Alicia Morgans: Hi. I'm so happy to be here today with Professor Cora Sternberg, who is joining me from New York after a wonderful ESMO 2024 presentation, in which she discussed event-free survival, an analysis that linked this to overall survival in muscle-invasive bladder cancer.

Thank you so much for being here with me today, Professor Sternberg.

Cora Sternberg: Thank you very much. It's a pleasure to be here with you, you know that.

Alicia Morgans: Well, it is always a pleasure to talk to you. Why don't you take us through your presentation?

Cora Sternberg: So this is actually on, not disease-free survival, but evaluation of event-free survival, which is a little different because disease-free survival usually is something we do after we do perhaps a cystectomy, and then we look at the adjuvant things that can happen.

Event-free survival is done at the time of the initial therapy, and then it includes disease-free survival, recurrence-free survival, progression-free survival, overall survival, death from any cause. So they're a little bit different biostatistically. And these are all the biostatisticians who helped me with this project looking at event-free survival as a surrogate endpoint for overall survival in patients with muscle-invasive bladder cancer at the time that we start them, at the time that they start chemotherapy or immunotherapy, and then before they have cystectomy.

And we know that about 20% of bladder cancer patients present with muscle-invasive bladder cancer, which means it goes into the muscle layer of the bladder, but they don't have distant metastasis. And neoadjuvant cisplatin-based chemotherapy with radical cystectomy or radical cystectomy and node dissection is the standard of care, but up to 50% of patients are not even eligible because they can't receive cisplatin. So we have an unmet need there too. And there are novel treatments being evaluated, including immunotherapy or combination therapy.

And again, event-free survival is a common intermediate endpoint that's used in trials so we can have accelerated regulatory decisions while awaiting the long-term overall survival results. And it's a potential surrogate, clinical surrogate endpoint for overall survival.

So what we did was we identified clinical trials evaluating any kind of neoadjuvant treatments, followed by radical cystectomy for muscle-invasive bladder cancer. This also included patients with N-1 disease, and they had to also report event-free survival and overall survival outcomes. This was done from 2017 until 2023. There were six different databases used and retrospectively evaluated. And the broad definition of event-free survival, as I just already explained to you—disease-free survival, recurrence-free survival, progression-free survival—is normally considered in the literature as the definition. And the majority of the patients assessed at the trial initiation, and we have 15 studies that we found. Two of them were published twice.

I won't go into all of the statistics, but the survival outcome associations of event-free survival for overall survival were evaluated by assessing the association between three-year event-free survival rate and five-year overall survival rate, between event-free survival and overall survival times, and between one-year event-free survival and three-year overall survival in each treatment arm of a trial.

And they also did some sensitivity analyses looking at only patients that had no N-1, only patients who had cisplatin-based chemotherapy. Because there's a number of trials included here also that had immunotherapy or carboplatin, for instance, and studies using only radical cystectomy as a definitive treatment by all patients to test how robust these results were.

And if you look at how this systematic literature review was done, 390 publications were identified from a literature review. Again, retrospective, 15 trials. There were six randomized controlled trials and nine single-arm trials, and there were 17 publications. As I mentioned, 17 publications, but two of them were published twice through the trials. And most trials were in patients with N-0 disease, patients usually were a median of 63 to 70 years of age. And the neoadjuvant trials included not just cisplatin, but they could have had carboplatin or they had chemotherapy in combination with a targeted therapy or even immunotherapy. And you can see here the breakdown on one side of the slide of how we get down to the 17 trials, the six randomized trials, and nine single-arm trials.

And this is the main result of the trial that the six eligible randomized clinical trials were included in the evaluation of treatment effect association between event-free survival and overall survival, and that was a sample size of almost 2,000 patients. And the therapeutic effect of event-free survival was significantly associated with the therapeutic effect of overall survival with an estimated coefficient of 1.26 and an R-square of 0.94. And what was explained to me clearly was that an R-square anywhere higher than 0.65 indicates a high level of correlation and good surrogacy. And the surrogate threshold effect for hazard ratio of event-free survival was estimated to be 0.88. And there were consistent associations between event-free survival and overall survival observed in all the sensitivity analyses as well.

