Steps Toward a Bladder-Intact Cure for Muscle-Invasive Bladder Cancer - Andrea Necchi

June 13, 2021

In an oral presentation at the 2021 ASCO annual meeting, Andrea Necchi, MD provided a discussion on combination immunotherapy, checkpoint inhibitors, with radiation or chemoradiation approaches to bladder-sparing. In this conversation with Alicia Morgans, MD, MPH, he highlights several abstracts including a US phase II study presented by Arjun Balar of immunotherapy with pembrolizumab combined with chemoradiation, hypofractionated radiotherapy combined with gemcitabine in patients with D2-D4-N0 muscle-invasive bladder cancer, and a multicenter study, presented by Javier García del Muro, combined immunotherapy with durvalumab and tremelimumab and radiotherapy as a chemotherapy-free strategy for bladder preservation in muscle-invasive bladder cancer in the same patient population. He highlights the differences between the studies and their endpoints as well as a presentation by Matthew Galsky, HCRN GU 16–257, a phase 2 trial of gemcitabine, cisplatin, plus Nivolumab with selective bladder sparing in patients with muscle-invasive bladder cancer. In closing, Dr. Necchi highlights two large phase III studies currently recruiting patients, that have the potential to establish the standard for therapeutic options in the near future.


Andrea Necchi, MD, Medical Oncologist, Department of Medical Oncology, Fondazione IRCCS - Istituto Nazionale dei Tumori, Milan, Italy

Alicia Morgans, MD, MPH Associate Professor of Medicine in the Division of Hematology/Oncology at the Northwestern University Feinberg School of Medicine in Chicago, Illinois.

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Alicia Morgans: Hi, my name is Alicia Morgans and I'm a GU Medical Oncologist and Associate Professor of Medicine at Northwestern University in Chicago in the U.S. I'm so excited to have here with me today Dr. Andrea Necchi, who is a Professor of Medicine and a GU Oncologist in Milan at San Raffaele. Thank you so much for being here with me today.

Andrea Necchi: Thank you Alicia and UroToday people for inviting me. It's a pleasure to be here.

Alicia Morgans: Always and of course. So thank you. And I wanted to talk with you a little bit about some of the abstracts that you discussed at ASCO 2021. We can start with the abstracts that were really looking into bladder-sparing through the use of immunotherapy and radiation. Can you tell us a little bit about them?

Andrea Necchi: Yeah. Thank you.

This year I had the pleasure to discuss three important abstracts that are focused on the bladder-sparing strategies in patients with muscle-invasive bladder cancer. The first two of these abstracts are studies that are aimed to combine immunotherapy, so checkpoint inhibitors, with radiation or chemoradiation in a bladder-sparing approach. The first abstract, presented by Arjun Balar, is a US Phase II study of immunotherapy with pembrolizumab but combined with chemoradiation, hypofractionated radiotherapy combined with gemcitabine in patients with D2-D4-N0 muscle-invasive bladder cancer. And the second study is a multicenter Spanish study, a European study, presented by Javier García del Muro, who is combining a chemotherapy-free regimen and combining immunotherapy alone, any particular combination immunotherapy with durvalumab and tremelimumab with radiotherapy as a standard fractionation in the same patient population.

There are differences, a key difference between the studies and between the endpoints that have been used within the studies, in one case in the Balar study, we have a chemoradiation approach as a foundation for combination therapy. On the other side, we have radiotherapy alone combined with immunotherapy. These may have generated some bias when comparing the outcomes. One way, we have in the U.S. study, the hypofractionated radiotherapy. And on the other way, we have a standard fractionation and there may be some difference in the efficacy, according to recent data presented by UK colleagues in the type of fractionation in relation to the outcomes of the efficacy in these patients. And in particular, what I would like to stress is the fact that all of these studies are focusing on clinical endpoints.

There will be differences between the studies. In one case in the Spanish study, we have the primary endpoint of clinical complete response. On the other case, in the Balar study, we have the endpoint of survival, namely the bladder intact disease-free survival. If we focus on the definition of clinical complete response, we acknowledge some difference between the studies, because in one case, in the Balar study, we have the definition of CR as a complete response, as the absence of any viable residual cancer, [inaudible 00:03:23] cystoscopy, and then biopsy after treatment. On the other case, in the Spanish study, we have the definition of CR, including any non-muscle-invasive residual disease. This may generate some concern and some discussion when looking at the results, of course. And also the survival endpoints, the types of endpoints that are used across the studies, not only these studies but also when looking at the literature are a bit different.

