The Uromigos Episode 106: Summary of the 3 Cystectomy-Sparing Neoadjuvant Trials at ASCO 2021

The Uromigos and Andrea Necchi examine 3 interesting neoadjuvant IO-based phase 2 trials and whether this approach can avoid cystectomy in a subgroup of patients as well as the path moving forward.

Study 1 discussed: Phase 2 trial of gemcitabine, cisplatin, plus nivolumab with selective bladder sparing in patients with muscle- invasive bladder cancer (MIBC): HCRN GU 16-257 (GALSKY)

Study 2 discussed: Pembrolizumab (pembro) in combination with gemcitabine (Gem) and concurrent hypofractionated radiation therapy (RT) as bladder sparing treatment for muscle-invasive urothelial cancer of the bladder (MIBC) (BALAR)

Study 3 discussed: Phase II trial of durvalumab plus tremelimumab with concurrent radiotherapy (RT) in patients (pts) with localized muscle invasive bladder cancer (MIBC) treated with a selective bladder preservation approach: IMMUNOPRESERVE-SOGUG trial.

Episode Transcript

Brian:
Hey, welcome everyone to another year, Uromigos ASCO podcast. We’re proud to be joined today by Andrea Necchi, bladder cancer expert from Italy. And we’re going to have Andrea, I’m going to have you introduce yourself and then I’m going to actually turn it to Tom for a brief summary of these three-bladder sparing, immunotherapy abstracts. So, if you want to go ahead and introduce yourself, that’d be great.

Andrea Necchi:
Thank you. Thank you, Brian. And thank you, Tom. It’s exciting be here and thank you for the invitation. I’m Andrea Necchi, I’m a medical oncologist and director of geomedical oncologist [inaudible 00:00:49] and Associate Professor of Oncology at Vita-Salute San Raffaele in Milan, Italy.

Tom:
Andrea, thank you for joining us and firstly it’s a real pleasure for you to be here. Brian and I have been tracking your work and it’s fantastic that you’re able to join us. ASCO’s coming up and you are summarizing these three abstracts, you know, as much as anybody else in the world does about neoadjuvant immunotherapy with your pure one trial.

In the trials that you and I did we gave neoadjuvant therapy and then we performed a Cystectomy, these three studies are doing something slightly different in that they’re giving neoadjuvant therapy with immunotherapy, but they’re either pursuing a completely bladder sparing approach or they’re then giving chemo radiation.

The first trial was Matt Gowski study, where he gave chemotherapy, which was [inaudible 00:01:45] platinum-based chemotherapy with nivolumab and he didn’t perform, or his group didn’t perform surgery. And those patients that had a CR by cystoscopy, those patients their relapse-free survival at about a year was 78%. So, essentially what he was showing was that you can observe a group, or it looks like you might be able to observe a group of patients without surgery. So that was number one.

The second trial was Arjun Balar study. And what he did was he used chemo immunoradiation. So, triplet therapy plus immunotherapy instead of cystectomy, and he showed one year disease free survival rates of 77%. And then the third group from Spain gave durva treme and radiation therapy as essentially a triplet. There was an immune, there was a neoadjuvant period, of course, and again, they showed a six-month disease-free survival level of about 76%.

So, the follow ups short, but the outcome data looks pretty good. The relapse data looks pretty good. Andrea, you’ve looked into this in much more detail than I have. What do you make of these three abstracts? Which ones do you like and what are the strengths and the weaknesses and where do we go next?

Andrea Necchi:
Thank you, Tom, so, as you said, these are three outstanding abstracts that may open the door to a new avenue potentially of bladder cancer research or in the future, a clinical practice, perhaps. Let’s start first comparing the studies where using radiotherapy combined with immunotherapy or chemoradiotherapy, combined with immunotherapy.

There are key difference in the features between the two studies, because in the Balar study, we have the role of, and the use of chemotherapy, which inside have been together with the radiation, which was completely circumvented by the Spanish study, which combined immunotherapy alone, the combination of immunotherapy with the radiation, we have the use of hypofractionation in the blood study while standard fractionation was used in the immunopreserve study. The two studies actually lack any adjuvant period.

So, these are studies which are exclusively concerned on the [inaudible 00:04:15] radiation approach I would say there is a key role which is still pending of biomarkers to select patients more and more deeply.

But what is most important is the first view to me is the need to harmonize definition of the endpoints, the clinical endpoint, because if we look at these two abstracts and the two studies, and we will look later on at the Gasky study, we have definitions of complete responses, clinical complete responses that are not completely overlapping because in the Balar study, we have the definition, which is quite conservative.

