Dr. Alan H. Bryce, MD presented “Immunotherapeutic Agents in Metastatic Bladder Cancer” at the 26th Annual Perspectives in Urology: Point-Counterpoint, November 10, 2017 in Scottsdale, AZ

How to cite: Bryce, Alan H. “Immunotherapeutic Agents in Metastatic Bladder Cancer” November 10, 2017. Accessed Jun 2024. https://grandroundsinurology.com/Immunotherapeutic-Agents-in-Metastatic-Bladder-Cancer/


Dr. Alan H. Bryce, MD, discusses the use of immunotherapy for metastatic disease treatment, the proven survival benefit of certain immunotherapeutic drugs, and summarizes recent advances in immunotherapy as a whole.

Immunotherapeutic Agents in Metastatic Bladder Cancer


All right.  Thank you for having me.  As you heard, Dr. Castle and I coordinated a bit to try and make sure we weren’t overlapping too much but still cover the topic at hand.  You know, as you’ve already heard a lot has changed in advanced bladder cancer in recent years.  We went the better part of two decades without a new drug in this field and with little change in the management of advanced disease, and so I’ve been hearing a lot of talks over and over at national meetings about do more neoadjuvant therapy.  It’s the only thing we can do to move the dial, but happily, we’re in a new era in the treatment of advanced disease with these immunotherapeutic drugs.  It’s certainly significantly changed the management of advanced disease patients, and it remains to be seen how far that will take us, but I want to give you a broad overview of the new drugs that have come out, where they fit in, first, second-line therapy, and some of the practical issues surrounding their use.  

So we’ll talk about the clinical activity of immune checkpoint inhibitors in urothelial carcinoma, the efficacy and the potential toxicities of these therapies.  All right.  So we’ll start with our audience response questions.  Which of the following drugs have demonstrated an overall survival advantage in the second-line treatment of metastatic urothelial carcinoma.  Docetaxel, pemetrexed, paclitaxel, pembrolizumab, and bevacizumab.  

All right.  25 responses.  All right.  Looking good.  Let’s talk about this further.  What immunosuppressive ligand is expressed by bladder cancer cells in order to evade the immune system?  A bit more esoteric clearly.  

All right.  All right.  So this is the basic mechanism of action at play.  This is review of immunology 101 going back to medical school.  The beginning of the immune response starts in the lymphoid tissue when antigens are taken up by the antigen-presenting cells, complexed onto MHC class 1 and class 2 molecules, and then presented to the CD4 and CD8 T-cells present there in the lymphoid tissue.  The CD4 cells, remember, act more in a helper role producing cytokines to then stimulate the CD8 cells, and the CD8 cells are then responsible for migrating throughout the body, proliferating, and finding the offending pathogen, whether it be bacteria or whether we’re talking about a tumor.  Within the tumor micro-environment so the TME you see there on the right side of the slide, the CD8 cells should complex or recognize the tumor, begin the immune response with help from the TH4/CD4 cells with help from the macrophages, but part of what happens here, oh is this a laser pointer?  No.  So part of what happens here is while you have stimulation of the CD8 cells, you also have regulation of the immune response through the inhibitory or co-inhibitory molecules if you will.  So this is PD1, this is an inhibitory receptor on the surface of the CD8 T-cell.  PDL1 is the stimulator of inhibition, so ultimately what you have is the same time that stimulation of the immune response is happening here through MHC Class 1 and 2 inhibition is happening through PDL1, PD1 interaction, and this is why we don’t all dissolve into a pool of autoimmunity with every infection we get because the immune system gets appropriately shut down while at the same time that it’s being stimulated.  But what we find in tumors is that many of them will vastly over express PDL1, so even though the CD8 positive T-cells are being appropriately stimulated over here in the lymphoid tissue, when they migrate over to the tumor and they recognize the tumor, they are immediately strongly inhibited thus shutting down the immune response.  