So my first big consideration is that we should definitely harmonize in the near future the type of clinical endpoints that we will use in this type of study when looking at the bladder sparing approaches.

And then the other point is that the actual contribution of immunotherapy over the benchmark chemoradiation or radiation approach.  The data are very promising from both of these studies. The Balar study reported the 80% CR rate and both of these studies, the Balar study and the Spanish study report, the one-year disease-free survival or bladder intact disease-free survival approximating 75%, 80%, which is promising despite the follow-up, [inaudible 00:04:40] "Is this too short?" And the question is here, [inaudible 00:04:43] "How can dissect or discern the contribution of immunotherapy over the benchmark?" Because if we look at the benchmark literature, we know that data from chemoradiation studies reported similar findings in short term, in terms of a CR, in terms of survival endpoints. So we definitely need randomized studies that are already ongoing in two to 12 [inaudible 00:05:13] second. The road for immune radiation approaches as a bladder-sparing approach is in the near future and potentially set new standards.

Alicia Morgans: I agree. And I appreciate that you really have been able to draw out the differences between these studies and the endpoints for muscle-invasive bladder cancer when you're not actually doing a cystectomy, I think is really challenging. And that is why we may see some differences between these studies. And of course, we're not able to compare the addition of immunotherapy because these are single-arm trials. What are your thoughts? I know there are some ongoing studies, will these ongoing studies help to answer some of the questions that are left behind by the two abstracts you have really discussed today?

Andrea Necchi: Yeah, we have in particular, we have two big phase three studies that are recruiting patients these days. The KEYNOTE-992, which is a pembro chemoradiation study versus chemoradiation, which is a phase three study, which is running worldwide and may provide us with a definitive answer to the question of the contribution of a pembrolizumab. And another study, which is led by the [SWOG inaudible 00:06:27] in the United States, is using atezolizumab combined with chemoradiation versus the standard of care. So these two big phase III studies may set the standard potential for therapeutic options in the near future.

Alicia Morgans: Wonderful. And then just before we move on to your final abstract, in terms of safety, did everything look fairly tolerable? Were there any new safety signals in these studies that you wanted to highlight?

Andrea Necchi: Based on the data that Balar and García del Muro reported, we don't see any major issue, at least in providing patients with this type of approach.  A combination of immune radiation, all of the studies overcame phase one and the phase one portion and the phase one feasibility part without any concern in safety and without any extra safety signals, extra toxicity. So the data in terms of safety are pretty much overlapping the data from immune checkpoint inhibitor trials already available by us on the other side, without any issue related to side effects.

Alicia Morgans: Fantastic. So these may lead us to future options where we integrate immunotherapy into a bladder-sparing approach, and several phase three trials are on the way to help answer that question. And very importantly, no new safety signals to hold us back. So, definitely more to come. Thank you for outlining that. So switching gears a little bit, let's talk about the abstract presented by Matt Galsky and his colleagues where a chemoimmunotherapy approach was used without a local therapy given to the bladder. Can you tell us a little bit about that?

Andrea Necchi: Yeah. The study by Matt Galsky is a fantastic study.  It's a totally different approach to sparing the bladder in muscle-invasive disease. It's targeting something that I would like to call the near target endpoint of this type of study, sparing the bladder without any radical approach on the primary tumor, either radiotherapy or radical surgery. In the Galsky study, patients received four cycles of gem/cis and nivolumab, and the patients were reassessed with clinical imaging and [inaudible 00:08:48] achieved a clinical complete response were offered a four-month adjuvant period of nivolumab instead of radical cystectomy. So the patients who achieved a complete response had to choose between a cystectomy and an adjuvant period of additional immunotherapy. So it's stunning to realize that the vast majority, almost all the patients of the 31 patients who achieved the complete response, actually decided to receive, to undergo immunotherapy [inaudible 00:09:22] of the treatment instead of receiving any radical cystectomy, meaning that patients are with us.

