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Daniele Raggi: I'm going to show you an overview on the ongoing clinical trials in bladder cancer. These are my disclosures. So the agenda, let's start with the non-muscle invasive bladder cancer, so more advanced disease, muscle invasive disease, and of course, in delayed metastatic setting.

Let's start with the with BCG-unresponsive disease. This is the oncologic story so far. Let's start from the early 90s, with BCG approval, and then going through the late 90s with Valrubicin, the first FDA approved intravesical drug for BCG-unresponsive, and then we finally arrived to 2020 with approval of pembrolizumab. That is the first new agent approved for CIS BCG-unresponsive disease, followed by the data of the KEYNOTE-057 trials.

So in the last two years, we have now three new compounds FDA granted for the approval, the pertuzumab and nadofaragene, and obviously, the last interleukin-15 superagonist, NAI.

This is the organ-sparing landscape in 2022, this year.

This is an organ-sparing approach to the BCG-unresponsive disease. As I show you in this box, in the last two years, we have an increase of the interest of the publications on GU. For example, GU ASCO, or ASCO annual meeting of new compounds, and this is very, very important for us.

Let's start with our clinical trials. This is the KEYNOTE-676 cohort. Cohort A, so in BCG-unresponsive disease, high-risk disease, T1, high-grade Ta, with or without CIS, the risk stratification by the PD-L1 expression, and the disease history, in terms of amounts of relapse. So we have randomization one-to-one, to receive the standard of care control arm, so the BCG challenge substantially, versus the BCG plus pembrolizumab, with the primary endpoint, a complete response rate.

This is the cohort B of the same study, disease for BCG-naive disease. So we have a very high-risk disease. Again, T1, high-grade Ta, with or without CIS, stratification by PD-L1 expression, and the presence or absence of CIS.

Once again, we have the BCG control arm, versus the pembrolizumab every six weeks, with full BCG maintenance course or reduced maintenance course of BCG. In this case, the primary endpoint is the event-free survival.

Let's go to another clinical trial, the SunRISe-1 clinical trial. This is a combination approach of IO and a new device. The TAR-200 is an intravesical gemcitabine device, so we have, in this case only patient with CIS BCG-unresponsive, with or without papillary disease. We have three cohorts, the one cohort with cetrelimab alone, chemotherapy, TAR-200 alone, or the combination of both treatments. Also in this case, we have the primary endpoint, complete response rate.

As you know, we have a strong rationale for targeting FGFR mutation, especially in non-muscle invasive disease, because we have a positivity of the mutation or fusion genes in 40 to 70% in non-muscle invasive disease.

This is the background for the THOR-2 study in selected the patient harboring mutation or fusion of FGFR genes. And we have three cohort in this case, the first cohort with papillary disease, BCG responsive disease, randomized two-to-one to receive erdafitinib orally, a TKI, and effective inhibitors, versus investigator choice intravesical chemotherapy. In this case, we have the primary endpoint's relapse-free survival.

The second cohort is for CIS disease with or without papillary disease. We have the administration with only one arm with erdafitinib, with the primary endpoint, complete response at six months. And in the third cohort, we have the BCG-naive disease intermediate-risk. Again, erdafitinib alone, with primary endpoint, complete response at three months.

Let's move to the more advanced disease, muscle-invasive disease. This is the background. We know that cisplatin-based chemo is the standard of care. Again, we know that adjuvant nivolumab improves disease-free survival in various risk disease, and neoadjuvant IO is an interesting approach, and we have a need for predictive biomarker.

This is the algorithm of treatment. We have patient, radical cystectomy candidate, or candidate who have a broader preservation. So in radical cystectomy candidate patient, we have to administer neoadjuvant chemo if cisplatin ineligible, followed by radical cystectomy, and then adjuvant nivolumab, only in selected very high-risk patients.

This is our clinical trials, these are San Raffaele Hospital, for cis-eligible patients. And we have other three clinical trials in the cis-ineligible patient candidate to radical cystectomy.

This is one. Let's start with ongoing sponsored clinical trials. This is the OPTIMUS Phase II trial for cisplatin ineligible or refusal patient, stratified by PD-L1 expression. Only one arm of treatment with retifanlimab, radical cystectomy, and then, observation only. This is very, very interesting. The primary endpoint of this study that is a biological endpoint with represented by the change from baseline in CD8 positive lymphocyte within the resected tumors.

This is the KEYNOTE-905 Phase III clinical trial against cisplatin ineligible patient. We have one arm of control arm directed to cystectomy and then observation only. The pembro arm, so perioperative treatment with pembrolizumab. And the combination arm, perioperative with pembro plus enfortumab vedotin anti-nectin-4.

This is our other sponsored clinical trials, the KEYNOTE-B15 Phase III trial in cisplatin eligible patients. We have the randomization to the standard of care treatment, so chemo gemcitabine plus cisplatin, versus pembro plus enfortumab, radical cystectomy, and then adjuvant treatment only in the experimental arm.