So this goes back to that age old conversation.  For over a century research has gone on saying that the immune system should clear cancer, that cancer is a failure of the immune response and that the immune response should be the appropriate treatment for cancer.  

Why did it take 120+ years in order to come up with the first effective therapy?  Well, it—this is mechanism, right?  So the science underlying modern immunotherapy wasn’t accidental.  This was very  much modern laboratory science discovery of these inhibitory molecules first by our colleagues in Mayo Rochester in fact that allowed us to then design drugs to inhibit the inhibitory mechanism for the immune response.  So remove inhibition to activate the innate immune response.  

All right, so this was systemic therapy in 2015.  Right?  It was really simple.  First-line therapy, if you’re cisplatin eligible, you get cisplatin-based chemotherapy.  It could be gem/cis.  It could be MVAC.  If you’re ineligible, we might substitute taxanes or carboplatin, and in the second line there was no standard.  Everything up to this point, we had a variety of second-line drugs, right, the taxanes, pemetrexed what not, these are single-arm Phase 2 studies up until the modern check point inhibitors no drug had ever proven a survival advantage in a randomized clinical trial in the second line.  So this is all just limited small studies where we were looking at response rates, and so this really was clinical trials territory, and the median overall survival in these patients post first-line platinum is something on the order of 6 to 7 months, so very abysmal outcomes.

So here is the second-line data.  Again, these are small series.  I mean look we’re talking 14 patients, 30 patients, this is what second-line therapy was based on, response rates on the order of 7 to 27%, very poor.  So into this space, came this next generation of immunotherapeutic drugs.  And I’m going to just walk you through a handful of the studies, kind of giving equal treatment to each of the various drugs out there because there’s a lot of them now.  These antibodies are targeted to either PD1 or PDL1, right, so some of the two different halves of this interaction receptor and ligands because we’re talking about cell surface proteins in both case, either side of the interaction can be targeted, and there’s slight variations, theoretical perhaps in terms of the significance of targeting one side of that interaction or the other.  We walk through that, and the very first drug we saw with positive results with atezolizumab, so you might remember when this received its breakthrough designation by the FDA, and it was based on this study, a single-arm phase 2 study, 310 patients all of whom received atezolizumab.  They underwent tumor assessments with imaging every 9 weeks for 12 months and then every 12 weeks thereafter, and I took this picture from the phase 1 study, but it tells you the same thing.  This is just the example.  I mean you can see the retroperitoneal lymphadenopathy here, and a very impressive response.  So again immunotherapy not chemotherapy and this then is looking at the overall survival on an intent to treat basis based upon the staining for PDL1.

Now I’m going to walk through this for all of these studies, and what you’re going to find in a consistent theme is we all would like to think that it’s a very simple biomarker.  We’re talking about PDL1 expression on the tumor as a target.  Therefore IHC for PD1 ought to tell us who is going to respond and who is not going to respond, and you’re going to see that the results are very different drug by drug, and this is a theme that has been carried out throughout the various cancers that we’re treating with immunotherapy, lung cancer, melanoma, bladder cancer, head and neck, I mean on and on.  So what you see here is that patients who have the highest level of expression have the best progression free survival here and overall survival.  At 12 months, about 48% of patients are still alive if they strongly express PDL1.  Now, this is impressive.  Remember 6 to 7 months was what we expected from chemotherapy, so once we start getting close to a year we get pretty excited.  But even in the non-responders, you are looking at 6.5, 7 months, so equivalent of chemotherapy so even non-responders, even in the non-expressers, this is equivalent to chemotherapy.  

