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Ashish Kamat: Hello, everyone. And welcome to UroToday's Bladder Cancer Center of Excellence. I'm Ashish Kamat, Professor of Urologic Oncology at MD Anderson Cancer Center. And it's a pleasure to welcome once again to our forum, Professor Nimira Alimohamed, joining us from the University of Calgary, Canada. Dr. Alimohamed, gave this really excellent talk at ASCO GU just a few weeks ago. You and I talked again in person in San Francisco. And it's lovely to welcome you back to the stage, so you can actually teach our audience and re-give your talk that you gave at the ASCO Plenary. So with that, thank you for taking the time. Welcome, and take it away.

Nimira Alimohamed: Thank you for having me. So I will take you through my thoughts on the potential impact of ctDNA in the perioperative management of muscle invasive bladder cancer. I've been taught to give my key takeaway points first. So I hope to show you by the end of this presentation that ctDNA is an important prognostic biomarker in muscle invasive bladder cancer. The detection and dynamics of ctDNA are both important. And we hope that in the future, ctDNA-guided treatment may improve survival and quality of life for patients with muscle invasive bladder cancer.

As a bit of introduction, we know that the standard of care for eligible patients with MIBC is cisplatin-based neoadjuvant chemotherapy, followed by radical cystectomy, with the option of adjuvant nivolumab for patients who have high-risk disease after those treatments. We've also seen recently that perioperative chemoimmunotherapy with durvalumab has demonstrated improvements in overall survival. Regulatory approvals are pending here in Canada and, I think, there in the States as well. We also know that bladder preservation is increasingly being utilized, both for patients who are eligible for cystectomy and those who aren't.

The detection of ctDNA after curative intent treatment signifies the state called molecular residual disease, or minimal residual disease. And that can predict recurrence prior to imaging. A variety of ultra-sensitive ctDNA assays have been evaluated. Some are tumor-agnostic, and some are tumor-informed. Dr. Wyatt gave an excellent presentation on some of the technology. And you can find that on the GU ASCO website as well.

What are some unmet needs in this disease state? So many patients are ineligible for our current neoadjuvant chemotherapy. We don't have a validated biomarker to predict response. And these regimens come with significant toxicity. We also know that bladder preservation is underutilized. And there's a significant impact to quality of life with a cystectomy. We also know that adjuvant immunotherapy may overtreat some patients. And despite all of these treatments, up to 50% of patients will recur. So the hope is that, number one, novel therapies and combinations are expected to improve survival. And we'll likely have some data in 2025 with novel perioperative regimens. And also that ctDNA has the potential to address some of these unmet needs.

Let me take you through some of the data in patients treated with neoadjuvant chemotherapy. So this was one of the earlier studies which highlighted the prognostic relevance of ctDNA in patients with muscle invasive bladder cancer treated with neoadjuvant chemotherapy. This was a small study, and 17 patients were treated with cisplatin-based chemotherapy. ctDNA was evaluated at baseline, so at TURBT time, and prior to each cycle of neoadjuvant treatment and prior to definitive therapy. This ctDNA evaluation was done using a patient-specific panel of eight genes. And what this study showed us was that the detection of ctDNA, pre-cycle two of neoadjuvant chemotherapy, indicated early disease recurrence with a high sensitivity and specificity.

Another important study was done by Christensen et al. And there's been a lot of information that has been gleaned from this prospective study, enrolling 68 patients with muscle invasive disease also treated with neoadjuvant chemotherapy. In this evaluation, ctDNA was evaluated at baseline, after neoadjuvant chemotherapy, and then during a surveillance period. The Signatera assay was used in this study. At baseline, 41% of patients with muscle invasive bladder cancer had detectable ctDNA, and those patients with detectable ctDNA had inferior recurrence-free survival. After neoadjuvant chemotherapy, ctDNA was detected in 13% of patients. And again, those patients whose ctDNA remained positive after neoadjuvant chemotherapy had inferior survivals.