So, the lack of any viable cell in the cystoscopy and biopsy after treatment, including any non-muscle invasive disease, while in the Spanish study, CR was defined a breed in a way more broadly, by including the non-muscle invasive residual disease, this may raise some bias when we’re looking at the results. And in the Gasky study, we have the consideration of residual low grade non-infiltrating disease to be associated or to be considered as a complete response.

Andrea Necchi:
So, this is my first take from this.

Brian:
Andrea, can I interrupt and ask? What do you think is the right definition?

Andrea Necchi:
Actually, the answer is we don’t know. We need prospective validation potentially in randomized studies, but it’s striking to realize that we are struggling against, so many times, against the issue of tissue biomarkers to mobile markers of [inaudible 00:06:07] to mobile markers. But actually, we lack a clear definition, a clean definition of a clinical endpoint, especially in these particular studies that avoid the voice surgery. So, we lack the pathologic computer response definition, which is the only, let’s say validated biomarker surrogate endpoint for survival.

Brian:
I mean, in some ways what you care about is bladder preservation here. So, including non-muscle invasive may not be a bad thing. You don’t necessarily care if patients recur with non-muscle invasive disease.

Andrea Necchi:
Exactly, exactly. And also if we look at the survival endpoints again, we have and if we look at the survival endpoint across the studies, also, including the study that we published with the chemo radiation, we have a very high [inaudible 00:07:05] in the definition and use of endpoints, because in these studies, we use the bladder intact disease pre-survival definition, which is not completely overlapping to the endpoint of a local regional disease control, like in the UK radiotherapy studies or other definition, like more general disease for survival definition of other studies. So also, when looking at the survival endpoints we clearly have the need for [inaudible] of endpoints. This is the first week.

Tom:
Andrea, so the next piece, I guess, is that you managed to show with just single agent pembrolizumab and three cycles, a path CR rate in the region of 40%, and then of course you then perform cystectomy and the data for the neoadjuvant trials followed by surgery shows disease free survival, or relapse free survival in the rate of about 80%.

Andrea Necchi:
Yeah.

Tom:
How does the data that you look in front of you with these three abstracts compare to that? Are number one, these more aggressive patients, number two, is, are relapses occurring more frequently?

Andrea Necchi:
Yeah. Your point is very well taken. Actually, we don’t know which may be the contribution of short course, neoadjuvant immunotherapy means two or three courses on neoadjuvant immunotherapy. So, what is actually the role of maintenance of adjuvant period of immunotherapy like [inaudible 00:08:44] did after the achievement of a computer response with the chemo immunotherapy, with the maintenance, with the tail of, of adjuvant and [inaudible 00:08:55] period that actually the early studies in the preoperative approach you are using immunotherapy, where I’ve moved in the post-direction.

So, in a direction of limiting the number of immunotherapies, actually based on the short follow up that is already achieved with all of these studies, the data seem to be overlapping in terms of the anticipated or planned, or projected survival outcomes. I mean, progression for survival or event for survival or overall survival.

Tom:
How do these compare to let’s go back three or four, four years in time, or standard of care. Let’s look at cystectomy alone or neoadjuvant chemotherapy and cystectomy, how do these approaches, and I’m not talking about standard of care, this isn’t going to be adopted yet, and we’ve got to do randomized trials, but in terms of, is this data promising enough to perform randomized trials?

Let’s talk about the radiation studies first. And if that was the case, which combination looks most promising in your mind, is it the immune combination? Is it the chemo combination or is it that triplet cell therapy that Arjun Balar disputed.

Andrea Necchi:
Yeah, if we look our focus is on exclusively on the survival endpoints, it’s difficult to envision a tracking difference between the studies, but there are one, or there are features in the current studies, in the immune radiation or in the Gaski study that actually define the studies as potentially unique. And the studies that may provide the strategy that may change the way we conceive the entire treatment of the entire management I will say of these patients. If you look at for example, the Gaski, the Gaski data, we have the complete response by avoiding any radical local therapy on the primary bladder tumor is substantially lower.

Tom:
Andrea, can we come to that in a second, before we get there, could you try and address the issue about which of the radiation regimes you would take forward in a randomized trial? So, let’s just focus on those two studies. One’s used immune combination therapy. The other one’s gone with chemo immune combination. Is there, do you have anything? And they’ve used slightly different radiation protocols. If you had to write a randomized phase three radiation trial tomorrow, which would you take forward and why?

Andrea? Brian, are you there? Oh, well, it looks like Andrea has got a bit confused by that question, or he just is opposed to it more likely. Should we see if he comes back?

