BCG Unresponsive Non-Muscle Invasive Bladder Cancer

These are my disclosures.  So, I have an investigator-initiated trial that was looking at Dan Theodorescu’s COXEN model for predicting response to intravesical therapy, that’s Endo.  We have two clinical trials that I’ll talk to you about, FKD and Viventia in BCG unresponsive disease.  I’ll tell you about a trial that Peter Black is PI of.  We have funding from Roche and Genentech through SWOG for that trial.  A year ago I did an advisory board for Ferring who is here today, and then I serve as a consultant for these companies who are developing drugs in various spaces in non-muscle invasive disease.

These are the objectives.  This is what I’m going to try to cover, and I’m going to go ahead and move on.  I’ll come back to all of this stuff.

First and foremost, and I think Sam’s done a beautiful job of educating us about the indications for BCG.  So, high-risk disease we know what that is, standard of care’s induction.  BCG we know about maintenance, and then the various recurrent states would be if you recur after induction with BCG then you can get more BCG, maybe BCG and interferon, and you should know that BCG is FDA approved, as David pointed out, both for carcinoma in situ and for high-risk papillary disease.  So, we’re using it for the FDA-approved indication.

Three years of maintenance, generally using the SWOG 8507 schedule, which is three weeks of BCG at three months, six months, and six-month intervals out to three years for patients who are continuing to tolerate it and continuing to maintain a disease-free state is the standard of care.  The data behind it was published long ago.  It has a statistically significant improvement in both recurrence free survival and an endpoint that essentially was the equivalent of progression-free survival.  This is the recurrence-free survival curve here, and these are the numbers that you could kind of wrap your head around and share with your patients in terms of what they can expect with regard to two-year and five-year recurrence-free survival with and without maintenance.

Another interesting thing, and it’s so important to get this right, to get this timepoint right.  So, the six-week evaluation, I’m sorry, six weeks after induction of BCG if you started with carcinoma in situ please take that patient back to the operating room and re-biopsy those areas, do cytology, and determine the pathologic response to treatment.  It may not be as imperative if you started with papillary disease only to go back and biopsy them, if the cysto and cytology is negative, but the status of the bladder at three months, and that’s what this study shows.  It’s one of many studies that shows the importance of that initial evaluation in terms of subsequent outcome.

And then without going into the details the randomized trial that Sam referred to, the EORTC trial, which compared one-third dose/full dose, one year maintenance/three years’ maintenance, confirmed if you will, or affirmed the need for three years of maintenance in patients with high risk non-muscle invasive bladder cancer.

I’m going to tout our journal a couple of times during this talk, as a disclosure which I didn’t put in there, Dan Theodorescu and I are co-editors of the Bladder Cancer Journal.  There’s some copies back there, and I’ll highlight this paper because I think it’s actually quite helpful because it clarifies it a little bit around the timing of recurrence after BCG.  So, the BCG unresponsive state requires a definition of recurrence within six months of the last BCG.  I’ll come to that, or a relapse after an initial complete response.  And this is work from Mike O’Donnell using his huge database, and it suggests that that interval may be a bit longer.  In other words, the interval of disease-free state is patients who have a longer interval, say greater than 12 months, have a much better outcome and may respond to additional BCG.  That’s essentially the take-home message of this paper.

About 2012 with the leadership of Colin Dinney, who probably most of you know as Chief of Urologic Oncology at MD Anderson, Colin reached out to the FDA, the FDA reached out to Colin and a number of people because as you know, well you may not know, that the only drug prior to the approval of atezolizumab, which you’ll hear about later, this past May was valrubicin in 1998.  We were a desert in this disease.  Right?  And so, the FDA was, companies were coming to the FDA, trying to get approval for their trial designs and it wasn’t working.  And so, they reached out to a number of folks, and as a result what you have, this is just a few of the publications, that essentially provided guidance from the FDA to the drug development business, whether you’re in pharma or whether you’re in academics, in terms of how to design trials, in this case single-arm trials, to get approval for drugs in this specific disease state of BCG refractory, BCG unresponsive disease.

Jonathan Jarow, who is a urologist who moved over to the FDA has been immensely helpful, and sort of asked a bunch of us to get together and actually come up with a definition of BCG unresponsive.  That’s the second paper.  And then there’s some additional guidance.  It was published in 2015, and I’ll refer to the most recent guidance which came out in November 2016.  But here it is, this is the slide sort of giving you the definition, and it’s very precise.  You have to have had at least five plus two, so five of six of the induction courses, two of three of the first maintenance, and then starting with high-risk disease, and recur within about six months of the last dose of BCG.

Essentially what we were asked to do is define a patient population for whom you shouldn’t give more BCG, in other words, that it’s highly unlikely that that patient’s going to respond, and there’s some risk that they may progress while you’re doing some other form of therapy.  We added the high risk, the real high-risk patients, the T1 high-grade disease, after induction.  So, the standard of care with some caveats for a patient who has a T1 high-grade tumor following induction BCG is radical cystectomy.  Now, I’m not talking about the 5-mm microinvasion of the stock or the lamina propria, those I think don’t fall really under this category, but that’s a group of patients for whom, as Sam said, the so-called expert community feels like radical cystectomy is the standard of care, and that essentially this BCG unresponsive state they’re highly unlikely to respond to additional BCG.

