Petros Grivas: Hello, I'm Petros Grivas, I'm an Associate Professor at the University of Washington in the Fred Hutchinson Cancer Research Center and an Oncologist at Seattle Cancer Care Alliance. I'm very excited and happy today to host Professor Toni Choueiri. He's a Professor of Medicine at Harvard Medical School, and he's the Director of the Lank Center for GU Oncology in Dana-Farber Cancer Institute. Hello, Toni.

Toni Choueiri: Hi, Petros. Thank you for having me.

Petros Grivas: And I also am really happy to see Dr. Sumante Pal, Monty is a Professor of the City of Hope Comprehensive Cancer Center. Monty, welcome.

Monty Pal: Hey, thanks Petros for having me.

Petros Grivas: Two phenomenal individuals in the field of genitourinary cancers, both of you with fantastic contributions in practice-changing data. I want to discuss with you guys the evolving landscape in the first-line metastatic RCC, and we saw ASCO GU the work that Toni you co-lead it and was published in the New England Journal of Medicine from the CLEAR trial evaluating Pembrolizumab Lenvatinib combination versus sunitinib. And this definitely in my opinion, is changing practice and adding another combination in the frontline setting. Could you briefly summarize the results of the study, Toni? And again, I think for the audience, this is published in the New England Journal of Medicine and presented by Dr. Motzer at ASCO GU.

Toni Choueiri: This is hopefully one of the last, if not the last study that utilized a sunitinib as the control arm, this was a three arm study with sunitinib control versus lenvatinib plus pembrolizumab, so the VEGF IO arm versus lenvatinib everolimus VEGF inhibitor arm, over a thousand patients study that started years ago, and in the interim the standard chain and then this study is an untreated metastatic clear cell RCC patients. So we're really waiting for CLEAR to read after checkmate 9ER, really the results were quite compelling. And the VEGF IO arm of length pembrolizumab resulted in a median progression free survival approaching 24 months. So two years with a response rate, the highest today at 71% and amount which at 16% are complete responders. So this was statistically significant with all the endpoint of response rate PFS OS in VEGF IO arm.

Now in the levatinib non IO arm, the levatanib alignments, this was a very intriguing combination simply because currently in a good risk patient and in usually non IO containing regimen, really do not have a combination that is a standard. So that combination is approved post VEGF TKI, but would it be any use in frontline RCC. That's what CLEAR tried to answer. So response rate with higher statistically significant PFS or more prolonged, however, with OS this study, this arm didn't take a hit OS if anything the hazard ratio for OS went [inaudible] over one.

So certainly not the same benefit, magnitude benefit than [inaudible] pembrolizumab. The side effects were manageable overall. There were some toxicities and one of the things was when levatinib in the control arm those were different 18 was everolimus and 20 was pembrolizumab was over 50% of patients needing those reductions. Still, we don't know in any TKI in renal cell, what's the optimal dose for [inaudible]. That's about the exposure you have to play around with the goals. 20 may have been a bit on the high side, but certainly the combination of pembrolizumab then is going to be a player in the first line RCC setting.

Petros Grivas: Thank you, Toni. And congratulations on this amazing practice changin study. Monty, I know you did a fantastic job commenting on the evolving landscape in for line RCC. What are your comments? Now we have what I call the embarrassment of riches, right? Toni presents the checkmate 9ER at ASCO GU as well. And can talk about that in a second, but what is your take on this and how would you approach it for land setting?

Monty Pal: I think I've given all my comments away for free on Twitter already and kind of a big, sort of a dialogue on this particular topic, but just to really quickly summarize and it's just amazing to have three VEGF IO and one IOIO option to choose from in metastatic patients. I think what it all sort of boils down to now is that when you look across endpoints like response rate, progression-free survival OS you know, the three classical endpoints. So we've always focused on all these VEGF IO combos are hitting that. Just slightly varying degrees perhaps, but we got to stay away from these cross-trial comparisons just because of some imbalances and baseline demographics. I think the one thing that's so critical to keep in mind as we look across these data sets is how our patients are feeling on these regimens.

I give Toni and his team a lot of credit for the work they've done in checkmate 9ER to produce quality of life data. And it really does look as though quality of life is gradually improving and steadily better with cabozantinib and nivolumab versus sunitinib. As you look to that QLL data, that's really important. And then there's the boots on the ground experience using these regimens? I recently chaired a study looking at two dose levels of Levatinib at 18 and 14. And frankly, I think that the cumulative result was that both 18 and 14 are tough, 14 really lent no significant advantage over 18.

Now, when we go to the 20 milligram dose, that's being proposed in the frontline setting, I just wonder how patients are going to sort of respond to this in practice. And it kind of bears out in the study, lots of drug discontinuations and so forth for both levatinib, pembrolizumab, and the CLEAR trial. So I think that, based on these multiple compelling data sets that Toni and his team have produced, I'd probably lean towards cabozantinib and nivolumab frontline.

Petros Grivas: Interesting. And as you pointed out one day we have ipi/nivo we have pembro/axi, cabo/nivo and now pembro/lev four options there. Any particular subset of patients Toni, you can think, for example, patients with brain mets, or patients with primary tumor in place, which we know is probably a negative prognostic sign in this setting. How would you approach a patients like this Toni with the patient, with brain mets at the second patient with a primary tumor place?