Now, in pembrolizumab we had the first randomized clinical trial.  So this is a Phase 3 of pembrolizumab versus chemotherapy and this data came out after the atezolizumab.  I’m kind of walking you through this chronologically.  Randomized clinical trial, 542 patients, again patients who had progressed after platinum or progressed on platinum therapy or after, generally defined as 12 months, and when you say 12 months you’re talking about actually people who did fairly well.  It was investigator’s choice chemotherapy because this was run in Europe and the U.S. and there was some disagreement about what the control chemotherapy should be, but here is the overall survival.  And so this is the only one of the drugs that has a clear overall survival advantage on a Phase 2 clinical trial, first randomized Phase 3 clinical trial with an overall survival advantage in the second-line setting, and here you see a clear overall survival advantage, pembrolizumab versus chemotherapy, but what I would have you pay attention to is this down here.  This is the progression-free survival curve, and this is a characteristic PFS curve for immunotherapy.  We see this over and over again in different malignancies, no separation early.  Okay.  Immunotherapy doesn’t have an immediate impact.  You have your immediate progressers.  You would think early on if you choose an arbitrary endpoint and you said we want median PFS well the median PFS here is hardly any different.  In fact it’s worse for immunotherapy although that’s not a meaningful separation.  But then what you end up with is late separation that then proves to be durable, okay, so you get a minority of patients who benefit and yet when they benefit the benefit is ongoing.  Okay?  So this is characteristic of immunotherapy, a minority benefit, and yet the duration of benefit is such that ultimately you end up with a meaningful advantage in overall survival.  So again one of the points we always have to emphasize is don’t pick arbitrary cut points.  We don’t talk about median overall survival.  We talk about hazard ratios because if you cut it off here, and you say that is what is significant, then you are missing this.  

All right, so nivolumab, here again single-arm Phase 2 study, another one of the PD1 inhibitors, so atezolizumab was PDL1, pembrolizumab/nivolumab either PD1 so the immune side of the interaction.  270 patients, again platinum refractory so second-line therapy, and here again what you see is an impressive overall survival, you know, going out to twelve months so here is your median.  It’s approaching something close to 12 months, again much better than what we expected from chemotherapy, but in this one what I’m showing you here is the separation based on expression of PDL1.  

Now, for nivolumab each company has their proprietary test.  For this test they choose an expression of 1% as their cut point.  Greater than 1% you have more durable, better overall survival.  If you have less than 1% it’s less but nevertheless, you look here and the 50% is still at least on part with what you would expect from chemotherapy.  And then durvalumab I’m sorry I think the reference I think is—the text is black so you can’t see it.  My bad there.  Durvalumab, so this is from ASCO GU.  This wasn’t yet in paper form.  It’s another one of these drugs targeting PDL1 and what this is is a waterfall plot.  So this is every patient treated.  Up means tumors grew.  Down means tumors shrunk, and you can see the inflection point for growth versus response is very impressive.  A majority of patients get some response.  One of the reasons you’re seeing more and more of these waterfall plots in oncology nowadays is because we recognize that when you talk about RECIST criteria and draw this arbitrary line for percent response, RECIST fails to express what is going on here.  Okay?  It’s not as if there is a difference, a clinical difference between a 29% reduction in tumor and a 31% reduction in tumor.  And drawing an arbitrary line at 30% really fails to express what is truly going on.  So this is why we are starting to get away from talking about true RECIST response rate and starting to look at things like waterfall plots.  They give you a real sense of every patient who was treated, and with durvalumab you see this familiar story, the patients who express more PDL1 have higher response rate.  These low expressers have a much lower response rate, but nevertheless, you still see responses.  It’s always an important part of the story with immunotherapy.  Even low responders you see some responses, and if you’re talking about a disease state where nothing else works and you’re out of options, you’re not going to deny your patient a chance at response, however, small even if there is no other—if there are no other options.  

