Advanced Bladder Cancer Clinic: Are you Ready? - Neal Shore
December 18, 2019
Neal Shore, MD, Medical Director for the Carolina Urologic Research Center, Myrtle Beach, South Carolina, USA.
Gordon Brown, DO
Tom Jayram, MD
Neal Shore: So, once again, it's a pleasure for me to do the presentation today. Which, unfortunately, a really good friend, Noah Hahn was unable to make it. So, I put together the presentation. And I just wanted to say this is on an advanced bladder cancer clinic. We have as the title, "Are You Ready?", and I'm telling you, you have to be ready. And I'm going to make the case for you today that you have advanced prostate cancer clinics, now's the time to be developing your advanced bladder cancer clinic.
So, just as an overview, what we see here in the stippled rectangular box is there's been a tremendous amount of advancement in frontline metastatic bladder cancer. Where there was typically, we had platinum-based therapies, whether it was MVAC, Dose Dense MVAC, gemcitabine, and cisplatinum. And then, we had a real lack of a paucity for second-line therapy. Well, then the big thing that really changed so much is our understanding of immune checkpoint blockade in cancer. And it's a little bit of a busy slide, but essentially, what you're able to see is understanding the receptors, the programmed cell death PD receptor and PD ligand that stimulates the receptor. Now, these can be present both on the immune cell and then on the T cell. And you see to the far right here are what we describe as these checkpoint inhibitors or CPIs and they have an anti-PD-1 direct receptor blocker. And that would be drugs that you've heard of such as nivolumab and pembrolizumab. And the ligand blockers are atezolizumab, avelumab, and durvalumab.
So, I want to quickly go over the frontline for advanced because I think the wheelhouse ultimately are in three different categories for uro-oncologists. So essentially we had five drugs that got approved based upon these really well done global Phase III trials, which showed the value of both progression-free survival and survival benefit in these five drugs that are out there today. And ultimately we looked at combinations and trying to update and some studies trying to understand, "Well what about for patients who would be platinum ineligible?". And one of the things that came out of this was an FDA alert about a little over a year and a half ago was the importance of doing what's called immunohistochemistry or IHC testing for PD-L1, which is not a difficult test to get. It's fairly routinely done in pathology centers and academic centers, but you can outsource this in your own labs, it's not expensive to do.
Why is this important? Because, ultimately it was found that it's not really all-comers that necessarily benefit from immuno-oncologic therapy with PD blockers, it's about 25% to 30% of the patients. Now that may be perceived as bad news, the good news is what people describe as the tail of the curve. There are some patients who have sensational responses in a disease that heretofore once you progressed on frontline first-line metastatic platinum-based therapy you were looking at a three to six-month survival.
So here's just one of the particular studies showing objective response rates based upon complete and partial responses. But what's particularly interesting is this tail of the curve in a particularly virulent disease of metastatic urothelial cell carcinoma. So let's move quickly over into where urologists would say, "Okay, well, advanced bladder cancer patients, they're elderly, they're smokers, oftentimes they're heavy drinkers, they have multiple other comorbidities." Well, just like in advanced prostate cancer, when we take a therapy that is done so well in a very end-stage patients, multiple lines of therapy, how could it benefit moving it up?
So let's think about where some of those examples could be. And you see over there non-muscle invasive bladder cancer. I'm going to talk about patients who have high-risk, non-muscle invasive bladder cancer who have failed or what we describe now as being BCG unresponsive. And we'll talk about trimodal bladder sparing strategies, inclusive of aggressive TURBT, chemoradiation and possible use of an oncologic therapy as well as also in neoadjuvant therapy as well. So these are things that should become particularly interesting to you. But before we get to that, let's talk quickly about intravesical therapies that are basically going to come out fairly soon. We have traditional drugs that we've used that have really been not particularly helpful in patients who have failed multiple courses of BCG induction and second courses of induction and or induction and maintenance. And you see the list here we have valrubicin, which is basically of limited value at 8% response rate at one year's time.
