EV-103 is a clinical trial in patients with metastatic urothelial cancer who have never had treatment for metastatic disease. The data that we’re reporting here is from the dose escalation and the first cohort on this study. It’s about 45 patients looking at the combination of enfortumab vedotin, which is an antibody drug conjugate directed against nectin-4 on the surface of urothelial cancer cells, that drug, in combination with pembrolizumab which is a PD-1 antibody, essentially an immune therapy. Both of these drugs are actually already FDA approved as monotherapy by themselves in urothelial cancer and there is some preclinical evidence that when cancer cells are treated with enfortumab vedotin that it actually induces an immune response. The idea is to look at the combination of EV, enfortumab vedotin, with pembrolizumab, the idea being that by itself enfortumab may induce an immunogenic cell death or essentially draw immune cells into the tumour microenvironment. The thought is to add pembrolizumab to increase that immune response.

The study accrued 45 patients and we essentially dosed with EV and pembrolizumab on a three-week cycle: they got EV on day 1 and day 8 and pembrolizumab just on day 1. The baseline demographics were mostly men in the study, most of them had good performance status, either ECOG 0 or 1. The majority of patients had visceral metastatic disease so this was truly metastatic bladder cancer. About a third of patients had liver metastases which are considered poor prognosis and about a third of patients had a high PD-L1 score, the majority of patients or the plurality of patients had low PD-L1 scores but it was a mix. What was really exciting was that when patients were treated with this combination 73% of them, actually 73.3%, had at least a partial response to therapy. They had some clear response to therapy and compared to other regimens that are approved for this patient population that’s very high.

I should mention, I may not have been clear when I first introduced the study, this study is being done in patients who have metastatic urothelial cancer but are not fit or not eligible to get cisplatin based chemotherapy. Cisplatin is considered the standard of care chemotherapy but it can be very hard on the kidneys and on the nervous system and about half of patients are not eligible to get cisplatin. So in this patient population which was already a little bit at worse prognosis because they’re not able to get cisplatin we saw this very impressive response rate. Not only was it 73% response rate but over 15% of patients had complete responses meaning the disease was not visible on CT scans after treatment. What was pretty exciting about this as well was that most of the responses, almost 90% of the responses, were observed at the very first CT scan, so within the first 6-9 weeks almost all the patients who were going to respond responded.

The other interesting points for the study were that not only was there a high response rate but the responses appeared durable. So the median duration of response for a patient who starts responding is over 2 years, it was 25.6 months, which in urothelial cancer is quite long. Most other drugs the median duration of response is usually measured just in months, it’s usually less than a year. So the fact that we are seeing this really long duration of response obviously is a very good sign for patients because some of these patients even at the time of the data cut-off are still responding to therapy.

It’s a single arm study so we can’t really compare it directly to another study, at least not in a statistically valid way, but the median PFS was over a year and the median overall survival was 26 months which, again, is very impressive for this poor prognosis patient population.

The side effects of the therapy, this is an update, the data had already been presented previously. So the side effects of the therapy, we didn’t really see any new signals or new side effects that we hadn’t known about before. They’re actually very consistent with the individual side effect profiles of enfortumab vedotin and pembrolizumab. So at least from the initial data we present here at ASCO it doesn’t seem like there’s any kind of synergistic toxicity or combination toxicity of the two drugs. The most common adverse event was peripheral neuropathy, that was seen in over half of patients. Fatigue was quite common and then rash and other types of dermatologic toxicities were seen as well. The skin reactions happened in about two-thirds of patients; they were only severe in 20% of patients, meaning grade 3 or above. The median time to onset for the skin toxicity was generally within the first cycle, so patients knew very quickly if they were going to have any kind of adverse event like a rash or other skin toxicity. The neuropathy took a little longer to develop, it was about 2-3 cycles in that we saw the initial neuropathy. Most patients who had dermatologic toxicity, the dermatologic toxicity got better, in fact 90% of the patients were able to have some resolution or improvement in the dermatologic toxicity. About two-thirds of the patients who had neurologic toxicity, mostly peripheral neuropathy, had improvement in the peripheral neuropathy with either treatment break or dose reduction or discontinuation of the drug so while it does occur it seems like it is at least treatable for some patients.

The other side effect or adverse event that was of special interest was hyperglycaemia. This has been reported in multiple studies of enfortumab vedotin before. We actually only saw it in a minority of patients, only 11% of the patients had any hyperglycaemia, and these were again manageable in all the patients with either treatment discontinuation or medical therapy. We didn’t see immune mediated side effects at any higher rate than we would expect with just giving pembrolizumab alone so that was somewhat reassuring.

So this regimen, this combination of enfortumab vedotin and pembrolizumab demonstrates very promising activity. We’re seeing response rates and durability, duration of response, that we’ve really never seen before in a cisplatin ineligible front line urothelial population. So the data presented here is one cohort, or really two cohorts, of a much bigger study. Currently there’s an ongoing randomised cohort which compares enfortumab vedotin alone to enfortumab vedotin plus pembrolizumab. This is going to really give us a better sense of what the true activity of each drug is by itself as well as the combination. There’s a phase III trial, actually, in the same patient population which is looking at enfortumab vedotin and pembrolizumab in the front line setting, that’s EV-302. That’s going to be a much bigger confirmatory study for the findings here so we expect those findings likely in the coming years and that will really give us the highest level evidence of the activity of this regimen.