The EV-302 study is a large randomised phase III frontline metastatic bladder cancer study. It was presented and published about a year ago and it was transformative. What it showed was the combination of enfortumab vedotin and pembrolizumab outperformed platinum-based chemotherapy, GemCis or GemCarbo, in a big randomised phase III study. The initial analysis showed response rates of about 70% which were much higher than that of chemotherapy, they showed hazard ratios for progression free survival and overall survival both less than 0.5, so more than a doubling in progression free survival and more than a 50% reduction in the risk of death. We also showed a CR population – 30%, or approximately 30%, of patients had a complete response.
This updated data now gives us median follow-up of 2½ years. One of the potential criticisms of the previous study was that the OS data wasn’t yet particularly mature, although it was statistically significant. What we’ve showed with this updated data is response and PFS are about the same as you would expect but the OS, now more mature, remains with a hazard ratio of 0.51, so about the same, still showing a 50% reduction in the risk of death. The median value at 34 months, if you go back in time, when I started we were looking at about 12 months overall survival. So getting closer now to three years and this is significantly longer than we saw in the control arm.
We also looked at those 70% of patients who responded and the 30% of patients with complete response. The 70% of patients who responded, their duration of response, median duration of response, was two years. And of the 30% with CR, at two years 75% of those patients still had not progressed. This is a huge difference from the way we used to treat bladder cancer. I think it’s incredibly important data because as time goes by and we get these more mature data it reflects what I’m seeing in my clinic which is the patients who I’ve treated with EV/pembro seem to have different outcomes compared to previous platinum-based chemotherapy. It represents a huge shift in the disease.
One of the key questions moving forward, of course, is going to be around tolerability – do these complete response patients need to go on EV/pembro for how long? We don’t know the answer to that question yet. We know that pembro is given for two years, my experience is the majority of patients on enfortumab vedotin require dose reductions and dose alterations. Early skin toxicity and later peripheral neuropathy both require attention. So there’s an important piece around education and training for this transformative regime to make sure we get the most out of it and the most benefit for our patients.
What is the clinical significance of these results?
The clinical significance of these results are, I think, quite clear. The initial analysis, which was the final analysis because it was a positive trial, showed us that EV/pembro was transformative and changed practice. But there was some uncertainty about two issues which are addressed today. Firstly, could we maintain that impressive OS hazard ratio and the answer is yes. So the long-term results, or the longer-term results, are as good as the initial results. The second piece is that we now know more detail about that CR population and the responders and they do do exceptionally well compared to historical results. So we’ve got a lot more clarity and a lot more granularity around the detail of this study and it makes us more confident, in my opinion, that this is a transformative, long-term regime and not just great initial control of disease.
What is next for this study?
What is next for this study? What is next for EV/pembro? I think both of those questions are worthwhile considering briefly. The next thing for this study, we’ve seen quite a lot of data, we’ve seen the quality of life data, we’ve seen the subset data, we saw more subset data in this trial showing benefit across broad subgroups of patients. I think the next big chapter for EV/pembro is going to be in the muscle-invasive space. Instead of looking at advanced disease, M1 T4b disease where the cancer is going to progress and kill patients quickly if don’t get great control, and EV/pembro is good at that, what about in that muscle-invasive space where half the patients are currently being cured by surgery but the cancer is coming back in the other half and can we increase the cure rate by giving them EV/pembro rather than neoadjuvant chemotherapy? That’s an incredibly important question. I think we’re going to look at the results of those trials in the not too distant future. There are actually three trials – there’s EV/pembro versus platinum-based chemotherapy in cisplatin eligible patients; there’s EV/pembro versus cystectomy alone in ineligible patients and then there’s the VOLGA trial – durvalumab/ tremelimumab/EV versus cystectomy. So that’s three big randomised trials. That’s going to be an incredibly important space. I think we’re going to cure a lot of those patients.
Then there’s a final chapter to come after that which we’re talking about but we haven’t addressed yet which is about the bladder-sparing approach and whether actually we need to do cystectomies on these patients and whether EV/pembro can cure patients without cystectomy. That, I think, is super-exciting.
