Laura Marandino: Thank you. Let's switch now to trials enrolling patients with renal cell carcinoma at our institution. These are my disclosures. You can see here this slide is quite empty and this was just the situation just 6 months ago. Luckily the situation really changed during this last period thanks to the hard work of some people. Let's start with non-metastatic renal cell carcinoma and M1 NED disease.

As Dr. Capitano showed, the KEYNOTE-564 trial established a new standard of care. So in reality, the first standard of care in Europe for the adjuvant setting of high-risk renal cell carcinoma. Then the drug was approved by the FDA, by EMA. However, the drug is not reimbursed here in Italy. We also know that this setting is quite challenging for perioperative strategies, and in fact, we heard about these three negative trials of immunotherapy at ESMO 2022.

As I said, we don't have the opportunity to administer pembrolizumab as adjuvant treatment for renal cell carcinoma patients, however, we have the opportunity to offer to our patients here the LITESPARK-022 trial. This is a randomized phase III trial of belzutifan plus pembrolizumab versus pembrolizumab for adjuvant risk renal cell carcinoma. Basically, these are the main criteria. This trial includes patients with intermediate high-risk, which means pT2, grade 4, or sarcomatoid, pT3, or high-risk disease, which means pT4 N+ disease. Also, the population of M1 diseases is included, so those patient who had a radical resection of metastasis at the time of nephrectomy or within 2 years from nephrectomy. Only 12 weeks are allowed between surgery and randomization, so this is very important for urologists here because we need to discuss very early the cases of this patient.

As I said, the control arm here is pembrolizumab and this is the only study which has pembrolizumab as an active control arm. The experimental arm is belzutifan plus pembrolizumab. Belzutifan is a second-generation small molecule HIF-2 alpha inhibitor, which means that it wants to target angiogenesis at its most proximal source, which is different from other TK inhibitors such as cabozantinib or axitinib. As you can see, they act at a peripheral site. We know that belzutifan shows a very interesting response rate, both in Von Hippel-Lindau syndrome as well as in very pretreated patients with advanced renal cell carcinoma. The primary endpoint of this trial is disease-free survival, while overall survival and patient-reported outcomes are secondary endpoints.

Let's switch to first-line metastatic renal cell carcinoma. We know that now, basically all patients receive IO combination treatment, so doublet therapy based on IO/TKI or IO/IO. The combination of Axi-Pembro, Cabo-Nivo, and nivolumab-ipilimumab are reimbursed here in Italy, so our options for our patients. This trial really showed very interesting results in terms of overall survival, objective response rates, and also duration of response. However, there are still patients who have primary resistance or develop acquired resistance, so, of course, there is the need to do more for all patients.

There are trials that now are trying the strategy of just adding drugs, so triplet therapy, and this is one of the trials. The LITESPARK-012 trial. This is a first-line trial for clear cell carcinoma, and the control arm here is pembrolizumab-lenvatinib, which is the combination with the highest objective response rate so far in renal cell carcinoma. The first experimental arm wants to test an intensified immunotherapy strategy by adding a CTLA-4 inhibitor to pembrolizumab lenvatinib, and in this case a co-formulation of quavonlimab, the CTLA-4 inhibitor, and pembrolizumab is used. With the second experimental arm, they want to test if an intensification of the anti-angiogenic strategy is successful by adding belzutifan to pembrolizumab plus lenvatinib. In this case, progression-free survival and overall survival are the primary endpoints and the true triplet arms are compared to the doublet arm.

Let's switch now to second and further lines of treatment. Of course, now the biological and clinical nature of our second and third-line treatment patients is changing, because basically before, those patients were only treated with mono TKI therapy, but now basically patients who have progressed to a combination strategy, so we can hypothesize that. These are different patients from what we are used to before. So we need, of course, trials in this setting. We can offer our patients the LITESPARK-011 trial. This is a randomized phase III study which compares, in second and third-line treatment, the combination of belzutifan-lenvatinib versus cabozantinib. In this case only a maximum of two prior lines of treatment are allowed, and the last prior treatment shall be an anti PD-1 or PD-L1 therapy.

This is the experimental arm. The combination of lenvatinib plus belzutifan, why this combination? Lenvatinib is a tyrosine kinase inhibitor, which is against the VEGFR receptor, but also other receptors such as FGFR. We've already spoken about belzutifan. The aim is to inhibit multiple oncogenic pathways as well as to enhance VEGF inhibition. Primary endpoints of this trial are both progression-free survival and overall survival.

Let's switch to non-clear cell carcinoma, starting with papillary renal cell carcinoma. This is the most common subtype of renal cell carcinoma, however, still, this is a rare disease and we know that it's even harder to produce robust evidence in this setting. Of course, clinical trials are required in this disease and I think that it's very interesting that papillary renal cell carcinoma is that the percentage of MET-driven tumors is high, it's even higher in papillary type 1. Of course, this could be used as a potential target for treatment.

We have these biomarker-driven trials for advanced first line treatment for patients with papillary renal cell carcinoma. In this case there are two-part screening, because only patients with MET-positive tumors are selected for the trials. The selection is done by next-generation sequencing. No co-occurring fumarate hydratase mutation should be detected. There are three arms in this case. The control arm is sunitinib, which is reimbursed in our country for this setting, and the first experimental arm is the combination of savolitinib plus durvalumab.

Savolitinib is an oral, potent, selective MET tyrosine kinase inhibitor. This drug showed in the SAVOIR study, interesting results in patient with MET-driven papillary renal cell carcinoma. However, the trial was early closed, so it was not possible to derive a final conclusion. The drug, in combination with durvalumab, showed interesting results as well in the advanced setting in patients with MET-driven papillary renal cell carcinoma, in the CALYPSO study. There is another arm here, as you can see, the durvalumab monotherapy. In this case, a crossover is allowed only for this arm in case of progression of disease. The primary endpoint in any case is focused on the comparison of durvalumab-savolitinib versus sunitinib.

Let's finish with the last trial. This is a phase I trial, STELLAR-01. Dr. Capitano already talked a little bit about this. XLO92 is a novel multi-target inhibitor of receptor tyrosine kinase such as MET, VEGFR, but also targets pathways associated with tumor immune suppression. Another thing that is interesting, is its relatively short half-life, which is, of course, interesting in terms of management of the drug. Dose escalation results have already been presented and the recommended phase II dose is 100 milligrams. Now, here at San Raffaele, we have the opportunity to include patients in the expansion cohorts. So both the monotherapy strategy and the combination with atezolizumab. Both patients with clear cell renal cell carcinoma can enter the trial. Patients treated with a maximum of three prior systemic treatments. This is true also for non-clear cell carcinoma, and for these patients, also the expansion cohort with immunotherapy exists.

This is just to show that in the last 6 months the opportunities for our patients really increased, both clear cell, renal cell carcinoma and non-clear cell. There is, of course, much work to do. With that, I want to really thank people who are not talking today, but who are really essential for running all these trials. So our research nurse, Greta, and our three study coordinators, Rosella, Daniela, and Tiziana. Thank you.