If we may provide them or suggest to them an intelligent approach within clinical trials that are aimed to avoid any potential, huge side effect from radical surgery or radical treatment of the bladder. So this is potentially a very important, note-worthy result in this study. The bad thing is that by avoiding any radical local therapy, radiotherapy, in particular, we may lose a substantial proportion of CRs because about 48% of CRs have been, clinical CRs, have been achieved in this study compared to 80% or 88% from the radiotherapy, chemoradiation, and immune radiation studies. So we definitely do lose something in the short term, but if you look at the long-term findings, so the bladder intact disease-free survival, which is the primary endpoint of this single-arm phase two study, the patients who achieved the CR actually at the one-year bladder intact disease-free survival, approximating 80%, the number is still pretty unstable because the follow-up is maturing.

But as a matter of fact, this type of proportion that is achieved is reported that the short term, which is note-worthy is because these patients actually avoided any side effects related to radiation. It's a potentially completely new strategy that may arise in [inaudible 00:10:59] near the potential questions related to the fact that this may be the next step because it would not be so easy to envision a future of randomized studies by choosing between this type of approach and the standard of care because here the standard of care is completely challenging in a totally different strategy. So it would be interesting to see also from the regulatory point to which would be the next step of this type of approach.

The other issue is related to the biomarkers. Of course, if we aim to raise the bar in avoiding any radical local therapy, we have to raise the bar, identifying reliable biomarkers and validating biomarkers in this context. Unfortunately from the Galsky study, we have the confirmation of the association between the ERCC tumor mutation and the complete response, clinical complete response, but it was not the case for others [inaudible 00:12:00] genes that have been reported by other authors to be associated with the benefit of cisplatin-based and neoadjuvant chemo. But it was not the case here. So in terms of biomarkers, we have to invest a bit more in order to have in our hands, something that could be consistent across studies. And then secondly, if this can be translated into real-world practice and maybe reliably associated with the benefit from treatment.

Alicia Morgans: So interesting and so important. I think, like you said, to really turn the treatment paradigm on its head.  How much toxicity do you really think that we are saving by emitting the radiation from this type of approach?

Andrea Necchi: Yeah, so this is an insightful question because actually, the toxicity, which is reported from the studies is very heterogeneous because in the UK studies, chemoradiation studies, reported the treatment that was in general, quite tolerable with minimal side effects.  We may have an issue related to their rate of salvage cystectomy based on local relapses or issues related to the surgical need for removing the bladder to the side effects of radiotherapy. So avoiding such a kind of exposure would be great for the patients. If we also consider the fact that we may have this small fraction of extra toxicity related to the additional immunotherapy then we may have to the standard chemotherapy. So it's a trade-off between the local side effects and systemic side effects.

My impression is that in general, as demonstrated also in the patient disposition within the Galsky study, patients would prefer to be exposed to a minimal risk of exposure to systemic therapy side effects, rather than being exposed to local side effects. It's of course, something that may be questionable, of course, that may be discussed with the patient. So patients should be the driver of this kind of decision, of course, in a multidisciplinary way. But of course, this type of approach may open up new doors and that may be our next decision, a third decision added to this surgery, and the radiotherapy options to provide to these patients. And this actually follows the path to other similar studies, like the RETAIN study that has already been presented earlier this year, that actually provided again, in selected patients achieving a complete response to standard chemo, observation alone, instead of any other therapy on the primary tumor. Of course, we need more, more follow-up time, longer follow-up time, but the impression is that we are on the right path.

Alicia Morgans: I couldn't agree more, but really that question I think will continue to be raised in my mind as we continue to see where this moves forward. When patients are faced with a decision between cystectomy and immunotherapy, I think that can be more clear than if they might have been offered a bladder-sparing radiation approach. Who knows? But I think that you hit the nail on the head when you said that we need to talk to the patients about it because, at the end of the day, it is their decision and their preferences. And we actually don't know what they are unless we ask. So thank you so much for discussing these abstracts and sharing your insights with us, incredibly helpful. We appreciate your expertise.

Andrea Necchi: Thank you for the invitation. Thank you. And thank you for your attention.