clear cell subtypes are so much more difficult to treat, right?

David Braun: Yeah.

Pedro Barata: They tend to respond not as well to the therapies we have available, right?

David Braun: Absolutely.

Pedro Barata: And a lot of us don't even think that immunotherapy would be an option for those subtypes. So it's so important that you actually can personalize the treatment for those kinds of difficult-to-treat diseases.

David Braun: Absolutely. And for the rest of it, I hope those other things, those next-generation things that in the coming years we'll see those trickle down to the clinic and be actionable. I think it's hard because biology is complicated, and so at the end of the day, looking at one thing at a time is hard to really get a hit with that. And as we start to integrate different features of the tumor or the immune microenvironment, the host, the circulating immune system, I think we'll make progress in biomarkers, but it's challenging. And so, what do we do today? We use something that we know. And that's something that's been around for a long time, and it's tried and true, and really looking at the histology, it's so important.

Pedro Barata: I love it. That's so important. David, thank you so much. Again, fantastic job. I think it was a fantastic overview you did at ASCO GU in San Francisco. And so, I just invite everybody to go and watch it if they had the chance, because it's a fantastic overview. And it really brings you up to speed about what we can do in the clinic, as you said on Monday, to offer the best treatment to patients who come to see us.

David Braun: Thank you so much.

Pedro Barata: Thank you so much.

David Braun: I appreciate it.

Pedro Barata: Appreciate it.

David Braun: Yep.