All right, avelumab, and this is the last one of the five drugs I’m going to walk through, and then I’ll start comparing them a bit.  With avelumab it’s a Phase 1B, 44-patient study so this drug is behind the others in terms of development.  You see an objective response rate, 18%.  We’ll compare this in a bit, but durability so 75% of responders still responding at six months.  Disease control rate, that is that inflection point on the waterfall plot about 52%.  So here is what we end up with.  We look at these five drugs, all of them with positive results, all of them  making their way into the guidelines, and you see this overall response rate hovers somewhere around 20%.  This is the RECIST response rate, that arbitrary cut point, not terribly impressive, but nevertheless better than what we saw with chemotherapy.  You compare high expression of PDL1 to low, and across the board you always do a little better when you have higher expression except here with pembrolizumab where it doesn’t seem to have mattered.  Each of these drugs uses a different assay, the proprietary assay of the company, and you just can’t compare assay to assay.  You have no idea how to compare these results.  Median overall survival again more impressive than what you would expect with chemotherapy, but keeping in mind, I mean the bigger studies have lower overall survival than the lower ones, and this isn’t surprising, right?  These smaller studies are phase 1 studies, and happens on Phase 1 the oncologist is much more careful what patients you pick.  It’s all patient selection.  Phase 1, first in man studies.  You haven’t treated patients before.  You don’t know how it is going to go.  So these tend to be healthier patients on these studies than you see on larger randomized trials or 2, 3, 400-patient studies.  

Response kinetics, as I was getting at in that PFS graph we were looking at earlier is an important point to keep in mind here, so I have the—what we call swimmer’s plots from two of the drugs.  So the swimmer’s plot is again you have each of the patients, and we—the analogy here is this is a swimmer in their swim lane.  Okay?  This line represents a patient on a drug, here pembrolizumab, here the chemotherapy on the control arm, arrows at the end mean the patient is still on the drug at the data cut point.  X’s at the end means the patient has progressed and come off drug.  The yellow dot tells you when response was first detected, so radiographic RECIST response, and what I would have you get out of this is multiple things.  One, the median time to response is somewhere around ten weeks or nine weeks in this study, nine weeks is when they did the imaging.  Very few patients are going to respond earlier, and that’s because very few patients have disease assessed earlier than that.  But what shouldn’t be missed is that some of the responses are happening out here at six months, and when you compare the chemotherapy to immunotherapy, here again you see that there is a much larger proportion of responses that come very late in the disease course.  With chemotherapy you know pretty quick.  You know by that 9, 10-week mark if the patient is responding or not whereas with immunotherapy you are not sure.  In fact, a common phenomenon we see with immunotherapy is sometimes the tumors get a little bit bigger at that first scan here at nine weeks and then subsequently shrink, and we can wave our hands with explanations of this.  We don’t think it’s flare.  We really talk about this as inflammation, right?  You induce an immune response.  I mean what happens when you have an infection anywhere in the body of an immune response you get swelling, you get engorgement.  Right?  We think that is what is happening in the tumors, and then you get these patients who respond much later.  So of course that makes interpretation of response much more difficult.  How do you know who is responding versus who is pseudo-progressing, as we call it.  The other thing to take out of this is look how many patients are still on therapy, all of these yellow arrows, ongoing therapy more than 12 months out.  Chemotherapy cannot be tolerated for 12 months.  These regimens that we talk about for these bladder cancer patients, this is not something that people can stay on.  Remember pembrolizumab is the same drug that President Carter got for his melanoma.  He was a very frail 90-year-old man.  You remember seeing those news press conferences with him.

Immunotherapy is something that can be given to very poor performance status patients because the toxicities are very mild for most patients and manageable, and I’ll get into that a bit here.  

So durability of response, and that is what I was showing you with the swimmer’s plot.  For those patients who are responding, patients responding more than six months is greater than 75%, and in fact patients responding more than 12 months for some of these drugs where the data is going on longer is still exceeding two-thirds.  This is durable response.  What we don’t know is how long that response will go on, you know, the very first tumor that was treated with immunotherapy, the first positive clinical trial with immunotherapy if you exclude allogeneic stem cell transplant would be ipilimumab in melanoma.  Remember melanoma was a terrible disease not very long ago with no effective treatments, and with ipilimumab we now have 10-year survival data showing that over 20% of patients who receive ipilimumab are still disease free at ten years.  I would call that cure.  Okay, ten years disease free is cure.  We have no idea yet if that is going to translate into bladder cancer.  In lung cancer, we haven’t seen it.  In kidney cancer, not so much.  Go tumor by tumor and the durability response is different.  But I will tell you that bladder cancer is tracking better than most of those other malignancies.  It’s not quite at the melanoma level, but it is looking that way.  So there’s reason for optimism.  How many patients are still going to be responding at two years, at three years, at five years?  We don’t know yet, and only time will tell, but again there’s reason for optimism here that we certainly didn’t have just two years ago.  

