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Joep de Jong: Hi, everybody. My name is Joop de Jong from the Erasmus University Medical Center in the Netherlands. I'm here today in Las Vegas at AUA 2025, and we are very thankful for UroToday to be hosting this discussion with Dr. Packiam. It's a pleasure to have you here, and you have been working on evaluating the effectiveness of gemcitabine docetaxel for non-muscle invasive bladder cancer for which the research community but, above all, the patients will be very thankful. Could you enlighten us a little bit on why this is an important treatment option for those patients?

Vignesh Packiam: Absolutely. So, thank you and UroToday for having us for this discussion. Gemdoce was first devised in the early 2000s, and the first publication of it was 2015. This has been a great treatment option for patients with BCG unresponsive or BCG-recurrent disease. And with the ongoing BCG shortage, which is impacting us internationally, it's been increasingly looked at in the BCG naive setting as well.

So in 2023, we published a cohort of over 300 patients with treatment-naive, high grade NMIBC that either got BCG or gemdoce. And we actually found in that study that the high grade recurrence free survival from gemdoce was higher than that of BCG. So it seems like gemdoce is working as well, or potentially a little bit better than BCG in that setting, which I think is helpful for patients to have that additional option. And right now, gemdoce is undergoing prospective randomized evaluation being compared to BCG.

Joep de Jong: What I'm curious about is that your group but also some other groups have evaluated gemcitabine docetaxel, and the effectiveness range has been slightly different. And I know you probably have thoughts on why that would be. Could you elaborate a little bit on that?

Vignesh Packiam: Yes, absolutely. So, just to step back, one step, gemdoce was first published in 2015 by Mike O'Donnell, who kind of devised the regimen. And when he initially started giving this to patients, the induction was given just like a standard intravesical therapy, once a week for six weeks. And if disease-free, patients were recommended to continue on with monthly maintenance for up to two years.

Now, this was not designed using a prospective trial. This was kind of what was used in practice. And when other folks started using gemdoce, some used different maintenance protocols. And we've found that if maintenance is shortened or skipped, especially in patients with high grade disease, that will result in a lower RFS by about 10% to 20%.

Joep de Jong: OK. Yeah, I think this is very important, and that's also why the whole community is excited that the BRIDGE trial is getting out in the next couple of months or years. And we're all, also from the Netherlands, excited to see the noninferiority for gemcitabine docetaxel.

On the other hand, it yields a new research subject. And I think that's also what we can talk about today is the biomarkers. Like, how can we stratify patients for either BCG or gemcitabine docetaxel? And I know we have been working on it together. Like, would you elaborate a little bit on that?

Vignesh Packiam: Absolutely. So, you know, BCG has been the gold standard for this space for almost 50 years now. Gemdoce has some really promising data that's about 10 years old, and again, retrospective studies are showing they're both about equally effective.

The prospective studies will confirm that. But I think the next question is, can we select which patient is more likely to respond to each therapy so we can do a more precision medicine type approach? And that's what new biomarker studies like the work that we've collaborated on are going to show us.

Joep de Jong: Yeah, and luckily, we're not the first to look at the biomarkers within this setting. Like, there has been research for the whole spectrum of non-muscle invasive bladder cancer by the UROMOL consortium. I know the Linde Group from Sweden has acknowledged subtypes, but they specifically determine the luminal versus non-luminal subtypes, and they state that the non-muscle invasive bladder cancer is mostly only luminal. What do you think about the present models and their applicability to the setting that we're now looking at?

Vignesh Packiam: So UROMOL is a huge, amazing effort, some of the earliest subtyping that's been done for non-muscle invasive bladder cancer. And that's really pushed our field forward tremendously. One caveat with the UROMOL cohort is that it's not a pure, high grade, non-muscle invasive bladder cancer cohort. That cohort does include some patients with low grade disease, some patients that did not get BCG or other intravascular therapies. So that's one of the limitations of the UROMOL cohort if we're trying to look for truly predictive biomarker.

Joep de Jong: Yeah, and in context of that is that at the AUA, you are presenting the work that we've been pursuing within the high risk, non-muscle invasive, treatment-naive setting. What do you think are the benefits for looking at this setting only?

