Pooja Ghatalia: Yeah. Thank you, Betsy. So as you know that in our patients with muscle-invasive bladder cancer, offering an option of bladder reservation for some patients is very important. And we know that a lot of patients now with the even more efficacious neoadjuvant treatments, we may be able to attain path CR rates in 50 to 60% of patients. And an important question would be that, do all of these patients need cystectomy? Could we offer avoidance of immediate cystectomy to some? And that's what has led to these response-adapted bladder-sparing trials, that some of which have been completed. As you know, the first RETAIN-1 trial by Dr. Dan Geynisman was published last year, and that was one of the examples of such a conducted response-adapted trials. We know that a lot of patients were able to keep their bladder intact, but we still had several patients with local recurrence and metastases in that study. And so, we need to identify better biomarkers to be able to further improve our strategies. And so, I could tell you a little bit about the RETAIN-2 trial, which was built upon RETAIN-1.
Patients with clinical T2 to T3 N0, M0 MIBC patients received three cycles of neoadjuvant dose-dense MVAC plus nivolumab therapy. We also used a mutational biomarker that was tested in the pretreatment tissue. It was previously shown to have response to cisplatin-based chemotherapy. After completing this treatment, patients received a clinical staging, which included endoscopic assessment with biopsies, CT scans, and urine cytology. And then based on whether a patient had a clinical response and presence of a mutation, they were either allocated to active surveillance or an intervention was recommended, which could either be cystectomy, chemoradiation, or intravesical therapy based on the type of response that they had and the patient's wishes. And as you know, that this was a positive study, we had about 70% of patients who were metastasis-free at two years. And note that not all patients have completed two years follow-up, so we expect that number to be even higher with greater follow-up. And the estimated two-year MFS for all comers was 83%. I think there is still room to improve, since in our active surveillance patients, we had about three patients metastasize. There were four patients who needed salvage cystectomy or chemoradiation. And so, a lot of our work has focused on looking at other biomarkers, including ctDNA, and I could discuss that information with you.
Betsy Plimack: So, I think to summarize the RETAIN experience, especially RETAIN-2 with immunotherapy, shows similar metastasis-free and overall survival from cystectomy for all cohorts using similar regimens.
Pooja Ghatalia: Yes.
Betsy Plimack: But with a subset of patients who are doing well on active surveillance, bladder spare without radiation. So I think this is really a milestone, I think, in how we think about cystectomy in the setting of really effective neoadjuvant therapy. So you did pool the ctDNA from RETAIN-1 and RETAIN-2, and you had some really interesting findings in terms of those patterns.
Pooja Ghatalia: Yes. Yes, absolutely. We had about 111 patients between RETAIN-1 and RETAIN-2 for whom we had ctDNA data available. And I can summarize some of the key findings. So I think the first one was that ctDNA is an extremely strong prognostic marker for metastasis-free survival and overall survival. Both the baseline ctDNA, the post-neoadjuvant ctDNA, as well as the ctDNA dynamics between the baseline and the post-neoadjuvant therapy, they really inform us about prognostic information. I think the second important piece of information is that ctDNA is great at detecting metastatic disease, but not so much local recurrence. And that included patients who had cystectomy. ctDNA was not able to accurately predict ypT-0 in a lot of patients. Almost 70% of patients who had ypT-2 or greater disease at the time of cystectomy were ctDNA negative. And the third important point is, what can we get from our data to design future trials?
And so, we tried to stratify our patients based on the type of treatment that they had, so cystectomy versus active surveillance and the post-NAT ctDNA status. And what we found is that patients who are ctDNA-positive, they did really poorly even after receiving cystectomy. So these are the patients we worry a lot about and offering them cystectomy may be too radical. Maybe intensifying their systemic therapy or offering maybe chemoradiation could be an option to consider for those patients. And conversely, we saw that patients who were ctDNA-negative who went on to receiving cystectomy had outcomes that were very similar to patients who are ctDNA-negative who received active surveillance. And so, we cannot draw definitive conclusions based on that, but it does help us to possibly conclude that patients who are ctDNA-negative who also have no residual disease in their bladder at the time of clinical re-staging could be offered active surveillance and avoid immediate cystectomy.
Betsy Plimack: Right. Excellent. And the key question is now that we have EVP in that space, we have even more effective therapy. In your clinic on Monday, if you have a patient who has a clinical complete response after EVP and is ctDNA-negative and says, "I really don't want cystectomy," would you support their decision?
Pooja Ghatalia: That's a great question. I would say that the data can be applied to different other systemic therapies. So for example, even RETAIN-1 and RETAIN-2 had different regimens, one with IO and the other without. And we saw that the data were very consistent between the two trials. So I do think that this data was probably applicable once we start using EV and pembrolizumab. With that really efficacious regimen, I think I would consider offering them an option of avoiding immediate cystectomy and potentially putting them on a clinical trial that has that option and maybe also considering doing some maintenance immunotherapy, like it was done in the HCRN trial.
Betsy Plimack: Right. Pooja, thank you. Real important work. Thanks for sharing your thoughts.
Pooja Ghatalia: Thank you for those insightful questions.