Notably, those patients whose ctDNA was still detectable after neoadjuvant chemotherapy, after surgery, that post-cystectomy detection was the strongest predictor of recurrence-free survival. So 13 out of 17 patients recurred when they were ctDNA-positive after surgery, whereas if you were ctDNA-negative after surgery, none of those patients recurred during the study follow-up. An updated analysis of this data set with a median follow-up of 68 months highlighted the importance of ctDNA dynamics. So in those patients who had clearance of ctDNA going from positive to negative, that was correlated with pathologic downstaging and improved recurrence-free survival with a significant hazard ratio. So this decrease in ctDNA or the clearance may be an early marker of disease response. The study also highlighted that there's a lead time from the detection of ctDNA to radiographic evidence of disease. And on this study, it was about 123 days, or about four months.

Another analysis in the real world also showed us the importance of the prognostic role of ctDNA. This was a retrospective analysis of 167 patients with muscle invasive bladder cancer. And they had evaluation of ctDNA pre-radical cystectomy, after radical cystectomy, and again during this surveillance window. These patients were treated across many institutions and had diverse treatments. And again, the Signatera assay was used here, which is a tumor-informed ctDNA assay. The detection of ctDNA at all time points was correlated with a shortened disease-free survival. And again, that surveillance window—so after definitive treatment, if you have detectable ctDNA—that has the high risk correlation with inferior outcomes.

Now, what about in the immunotherapy era? Let's look at some of the studies which have evaluated ctDNA in patients treated with immunotherapy. The ABACUS study evaluated neoadjuvant atezolizumab. This was a single-arm, phase II study, patients who were cisplatin-ineligible or refusing. They received atezolizumab for two cycles and then went on to have a radical cystectomy. This study had an exploratory analysis of 40 patients with sequential ctDNA evaluation. It was tumor-informed testing as well. And this graph is a little bit complicated, but I wanted to highlight that, if you were ctDNA-positive, that was highly prognostic at all time points—so at baseline, after neoadjuvant atezolizumab, after surgery.

Three patients had ctDNA clearance. So those are these patients here who've started in the red and gone on to become blue. And those patients also achieved a pathologic complete response. In those patients who were ctDNA-negative at all time points, there were no relapses in that patient group.

Another study looking at adjuvant treatment in muscle invasive bladder cancer, a big, important study was the IMvigor010 study. Patients were enrolled with high-risk, resected, muscle invasive, or upper tract disease. There were over 800 patients enrolled. They were randomized to receive adjuvant atezolizumab for a year or observation. And as we know, this was a negative study. So disease-free survival in the intent-to-treat population was not significantly different with atezolizumab versus observation. Despite being a negative study, the ctDNA analysis was very informative. So as you can see here, at the bottom half of these Kaplan-Meier curves—on the left is disease-free survival, on the right is overall survival—those patients are the ones who were ctDNA-positive.

And it is here that we see the benefit of adjuvant atezolizumab. So this was in a biomarker-evaluable population, looking at the benefit of adjuvant atezolizumab. In this study, ctDNA was detected in 37% of patients after surgery. And those patients had inferior disease-free survival and overall survival. But those patients also benefited with adjuvant immunotherapy.

Further biomarker analysis in this patient population looked at different time points—so cycle one, day one, and cycle three, day one. And you can see here that patients who had clearance of their ctDNA with adjuvant atezolizumab had improved overall survival. And you can see this stratification by complete clearance versus a reduction versus less than 50% reduction. So a decrease in ctDNA with immunotherapy may be an early marker of treatment effect.

The study also looked at—not only is clearance important, but should we evaluate at multiple time points? And the short answer is, yes. So if we look at ctDNA evaluation at cycle one, day one, and cycle three, day one, that had increased sensitivity for predicting relapse than cycle one, day one alone. Notably, it was also important to comment that, in that ctDNA-negative group at both time points, 32% of patients still relapsed. The lead time here was, again, about 3.8 months before clinical recurrence—so ctDNA detectable about four months before we see imaging-detected recurrence.

