Pedro Barata: Hello, everyone, and welcome to another video for UroToday. My name is Pedro Barata. I'm a GU oncologist out of University Hospitals Seidman Cancer Center in Cleveland, Ohio, and we're covering ESMO 2025 in Berlin. One of the works that really caught our eye and really caught the eye of the committee to select it for an oral, it was a fantastic work from Femke Burgers, Dr. Burgers. She's a medical doctor doing PhD now at the Netherlands Cancer Institute. Welcome, Femke.
Femke Burgers: Thank you. Thank you for inviting me.
Pedro Barata: Absolutely. I hope I'm pronouncing it correctly. My Dutch is not perfect.
Femke Burgers: Yep.
Pedro Barata: It's quite interesting, this investigator-initiated in kidney cancer, that you're going to show us because of a lot of reasons. You are exploring a neoadjuvant concept, it's an investigator-initiated study that you and your colleagues led there, and it's exploring a new mechanism of action that we know from the melanoma world and we're trying to bring it to kidney around LAG-3 inhibition, a novel checkpoint inhibitor. So congratulations. Great job. I'm wondering if you would like to kind of walk us through a little bit of what you showed us in Berlin, if that's okay?
Femke Burgers: Yeah, thank you. Yeah. So indeed we have conducted an investigator-initiated trial, a neoadjuvant trial, and, well, as we know, patients with locally advanced renal cell carcinoma have a high risk to develop local regional recurrence or distant metastasis after surgery. And we know from the KEYNOTE-564 trial that adjuvant pembrolizumab improves the disease-free and overall survival. But in other cancer types we do see that neoadjuvant immunotherapy also shows very promising results. In melanoma it has been shown that neoadjuvant immunotherapy is even better than adjuvant immunotherapy, and so far in RCC, the clinical benefit of neoadjuvant immunotherapy so far is still unclear.
Most evidence is coming from small single-arm studies, so it is needed that we really investigate the possible efficacy of neoadjuvant immunotherapy in RCC. And that's what we did in our trial. So the NESCIO trial, it is an investigator-initiated and randomized, non-comparative, open-label, phase II trial, and it has a Simon's two-stage design, while the patients that we have included are patients with histologically confirmed resectable clear cell renal cell carcinoma without any history of distant metastasis and an intermediate-to-high-risk profile, which was based on the clinical TNM staging and a tumor biopsy grade. They were also not allowed to have received prior immunotherapy or be using immunosuppressive medications. In the first stage, 42 patients were equally randomized to receive either nivolumab, ipilimumab plus nivolumab, or relatlimab plus nivolumab, with all treatments given in two courses every three weeks and then followed by a nephrectomy, and we made a baseline CT scan and we made a CT scan at week 6.
The primary endpoint of this study was the pathologic response rate, and this primary endpoint was met in the patients that were treated with ipilimumab plus nivolumab and in the relatlimab plus nivolumab treatment arm. So neoadjuvant treatment with Ipi-Nivo resulted in two near complete pathologic responses, and this means that 10% or less viable tumor cells were left in the resected tissue, and treatment with relatlimab plus nivolumab resulted in one partial pathologic response, meaning between 10% and 50% viable tumor cells were left, and one complete response, meaning no viable tumor cells were left at all. So all patients have received both treatment cycles. We have observed one delay of surgery in one patient that was treated with nivolumab monotherapy.
He received surgery after 2 weeks plus 1 day due to immune-related nephritis. And we have observed two deaths. Both were unrelated to the disease or to the study treatment. And while the grade 3 or higher immune-related adverse events were the highest in the combination arms, most high was in the ipilimumab plus nivolumab arm where we saw a percentage of 42.8% of patients having these grade 3 or higher immune-related adverse events, whereas this was 6.7% in nivolumab monotherapy arm and 14.2% in the relatlimab plus nivolumab arm. And surgery-related adverse events were not seen in patients treated with nivolumab, whereas this was around 30% in the combination arms. Also, when you look at the surgical complications, according to the Clavien-Dindo classifications, this was not seen in the nivolumab arm, the grade 3 or higher, and this was 40.3% in both combination arms. With a median follow-up of 21.9 months, the 18-month event-free survival rates were 93% for treatment with ipilimumab plus nivolumab, 77% for treatment with relatlimab plus nivolumab, and 72% for treatment with nivolumab monotherapy. And the 18-month recurrence-free survival rates were 93% for Ipi-Nivo, 83% for nivolumab monotherapy, and 77% for relatlimab plus nivolumab.
