Transcript: Thomas Powles on CREST
Thomas Powles, MBBS, MRCP, MD
Interview recorded April 2025. All transcripts are created from interview footage and directly reflect the content of the interview at the time. The content is that of the speaker and is not adjusted by Medthority.
The rationale for the CREST trial is relatively straightforward. We know immune checkpoint inhibition is active in urothelial cancer. We've tested it in heavily pretreated patients. We've tested it in muscle invasive disease. We're now moving with PD-1 inhibition into non-muscle invasive bladder cancer. This is very early in the disease, and we're testing a drug called sasanlimab in BCG-naive, non-muscle-invasive bladder cancer. It's a big, randomised Phase III study of 1,000 patients. It's sasanlimab, which is a PD-1 inhibitor, plus BCG versus BCG alone. The primary trial has already been presented at AUA a couple of weeks ago. Neal Shore demonstrated this was a positive study. So in BCG-naive, non-muscle-invasive bladder cancer, high-risk disease, what he showed was a reduction in the risk of an event, that's basically local recurrence or metastatic recurrence of disease, with a hazard ratio of 0.68. So that was a reduction, that's a positive randomised Phase III study. What we're doing here today is we are looking at some of the key subgroups.
Those key subgroups include CIS and T1 disease, that's a higher risk subgroup. We're trying to link that with the biology, the PD-L1 biology of the disease, and essentially, the top line of what we showed is while there may be some enrichment, particularly in that carcinoma in situ subgroup, it's difficult to explain all the results with just those subgroups. It was an incomplete enrichment, number one, and number two is we struggled to link it with the PD-L1 biology. You'll know that the PD-L1 biomarker in this disease, we've struggled with that a little bit later, and that's still the case. So the top line results of the CREST trial are as follows. We've already shown an event-free survival advantage with a hazard ratio of 0.68, that's been presented, but what we show here in the CIS population is a hazard ratio of 0.53, and in the T1 population, a hazard ratio of 0.63. So there does seem to be some enrichment, particularly in that CIS population. When we look in detail at this subgroup, we can show a couple of things. Number one is we can show in the CIS population, that event, that reduction in event seems predominantly in local disease, number one, and number two, in that CIS population, we also showed PD-L1 expression is lower than in the other population, so enrichment but lower PD-L1, and then when we tried to link PD-L1 as a predictive biomarker, we were unsuccessful, either in the ITT population or indeed in these subgroups.
The final thing that we wanted to show was in the CREST trial, there was a third arm, which hasn't been talked about very much, where we gave the sasanlimab and the BCG, but we didn't give them maintenance BCG. And in every subgroup we looked at, we showed the maintenance BCG appeared to be important. That's a really important take-home message. And then finally, of course, we represented the adverse event profile, and essentially, it's consistent with the adverse event profile that you'd expect for a PD-1 inhibitor in this disease. So in summary, in this study, we have a positive study, we have a 32% reduction in the risk of cancer events associated with sasanlimab, subcut with BCG induction and maintenance. In the data presented today, while there was some enrichment in the CIS population, it was incomplete. We were unable to link it directly with the biology in terms of the PD-L1 expression, and maintenance BCG is important. I'm excited about non-muscle-invasive bladder cancer and immune checkpoint inhibition for lots of different reasons.
The first is the future of these drugs has always been around moving them earlier in the disease, in my opinion, and now, we're showing the CREST trial is positive for event-free survival. There's also been a press release for a similar study with durvalumab in a similar setting with a similar design, which is also positive. Now, I don't know the result of that trial, but the press release is a second trial in this space that's positive, showing some consistency, the early immune checkpoint inhibition, it can reduce the risk of relapse. So this space, I think, is important.
There is a question, of course, about the risk-benefit ratio. Some components of non-muscle-invasive bladder cancer are not lethal, and therefore, we need to work out immune checkpoint inhibition associated with some life-changing toxicity. So there's a balance to come to there, and CREST, and to some extent POTOMAC, when we see the results will help us define that. It's also true in the CREST study that we need to try and identify those groups that do benefit. Now, I've spent a lot of my career trying to look at biomarker expression and correlate that with outcome in urothelial cancer with mixed results, to be honest. I'm not sure that's directly because of me, but I think others have struggled too in this space, and we've shown today the PD-1 biomarker isn't fabulous in this setting.
We've shown that before, but we need to look at other biomarkers for sasanlimab and BCG, 'cause if we could find those patients that benefit the most, then that risk-benefit ratio is gonna be more favoured in the benefit category. So I'm excited about that biomarker expression. I'm also excited a little bit about that BCG, that third arm, that maintenance BCG, are there biomarkers associated with the need for maintenance therapy? So I'm excited about biomarker research, and then finally, I think it would be exciting to look at more mature follow-up. The CREST study was published in Nature Medicine in the concurrent time with my publication today. Neal Shore is the first author of that, and we, as a group of authors, are really keen to explore this area more to try and work out more mature data, but also more biomarkers and trying to find out who benefits and how much.
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