So all of that brings me to talk about now the ongoing studies in muscle invasive bladder cancer that have already shown us some data with ctDNA. The VOLGA study, we saw results of this presented at ESMO last year. As a reminder, this is a phase III global study which has enrolled patients who are cisplatin-ineligible with muscle invasive bladder cancer to receive durvalumab, tremelimumab, and enfortumab vedotin. They go on to receive a radical cystectomy. And then there's a durva–treme adjuvant portion. This study is ongoing, and there's multiple arms. The data that has been presented to date is the safety run-in cohort of those patients treated with the combination of these three agents and the ctDNA analysis.

So ctDNA was evaluated at baseline and after three cycles of durva–treme and EV. And as you can see here, there were several patients who had ctDNA clearance. So in five patients, ctDNA cleared with these treatments. And those patients had a pathologic complete response. Notably, patients who were ctDNA-negative at both time points also were downstaged. And those who were positive at both time points were upstaged at the time of pathologic assessment after radical cystectomy. So this is, again, highlighting, is this an opportunity to adjust our treatment plan? If we don't have clearance of ctDNA, should we be doing something different?

The TOMBOLA study is evaluating immunotherapy at the time of molecular relapse. So this is a ctDNA-based intervention study. And 190 patients are enrolled using a tumor-informed approach. ctDNA is evaluated prior to neoadjuvant treatment, prior to radical cystectomy, and then monthly for several months afterwards until two years. Upon ctDNA detection, the intervention is treatment then with atezolizumab for 18 cycles. The objective of this study is to determine if immunotherapy at the time of molecular relapse improves outcomes. The primary endpoint is a complete response, defined as ctDNA negativity and negative imaging after treatment.

And our early results—preliminary results—have been reported. Those patients who were ctDNA-negative, only 2 out of 66 patients relapsed. And 56% of patients were ctDNA-positive after cystectomy. They received atezolizumab. And more than half of those patients converted to being ctDNA-negative with no evidence of disease on imaging. So further data from this study will be very interesting and informative.

The IMvigor011 study is another important study in this state, looking at adjuvant atezolizumab in patients who are ctDNA-positive. So the questions this trial is hoping to answer is, can serial ctDNA testing better select patients for adjuvant immunotherapy compared to giving this to all comers, as we saw in the IMvigor010 study? So can we spare some patients from unnecessary toxicity with adjuvant therapy when they may not need it? This study has completed accrual and is ongoing. There's some preliminary data from the surveillance cohort. So the surveillance cohort are patients who have had resected muscle invasive bladder cancer who remain high-risk. They have serial ctDNA testing and imaging every 12 weeks. And if their ctDNA remains negative, they're on this surveillance cohort.

An exploratory analysis with 171 patients, a median follow up of 16 months, has shown us that those who remain ctDNA-negative with serial testing had favorable outcomes. So overall survival was 100% at 12 months, 98% at 18 months, and very few patients relapsing on this study. So there's increasing confidence in this surveillance approach for patients who have persistent, undetectable ctDNA. And again, it will be important to wait for the final results of the entire study.

The MODERN study is another study that is ongoing that is using ctDNA to guide escalation or de-escalation of adjuvant therapy. So in patients who are ctDNA-positive, they'll be randomized to adjuvant nivolumab or adjuvant nivolumab plus relatlimab. Those who are ctDNA-negative will be randomized to receive nivolumab or surveillance followed by nivolumab if their ctDNA becomes detectable. So really, this trial is going to answer those important questions of which patients need additional treatment. Does escalation of treatment provide benefit? And do ctDNA-negative patients benefit from immunotherapy up front, or can we wait until we see the detection of minimal residual disease?

