Félix Guerrero-Ramos: Thank you. Thank you, Ashish.
Ashish Kamat: So Felix, there's been a lot of interest around this topic. There have been several plenaries, editorials, debates about the BCG plus immune checkpoint inhibition for high-risk non-muscle-invasive bladder cancer. And you did an excellent job at GU ASCO, so we'd love to hear what you said there, and I'm going to pick your brains a little bit after you're done with your talk, so please take it away.
Félix Guerrero-Ramos: Thank you so much, Ashish, for the invitation. Thank UroToday, and hello everybody. I will do a summary on my position at GU ASCO last February in San Francisco, and I'll speak about the combination of systemic immune checkpoint inhibition with BCG for BCG-naive with non-muscle-invasive bladder cancer, and showing that this is not such a good combination of BCG might be enough. So here you can see the design of the different clinical trials. There are two very similar clinical trials. They are the CREST trial on the top of the slide and the POTOMAC trial at the bottom of the slide. They're all having a control arm of two years of BCG induction plus maintenance, and they have two interventional arms. One arm where they combine BCG induction plus maintenance with one year durvalumab or two years sasanlimab, and another arm where they only have all the maintenance IO with only BCG induction. Then we have another trial, which is the ALBAN trial. This trial was negative. We'll see now. And this trial had a slightly different design.
This is from the French group that enrolled French patients, some from Belgium, and also some from Spain. And there's a comparison between one-year BCG and one-year BCG plus one year atezolizumab intravenously. ALBAN is a negative trial. It didn't reach the primary endpoint, which was event-free survival. So we'll focus on the two positive trials that we have recently seen reported. The first trial to report positive results was the CREST trial. There was a positive hazard ratio of 0.68 in the primary outcome, which was event-free survival. Event-free survival is defined as high-grade recurrence, progression to muscle-invasive or more advanced disease, persistence of CIS or death due to any cause. And this is the same endpoint as in the POTOMAC. In the POTOMAC, they call it disease-free survival, but they are the same. And here we see that at three years, there is an absolute benefit of 7.3% when you add sasanlimab two years to BCG two years as compared with BCG maintenance for two years. If we look at the POTOMAC trial, we also have a positive primary endpoint, which as I said, is defined the same as in the CREST trial. In this trial, the benefit is slightly lower, 4.4% at three years.
And probably this benefit, the small benefit is due to the [Inaudible] thought about the BCG performance. As we see in the introduction of the paper, we see that the expected high-grade recurrence rate for BCG was 30% at two years, and within the trial, it was only 18%. So it looks like BCG behaved much better in the trials than we classically thought. This is not new. We have this series which was already published five years ago. This was led by Professor Kamat, and we see that for EAU risk group high-risk patients, BCG is performing in the current series much better than the historical data than we had. So BCG is behaving really better than we really thought. We learned also that in the other interventional arm, we see that if we don't have maintenance, BCG maintenance with the IO, this won't be superior to BCG induction plus maintenance. So here we have also reassured the relevance of the maintenance schedule when we are administering BCG. And this happened both in the CREST trial, as you can see here, and also when adding durvalumab in the POTOMAC trial. So one of the conclusions is that we need maintenance. The big drawback of these combinations is toxicity. You can see here between 20 and 30% of patients with Grade 3 or higher treatment-related adverse events, and also quite a significant incidence of immune-related adverse events.
To sum up and see the difference between efficacy and safety, we see that in our patients with the combination, we should treat 14 to 20 patients to avoid one event, which is mainly high-grade recurrence, and we need to treat only three to five patients to have a Grade 3 or higher adverse event. The thing is also that after BCG, we know that less patients are having a BCG failure than years ago, and we know that there are several approvals by the FDA for those CIS, BCG-unresponsive tumors. You can see it here. And maybe the problem is that they are only for CIS, but we also have very promising data for papillary only. So we are really not having a big number of patients whose tumors are recurring after BCG, and we have good tools to treat these patients after high-grade recurrence when they have received BCG. So the conclusion is that BCG is a must in non-muscle-invasive bladder cancer. Must because maintenance achieves an excellent efficacy because it is an inexpensive therapy. We have and we are having more second-line effective therapies, and BCG has a tolerable and very well-known safety profile. Of course, we will have to look for those patients who do really have a benefit from the combination of BCG with systemic immune checkpoint inhibition. This was also, we can discuss. Thank you very much. Ashish.
Ashish Kamat: Thank you so much, Felix. I mean, that was, again, an excellent presentation you gave in San Francisco, and of course here today. I think you raised certain very important points, and I just want to clarify for the audience that... My personal opinion, and I'm sure you shared this too, is the trials were done, the patients participated, they're positive trials, and we support any such clinical trial. So obviously these trials are positive, and at least from my perspective, editorially, I want to say we're not saying that the trials are not good trials, or that the drugs shouldn't be approved. But assuming that these drugs are approved, Felix, if you have a patient in front of you in clinic, I agree, we have to have this discussion with a patient, let them know that it only affects recurrences, let them know the toxicity. But there might be some patients that you are still considering, okay, for this patient, I might actually offer the combination. Could you share with us which those patients might be?
Félix Guerrero-Ramos: Well, first of all, I completely agreed with your first statement and thoughts. In fact, I'm co-author of two of the publications of the CREST and POTOMAC, and I've been recruiting these trials. And happy we have new alternatives. For sure, this is something good for patients, not for every high-risk patient. We must highlight that some patients in these trials were labeled as high risk based on the definition of EAU 2016 of those tiny high-grade TA tumors were considered as high-risk. So I'm sure these patients will not have a big benefit. But we have seen other reports, for example, from the [inaudible 00:08:10] trial where they show that in the very high-risk patients, there is a big impact when you add the combination. And remember that these very high-risk patients have upfront radical cystectomy as the first-line therapy, and if they refuse, they will have BCG.
So I think in these patients, we might be able to avoid cystectomies if you use the combination which has much more efficacy than BCG. Also, in the subgroup analysis from the CREST trial, we have an impact in CIS and there is a 25% difference in the patients who are remaining disease-free after three years when you treat them with BCG with IO as compared to BCG alone. And of course, we have to individualize and see some of the subgroups. For example, those multiple T1 tumors with CIS or even multiple T1 tumors with a bulky disease. Probably in these patients who are at the higher risk of micrometastatic disease, we are having the benefit of this combination.
Ashish Kamat: So well said. I mean, you summarized all the risk groups, but I think one important point that I want to make there is that the high-risk category of bladder cancer is high risk in the BCG-naive setting. I mean, that's how we defined it. And more recently, we've managed to get the intermediate-risk bladder cancer patients substratified, which is very important for personalized therapy. I think we now need to work on the high-risk patients. If it's a small, like you said, tiny TA high-grade tumor, yes, that is high risk. But is it worth it for the patient to have massive toxicity, potentially lifelong hypothyroidism for preventing that recurrence? Clearly for T1 high-grade, like you say, multifocal where the option is losing the bladder, or having metastatic disease, that's a completely different B. So very well summarized. I really like that. Felix, always, we could chat forever, but in the interest of time, I want to thank you for joining us today, and congratulations on a wonderful plenary.
Félix Guerrero-Ramos: Thank you, and thanks to the audience for watching, and looking forward to seeing you again soon.