And here we look at all the different analyses that were done. I think without going through how many patients were in each one of these, you can see here in figure 3A, the three-year event-free survival was significantly associated with five-year overall survival. Again, the R-squared is higher than 0.65. And then if we look at figure 3B, the median event-free survival was significantly associated with the median overall survival time. And then if we look here at 3C, one-year event-free survival was significantly associated with three-year overall survival. Again, an R-squared of 0.70.

So all of these are highly statistically significant. And this is a list of all the different trials. There are 21 different trials that we looked at, you could see at the bottom of this slide.

So in conclusion, there were strong associations consistently observed between event-free survival and overall survival for both treatment effect measures and survival outcome measures based on landmark survival rate and also median survival time.

The study findings support the use of event-free survival as a valid surrogate endpoint for overall survival in muscle-invasive bladder cancer following neoadjuvant treatment, which may assist regulatory and reimbursement decisions regarding relevant new therapies in the future. And the results of this study may be generalizable to different types of neoadjuvant treatment for muscle-invasive bladder cancer and a broad patient population, and even in perioperative settings, which can be evaluated in future studies when data become available.

Thank you very, very much.

Alicia Morgans: Fantastic, Cora. That was really quite an analysis that you did with the team. Can you tell me just in your own words, as succinctly as possible, why is something like this important in bladder cancer in particular? Why don't we just wait for overall survival, as some people have suggested that we could consider?

Cora Sternberg: We're very fortunate now that the whole field of bladder cancer and urothelial cancer has changed, and we have a lot of new therapies such as antibody-drug conjugates and immunotherapy that are really prolonging survival. So I think that some of these... This was a retrospective study, it doesn't even include what patients had afterwards, so that many people will be living longer. And if we have to wait until we have overall survival data from all the studies, I think it will take a lot longer.

So in the future, looking at an analysis like this and being able to use event-free survival in perhaps randomized studies or even in well-done single-arm studies that report landmark analyses, and you can calculate the event-free survival, it could help regulatory authorities in the future not have to wait for the overall survival, which could take years now. It's lucky that we could take years because we have so many new treatment options.

Alicia Morgans: Absolutely. And it's so interesting to me because this, from my perspective, is something that I would imagine is very important to patients and certainly to their loved ones. But it's interesting because as the survival gets longer after an initial progression event, and we've seen this in prostate cancer, it can be harder and harder to show that there's a correlation between an event-free survival, or in the case of prostate cancer, a progression-free survival event and ultimate survival.

So is there a pendulum that swings that maybe we're in a sweet spot now with urothelial carcinoma, but we may have to re-demonstrate this in the future as we have longer and longer survival with further and further therapeutic options?

Cora Sternberg: I'm sure. I mean, we have new trials that were just presented at ESMO. Some have neoadjuvant therapy and adjuvant therapy, and I think we have to really analyze what's going on. And then not only that, I mean, this was a retrospective analysis of databases. It wasn't an individual patient-based analysis, so it doesn't really include all the treatments that they had afterwards. And I think that that... things that we have to criticize about this particular study, but I think that for regulatory purposes, it's extremely useful for the time being. I think in the future, this will have to be redone and put in newer studies because the newest studies just presented in ESMO, for example, are not in here.

Alicia Morgans: Absolutely. So always more work for us to do, I imagine, Dr. Sternberg. It keeps us asking questions and keeps us answering them too. So I guess as you consider this work, and I so appreciate that you present these kinds of studies that help us not just move an individual treatment forward, but really move forward in our thinking in the field, as you think about this study, what would your message be to listeners and investigators who are trying to make a difference in urothelial cancer?

Cora Sternberg: Well, I think for investigators and for agencies who have to approve therapies, the fact that event-free survival is so correlated with overall survival, at least in these studies, is a very important endpoint to consider and not necessarily have to wait for overall survival. They could at least give accelerated approval, let's say, for certain therapies, and then perhaps wait the years until we have the overall survival. The authorities like to do that, to give an accelerated approval if they think that something is useful, and then they wait for perhaps a phase III trial or the overall survival data, but this way they could give accelerated approval for newer therapies that are coming along.

Alicia Morgans: I think this absolutely is so critical for patients, especially as they are waiting for these new therapeutics to be developed and approved, really something that's important to them. Because disease progression, these events, as you've described them, absolutely change the way that they live their day-to-day and certainly change their mindset and the way that they feel as well. So very important and so critical that it is actually tied to overall survival.

Thank you so much for doing the work, and thank you for your time and your expertise today.

Cora Sternberg: Always a pleasure with you. Thank you.