I've talked a little bit about bladder preservation and ctDNA. We know that, as we improve our systemic therapy options, this may allow more patients to save their bladders. Some studies that have evaluated this option have had different definitions of a complete clinical response. And a significant number of patients in these studies, which have already been reported, who have received active surveillance, have recurred. So can the incorporation of ctDNA into response assessments improve outcomes and allow for more patients to preserve their bladders? One study that's going to incorporate that is the NEO-BLAST study. The PI is Dr. St-Laurent here in BC in Canada. And this is going to look at ctDNA in addition to MRI imaging, in addition to TURBT, and repeat imaging after standard-of-care neoadjuvant chemotherapy to try to select patients better for active surveillance versus different options for definitive local therapy.

So there are many challenges with incorporating ctDNA into clinical decision making. This technology is costly, and there's a lack of access outside of major academic centers. Prospective data is coming, but it is coming, and validation is pending. And so we can't make any conclusions without that information. Also, we're in an era where technology is rapidly evolving. Our systemic therapy is rapidly evolving. And treatment paradigms are changing so quickly, that this will pose further challenges to data interpretation.

So today, does ctDNA change practice for patients with muscle invasive bladder cancer? So currently, I think ctDNA is informative but not practice-changing yet. I wanted to give you some clinical scenarios. So if a patient has a TURBT, we would hope that, in the future, tumor is sent for molecular profiling. We can check ctDNA or if ctDNA is detectable prior to neoadjuvant chemotherapy. Maybe we'll recommend neoadjuvant systemic therapy, irrespective of ctDNA status. And we would still do that. However, in the future, perhaps if we're looking at the dynamics and the clearance of ctDNA, if a patient has positive ctDNA after two or four cycles of neoadjuvant chemotherapy, we might continue with our current treatment today, but I might image that patient sooner. I'd be worried about evidence of disease progression, knowing how important this prognostic marker is at this time point as well.

What about patients who have ctDNA detectable after definitive therapy? Currently, if those patients are high-risk, they would get adjuvant nivolumab. But in the future, hopefully we can use this technology and this test to better select patients for adjuvant immunotherapy. So as I mentioned in the future, maybe in the future, we can use ctDNA positivity at baseline to select the right regimen. Perhaps we'll be able to assess biomarkers on ctDNA to tell us which regimen is best for which patient.

During neoadjuvant chemotherapy, we might be able to adjust our treatment for non-responders. Maybe we can de-escalate treatment for responders and spare them toxicity after two cycles of treatment. Prior to definitive therapy, we can use ctDNA evaluation, I hope in the future, as part of that assessment of complete clinical response. And I hope that will guide our choice of definitive therapy or surveillance, which will then translate to an impact on quality of life. And in the adjuvant setting or surveillance setting, maybe we can treat at the time of MRD instead of treating everybody. Perhaps we can escalate or de-escalate based on the dynamics of ctDNA in this setting as well. And I hope that we can refine our imaging protocols based on ctDNA. Maybe we don't need to image as often. Or in those patients who we see ctDNA changing, we can image more often. And again, this will impact patients and their quality of life.

So in summary, we know that ctDNA is a prognostic biomarker in bladder cancer. Detection and dynamics are important. And I hope in the future, that ctDNA-guided treatment will improve survival and quality of life for patients with muscle invasive disease. So thank you for your time.

Ashish Kamat: Thank you so much, Nimira. That was a really nice summary. And thank you for giving that talk again. The way we look at ctDNA as technology is evolving. As you said, this is new technology. We have genomic profiling. We have better imaging. Now we have what patients have always asked for—“hey, is there a blood test you can do to detect cancer cells?” And I think the way you framed it is where we need to be really cautious about implementing this in day-to-day practice. But the evidence seems to be heading in the direction of us being able to use this.

And you and I had an excellent discussion. For those of our listeners that want to access our discussion, just look at the UroToday link. I'm sure it'll be there somewhere on the website. And you can hear everything that Dr. Alimohamed and I talked about at ASCO GU in San Francisco. So Nimira, thank you again for taking the time and sharing your wisdom and knowledge with us.

Nimira Alimohamed: Thank you so much for having me.