One trial that's gotten a lot of attention, it's up now for potential FDA review is the Keynote-057 study and it's based upon looking at cohorts, the larger cohort was the patient cohort A was CIS primarily, and the cohort B, which was a non-CIS cohort. And essentially these are just open-label study patients receiving pembrolizumab, a PD receptor blocker, also known as KEYTRUDA®, you may know by that name, given 200 milligrams intravenously every three weeks and looking at response rates. Well, the original initial data that was presented by Arjun Balar at ASCO essentially showed a really, a very impressive 40% complete response. 40% complete response rate in patients are BCG unresponsive, high-risk, non-muscle invasive bladder cancer. A recent update at ESMO shows that as you would expect six month, nine month, 12 month about 50% of those, roughly of those initial 40% responders were responding at 12 months.
So there have been, you know, so there are now just to so you understand this, there are numerous trials. The Keynote-676 is a Phase III trial with a similar BCG unresponsive theme looking at pembrolizumab in a Phase III trial. The POTOMAC not being done in the United States is in the BCG-naïve population comparing traditional BCG induction and maintenance versus durvalumab with BCG or durvalumab in combination with BCG. ALBAN, you can see in for purposes of time, is also being looked at with atezolizumab versus BCG alone.
We have another study that we presented and published in JCO just a year ago, which was in conjunction with the SUO CTC. Looking at intravesical, what we call INSTILADRIN® at that time, it's now changed to the FDA corrected it to Adstiladrin and essentially what this is, it's an adenoviral delivery of an interferon alpha-2B, a gene where essentially as you can read through the mechanisms of action here, but essentially given intravesically, incorporating into the cell milieu and basically creating a sort of a bio-reactor within the urothelium to dramatically increase interferon production within the bladder wall. So our Phase III data basically showed a 12 month CR of 35% in a population essentially of CIS patients. There was a smaller population, it was TAG-3 and T-1 disease as well.
So based upon that trial, we subsequently went to a Phase III trial, the results of that will be presented by Collin Dinney at the SUO in approximately one month's time. So there could, and that the dosing schedule for that drug is given once every three months. So very favorable dosing schedule. Here's a busy slide, but this is the VISTA trial and this was for another intravesical therapy known as Vicinium™. And essentially I'll let you kind of read through this fairly quickly and again you'll get copies of all the slides, this drug works and through dual mechanisms of action, it's a fusion protein given intravascularly. The schedule is a bit more rigorous, it's given like every two weeks for the first six weeks and then weekly for six weeks and then monthly thereafter over a 12 month period.
The take-home here was looking at again the same sort of BCG unresponsive CIS populations as well TAG-3 high-grade papillary and T-1 disease, seeing a response rate as you see in the, on the lower bottom in the purple box of about 17%. So certainly markedly better than the 8% rates of response that you've seen with valrubicin.
So what we now will have in front of the FDA within the next year will potentially be two intravesical agents and an immuno-oncologic agent for our patients with BCG unresponsive disease. So what about immunotherapy in the neoadjuvant setting? Well, we know that platinum, if you look to the far left data published by Bart Grossman some while ago, we know that platinum-based therapy is a marked benefit in a neoadjuvant setting to patients who have T-2 and higher disease pending radical cystectomy.
What you'll see here are two particularly important studies. They were Phase II and also presented at ASCO previously, the PURE-01 and the ABACUS. The take-home and these are patients who are felt to be platinum and eligible, they had T-2 or higher grade disease, it was all-comers, not based upon their IHC PD-L1 status and the rectangular boxes essentially showing you a pathological CR with given either three doses of pembrolizumab or in what the other trial was, two doses of atezolizumab. So not huge numbers, but really interesting and compelling signal for the benefit of giving IO therapy. So important to recognize that because now that we have numerous other Phase III trials that are looking at similar combinations of chemotherapy with IOs, chemotherapy alone, and you can see them outlined here as well.
So here's an area that I'm particularly excited about and in other parts of the world, the notion of bladder sparing surgery rather than going to cystectomy. And we all know that less than 5% of patients really want to have their bladders removed unless they have marked bladder dysfunctionality. So what can we do to help these patients? Well, here's a study that has been being done currently and this is essentially looking at, as I said, patients with T-2 or higher disease as a Phase II study. This was also reported by Arjun Balar, previously they get pembrolizumab. A maximal TURBT is another way of saying really go aggressive. It's okay to see fat and have perforations. And then with a radiation treatment, and this was done with gemcitabine. But what now has this is led to is this Phase III trial using atezolizumab through the Alliance and essentially chemoradiation plus or minus atezolizumab. There's another trial that's also being scheduled very, very similarly, maximal TURBT, chemoradiation plus-minus pembrolizumab. And I think these are particularly compelling.