And it is important to mention that none of these patients have received adjuvant immunotherapy because this was not yet approved as standard of care in the Netherlands at the time that we have conducted this trial. Interestingly, although the number of pathologic responses was low, the recurrence-free survival appears very favorable in this small group because all patients that have achieved a pathologic response are still alive and disease-free at the time of this analysis. In conclusion, a short, or we also call that sometimes an ultra-short, schedule of neoadjuvant immunotherapy for 6 weeks resulted in remarkable pathologic responses in a limited number of patients with intermediate-to-high-risk clear cell renal cell carcinoma. In this first stage, the primary endpoint of at least two pathologic responses was met in both combination arms, toxicity was manageable, with minimal impact on the timing of surgery, and preliminary survival results suggest favorable event-free and recurrence-free survival and especially in these patients that were treated with ipilimumab plus nivolumab and in patients that achieved a pathologic response.
Further mature survival data and translational research results will be reported in the near future and hopefully may help us define the optimal treatment strategy and identify the predictive biomarkers to determine, and that's important that we know, who are the patients that are most likely to benefit from neoadjuvant immunotherapy in clear cell renal cell carcinoma.
Pedro Barata: Femke, great job. Great presentation as well. This is super interesting because you're testing a LAG-3 inhibitor here with a checkpoint, and as you know the context, and you went through that quite nicely, there's been kind of some skepticism around neoadjuvant therapy, which is not standard of care yet, although we all do it for selected cases. But one of the aspects that we see or learn from the metastatic disease is perhaps the differential response in the primary tumor versus metastatic sites. So there's something about the primary renal mass that doesn't respond as well, and when we do neoadjuvant, a lot of times we're trying to help the surgeon to make surgeries more amenable or do a nephron-sparing surgery, so allowing to preserve more nephrons.
And it appears that we get more responses with the TKI, with targeted therapy on top of IO than an IO-based combo or IO-IO or dual IO, in this case. And when we saw this data initially, when I saw this, I kind of get the sense it was more aligned with that thought process, that there's some tumors that probably we're not going to get as much shrinkage. Is that the perspective that you guys got as you were enrolling patients? Because I also feel like the ultra duration of neoadjuvant, perhaps the responses could be even maybe a little bit higher if you continue more than 6 weeks, more than two doses. Is that your thoughts or insights of you and your group as you were enrolling patients? Did you get that perception, that, why the short duration? Did you get that perception of, "Boy, perhaps in the future, next steps could be to extend that," or as you said, maybe just select the guys, the patients, who are more likely to benefit from a pure IO-based approach? I'm wondering thoughts around that.
Femke Burgers: Yeah. Well, indeed, still we need to learn a lot in kidney cancer and the ideal schedule of neoadjuvant therapy in RCC. Well, we base this 6-week schedule also based on the neoadjuvant studies in melanoma, for example, and also it would be great, if we have a waiting time here also for about, well, 7 to 8 weeks, and in that waiting time, if you can give a neoadjuvant immunotherapy, that would be great if that's short. But indeed we do not know if we might extend this and if we might need to add an extra cycle to better induce that immune response. When we first started with this study, we might have hoped for a higher response rate, like, we might have also in other cancers, the pathologic response rates are higher with neoadjuvant immunotherapy. We might have expected that also in RCC, but there's something different happening. And maybe the tumors are quite big in RCC, so also maybe you just need to add one extra cycle for these big tumors to have a pathologic response.