Brian:
Yeah, it says connected, but I don’t, I don’t know if he’s there.

Tom:
Andrea, you might be on mute.

There he is. There’s not a mute. Remember my airport sounds? Oh, he dropped off. Let’s see if he comes back.

Brian:
Hey, Tom. Remember, let me just follow up to your question. The chemo in Arjun’s study was just low dose gem with radiation. So, it wasn’t real chemo, if you will. It wasn’t.

Tom:
No, it was plastic triplet therapy.

Brian:
Let me ask you a question while he hopefully reconnects, do you think let’s figure out whatever the most promising regimen is? Whatever his answer is, is a randomized trial possible? Can you randomize patients?

Tom:
We tried to do this in the UK of a study called the spare study, which Rob Hadar was involved with. I’m sure there are a number of other people, but, and I can remember the exact details of who, but it was a UK study and we did this, but we overcomplicated it a bit because we said at the end of treatment, there was a round, you had to look for path CR and you didn’t include these.

And it’s a really complicated issue, and it may not be possible to do a randomized trial in this space. The challenge that we have is that we don’t have that many randomized surgical trials. We’ve just established it as the standard of care.

But the really important issue is that if you are going to give chemo rad, you are going to have to follow those patients up from a bladder perspective for a long period of time with cystoscopies and checking.

And if your disease, or if your local relapse rate is relatively high and your disease-free survival is a bit wobbly. And I use wobbly and mean that there are relapses occurring. Inevitably people will join the two together and say that you haven’t really solved the problem.

So, I think the results would have to be really impressive, but actually when you look at these two data sets and our follow ups only 12 months, but we are getting to a 12-month period where you are looking at it and saying, well, about 80% of patients haven’t relapsed at that period. If that plateau occurs from there, this becomes a really attractive approach.

One of the questions is whether the immune therapy and radiation therapy is synergistic to one another. And we haven’t really managed to answer that question.

Andrea Necchi:
Do you hear me again?

Tom:
Yeah. We hear.

Andrea Necchi:
I’m sorry. I don’t know what happened, actually.

Tom:
I think you just went away to look, to do some swatting up on my question. We’ve seen that technique before Andrea.

Brian:
Okay. So, Tom was asking which immune-based regimen would you move forward in a randomized trial. Right.

Andrea Necchi:
Okay. So, it’s difficult to say based on the available data, because the data from studies that combined [inaudible 00:14:59] four antibody with anti-PD one or PD one antibody are likely in line with those involving use of anti PD one, or PD one [inaudible 00:15:10]. And it’s actually this observation is rather confirmed in these studies, because if we look at some kind of comparison between the Balar and the immuno service study, the rate of concrete responses is similar, is around 80%. And it’s the same for bladder intact survival outcomes.

So, it’s really difficult to say also because there is a [inaudible 00:15:43] in the patient population across studies, there might be with a node, but there might be [inaudible 00:15:48] in the biomarkers. So, I think that based on the data that we have so far limiting the exposure or potential extra toxicity of immunotherapy by using combination immunotherapy. So, using single Arjun therapy may be one of the most suitable strategies in this case.

Brian:
I was asking when your away about whether a randomized trial is even possible or necessary, or is it similar to say pembro and non-muscle-invasive disease where you could just do a big single arm study? You could show reasonable results and CR rates and avoidance of cystectomy. And that might be enough let’s put the regulatory issues aside.

But would a big single arm study with adequate follow-up because you know, cystectomy versus not is a big deal. So, it’s almost a little bit of apples and oranges in terms of a randomized trial. Like, could you just do a big single arm trial, and would that be adequate?

Andrea Necchi:
Well, I think that the best answer to your question, really insightful is the patient distribution in the Gaski study, because in the Gaski study to achieve the clinical CR had to choose between cystectomy or a strategy avoiding cystectomy.

So, the possibility of [inaudible 00:17:09] four months and 30 patients out of 31 decided actually to avoid cystectomy and accepted to receive [inaudible 00:17:20] but what does it mean, this actually mean that if you provide the patients with an intelligence strategy, they may circumvent the major issues in the treatment of the muscle invasive cancer.

So, cisplatin-based chemotherapy, radiotherapy, radical surgery, patients are with us and follow this strategy, if they’re promising this is just to say that this probably randomized studies probably needed from the regulatory perspective.

But I fully agree with the observation that in special cases or in trials in designs, like in very particular designs, like in the Gaski study, we may try as much as possible to circumvent the limitations of a randomized study, because I suspect the randomized studies will be very hard to be proposed to the patients.