Toni Choueiri: I mean, you put it very well. I think here we have an embarrassment of riches, which is great, better than having no drugs. So I think in my practice overall, when I start with something is VEGF IO or IOIO, and the rapidly progressive progressing patient was a lot of bone metastasis was a lot with primary in place where you need the response. Let's put it that way. There is no doubt that was VEGF IO, pembro/lev, cabo/nivo, especially cabo/nivo with bone metastases. The response rates are higher. We're talking about 42% with nivo IPI, you know, 55 to 70% was VEGF IO. So that's one. Now, if you say brain mets in the US mostly we approached brain mets by local treatment, whether SRS whole brain radiation or surgery. However, we have reported in the GU ASCO meeting just a couple of weeks ago on the activity of cabozantinib in two cohorts, one with progressing brain metastases and one that is not progressing.

And we show them intracranial activity over 50%. So that's interesting and of course retrospective, but it does support the prospective study that is being conducted by our friend's and colleague by the name  [inaudible 00:08:28] , which looking prospectively at the ethic cohort, the patient with brain met to see if there is any intracranial activity of cabozantinib and of course, the question is why. Primary in place here. If the patient is not eligible for cytoreductive nephrectomy, lot of patient now after CARMENA, you again, need patients that have, you need a place where you have a response rate, especially if this is symptomatic. And I would use VEGF IO interesting you checkmate 9ER. It's the study that has the lowest prior nephrectomy, 68% only. So you're right to that extent, I agree with Monty here that checkmate 9ER had patients that have more unfavorable risk, a group, whether more poor risk, less favorable, IMD risk, more kidney in place, more liver metastasis, just the nature of the baseline characteristics.

And of course what we do all of us here on this zoom call is a clinical trial when we have clinical trials. So we do have clinical trials that add drugs like COSMIC 313, three versus two drugs for clear cell intermediate and poor risk. We have PDIGREE also what it gives a nivo/ipi and  then introduces cabozantinib based on a response to that to nivo/ipi. We have other things planned. So an embarrassment of riches, also an option for trials, hopefully for patient, just to put that, to push the envelope more and more towards cure.

Petros Grivas: Absolutely. Thank you for this great [inaudible 00:10:15] points. Both of you, you have significant expertise in the field. That's the last point of the discussion today about the new kid on the block, a new mechanism of action Toni, you presented data on the hypoxia-inducible factor 2α (HIF-2α) inhibitor combination of the belzutifan (MK-6482) with cabozantinib at ASCO GU, and Dr. Bauer, I think presented data as well with this agent. Let me ask you to briefly summarize the key findings with this drug and then Monty can comment on it.

Toni Choueiri: Yeah. So two trials were presented. One for the first time, which is the combo of the [inaudible] inhibitor plus cabozantinib. And one has been presented before. So first the one that been presented before is from an extended phase one study, it was more follow up of the first in class new inhibitor that has been an elusive target. That too is a transcription factor. Up until recently considered undruggable, but some elegant crystallographic work from UT Southwestern, came up with the first-generation molecule.

And this was the second-generation molecule initially by Peloton acquired by Merck. And the drug goes into one of the pockets of HIF-2 and needs to inhibiting HIF-2α and not HIF-2α would then get dimerized. So that's proven to be efficacious overall in this population of refractory renal cell patients, [inaudible] was 25% response rate and relative safe anemia and hypoxia is all what we've seen, which on target the anemia due to [inaudible] degrees and hypoxia along the same lines, not [inaudible] but through inhibiting him through that has a role in the lung physiology and the vascular physiology.

I mean, this whole pathway is beautiful and led in part to this hypoxia oxygen sensing has led in part to the Nobel prize in physiology or medicine 2019, including my mentor collaborator, Dr. [inaudible], who came from medical oncology, if you want VHL as well as HIF-2 side of things. So we are glad to have that. And of course, the next thing is to combine, and perhaps for a maximum blockade of the whole pathway, you'll combine the HIF-2 inhibitor [inaudible] that has a track record as a single agent in refractory renal cell cancer. So we come back to the combination trial in patient was tumor progressed after one to two line of therapy and show the response rate 22%, but a lot of unconfirmed responses and why there was those reductions overall that toxicity was manageable with a long progression-free survival though. It's a bit unstable since the median follow-up is relatively short. So a good thing overall, and certainly that's the target is to look at in the future and in the present in the clear cell RCC.

Petros Grivas: Thank you, Toni and Monty. How do you place this in context with this amazing advances in metastatic RCC? How do you see this drug fitting?

Monty Pal: It's just amazing to sort of see this science evolve. I'd say I kind of wonder what it's like to kind of be in Toni's practice where you're seeing the patients in like right down the hall, you have a Nobel prize winner who's driven a lot of the science it's got to be incredible. I think that we really want for novel pathways and kidney cancer. if you look at our track record over the past couple of years there's been a lot of redundancy. A lot of multikinase inhibitor is primarily the focus on VEGF. So it's great to see something new added to the pipeline. So I'm quite optimistic about how things will go with this compound and hope to see it evolve quickly.

Petros Grivas: Do you see a potential combination strategy with it? And in which line would you envision this?

Monty Pal: I think Toni has really presented some compelling data. He cited all the caveats of the combination of cabozantinib with velzatidfan as he proposed there we've already heard about frontline trials looking at lenvatinib with this compound pembrolizumab it's the era of triplets and quadruplets now and in frontline therapy for kidney cancer. So I think that I can certainly see a compound like this moving up in our armamentarium.

Petros Grivas: And as your pointed out guys, Dr. [inaudible] mentioned this potential multi-drug combination early on as a pathway to try to eventually cure more people. So I think this is really amazing experience what we're seeing in kidney cancer and thanks to both of you for your great, amazing contributions, and also thank you for your time today and thanks to the audience. So looking forward for more discussions with you guys.

Monty Pal: Thanks, Petros.

Toni Choueiri: Thank you Petros, this is great.