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Longer-term follow-up of the CheckMate-274 trial confirmed that treatment with the anti-PD-1 therapy nivolumab (Opdivo) after surgery helped reduce cancer recurrence in patients with muscle-invasive urothelial cancer, according to a presented at the American Urological Association (AUA) annual meeting.

乌鸦传媒 brought together three expert leaders in the field. Moderator Alexander Kutikov, MD, is joined by Adam Reese, MD, and Laura Bukavina, MD, MPH, all part of the , for a virtual roundtable discussion. This last of four exclusive episodes covers their thoughts on the extended follow-up of the trial.

Following is a transcript of their remarks:

Kutikov: All right. Let's talk a little bit about CheckMate-274. Adam, your thoughts on this trial?

Reese: Yes, so I guess just in summary, this is a trial that's previously been published, so many people may be familiar with it. It's a phase III randomized controlled trial randomizing patients to nivolumab versus placebo. This is a different setting, so this is as adjuvant therapy after surgery for muscle-invasive urothelial carcinoma, so different than sort of the BCG [bacillus Calmette-Guérin]-unresponsive population that we've been talking about previously.

One thing that's important about this study is that patients who received neoadjuvant chemotherapy prior to surgery were eligible for the study. So a lot of the patients in the study population were those patients who had persistent muscle-invasive disease at the time of surgery, despite having received neoadjuvant chemotherapy.

So the initial report for this trial was published in the , I think in 2021. That initial report included all patients with urothelial carcinoma, so including those with upper tract tumors. And it was published when the median follow-up was, I think, around 20 months. The report that was presented at the AUA, it focuses specifically on those with muscle-invasive bladder cancer, so not the upper tract tumors. And it reports with extended follow-up. I think the median follow-up was around 3 years in the updated report.

So in the updated report, the study did meet their primary endpoints, which were an improvement in disease-free survival in the nivolumab arm in their intention-to-treat population. And then secondly, an improvement in disease-free survival in patients with PD-L1-expressing tumors.

They did do a subgroup analysis where the survival benefit appeared to be present regardless of PD-L1 expression of the tumor. The efficacy of nivolumab seemed to be a little bit greater in those that did express PD-L1, although there still was a significant benefit compared to placebo in the patients without PD-L1 expression.

As we talked about with some of the other agents, the adverse event rate here was relatively high, it was around 79%. But only 18% of those were adverse events that were grade 3 or higher.

So based on the data, the authors' conclusion was that nivolumab should be considered a standard of care for patients with high-risk muscle-invasive bladder cancer after radical surgery.

Kutikov: Perfect. Laura, I know you have a great interest in biomarker work. Thoughts on the fact that the efficacy was the same regardless of PD-L1 expression? This is one of these very big challenges here that we're not able to select out the patients who are destined to respond. Where do you think the field is going with that regard and overall thoughts about this trial?

Bukavina: Yeah, so you have to look almost at the confidence intervals for these. And if you look at the PD-1 expression, which they defined as over 1%, you actually do get a better signal in those patients. So you do get a little bit of a benefit. So you are able to sort of target those patients.

But PD-1 or PD-L1 have not been very promising in many trials. And unfortunately, as it stands, we don't have any -- aside from tumor mutational burden -- really none of the biomarkers in terms of the genetics or residual disease or ctDNA [circulating tumor DNA] is kind of ongoing, really have not been able to establish the population that we need to treat. Except ctDNA for adjuvant therapy.

So I certainly would argue that regardless of PD-1 expression, they should be given. However, in patients with higher than 1%, it certainly almost is unnecessary therapy in high-risk post-cystectomy patients.

Kutikov: Perfect. Adam, where do you stand with this in your practice?

Reese: To be honest, I have not given much of this as adjuvant therapy after cystectomy. I haven't had a ton of patients recently who have been eligible for something like this. But I do think the results are promising. This is a space that's been in need of an agent to treat these patients for quite some time. So I think the survival improvement that we're seeing with this treatment is impressive. And I think if it's durable and the toxicity profiles are low enough, I do think there's a promise in this treatment.

Bukavina: I think it's interesting. I think it's interesting how they removed upper tract, because we always extrapolate a lot of our data in muscle-invasive bladder cancer and upper tract, sort of upper tract from muscle-invasive bladder cancer. But we know that even though it's the same histology, it really is a different disease in terms of the response to immunotherapy. But we really don't know why. Genetically it looks the same, histology-wise it looks the same; however, it does not respond to immunotherapy as well. And actually some of the new trials coming out actually don't include that.

So if you look back at many of our adjuvant or neoadjuvant trials, they always almost had about 10% to 15% of upper tract. And now the new trials are actually excluding upper tract patients. Which begs the question, in a year or two, we're not going to be able to extrapolate the results from these muscle-invasive bladder cancer trials to our upper tract patients because they're just not going to be included in these trials. So should we be starting trials specifically in upper tract patients?

Kutikov: Those are super incredibly challenging. Decades went by without any data. I mean there are some trials that sort of finally gave us some answers about chemotherapy, although those are not perfect, but upper tract ... Urothelial disease is incredibly challenging, but upper tract is especially challenging.

Reese: I have to think that they have to report the data eventually. I mean those patients were included in the study. I think they weren't in this report, but I think eventually we will get those long-term data to see if it's equally effective in the upper tract population.

Bukavina: Yeah, no, specifically for this one, since they had the patients already, they will report it. I'm talking about the new trials that they're not even including. Because in the past, inclusion of upper tract patients actually hurt their trials because they have been less responsive. So the trials have learned not to include those patients.

Kutikov: Yeah. There's always strategy involving these trials and you don't want your signal to get washed out and you kind of bite off the questions that you can answer. Yes, trial design is an art. And sometimes you do have to take it sort of one disease state at a time. And like you said, Laura, the upper tract disease just appears to have such a different biology. Although, histologically it's very similar. And interestingly, one can lead to the other, right? Your upper tract disease can cede lower track, but they just behave differently.

But I think we'll wrap it up here. Thank you both for joining us and thank you, 乌鸦传媒, for the opportunity to do this roundtable. I hope people enjoyed it. Have a great day.

Watch episode one: Anti-PD-1 in BCG-Unresponsive Papillary Bladder Tumors

Watch episode two: Immunotherapy Combo Shows Promise in Tough-to-Treat, Early Bladder Cancer

Watch episode three: TAR-200 Led to High Complete Response Rates in BCG-Unresponsive Bladder Cancer

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