Let’s talk about a little bit of sort of what else is going on with these patients.  So, we’re pretty good, and I realize that this is focusing mostly on male patients, but we’re, you know, BCG can do a really good job of clearing the high-grade disease in the bladder, but as you know it’s not going to do anything for the upper urinary tract, and it’s not going to do anything for the prosthetic urethra or the membranous urethra in women, unless of course in males they’ve had a TURP and the bladder neck is open.  So, think about these extravesical sites as reservoirs for CIS in patients who recur after BCG.  Beware the patient with the persistent positive cytology, positive cytology meaning high-grade malignant cells, and a bladder that looks normal.  So, various detection tools that Mike just talked about may be useful in those patients, but you’ve got to look at these other sites.  So, they need some sort of upper tract evaluation, imaging, and then as I’ll show you a good way to sample the urethra.

The most likely place that you’re going to find CIS in the prostatic urethra is in the prostatic ducts.  The highest concentration of prostatic ducts is adjacent to the verumontanum at 5 and 7 o’clock.  Take a resectoscope and get a good chip from about mid-prostate out to the apex 5 and 7 o’clock, and it’s going to look normal almost invariably, and I’ll show you a case that’s illustrative of what you’re likely to find.  And the inset on the far right shows CIS in the prostatic ducts.

If you try to, you can’t treat that unless you widely resect essentially the posterior half of the prostate, and if for whatever reason you choose, and there’s lots of situations where you’re going to go down a path of bladder preservation.  If you get that on your sort of initial evaluation of the prostatic urethra the next step is a wide resection of the bladder and a re-resection to make sure that you’re not dealing with a stromal invasive cancer.

The involvement of the prostatic urethra post-BCG in this study was the most significant adverse feature for bad outcome in patients treated with prior BCG.  So, here’s the case.  This is a patient of mine who had a prior history of BCG and he comes back with a positive cytology.  There was some question about what was going on in his upper urinary tract that we resolved, cystoscopy was negative, bladder biopsy showed multifocal CIS.  Okay, now the time period is a bit longer than six months, so I’m thinking okay well maybe I can come back with BCG-interferon, or intravesical chemotherapy.  Like a good soldier I go and do the biopsies of the prostatic urethra.  He’s got ductal and acinar CIS, so this is noninvasive, it’s within the ducts, although has minimal invasion of the periductal soft tissue.  You see that, stop, do not pass go, the guy needs a cystectomy.  You can’t treat that with any kind of intravesical therapy.  We did that, PT0 had the CIS, no invasion, and he’s cured.  But had I not done that and gone and tried to do more intravesical therapy the next thing he has is a PT4 tumor with a 30 to 40% probability of lymph node metastases, and his survival probability drops off dramatically.  So, beware of extravesical sites.

I’m not going to go into this because I think Sam has done a beautiful job of educating us about where cystectomy is the standard of care.  Keep in mind that for medically fit patients who are accepting of radical cystectomy, radical cystectomy is the standard of care for BCG unresponsive disease.  But as we know, patients aren’t always accepting of it, they’re not as good, often in good health, and there are nuances here in terms of patients who don’t necessarily need to have their bladder out a priori.  This has been confirmed by, in addition to what you’ll see coming out of AUA, muscle invasive guidelines, pretty much all of the other guidelines are fairly, are very consistent.

Here’s the challenge, and here’s the problem.  And when I talk to patients I say that urologists, me included, have a hard time so-called pulling the trigger on radical cystectomy for these patients.  Why is that?  It’s a complicated operation, it has on a good day a 4 to 6% 90-day mortality rate, on a good day has a 15 to 25% major complication rate.  We’re going to get into a little bit of this in the afternoon.  It’s a serious deal, and you’re often dealing with elderly patients.  But the problem is is that if you wait to do a radical cystectomy when the patient has muscle invasive bladder cancer, which we would argue is an a priori indication, you take a big hit in terms of the survival outcome.  So, we have to be very meticulous and be willing to offer radical cystectomy, so-called early.  It’s not early, it’s just doing it at the right time, it’s just doing the right thing when the patient presents with a disease state that really cannot be managed any further with intravesical, or as you’ll see systemic therapy.

The outcome of radical cystectomy, especially in patients who have carcinoma in situ, is exquisite.  It’s 95% or better five-year survival.  There is not a drug on this earth, there’s not a treatment on this earth that gives you a better durable complete response rate in this disease state.  We’ve got a great tool as surgeons.  Arguably it comes with some risks, but the outcomes are really superb in patients who have a CIS.

But it doesn’t always, well you can’t do cystectomies on everybody.  We know that, and we have to have alternatives.  And one of the things that’s driving this field is exactly that.  The morbidity, the complexity of radical cystectomy, and all of the things that it does to a patient and caregivers, and so we have some options.  And I use this terminology or the phrase when BCG fails the patient.  This is Diane Quale, the immediate past president of Beacon who says, look, it’s not BCG–BCG failed the patient, that’s why the terminology is there.

