Exploring Bladder-Sparing Treatment Approaches in MIBC

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 the fourth part of this roundtable series, the panelists discuss recent updates on bladder-sparing treatments, including immunotherapy with chemoradiation and the combination of gemcitabine/cisplatin/nivolumab without cystectomy.

Watch part five of this series: ctDNA in MIBC and Adjuvant Treatments Versus Observation

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Dr. Tawagi:
I did briefly want to touch on alternatives to patients that do not want surgery because I feel like a lot of my patients do not want to pursue surgery. There were a few updates in this space at ESMO. I was wondering if we could briefly touch on immunotherapy with chemo radiation.

Dr. Grivas:
This was a Hellenic study, actually. It was great to see my friends and colleagues from Greece where I’m from originally doing a very nice randomized phase II trial, looking at the addition of checkpoint inhibition to the backbone of chemo radiation after TURBT as a method, as a tool to try to achieve blood preservation in patients who do not undergo radical cystectomy. So it was great to see that happening, and I think that phase II trial, it was very interesting. That’s why we had it in the program, of course. This trial, I think it’s still ongoing. Again, we need to have longer follow up.

The take home point was addition of the checkpoint inhibitor with chemo radiation backbone seems to have a promising signal in terms of reducing the chance of recurrence and metastasis. And I think it’s not practice changing yet, but it’s raising enthusiasm for the two large ongoing phase three trials we have in the United States, the S1806, which a cooperative group trial run by SWOG and with a participation of NRG, ECOG-ACRIN Alliance. It’s a cooperative group study, finished accrual back in February of this year. And hopefully, we’ll present some data in the future. This is chemo radiation plus minus pembrolizumab after TURBT.

And a similar study with a few differences is a Keynote-992 with chemo radiation plus minus pembro. So I think those two phase trials will define the role of the additional value of checkpoint inhibitors to the backbone of chemo radiation. But the Hellenic group study from ESMO was very promising, again, despite not being practice changing, I think, raises my enthusiasm to wait for those phase III trials.

Dr. Koshkin:
Yeah. Yeah, I will add to that by saying that we spent a lot of this extra conversation talking about trials that include radical cystectomy, because that really is right now the standard of care for the majority of patients. But I think the future really is hopefully bladder preservation, that especially now that I think we’ve gotten to the point where we have really good systemic therapies, much better systemic therapies than previously hopefully, such as the new immunotherapy ADC combinations like pembro and enfortumab that I think would be very active in this setting and would allow many patients to hopefully preserve their bladder and avoid radical cystectomy.

So both of these trials that you mentioned with the basically checkpoint inhibition and radiation are huge efforts, and one of them a cooperative group study and we’ll hopefully see the results of that reasonably soon. And that may expand, I would say, the use of this bladder sparing approach.

And there are other studies ongoing as well. Also, I’ll highlight a study that actually, hopefully, I’ll be opening at my site soon at UCSF, where we’re actually using, again, enfortumab vedotin and pembrolizumab as a radiosensitizing regimen in combination with bladder radiation, then followed by EV and pembro post-radiation as well. So yeah. I think there’s a real future to studies investigating this question, and hopefully excited as we are about Niagara today, hopefully 10, 15 years down the line, we’re talking more about studies and regimens that allow patients to preserve their bladder.

Dr. Grivas:
I think it’s a great point. And Karine, I think you raised a great question. I think bladder preservation has an increasing role. I would argue that even now is a standard of care for some patients. And of course, the big question is patient selection. And I know at all our institutions, we think about patient selection in appropriate setting based on tumor characteristics, patient factors, patient preferences, provided familiarity in that context. A multidisciplinary tumor board or multidisciplinary clinic is very useful whenever possible to have the different experts in the room as ideally co-located, but at least have these different options for the patients. Radiation oncologists, med-onc urologists, and Vadim is right. The majority of patients so far, at least in the US, they undergo radical cystectomy. That’s the most commonly used approach. And I think in the future, I agree with you, we’ll see more bladder preservation, and that may have different forms.

Another question I’m sure you will ask, Karine, is in the future, not today, are we getting to the future state whether we can cure some patients with systemic therapy alone? That’s a big question.

Dr. Tawagi:
Right. I mean, we did see the phase II gem-cis nivo, and most of the patients on that trial elected to forego cystectomy. And the question is, are those remissions going to be durable? Can we be having discussions with patients hopefully in the future where we’re offering them an option where perhaps they don’t have the local toxicity of radiation as well?

Dr. Grivas:
I think it’s a great question. That [inaudible 00:05:40] trial by Dr. Galsky, very promising in that regard. And it was a small, relatively speaking, phase II trial, small in the context, not a phase III, but still very promising and set the foundation for this discussion. And I think it was, if I remember, clinical complete response that was stringently defined based on imaging, MRI, cystoscopy, surgery, cytology, I think it was 43%. And I think all but one of those patients had a great long-term outcome based on the follow-up they had without cystectomy. So I think that the notion is there. And I think as we get better with systemic therapies, chemoplastic inhibition down the road, pembrolizumab, enfortumab, or maybe the Volcker regimen, how do we get better with these systemic therapies? Can we identify biomarkers to define clinical complete response in select patients? That’s the pursuit.