So, in summary, one can see that the anti-PD-1 or PD-L1 checkpoints have really revolutionized bladder cancer management, certainly in frontline disease for metastatic, for patients who are ineligible for platinum-based therapy. Clearly their approval in second-line therapy as well. So we have lots of different questions have emerged from these different populations based upon their PD marker status and there are a lot of different novel combinations that are ongoing. But I think the most significant impact is yet to come and that's in the early stage disease going from neoadjuvant possibilities to trimodal bladder sparing and high-risk non-muscle invasive bladder.
So you say, okay, well what about the practical considerations? Are these just going to be too toxic for us to handle? Well, I would say yes they are if you're not really dedicated to this, but I think most of you in this audience probably are dedicated to having an advanced prostate cancer clinic and at first, there was probably some daunting possibilities and barriers to entry, largely being around AE management and monitoring.
So immune-related adverse events. Essentially people describe it as if the lymphatic system goes there, which it goes everywhere, you can have an "-itis" and they can be kind of scary from an encephalitis to a pancreatitis to a hypophysitis, become panhypopit, et cetera. But the more common ones are really just the big three, which is you can get some pneumonitis, colitis and dermatitis. The rest of these all can occur but you have to be vigilant in terms of your patient education, your nursing education as well as your monitoring. So here is just a list of an of some of the adverse events that we're seeing in this trial that was published by Joaquim Bellmunt and essentially looking at 266 patients and you can see the grade three, four, fives albeit were relatively low, but they can occur and thus there has to be vigilance and one has to be cognizant of how they can occur. The any grades as you can see can occur as well. And as I said, they're typically usually are surrounding skin, lung and GI. You can see some issues around the thyroid that needs to be monitored as well.
So what's the principles for managing these? Well recognition education, letting patients know up front that these can happen and then it really is pretty kind of "cookbookish" to a degree if I can say that appropriately. Hold and start steroids for lower grade and your degree in aggressiveness is with the steroid infusion can really be tapered dependent upon grade two or grade three and clearly grade fours is discontinuation.
So there are some times where if you have particular problems that would require some other medications where you should not be remiss in getting a medical specialist to come and help you, whether it's a gastroenterologist or an endocrinologist. And I'm fine of saying from some of our medical oncology colleagues is that drug such as this causes you to start to channel your inner internist, and that's okay if you like doing things like that and if indeed you want to have an advanced clinic in taking care of bladder cancer patients. I would say the same is true for our advanced prostate cancer patients, too. it's not for dabblers. It's getting really complicated now, complicated I think in a very intellectually vigorous way and a great way to enhance patient care.
Let me run through some other things that are coming up quickly upon you as well in addition to great intravesical innovations and immuno-oncologic, so these are called antibody-drug conjugates and you can see the proposed mechanism of action. These sort of are geared to act somewhat like smart bombs where there's a drug conjugate, there's a payload taken to a receptor on the cell that ultimately comes in and should be the concept being rather targeted. And so we have a really some tremendous data that's been presented by Jonathan Rosenberg on a drug known as enfortumab vedotin. There are other variations of this and essentially what these are, are a nectin-4 targeted antibody. They're transmembrane, which allows for a cohesion or binding on the extracellular aspect and then internalization within the cell.
The payload here is MMAE, there are different payloads. There are going to be a series of these trials and certainly will further add in initially in the third-line of advanced bladder cancer patients. But just like with everything else, possibilities for combining with IO therapy and even potentially thinking about moving them up more proximately in the bladder cancer disease state.
So what about FGFR? Here's the drug that essentially, if you look at the avidity here, the frequency of the FGFR alterations you see it's about 15 to 20% in metastatic and non-muscle invasive. It's a wide range. We think it may be anywhere from 40 to 70% and so just again for purposes of time, the drug that's now out there called erdafitinib has now been approved. It is the first and only oral drug in bladder cancer. We have now an oral drug in bladder cancer approved in third-line setting. Basically, after patients have progressed in the metastatic bladder cancer disease state on platinum as well as IO therapy. But this drug as well as others, pemigatinib and others as well are now being looked at, of course, to be moved more proximately, which is the usual way we develop our scientific regulatory and research pathways. So this drug is now approved as of April 2019 here, just for your own purposes is a list of FGFR-targeted therapies with ongoing investigation.
