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Tiago Padua: Hi, everyone. Thanks, Andrea for inviting me. I'm really honored to be here as a speaker today, and I have been working in San Raffaele for the last year as an ESMO Fellow, and it has been an enriching experience, and I will talk a little bit about the ongoing clinical trials in rare GU tumors, so adrenal tumors, testicular cancer, and penile cancer.

We know we have so many challenges to treat these kinds of tumors: lack of guidelines, low recruitment, and also limited funds and opportunities, and international and multidisciplinary collaboration is essential to improve patient care, and the Global Society of Rare GU Tumors, led by Philippe and Andrea, is a case of success instimulating medical education, creating guidelines, and stimulating clinical research in this area.

Now, moving to the clinical trials. The first trial, it's adrenal tumors. It's a Phase 2 study to evaluate the efficacy and safety of belzutifan monotherapy in patients with advanced pheochromocytoma, paraganglioma, or pNET tumor.

Belzutifan, as Lara just mentioned, is already approved in the US for the treatment of RCC associated with VHL mutation, and if you look at PPGL tumors, we notice hypoxic signaling is also one of the major drivers of tumorigenesis, and we can find around 70% of VHL alterations in sporadic pheochromocytoma. And then there's reason to test this drug in this kind of tumor.

This is a Phase 2 trial with two cohorts. Cohort 1, it's with pheochromocytoma and paraganglioma. In Cohort 2 with pNET tumors. Each cohort with 70 patients. They will be treated with belzutifan 120 milligrams per day until toxicity or progress of disease, and the primary point is response rate, and a secondary point to have disease duration of response, PFS, overall survival, and safety.

The main inclusion criteria, patients older than 12 years, patients should have locally advanced or metastatic disease not amenable for surgery or curative treatment. Patients can be treated in the first line or later lines, but in first line patients should not be candidates or refuse systemic chemotherapy.

We have another ongoing clinical trial in adrenal tumors. I would like to share this website, AdrenalMass.org. It's a resource from the Global Society of GU Rare Tumors. Here you can find more information about adrenal tumors including other ongoing clinical trials.

Moving to penile cancer in locally advanced setting, patients with lymph node disease, we know that surgery, chemotherapy, and radiotherapy are options of treatment, but it's not clear how to sequence, how to integrate all these strategies.

And you have a very important trial, the InPACT trial. It's the International Penile Advanced Cancer Trial. It's a Phase 3 trial. Actually, it's the first Phase 3 trial in lymphnode positive penile cancer. And it has a very interesting design. It's a Bayesian design. So patients with penile cancer, N1, N2, N3, N0, this design allows true sequential randomization.

The first randomization, we tested neoadjuvant treatment, so what's the impact of neoadjuvant? Patients were randomized one to one to one to no neoadjuvant treatment. Arm B, TIP neoadjuvant chemotherapy, or Arm C, chemoradiotherapy as neoadjuvant treatment, followed by inguinal lymph node dissection, and based on the pathological report, patients would be classified in low risk of recurrence or high risk of recurrence. Patients with high risk of recurrence will be randomized again as the second randomization, INPACT Pelvic. Pelvic lymph node dissection or just surveillance.

And it's important to note that the patients who did not receive neoadjuvant treatment, they'll have the chance to receive adjuvant chemoradiotherapy. This will be important to understand the role of neoadjuvant or adjuvant treatment.

The primary endpoint is overall survival and the secondary endpoint DFS, safety, and rate of surgical complications.

The last report in ASCO GU this year, we have read almost 70 patients in the first randomization, and 10 patients in the second randomization. So we need to continue recruiting patients for this study, because we will answer a lot of questions in the treatment of penile cancer.

Moving to metastatic disease, we know it's a very poor prognosis for chemotherapy, the second-line chemotherapy is associated with low response rates, and you have a lot of clinical trials investigating monotherapy or other new agents.

Here's a sample of the ongoing clinical trials. We have clinical trials monotherapy in second or in first-line combined with chemotherapy, and you have an important trial, the ORPHEUS Trial, recruiting patients in Italy and Spain. ORPHEUS is a Phase 2 study to evaluate the efficacy and safety of Retifanlimab in advanced penile squamous cell carcinoma. So Retifanlimab anti-PD1, so it's a monotherapy trial for patients with metastatic disease, penile cancer. Recruiting patients in Spain, Italy in 13 sites. It's a single-arm Phase 2 trial with 18 patients. The main inclusion criteria, patients with T4, N3, or M1 disease. Treatment naïve or if it progresses to first-line chemotherapy. Patients will be treated with Retifanlimab every four weeks until toxicity or disease progression, and the primary point is a response rate, and for secondary objective to have safety and overall survival.

Now the recruitments closed. Probably they will have the results soon, the next conference. The estimated completion date in the clinical trials is December now, so maybe next year we have the results presented in the next conference.

And last, a very important trial in testicular cancer, the TIGER Trial. It's a randomized trial of TIP versus TI-CE as initial salvage chemotherapy for patients with germ cell tumors. We note that around 20 to 30% of patients with advanced germ cell tumors will require salvage chemotherapy, and as options of treatment you have conventional-dose chemotherapy with VIP or TIP, or high-dose chemotherapy with sequential stem cell transplantation.

And you have an important geographic variation around the globe. So, for example, the UK, it's preferred conventional-dose chemotherapy, and if you look to Germany and Indiana, US, it's preferred high-dose chemotherapy for these kinds of patients.

So it's we need the answer to this question, and the TIGER trial, it's a very important trial. It's an international collaboration including North America, Europe, and Australia to answer this question. So around 420 patients will be randomized one-to-one to TIP or TI-CE, the daily dose, high-dose chemotherapy. Patients will be stratified by prognosis, risk class, and continent, with the primary endpoint of overall survival. The main closing criteria, so seminoma, non-seminoma, patient with progressive disease at first-line chemotherapy, but patients must receive three to six cycles of cisplatin-based chemotherapy, and no more than one line of chemotherapy is allowed in the first line.

And you have good news about this trial. Feldman just published on Twitter that the recruitment was completed for this trial. It's a very important mark because it's a rare disease with difficult recruitment. Thanks to a lot of investigators, some of them here, so congratulations to all of them who work in this trial, and show us that doing clinical research in rare tumors is difficult but it's not impossible. We can do that together.

And with that, I finish and thank you for your time.