Pedro Barata: Hello everyone. Welcome back to another UroToday video. My name is Pedro Barata. I'm a GU oncologist at the University Hospital Seidman Cancer Center in Cleveland, Ohio, and we are covering great data being presented at ESMO 2025 in Berlin. And one of the highlights of the meeting, it was actually data presented by the one and only Dr. Cristina Suárez. She's a key opinion leader, world renowned GU oncologist. She comes out of Barcelona, Vall d'Hebron, a powerhouse for clinical trials. So I'm so happy to have Cristina joining us today. Cristina, welcome. Thanks for taking the time.

Cristina Suárez: Thank you. Thank you Pedro for the kind introduction and thanks for inviting me. It's my pleasure being here.

Pedro Barata: Of course. And again, congratulations. You did an amazing job. Not surprising. You always do. We did a great job around the KEYMAKER-U03 substudy, I think I'm pronouncing it correctly or label it correctly. And there's a lot of interesting things about this study that you presented. I like the fact that we are looking at data around the CTLA-4, from the sponsor, the LAG-3, the TIGIT, and you actually show us all that data within the same presentation, which was quite nice. So perhaps I would maybe ask you, could you walk us through the highlights of the data you just presented for context for the audience?

Cristina Suárez: Yeah, absolutely. As you mentioned, the KEYMAKER-U03, this is substudy 03A. So this was a first-line front-line trial. So key eligibility criteria was patients with histologically confirmed, locally advanced or metastatic clear cell RCC and with no prior systemic therapy and patients were stratified based on the IMDC group. The trial was divided into two phases. So we have a safety lead-in phase in which 10 patients were included per arm, and the objective of this part was to assess the safety profile, and then the randomized phase. So in this randomized phase, patients were randomized two-to-one to one of the four potential experimental arms or the concurrent reference arm that was pembrolizumab and lenvatinib. So in the experimental arms we could find favezelimab with its anti-LAG-3 coformulated with pembrolizumab plus lenvatinib, the anti-TIGIT coformulated with pembrolizumab plus belzutifan, not lenvatinib in this arm, the anti-CTLA-4 quavonlimab plus pembrolizumab plus lenvatinib or the belzutifan-lenvatinib-pembrolizumab arm.

Interestingly two of these arms, the anti-CTLA-4 and the belzutifan-lenvatinib-pembrolizumab arm are currently being investigated in a phase 3 trial, the LITESPARK-012. So the primary endpoint was overall response rate and secondary endpoints were duration of response and progression-free survival and overall survival. So looking at the baseline characteristics, all the groups were well-balanced. As per usual, most of the patients had an intermediate IMDC risk category tumor around 60% of the patients and around 60 to 70% of the patients had a prior nephrectomy. So looking at the primary endpoint, the primary endpoint as mentioned was overall response rate. And this really outperformed in the control arm. It was 80.6% for the control arm for lenvatinib-pembrolizumab, and this was not higher in any of the experimental arm. So in the anti-LAG-3 we had 63% of response, in the anti-TIGIT 42.5, in the anti-CTLA-4 71, and in the len-pem-belzutifan arm overall response rate was 77.5 with 12.5% of patients showing complete responses. So going to the secondary endpoints, median duration of response, PFS and OS, there was no benefit in the anti-LAG-3 arm, no difference, no benefit in the anti-TIGIT arm. Regarding the anti-CTLA-4 arm, we can see that at 12 months cut-off, the duration of response was numerically higher for the anti-CTLA-4 arm, 72 versus 55%, although the median duration of response was not different and no differences were seen in PFS and OS.

We'll see what happens with longer follow-up to this arm. And ultimately the belzutifan, lenvatinib, and pembrolizumab arm, so the median duration of response in this arm was 33.4 months as compared with the combination to the standard of care, sorry, that was 25.6 months. So duration of response at 12 months was 92 versus 55%. So this is a big difference we can say. And the exploratory hazard ratio for PFS we know it's exploratory is 0.45 with a median duration of response of 32 versus 21 months. And finally the median overall survival was not reached in any of the arms, but at 24 months the overall survival rate was 85% versus 67%. And again, we think this is an important difference. So here you have the key efficacy data just to have a global view of the data. As mentioned that the data were numerically higher for the combination of len-pem-belzutifan. And when we go to the adverse event summary, we can see that not big difference about grade three treatment-related adverse events.