This is the VOLGA trial, Phase III trial. Again, in cisplatin ineligible patient, we have a triplet combination with DURVA plus TREME plus enfortumab vedotin, with an adjuvant treatment with DURVA and TREMA after radical cystectomy. Arm with DURVA plus enfortumab and then DURVA plus the surgery, or the control arm without treatment. In these two studies, the primary endpoint are the PCR and the event-free survival.

Let's move to our academic trial. This is the SURE-01, SURE-02 Phase II critical trials. In the SURE-01 trials, we have the administration of four cycle of sacituzumab govitecan before radical cystectomy, and then management per standard of care. Or in the SURE-02, we have the combination of sacituzumab govitecan plus pembrolizumab, then radical cystectomy, and 12 months of adjuvant pembro. The primary endpoint of this study is the pathologic complete response rate.

Let's go to the third academic clinical trials, the NURE-Combo trials. This is a combination study of chemo plus IO. We have an assessment of the disease by CT scan, PET-FDG, and MRI, multiparametric MRI of the bladder, before and after the treatment. We have the administration of nivolumab plus nab-paclitaxel, radical cystectomy, and then adjuvant treatment up to 13 cycles with nivolumab. Again, once again, pathologic-complete response is the primary endpoint.

So today, I'm very proud to show you the first interim and safety analysis of this trial. This is the cohort one of the clinical trial. Only 13 patients, with the median age of 63. 61% of patients had only T2 disease, and the 46% of patient expressed the pure urothelial cancer after the TURBT. This is the efficacy data only in 11 patients, we have a complete response rate of 27.3%, with a downstage to non-muscle invasive disease in 72.7% of patients.

This is the safety analysis of 13 patients. We have all the patients underwent to radical cystectomy. This is very, very important, because of the safety of the combination in terms of surgery. We have two discontinuation of nivolumab only in the adjuvant setting, due to adverse events, and one nab-paclitaxel on the cycle four in the neoadjuvant treatment. We had one death, unfortunately, after the cystectomy, but not related to the experimental drug combination. This is the adverse events that we see in these 13th patients.

Let's move to the adjuvant setting. We in Italy, we don't have the opportunity to give nivolumab, so we have the IMvigor011 clinical trial. This is a well selected population, various risk population that underwent to serial ctDNA testing, when positive, were randomized 2:1 to receive adjuvant atezolizumab versus placebo, with a primary endpoint, disease-free survival.

Let's close with the three modality approach, so conservative approach. This is the KEYNOTE-992 Phase III trial. There is after maximal TURBT, the treatment we can current, chemotherapy plus radiotherapy with or without pembrolizumab every six weeks, with maintenance after the end of radiotherapy. And the SunRISe-2 Phase III trial, that had the control arm represented by chemo radio and cetrelimab plus TAR-200 has experimental arm.

Let's close my presentation with the metastatic disease. This is the backbone. Obviously, cisplatin or carboplatin-based chemo is the standard of care. Available maintenance in responders only show very, very interesting and promising data on improvement of overall survival. A minority of patient, unfortunately, received the second-line treatment, and we need to improve survival since the first-line setting.

This is the current paradigm after ASCO, and ESMO of this year, with the possibility to increase our opportunities. Sacituzumab govitecan, for example, added to checkpoint inhibitors, trastuzumab deruxtecan and enfortumab vedotin plus pembro in first-line, in cis-eligible or ineligible patient.

This is our studies in first-line metastatic setting, the EV-302 studies. These are patients with metastatic disease, chemo and checkpoint naive patients randomized to receive chemo, so gemcitabine plus cis or carboplatin, versus the combination enfortumab plus pembrolizumab, with a dual co-primary endpoint, progression-free survival and overall survival.

This is the TROPiCS-04 clinical trial. This is more for more advanced disease progression. Patient progressed after cisplatin or carboplatin-based chemo, and the checkpoint inhibitor. We have randomization to investigator's choice, chemotherapy versus sacituzumab govitecan, with primary endpoint, once again, the overall survival.

This is the THOR study, confirmative study, Phase II study, of patient with metastatic refractory disease with FGFR aberrations. Two cohort. One cohort for patient treated with prior PD-L1 inhibitors, so erdafitinib versus chemotherapy, the standard of care. Or for the cohort two, erdafitinib versus pembrolizumab, so second-line of treatment. Primary endpoint is the overall survival.

Let's close with the last study. This is an industry partnership with for early drug development. This is a Phase I/II trial of BT8009. This is an antibody drug conjugate against nectin-4 is similar to enfortumab vedotin.

This is the study. This is the Phase I/II Study of safety pharmacokinetics and the preliminary results. We don't have the part A that is the escalation dose of the Phase I, but we have here in hospital the part B and C, so the expansion cohort and the renal insufficiency cohort.

So to summarize, this is hard. The current enrolling Phase I, II, and III trials in urothelial cancer. I think that for our patient, this is a very, very good opportunity. See from no muscle invasive disease to have a pretreated disease. Thank you for your attention.