So I think future studies should really investigate can we use this short schedule or do we need one extra course? So we have discussed this and we have discussed to maybe add an extra cycle. Also, what you said about the goal of maybe helping the surgeon by shrinking the tumor, obviously that is great if that happens, if you see a great shrinkage of the tumor. But I think also with neoadjuvant immunotherapy, what's the most important goal is to reduce the risk of relapse. And it could be that maybe what you said, like, differences in characteristics of the primary tumor and the metastasis, that, for example, this neoadjuvant immunotherapy that you do not see a great shrinkage of the primary tumor, but that it works on those micrometastases that eventually will lead to the development of recurrence. So it could be that with this neoadjuvant immunotherapy, you do not see the big shrinkage and the big pathologic responses, but that it does work in reducing the risk of recurrence. But we cannot say that now for sure, because we need a longer follow-up time, we need to do extra research. But that's something that's in my mind, that I still think that maybe with also this low number of pathologic responses, like, lower than we have expected if you compare to other tumor types that it might reduce the risk of relapse.
Pedro Barata: Yeah. No, those are fantastic insights. And may I pick your brain on one last question before letting you go? How do you envision the 2.0 version of the study? Moving forward, what are you guys thinking? Are you leveraging LAG-3 inhibition moving forward? That's also being explored in the advanced setting, right?
Femke Burgers: Yeah.
Pedro Barata: Including, there's investigator-initiated studies also in the front-line metastatic disease. We'll see how this pans out. We did see a little bit of that data in one of the sponsor-based studies with KEYMAKER. Our friend Dr. Beckermann presented that data as well. But I'm wondering, in the neoadjuvant setting, what are you guys thinking as the next iteration of the trial here moving forward in this setting?
Femke Burgers: Yeah. Well, so far, based on the survival curves that we have so far, while it is preliminary, we only have a median follow-up of 21.9 months, and we want to first look at the results at 2 years. So we have to wait a few months more. But for now we do see that the treatment with ipilimumab plus nivolumab is doing the best. Patients there do the best. Well, we think that that treatment is the best. We do not compare, it's a non-comparative trial.
Pedro Barata: Numerically it looks better.
Femke Burgers: Yeah.
Pedro Barata: Numerically it looks better for the PD-1/CTLA-4, would you think of a triplet as next step?
Femke Burgers: Could be. Could be. I think that the most important next steps are we do need more neoadjuvant immunotherapy trials in RCC. And I think for now the most important questions are what you already said. How many courses do we need? Do we need maybe 9-week or 12-week treatment? I think that's more important and very important to investigate in future trials. And maybe triplet. However, for toxicity, also, the toxicity for Ipi-Nivo was quite high. It was the highest in this trial. So we have to be careful in a neoadjuvant setting.
We have to be careful with very high toxicity rates. I do think in the NESCIO trial we have also collected a lot of blood and tumor tissue, at baseline and at surgery, and for now we are focusing on the translational analysis. And I think for future trials it would be great if we have more background information of what really happens in the tumor. And if you can see these patients based on those, for example, immune characteristics of that tumor, these patients need, for example, triple therapy or longer treatment and other patients need less. And that's where we have to go in the future and we can learn a lot from melanoma in there.
Pedro Barata: Gotcha. Well, wonderful conversation. I'm so happy we got the chance to pick your brain around this investigator-initiated study. I know it takes a lot of effort. It takes a village to put this together.
Femke Burgers: Yeah.
Pedro Barata: Very interesting design. You were able to offer patients novel combination, novel approaches. It's very interesting. You really did a great job presenting at ESMO. It is a big crowd.
Femke Burgers: Thank you.
Pedro Barata: It was one of the most exciting sessions, and so congratulations, Femke. Really good. Well done.
Femke Burgers: Thank you.
Pedro Barata: So thank you for taking the time and I am sure we'll be talking again soon around kidney cancer.
Femke Burgers: Yes.
Pedro Barata: And congrats, your PhD is going well.
Femke Burgers: Thank you. Thank you. And thank you for the invitation here.
Pedro Barata: Absolutely. Thank you.
Femke Burgers: Thank you.