Robert Motzer, MD: Dr Rini and I co-chaired the IMmotion151 trial with atezolizumab plus bevacizumab. And I think one of the concerns is that the atezolizumab may not be the most active of our checkpoint inhibitors and may be less active than PD-1 inhibitors. Dr Rini, do you think that may have impacted on this trial? Or do you think the chapters closed here for this?

Brian Rini, MD: I think it could impact, as you say, PD-L1 inhibitors have been less active in combination. You mentioned atezolizumab, also avelumab, which is another PD-L1 inhibitor, both with PFS benefits but not OS benefits in a large negative adjuvant trial with Atezolizumab. So, to me, there's pretty definitive clinical data that PD-L1 inhibitors are less active, and that could be at play here. There's a trial, Rob, that I think you're chairing with nivolumab versus tivozanib. So that will at least in part answer that question. Is it a mechanism of checkpoint inhibitor issue here? I don't think that's the case. You saw the cabozantinib monotherapy arm perform really well in this trial. Those are almost frontline numbers. We have 40% response rates and a PFS of 10 and a half months. So, I think there's two reasons I'd hypothesize. One is checkpoint inhibitor therapy needed to be the most recent therapy, so those drugs and or the FT cell effected those drugs probably lingered. So, the arms may have been very similar in IO/TKI versus IO/TKI. And also, if you think about it, the patients who entered this trial are by definition those who are less immune responsive, maybe not nonresponsive. So, you're weeding out all those immune responsive patients, you're left with a very enriched angiogenic cohort. This is just hypothesis; we don't have biologic data yet. So that may be why you see high response rates in the cabo and why it would be hard to show a difference with the addition of an immune therapy, which is the difference between the arms. So, I think it's really important data. I think it was the most important data at ASCO, even though negative because this was happening in practice based on prior retrospective experiences, lenvatinib plus pembrolizumab trial that you were part of. But we just need to always be careful about anything short of a randomized trial. And we don't always have randomized data, but we need to be careful about implementing things in practice when we don't have randomized data because, and this is I think a good example. Again, the story is not completely told, there's another trial. And then the final thing I'll say is, what it doesn't really answer is the question, well, what if there was a longer gap between immune therapies? So, there was only one patient who had adjuvant pembro on each arm in this trial just based on the timing it accrued. But what if somebody failed adjuvant pembro or completed their year three years prior? We don't have those patients yet, of course, unless they were on trial. Or what if they got immune therapy frontline and now, you're talking about the fifth-line therapy or something. I don't think it answers that question, although the burden of proof is on proving that it works, not proving that it doesn't. So, I wouldn't do that in practice until there's proof that it works.

Robert Motzer, MD: Those are all great points from both of you on this study. Was there anything else just in the last minute before we switch over and cover the non-clear cell study? Was there anything else that caught your attention that you felt was mentionable in the clear cell RCC at the recent ASCO?

Brian Rini, MD: I think the non-clear cell data that I think we're about to go over was the next biggest data. There was a lot of real-world experiences, I always find that sort of marginally helpful. I know Monty Powell[ph] had some data around a T-cell imaging agent that was used. And so, we need more data on novel drugs and novel imaging. There was a little bit of that at ASCO, but hopefully in the future.

Robert Motzer, MD: Dr Ornstein, let's move on. In terms of the next large area that you see for clear cell RCC, is there anything that you just have on your radar screen that physicians should be aware of that you feel is going to be the next advancement for clear cell RCC?

Moshe Ornstein, MD: The next most obvious advancement would be the HIF-2 inhibition. And whether we see the results of the Phase 3 belzutifan trial and the highly refractory setting, belzutifan is approved obviously in patients with germline VHL mutations, and we'll see what its role is in clear cell RCC. And then once it, as many expect, is approved in the refractory setting, is there a role for it to move into the treatment-naive setting? Can we see it, if not replacing in some ways complementing the TKIs? And where ultimately the HIF-2 inhibitor will fall in the treatment armamentarium in terms of clear cell RCC? I think ultimately what we're really looking for, especially as we see some of the triplet data begin to emerge in ongoing triplet trials, is we're looking for either some combination of existing therapies or novel agents to have the best of both worlds, to see these high response rates and good PFS numbers upfront, and also to raise that tail of the curve and still have that benefit towards the end. I'm not sure that we have all the right tools yet. We're trying various combinations of existing agents and up and coming agents like the HIF-2 inhibitor, but that's really the next step. The next step is to say, we see that we can get to 70 plus percent responses upfront, can we maintain that or even increase that, and still also have high percentages of patients with deep PRs, CRs and landmark analyses at five, seven, nine years of those patients still being alive.

Brian Rini, MD: And I would just add, I agree that belzutifan, a HIF-2 inhibitor, is the most clinically advanced of the novel agents. It's being studied in pretty much every kidney cancer setting. So, it will find a home somewhere, maybe multiple places. I would say two other things, and these are much less developed as therapy targeting the myeloid compartment, myeloid macrophages, are clearly important in resistance and progression in kidney cancer. We don't quite have the drugs yet. There are some drugs in early phase one, early phase two. But I got to believe that that's going to be a way to augment therapeutic advances, specifically immune therapy. I think LAG-3 inhibitors, which have demonstrated activity in melanoma, need to be developed in kidney cancer. And then the last thing I'd say is the metabolic compartment. The first glutaminase inhibitor wasn't a success, but I don't think that's the end of the story and shouldn't be. And so, I hope there's more development of sort of drugs that target metabolomics moving forward.

Robert Motzer, MD: Well, thanks both. That's a great vision in terms of moving forward here.