Biomarkers for response, a variety of things have been looked at, and I don’t think we need to delve into this too deeply, but there are a lot of different biomarkers you can look at.  You can look at the PDL1 expression.  We can look at the tumor mutational signature.  Amongst all of the various cancers, bladder cancer ranks fairly high on the total mutational burden.  Remember being a smoking related malignancy, the mutational rate is quite high, the highest amongst all cancers, melanoma, and then lung cancer and bladder cancer are fairly high up there.  Head and neck is also up there, and in theory having a higher mutational burden should connote a higher response to immunotherapy, and when we think about this as being a probabilistic phenomenon. The more mutations you have, the more neoantigens you have, the higher the chance the immune system has to respond to therapy.  

Well, we can dig deeper into that and really talk about sub-types of bladder cancer.  The TCGA’s data set has this for example.  Luminal one type versus luminal two versus basal, and we start looking at this and we see perhaps luminal two has the higher response rate.  We see that in the Atezo data.  The nivo data looks at the interferon signature that’s familiar form other studies, chemokine signatures certainly might have some significance, but none of these are definitive yet.  So ultimately none of these need to be tested or evaluated before prescribing therapy for a patient.  

Median time to response, as I was talking about, 2 to 3 months, we recommend first imaging, depending upon the timing of the cycles, 9 to 11 weeks into treatment, and patients can continue to receive medication even if they progress initially because of this phenomenon of pseudo progression.  We don’t want to miss it keeping in mind in the second line you don’t have anything to do in the third-line.  I think you can see this, the toxicity profile, this is just from one of the drugs.  This is atezolizumab, but generally it’s fairly similar amongst all of the drugs.  But I’m not going to walk through all of them.  Grade 3/4 toxicity rate is about 16%.  Remember Grade 3 is when intervention is required, some kind of therapy, some kind of management of the toxicity.  Grade 4 generally you are thinking about hospitalized patients.  

Fatigue is the most common toxicity.  Fatigue, of course, in an advanced cancer patient is expected.  Rash, we see generally manageable, nothing too dramatic, some nausea, some decreased appetite, again these are very mild, not Grade 3/4.  The toxicities we worry about pneumonitis, so autoimmune inflammation of the lungs leading to dry cough, perhaps shortness of breath.  This can be an issue in patients who have pre-existing lung disease, or for example patients who have pre-existing interstitial lung disease, which has an autoimmune etiology and thus can be exacerbated by being on immunotherapy.  Autoimmune colitis causing diarrhea, not nearly as bad as what we used to see with ipilimumab, generally again very manageable.  The Grade 3/4 rate is very low.  Arthralgias, myalgias, neuropathies, almost any autoimmune disease you can think of can manifest, and as a general rules if your patient has an autoimmune disease going into this process, it will get work, it does affect whatever is innately already going on in the patient.  

But here is what we are looking at.  Overall Grade 3/4 toxicity rate somewhere in the order of 5 to 15, 16%.  This is why these therapies are very manageable and realistic even for the oldest kind of frailest patients.  

So this is systemic therapy in 2017.  It’s a very landscape than what we had.  I just showed you some of the studies.  I didn’t show you the first-line studies, but atezolizumab and pembrolizumab are now recommended by guidelines in the first-line setting as well.  When we say platinum refractory second-line, we’re also including patients who had neoadjuvant therapy and progressed within the first 12 months post-neoadjuvant therapy.  And in the second-line setting then you have five different drugs, which can potentially be used as well as then the traditional chemotherapeutics that we’re well familiar with.

Thank you.