ctDNA in MIBC and Adjuvant Treatments Versus Observation

A roundtable moderated by Karine Tawagi, MD, of the University of Illinois, featured discussion on the treatment landscape of muscle invasive and non-muscle invasive bladder cancer.
Panelists Petros Grivas, MD, PhD, of Fred Hutchinson Cancer Center, and Vadim Koshkin, MD, of the University of California, San Francisco discussed some of the latest practice-changing trials in the treatment landscape, as well as the potential of bladder-sparing treatment approaches and the use of ctDNA.

In part five of this roundtable, the panelists explore the use of ctDNA in the TOMBOLA and IMvigor011 trials.

Watch the final segment of this roundtable series: EV/Pembro and New Treatment Options for Metastatic Bladder Cancer

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Dr. Tawagi:
Guys, we briefly touched on ctDNA, we heard some updates from TOMBOLA. We had heard about IMvigor011. We’d love to hear about how you think about ctDNA in this space.

Dr. Koshkin:
Yeah, well, so I’ll briefly talk about TOMBOLA, which was another study presented at this meeting, at ESMO, that just happened. So it was actually a pretty great effort by the group from Denmark in looking at this question of basically using ctDNA to select patients to then receive adjuvant therapy. Actually, it was a non-randomized study, meaning, so the results of it are more, I would say, prognostic than they are predictive.

But there are a few things to learn from it. One is that patients who are ctDNA negative following surgery actually do really, really well. They’re very, very unlikely to relapse. And then patients who are positive, then those are the ones that we actually consider for adjuvant immunotherapy. That’s actually increasingly even what I do in clinic now. But we’ll have I think a more definitive answer about that from the IMvigor study.

Dr. Grivas:
Yeah, I agree. I think TOMBOLA trial, I remember back in the day when the data started to come from ctDNA in the new adjuvant setting and the colleagues in Denmark, a fantastic team there, we remember the paper by Christensen and colleagues with Dr. Dyrskjøt, this was 2019. And they saw, one of the first papers, that ctDNA can be prognostic. And if you have ctDNA clearance, it goes from detectable to undetectable. That’s highly prognostic. Or if you have ctDNA negative to begin with, that’s prognostic.

So we have of course to validate this data with longer follow up. And obviously, we have had a data set from the ABACUS trial and ABACO trial, new adjuvant immunotherapy trials showing the same thing that the ctDNA can be prognostic. And then we had the IMvigor010 trial that we published in Nature. That was an interesting experience because IMvigor010, as you both know, adjuvant atezo versus observation, negative trial. It was the first immunotherapy trial, the adjuvant setting to report. And our enthusiasm was high, but it was a negative trial.

But we said, “Let’s go back and learn something from it.” And ctDNA was prognostic post-cystectomy in those patients. As you pointed out, ctDNA negative patients do pretty well. Not perfect, but pretty well. But ctDNA positive had worse prognosis, high risk of recurrence or death. And the hypothesis was ctDNA predictive. Can ctDNA positive status predict response to adjuvant checkpoint inhibition? That was the hypothesis generated in the IMvigor010 trial that we published in Nature.

And based on that, we have three trials designed, TOMBOLA, that Vadim discussed. That was patients post-surgery and ctDNA negative, they get observed and they had a great outcome. The [inaudible 00:03:24] was very low and then ctDNA positive they got atezo. I think the TOMBOLA again contribute to this data set of the prognostic role of ctDNA, especially ctDNA negative patients do very well.

We saw that early from the IMvigor011 trial. I think the question remains about the predictive value in ctDNA positive patients. And I think the IMvigor011, which used ctDNA and then randomized patients to atezo or placebo. And the MODERN trial by Alliance Group, Dr. Galanis and colleagues in the US, that has two different questions, ctDNA positive patients, they get NIVO plus relatlimab, under LAG-3, versus NIVO. And the ctDNA positive patients, the ctDNA negative patients, they get NIVO or no adjuvant therapy. And I think this will answer both questions. So in the future, I think we’re going to find out more about the clinical utility and the predictive value question of ctDNA.

Dr. Tawagi:
Right, I think it’s very exciting that we might be moving to more of a risk-adapted approach when we’re thinking about adjuvant therapy. Obviously, that’s not how it was done in Niagara. So we may have kind of a clouded decision-making in the future as all of these studies accrue and read out. So right now, outside of a trial, are you routinely getting ctDNA in the perioperative space?

Dr. Koshkin:
I do it whenever I can, yeah. And they’re based on reimbursement and whether the patient is actually charged for it, which of course I want to avoid in all situations. Usually we’re able to do it. And so I do find it very informative. Again, as Petros highlighted, we don’t have definitive data for patients who are ctDNA positive that giving them treatment is for sure better than not giving them treatment.

But we do have, I think, pretty compelling data that those with positive ctDNA are very likely to progress and eventually develop metastatic disease. And so when I see that in a post-op setting, that they have positive ctDNA, that concerns me, that makes me really worried. So I don’t want to hold off on potentially giving them therapy in a curative intense setting. So that’s one of the reasons that I often do consider adjuvant nivolumab or maybe even other adjuvant therapies.

Dr. Grivas:
It’s an ongoing question. I think it’s one of the most interesting questions in the field. I personally think we need to see the clinical utility in the ongoing trials, especially MODERN and IMvigor011, to help me understand what is the real added value for the predictive question of ctDNA.

When a patient comes to me, if they have it, I will look at it for sure. I will not ignore it. I have not used it yet, to be honest. I have not ordered it myself because I’m not a hundred percent sure whether it will impact my decision making. Having said that, I see the value of doing it. I think it’s reasonable.

And especially if you are on the fence of doing or not doing adjuvant, it might help you and the patient inform this dialogue. Especially if ctDNA negative and the patient does not want to get therapy, it may make you sleep better at night. So I see the value of doing it. It’s a matter of [inaudible 00:06:41].

Dr. Koshkin:
Well, yeah. Let me maybe follow up on this. If you have a patient who’s, let’s say, had chemo. Like cisplatin-based chemotherapy, had surgery, have T2N0, so you’re really on the fence, right?

Dr. Tawagi:
Mm-hmm.

Dr. Grivas:
Yes.

Dr. Koshkin:
You wouldn’t be compelled to send ctDNA or you resist that temptation in the ways that I don’t.

Dr. Grivas:
I think it’s a great scenario. Great question because you put a borderline scenario there, neoadjuvant chemo radical cystectomy ypT2 and 0. Those patients were included in the CheckMate 274 trial and the AMBASSADOR. So if the patient is fit enough, I would consider giving them adjuvant nivolumab regardless of ctDNA, because I’m not fully convinced. Having said that, if the patient is still on the fence, doesn’t know what to do, I think it’s reasonable to order it and inform the dialogue.

Dr. Tawagi:
Totally.

Dr. Koshkin:
Yeah. Well, yeah, because I approach it from the standpoint of, yeah, it’s these patients are included in the adjuvant nivolumab trial population. So it’s technically, I mean, certainly reasonable to give it. But then if you’re considering and if the patient is asking you, “Well, what are the toxicities? Am I going to get,” like what we were talking about earlier, “Immune-related adverse events?” Which can be quite unpredictable. “So do I really need this?” And for me, if they’re ctDNA negative, we have great data that they probably will be okay. Right?

Dr. Grivas:
I think it’s a very reasonable approach.

Dr. Tawagi:
And until we have significant overall survival data, it’s really important to be thinking about all these things when you’re having that risk-benefit discussion with patients.