And the vast majority of patients will ask you to receive something different from let’s say the so-called standard of care arm. This is an issue that is already on, this is already in line in front of us in the randomized study, in this cisplatin eligible patients. So, when we have to randomize against radio cystectomy, and this might be even more an issue with this type of studies, like the Gaski one.

Tom:
Sorry, Andrea key question. From a biomarker perspective, there was some work done, all three trials. Is there any consistency around the PDL one biomarker? And is there any biomarker associated with response to radiation specifically?

Andrea Necchi:
I think that the data that are available also from the presented study are still not so consistent to envision a future or potential application of these, but two more associated biomarkers in routine practice. I think that in this clinical setting, the most promising biomarker is the one that you presented from the [inaudible 00:19:42] study.

So, I think that overall, for perioperative studies, and this may be the case also for immunoradiation studies, looking at the CTDNA clearance after an induction period or after radiotherapy also would be very, very promising.

If the data that you presented from [inaudible 00:20:10] would be confirmed in different clinical settings. But tissue rate Biomarkers also have been reported to be quite inconsistent also in the same patients and may change.

There is a shifting landscape of gene expression, for example, between pre and post therapy. And so, things may change why not treatment? So, in an interpatient, in an interpatient perspective, they seem to be very inconsistent.

Tom:
Brian, quick question from you. Final one from me, we’ll call it a day.

Brian:
Yeah. I just have one more. Does it worry you in Matt’s study, there was a nodal recurrence, in Arjun’s there was four distant recurrences in the Sogo study, there was a toxic death. Do those worry you, or is avoidance of cystectomy such a powerful driver that you’re willing to accept the chance that these patients might recur, distantly, et cetera?

Andrea Necchi:
Yeah, it’s another good question. Because the data from radiotherapy studies actually would favor the use of the bladder intact disease, free survival. If you consider within this definition, any the survival free of any muscle invasive recurrence or local regional recurrence or recurrence to the notes, the number of the proportion of patients who actually recur outside of the therapy field that is not so high.

So, one could say, okay, this may be a good surrogate for survival. But again, as I said, we don’t know which is the weight for the association with the overall survival, of course there is an issue of the risk of losing patients while avoiding any radical local therapy.

But I think that overall, if we also look at the data from similar studies that have been just released, like the retained study, which provided chemotherapy alone and not chemo immunotherapy with the similar strategy in patients that have achieved the CR who were subjected to observation alone, instead of any further treatment, the data in terms of metastasis free in that case, or disease-free survival more in general seem to be promising.

Also, you can also consider that also patients that well operated, that achieved the pathologic concrete response about 10% of them actually have recurrence in the follow up time. So, it’s not a 100% curative solution, the cystectomy. So, I think that based on the very early data, there seem to be a good safety to move forward with this strategy.

Tom:
Andrea what do you need to see? Let’s make the assumption you’ve said to me, us today that you, you like the single agent triplet, so immune therapy, yeah. Pembro chemo, trimodality therapy, essentially. What do you need to see before you would consider adopting this as a standard of care? Not for all of your patients, but for some of your patients. What do you need to see?

Andrea Necchi:
In this case. So, in this type of studies, we desperately need randomized studies because if you look at the Balar data, in terms of CR, these are pretty much in line with another similar study conducted in the UK, using fractional radiotherapy with [inaudible 00:24:03] and then the CR rate in this study, which was published by [inaudible 00:24:08] colleagues, was 88%.

But if you also look at the survival outcomes from the radiotherapy status, immunoradiotherapy studies and compare them with the local regional, the control rate, for example, from the Pivotal BC 2001 study from Nick James, survivors look quite similar, or the curves are quite close to the chemo radiation study, meaning that the contribution long term of an additional drug or different drug like immunotherapy is still to be dissected and discerned, and this should necessarily be done within a randomized study.

Tom:
A randomized trial with radiotherapy dissecting out whether immune therapy really helps. Andrea, that’s fantastic. This has been really, really interesting, Andrea, and I’ve got to tell you, the break at half time really helped and we should do that more often.

Brian:
We regrouped.

Tom:
It really allows me and Brian to regroup on our questioning, which is very helpful. Andrea, this has been fantastic. I can see you, obviously, you’ve given this a huge amount of thought. I totally agree that it’s an area that’s developing fast and I hope that you and I can meet and talk about it in more detail very soon.

Andrea Necchi:
Thank you. Thank you. Thank you both for your kind invitation. It was really a pleasure and looking forward to the discussion during the ASCO meeting.