So here are the conclusions. PD receptor blockers, FGFR-targeting therapies are now approved as non-chemotherapeutic options in advanced bladder cancer. Clearly there's a profound amount of trials going on right now, moving it into what urologists would be more comfortable in seeing. At the end of the day, the lot, the last bullet here is coordination and communication and a multidisciplinary team is what you have to do. That includes specialization within your own shop, your clinic, and collegiality within your clinic and collegiality and collaboration with your medical oncologists and medical specialists.
So how do we integrate bladder cancer care, the healthcare landscape as Dr. Hussain pointed out in prostate. It's changing so rapidly, but that's such a good thing and it should help us avoid some of the issues surrounded by the burnout of medicine and it gives you an opportunity to expand your specialty clinic. My last slide, lessons learned from prostate cancer management. There's a paucity of highly trained medical and GU-trained oncologists on the medical oncology side and on the urology side. Great career growth opportunity doesn't really matter where you in stage of your career and let me stop with that. Thank you and let's take some questions.
Gordon Brown: Neal, great job. I'm kind of highlighting some of the rapid changes in the field of both metastatic locally advanced in superficial high-risk bladder cancer. We certainly have been using this both clinically as well as on clinical trial within our practices. Tom, do you have any thoughts about how you're currently integrating these therapies?
Tom Jayram: Yeah, Neal, great, great talk. I think that for us it's all of this excitement in bladder cancer's become a vehicle. Really evaluate our current bladder cancer practices and for community urologists, the biggest, some of the biggest gaps are a non-Muslim base of disease. How many patients are receiving neoadjuvant chemotherapy prior to cystectomy and this has really become a vehicle for us to be able to look at that. And coincident with the BCG shortage, I joke around with people in my group that it's actually been a good thing for us because we've run a centralized process now where every BCG request gets evaluated and we're finding a lot of off-guideline, off-pathway utilization of BCG that certainly is going to represent an ability to improve. So I think with the metastatic space comes an ability for improvement in localized disease, which is going to help all of us.
Gordon Brown: As it relates specifically to the high-risk non-muscle invasive patient. You know you presented data from the Keynote-057 trial as well as from the, from Collin's trial looking at INSTILADRIN® they're both remarkable improvements of what we currently have. I mean it's light years ahead of VALSTAR®. Help me understand what your thoughts are as to which one of those you think might kind of result in the best outcome.
Neal Shore: Yeah, so I think it's a great question. I think, you know, we don't have the Phase III data yet on most for INSTILADRIN®. We're going to hear that at SUO in a matter of weeks. We saw the Phase II data, which was rather impressive. You know with IO therapy... Look, I know like you guys, I've given out all the, did the different IO therapies out there. I'm giving it in combination in CRPC and we're giving it obviously in bladder cancer studies. I'll probably defer on the question except only to say that this is a really important time for urologists to recognize that the treatment for advanced bladder cancer as well as all aspects of it. You know, we're getting new targeted agents and it's super important to be up to speed and so we continue to really want to advance educational programs around that.
Tom Jayram: I would say, Neal, any closing thoughts on lessons learned? I get that question a lot. After two or three years now, we've been giving immunotherapy for advanced disease and a lot of our groups now are using them in clinical trials. Do you have any thoughts to the group on what that infrastructure looks like? Because I would echo what you said in a sophisticated group, it advanced prostate cancer infrastructure, a research team, dedicated staff. I think it's certainly very doable.
Neal Shore: Yeah, no, I would agree completely what you just said. It takes specialization within the clinic. You know, if you want to be a great surgeon and a high volume surgeon, you may not be the best fit to be taking care of the metastatic patients or if you want to be the trialist a stay in your group. Some folks can do two things at once. Some could do three things at once. I'm probably good about doing half of a thing part of the time. So you have to know what your limitations are and you have to really work together and you have to have collaboration. And I think that's kind of been a little bit of the challenge historically in uro and a lot of the profession.