Vignesh Packiam: Yeah, so that'll allow us to more accurately look for predictive biomarker since we have a clean, kind of more homogeneous cohort with the caveat that all NMIBC cohorts are relatively non-homogeneous. But this is a more similar group where all the patients have high grade, non-muscle invasive bladder cancer that's treatment-naive. This cohort was coming from University of Iowa. It's 143 patients with treatment-naive high grade disease that got either BCG or gemdoce. And we took the tissue from these patients and then submitted them for sequencing with Decipher.

Joep de Jong: Yeah, and the sequencing we performed with Decipher Bladder has been mostly known in the muscle invasive bladder cancer setting. So therefore, I think your study is very novel. What they did for prostate cancer is they really leveraged the GRID, the Genome Resource for Intelligent Discovery.

And I think that's also what we're trying to do now is that we use the grid for profiling bladder tumors and then see what kind of signatures we have to look at for potential clinical applicability. And we welcome collaborations. But more importantly is that-- what do you think we should look at at the grid to potentially see biomarkers for this setting that we're now doing research for?

Vignesh Packiam: Yeah, great question. And I agree with your point about this being a unique cohort. Decipher bladder is approved for T1 through T4 bladder cancer. But with this project, we actually also were able to look at TA and CIS as well in addition to T1 disease.

GRID has been wonderful because it allows us to look at a multitude of different sequences, over 100 different types of mutations. And the other nice thing about GRID is that it allows for those to be put together into various different subtyping schemas. So in addition to the Decipher luminal or non-luminal classifications, it can also tell us information on what UROMOL subtype the tumor is, what BRS subtype the tumor is. So having all of those additional classifications is really useful, especially at this early stage of looking at subtyping, where we're not totally sure which one is the best way to sequence these patients.

Joep de Jong: Yep. And then last detail, if I may, is that it's very nice you highlight also the BRS. The BRS has been developed in Rotterdam in the Netherlands, but it has been proposed for high risk tumors invasive bladder cancer with BCG response. And the BRS 3 does the worst. Interestingly, the Sweden group from PI Gottfried Schroeder, they put out that you can predict the BRS by looking at microenvironment-related signatures only. And not that I don't want to get too much into the weeds, but do you also maybe think that we should look at immune or stromal infiltration for future biomarkers in this setting rather than only the tumor subtypes?

Vignesh Packiam: Absolutely. So, part of the reason why BCG has kind of been the king for the last 50 years is clearly, it is capitalizing on the fact that bladder cancer is an immunologic type disease, and BCG is an immunologic treatment. Clearly, the tumor microenvironment is a big factor in the treatment's efficacy. So it'll be really important to look at that in addition to just tumor rare characteristics.

Joep de Jong: I was also wondering, like, what are your thoughts on the results so far from the biomarker analysis?

Vignesh Packiam: Yeah, so the results of the study are very interesting. We were able to subtype these tumors according to various different classification schemas. So when we look at Decipher Bladder subtyping, about 85% of the cohort was defined as luminal and 15% were non-luminal.

We didn't see a clear difference in outcomes in the luminal versus non-luminal patients, which is different than what we see in the muscle-invasive setting. We also looked at prior classification schemas, including UROMOL, BRS, and the T1 subtyping score that was developed by Josh Meeks. Again, in our cohort, we didn't see a clear stratification within the different subtypes within those schemas.

But when we look at immune signatures, we did find that patients with a low immune signature score did not have much of a significant difference in outcomes between gemdoce and BCG. But patients with a high immune infiltration score showed that they did better with gemdoce compared to BCG, suggesting that this might be a predictive rather than just prognostic marker. But I think a lot more work has to be done.

Joep de Jong: Which is, like you said, it's exciting because it means that even though we can acknowledge that the non-muscle invasive bladder cancers are generally luminal, considered one subtype, if you look at that classification, there is granularity to look at in terms of immune or microenvironment-related scores to delineate outcomes differential to the therapies you are evaluating.

Vignesh Packiam: Yeah. Absolutely.

Joep de Jong: Well, this conversation has been wonderful, and I'm just thrilled that you are taking the biomarkers from the extensive research efforts of the community, which has been fantastic, to the next level, in this specific treatment setting that you have been pioneering us for with the gemcitabine docetaxel efficacy. So, thank you very much, and thanks to UroToday for this opportunity to talk with you about it.

Vignesh Packiam: Thank you.