I’ve listed some of the options, so you can come back with a combination immunotherapy, BCG-interferon, and I’ll show you some data on that.  There’s the answer to the second ARS question, valrubicin is the only FDA-approved drug.  When you’re talking to patients about this I think you have an obligation, we have an obligation to tell them about this drug but you’ll see some of the other stuff I tell them, and then there’s some other options.  I’m going to run through all of this very quickly.

BCG plus interferon.  This is Mike O’Donnell’s work.  He did a masterful job years ago of pulling together the urologic community basically do kind of a registration study testing this combination in various different BCG states, failure on what we would now call unresponsive CIS/non-CIS, and if you were going to pick a paper this is the one I would take a look at.  But so what you see on the left is the outcome based upon the number of courses.  And what you can see is that in patients with CIS a third course of BCG has no place in this disease unless there’s been a very long interval of complete response, you know, certainly two or three years you can come back and maybe re-induce them.  And then you see on the right the pattern of failure based upon the, I’m sorry, the pattern of outcome based upon the timing of recurrence, 12 months or less than 12 months.  So, the earlier you recur the higher risk you are, and that would qualify as the BCG unresponsive state.

Here is the data on valrubicin, the most recent published paper was in 2013, and what you see here is while, and I would argue that the initial complete response rate is really the lower limit of what we’re trying to achieve, but the problem is that at two years only 7% of the patients are disease free.  And I think that’s why the community hasn’t necessarily embraced this drug, even though it’s the only drug approved in that space.

I really was, I enjoyed listening to David’s sort of recounting the experience with SWOG.  I’ve learned at his, on his knee so to speak taught me a lot, and we’re continuing really all of the fine work that David did under Ian Thompson’s leadership.  I’ll show you some of the stuff that we’re doing in just a sec.  This is one of them.  We did a BCG unresponsive trial with gemcitabine.  The data are a little bit better than valrubicin, so it’s an option.  Anybody have experience with intravesical gemcitabine?  Raise your hand.  So, I would encourage you to take a look at some of this data and some of this stuff I’m about to show you because it’s actually a pretty good drug in this space.  Docetaxel is another one.  Jim McKiernan at Columbia has done, spent years working on this in various iterations.  This is one of the more recent studies that they’ve published.  You can see the curves look similar to gem, better than valrubicin.  This is really cool stuff.  There’s a variety of devices designed to increase delivery of chemotherapy into the wall of the bladder.  You can microwave it, you can cook it.  There’s a variety of different ways to heat it, and this is really exciting stuff, and a lot of this work has been done in Europe.

And then there’s combination chemotherapy.  This is kind of what we’re currently using for patients in the off clinical trial.  So, this is looking at gem/mitomycin.  So, sequential gemcitabine plus mitomycin, and you can see the curve, the overall curve on the left, curves on the right stratified by CIS in high-grade papillary disease.  And more recently gemcitabine/docetaxel.  We’re treating our third patient with this.  This is, these combinations have been developed by Mike O’Donnell, taking into, sort of following the steps of the medical oncologists with combination chemotherapy, taking advantage of how they affect different aspects of the cell cycle, different mechanisms of action, non-overlapping toxicities.  And you can see in this paper that those data look pretty darn good out to two years.  So, almost a near doubling of durable response rates.  So, this is another option, fairly easy to do, easier than you would think.

And then let me just finish with the clinical trials, and just reference the guidance document.  This is available online through the FDA, put out in November ’16.  It’s not terribly different than the guidance that they published in 2015.  These are the specifics, I won’t go through them but the take-home message is that single-arm trials are appropriate in this disease state where there’s not a reasonable comparator that the community or the patients would be comfortable being randomized to.

This is a list, a partial list of clinical trials.  I’m going to highlight two.  We have funding through FKD, which is a Finnish company that’s taken the add interferon, adenoviral-mediated interferon that Colin Dinney has developed through a series of phase I/phase II trials.  The phase II trial was a positive trial, and this is the treatment scheme, and the assumptions around this are to achieve an initial complete response rate that’s durable at 12 months, and the lower bound of the 95% confidence limits is about 18% assuring that if it meets its primary endpoint the FDA would approve a drug that’s at least incrementally better than valrubicin.  And this is just kind of the benchmark for design of other studies.  The interferon is given at three monthly intervals over the first year.  If the patients maintain a complete response they’ll get treated into year two.  That study is being launched as we speak.

And then just a shout out to Peter Black and Parminder Singh who have developed in collaboration with Roche and Genentech atezolizumab, which is targeting PD-L1.  We’ll get into that this afternoon.  It’s obviously a systemic therapy, the same disease state.  This is the schema, and treatment out to 12 months and looking at initial CR, and looking at relapse-free survival out farther past 18 months.

Just a take-home message; these are high-risk patients.  We know that.  These are the patients that we really have to get everything right upfront because they are at higher, much higher risk for progression.  Understand sort of where we need to pull the trigger so to speak on radical cystectomy.  Remember that radical cystectomy if it was a drug would be knocking the socks off of everything in terms of the durability of the complete response rate, long-term in patients who don’t have muscle invasive disease.  So, thank you all.