Maybe the one with higher percentage of treatment-related adverse events was the anti-LAG-3 arm. And when we look at treatment-related adverse events leading to discontinuation or serious treatment-related adverse events, we can see that the percentage in the len-pem-belzutifan were not higher than in the control arm. And this is also very interesting. Most common adverse events as we can imagine, regimens containing lenvatinib we found hypertension, regimens containing belzutifan we found anemia but no surprises in adverse events. So in conclusion we could say like belzutifan-pembrolizumab-lenvatinib and quavonlimab-pembrolizumab-lenvatinib have similar overall response rate compared to pembrolizumab-lenvatinib and responses were potentially less favorable in the anti-LAG-3 and anti-TIGIT arm, and belzutifan-pembrolizumab-lenvatinib but not the other arms may have been associated with higher proportional complete response rate, prolonged duration of response and prolonged progression-free survival compared to pembrolizumab arm. So this combination, belzutifan and the anti-CTLA-4 pem-lenvatinib combination are being studied as mentioned before in the phase 3 LITESPARK-012 trial where the primary endpoints are progression-free survival and OS. So we'll see what happens with LITESPARK-012. We are very excited about the results.

Pedro Barata: Cristina, great data. This is super, super interesting data, super exciting to see this and so well done. I think the way my take home points from the data you presented is number one, the control arm continues to perform very, very nicely, right. Lenv-pem 80% response is quite remarkable. The second is I was a little bit underwhelmed by the LAG-3 inhibitor arm. A little bit more toxic than I expected, but also I don't see a lot more there. But finally to your point, that triple therapy with belzutifan, and the duration of responses, it's really, really striking to see and as you pointed out, this gives us even more appetite. It's like a great teaser for the LITESPARK-012. Do you agree with that? And what are your insights from being an investigator on this study is kind of what you got the sense from you and the other investigators, and do you really think this triplet might be the first triplet available if it turns out to be a positive study? We're guessing of course.

Cristina Suárez: Okay. I will start with the last question. I don't have the crystal ball, but I would say yes, it's really exciting and in my experience I have many, many patients with these combinations and the duration of response and the experience is really good. So hopefully we'll see what happens. And yeah, I completely agree with your summary. We were quite disappointed with the anti-LAG-3 arm. All of us were expecting great things with the LAG-3 in this trial and other trials, and we are quite disappointed with the LAG-3. In fact, enrollment in this trial was stopped early based on the recommendation from the data monitoring committee based on the toxicity. So yeah, we were quite disappointed with this arm. Nothing to say about TIGIT, so no big efficacy. So we'll see what happens with, yeah, very excited about the triplet and we'll see what happens with CTLA-4, but we also expected maybe more from this arm. So I think if we should pick up the winner, we would say lenv-pem-belzutifan for sure.

Pedro Barata: Right. So it sounds like if you were the sponsor, if you were to go back and design the phase 3, you might have designed it the same way with that triplet, right, when you put it all into perspective?

Cristina Suárez: Yeah, we will probably avoid the anti-CTLA-4 arm.

Pedro Barata: Yeah, no, that's a fantastic point. Cristina, this is amazing. Great job. Really practice informative. I think it helps us to kind of guide where we're going to go in the future. I think we have a little bit more clarity today on TIGIT and also on LAG-3 in kidney cancer, which is not necessarily aligned with what we've seen in other cancers. I'm thinking LAG-3 in melanoma, it seems to be a difference there, right? So kidney cancer is not melanoma. That's ...

Cristina Suárez: Yeah, we're realizing that.

Pedro Barata: Right. Well, congrats. Thanks for taking the time to be with us, and I'm pretty certain we'll be talking soon again for more important data that you present. And again, congratulations for the great job.

Cristina Suárez: Thank you very much for the invitation.