On behalf of the co-investigators involved we were very excited to present the interesting results of the TROPHY-U-01 Cohort 3, phase II trial of sacituzumab govitecan, an antibody-drug conjugate against Trop-2 linked with SN-38 which is a metabolite of irinotecan, combined with pembrolizumab anti-PD-1 in patients with metastatic urothelial cancer that progressed on platinum-based chemotherapy. So this is second line after platinum-based chemotherapy progression in patients who never received a checkpoint inhibitor before.

As I mentioned, sacituzumab govitecan is a first in class Trop-2 antibody-drug conjugate and it has approval in breast cancer as well as urothelial cancer, specifically in metastatic urothelial cancer, after platinum-based chemotherapy, after checkpoint inhibition as single agent, based on Cohort 1 of the TROPHY-U-01 trial that was published in The Journal of Clinical Oncology in 2021 by Dr Tagawa, myself and colleagues.

So in the study that I’m presenting today to you, this is the second line setting platinum refractory disease, immunotherapy naïve. Patients received a combination of sacituzumab govitecan, let’s call it SG, 10mg/kg on days 1 and 8 every 21 days and pembrolizumab on day 1 every 21 days. Treatment continued until progression or unacceptable toxicity. The primary endpoint was objective response rate by investigator review using RECIST 1.1 criteria.

We had a total of 41 patients that enrolled and used this dose that I told you. We wanted to see at least 13 responses out of 41 patients to strengthen our hypothesis of a response rate of 20% or less. In terms of baseline characteristics we saw that a significant proportion of patients, overall 60%, had visceral metastases and approximately 30% had liver metastases. Patients had received platinum-based chemotherapy, about half of them in the perioperative setting, neoadjuvant or adjuvant, and the other half in the first line setting of metastatic disease.

If we focus the attention in those who received platinum-based chemotherapy for first line metastatic urothelial cancer the response rate was only 15% which is almost three times lower compared to what we see with platinum-based chemotherapy. The median time between the last chemotherapy dose and the screening in this trial was 1.6 months so the progression after the end of chemo was about a month. So it shows how difficult this population is with rapid progressors and platinum-refractory parameters, platinum-refractory patients. Despite these challenging characteristics, the objective response rate was 34% with one complete response and 13 partial responses. Additionally, 11 patients had stable disease as best response with a clinical benefit rate of 61%. Median time to response was 2 months and with a median follow-up of about 6 months the median duration of response and median overall survival were not reached yet. Median progression free survival was 5.5 months.

Toxicity-wise we saw what we had expected for each drug by itself – sacituzumab govitecan can cause neutropenia, anaemia, diarrhoea and nausea, fatigue and pembrolizumab can cause in a proportion of patients immune related adverse events. The combination was feasible; the treatment related grade 3/4 adverse event rate occurred in 59% of patients and 39% of patients had a reduction in the sacituzumab govitecan dose because of treatment related toxicity. There were no treatment related deaths and 10 out of 41 patients, a quarter, received either topical or oral steroids, specifically 4 out of 41, 10%, received oral steroids which is exactly what you expect with pembrolizumab alone. 29% of patients had growth factor and the percentage of febrile neutropenia was 10%, so 4 out of 41. None of those 4 patients had received prior growth factor.

So, to conclude, in this platinum-refractory population, hard to treat population, the combination of SG plus pembrolizumab showed encouraging promising anti-tumour efficacy with an object response rate of 34%, meeting the primary objective. Clinical benefit rate was 61%, median PFS 5.5 months. The combination had a manageable safety profile with no new safety signal and no increase in the immune related adverse events that needed steroids.

The data are not practice changing yet, however, further evaluation of the combination, either in the platinum refractory setting or even in earlier lines of therapy, for example the front line setting. We have ongoing cohorts, other cohorts, and the TROPHY-U-01 will look at sacituzumab govitecan as single agent, in the second line setting after progression on first line checkpoint inhibition and will also look at the Cohorts 4 and 5. We’re combining those cohorts – SG with cisplatin with or without avelumab as induction and then maintenance immunotherapy with avelumab plus SG. These cohorts are ongoing with no data yet and, of course, we have the TROPiCS-04 trial, this is in the third line and beyond, after platinum-based chemotherapy, after checkpoint inhibition and potentially it’s allowed to have prior enfortumab vedotin if the investigators decide to do so. The TROPiCS-04 trial randomises patients to sacituzumab govitecan single agent versus taxane single agent or vinflunine in Europe. That’s a phase III confirmatory trial trying to validate the results of Cohort 1 as a monotherapy in patients after prior platinum-based chemo and after checkpoint inhibition.

So we’re very excited about the data; again we’re going to continue the programme in development and we’re going to look at biomarkers and have a longer follow-up. We’re very excited to have presented this data to ASCO GU 2022 and looking forward for further development with this programme. Everybody stay safe and thank you for your attention.