Biomarkers in Bladder Cancer

December 12, 2023

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Yale Cancer Center Grand Rounds | December 8, 2023

Presented by: Dr. Fed Ghali

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00:00Good morning, everyone.
00:03It really gives you a great joy to introduce
00:05the speaker for Grand Mound today.
00:07Today's speaker is Doctor Fad Galley.
00:10He's our new recruit.
00:11He joined us in August
00:13last year from Fred Hutch.
00:15So he's a urological oncologist who
00:17specialized in taking care of patients
00:19with bladder and the urinary tract
00:21cancers and also test his cancer as well.
00:24He finished his medical school at
00:26Geyser School of Medicine at Dartmouth.
00:28He then wanted to, you know,
00:29UC San Diego for his surgical
00:32internship and residency.
00:33And then he went on to University of
00:36Washington in Seattle for his suicide
00:38of urology on College of Fellowship.
00:40And then he joined us as a
00:43faculty last August.
00:44His research interests include
00:46designing clinical trials,
00:48environmental development
00:48and urinary tract cancers,
00:50and he has received multiple
00:53awards and grants and publications.
00:55Dr.
00:56Gatti for those two years,
01:03great. Thank you all for being here.
01:05It's really an honor to get
01:06to speak with all of you.
01:07Like Doctor Kim has said,
01:09I started just about three
01:10months ago so this is early in
01:12my in my stay here at Yale.
01:14But it's it's it's really been
01:15such a pleasure to meet all of
01:17the other faculty and get to take
01:18care of patients with you all.
01:20So thanks for having me.
01:24I'm going to speak today about biomarkers
01:26within bladder cancer and this is sort of an,
01:28it's a very, this is a broad title and
01:29it's a bit of an ambitious maybe title.
01:31So I think what's maybe more appropriate is
01:34examples of biomarkers within bladder cancer.
01:36And I'll sort of weave in a little
01:38bit of overview of how we take
01:40care of these patients,
01:41talk about some of the work that we've
01:43done and some of the work that's ongoing.
01:45That's exciting disclosures,
01:48none that are, none that are relevant
01:51here and none that are ongoing.
01:53And so like I say,
01:54we'll sort of talk briefly about
01:56an introduction to bladder
01:58cancer patients and care,
02:00we'll talk about non muscle invasive
02:02bladder cancer which is sort of the early
02:04part of the Natural History of the disease,
02:06talk about advanced bladder cancer and
02:08some of the ongoing clinical trials.
02:09And then hopefully have some questions,
02:11some time for questions at the conclusion.
02:15So to start, bladder cancer is a common
02:19and unfortunately lethal illness.
02:21It affects about 82,000 Americans
02:23per year and approximately 17,000
02:25Americans succumb to the disease.
02:27So 5th or 6th most common cause of
02:29cancer death depending on the gender
02:31of the patient and the prime the the
02:35majority of patients that they experience
02:38bladder cancer are in Medicare age,
02:41so sort of 65 years of age and older.
02:43So you can see here from from sincere
02:46data that approximately 80 to 85%
02:48of patients with bladder cancer
02:50are are elderly and those are the
02:52patients that bear the brunt of the
02:54mortality of bladder cancer as well.
02:56And so and so this is really a disease
02:59that affects primarily elderly,
03:01the elderly patients,
03:02although of course not exclusively
03:053/4 of patients that present
03:07with bladder cancer, however,
03:08do present in an early stage of the
03:10disease what we call non muscle invasive.
03:12And so you can see in the schematic,
03:13which I am using here without permission,
03:15without permission,
03:16so hopefully that's OK.
03:17But this is a schematic from the
03:19Internet and shows you could see
03:22that tumors in most patients present
03:24in a fairly superficial stage of
03:27the disease where either the mucosa
03:29or the lamina propria are involved,
03:31but not the deeper muscle layer
03:34of the bladder.
03:35And this is really a distinct
03:37clinical entity because we can
03:38often treat these patients with
03:40bladder preserving modalities.
03:42So these patients can be treated
03:44with endoscopic resections of the
03:46tumor and then intra vesicle therapy.
03:48So we can actually instill a catheter
03:50in the bladder and give either
03:52immunotherapy in the form of BCG or
03:55chemotherapies in the bladder and
03:57and preserve preserve their bladder
03:59in this early stage of the disease.
04:02Unfortunately though recurrences
04:03are very common.
04:04Bladder cancer has a very not especially
04:06non muscle invasive bladder cancer
04:08has a very high recurrence rate.
04:10So this is a study from the
04:11University of Miami, Rich ET al.
04:13And it's a really well done study.
04:15It's approximately 500 patients
04:16that they've taken care of with
04:19really meticulous data review and
04:22these patients were stratified
04:23into risk strata that we use in non
04:25muscle invasive bladder cancer and
04:27they tracked progression despite
04:29standard of care therapy.
04:30And what you can see here is progression
04:32free survival or recurrence free
04:34survival I should say rather than
04:35progression is pretty significant.
04:37The very top line here the the black
04:40line is low risk patients and you can
04:43see after a few years approximately
04:45half of them will have experienced a
04:47recurrence in the bladder requiring
04:49repeat surgery and so on.
04:51High risk patients have even higher
04:53recurrence rates in in this series
04:55pretty significant rates of recurrence.
04:57So to deal with this,
05:00one of the things we do is we put
05:02patients on long term surveillance
05:04of their bladder cancer and this
05:06is done through routine cystoscopy.
05:08And I like this image image because
05:11it it makes me feel uncomfortable
05:12when I look at it.
05:13It's sort of highlights I think the
05:16discomfort that patients experience
05:17undergoing this procedure And cystoscopy
05:20is really a useful tool in urology,
05:22but it's got major limitations.
05:24For one,
05:25it's not perfect.
05:26It has you know approximately a
05:2870 to 80% sensitivity for bladder
05:31cancer recurrence depending on
05:33the series that's looked at it,
05:36it's uncomfortable.
05:37Approximately 30 to 35% of patients
05:40report experiencing significant anxieties
05:43from cystoscopy and it's expensive.
05:46So here are a couple of references
05:48that we won't go into,
05:49but these are references that
05:50really highlight the significant
05:52cost to the healthcare system for
05:54long term surveillance of bladder
05:55cancer making it one of the most
05:57expensive cancers to to care for.
06:00And so for those reasons I,
06:01I I think there are lots of reasons why we
06:04sort of you can see I made
06:05my own my own figures here.
06:06But you can see that there's a real
06:08strong indication for biomarkers in the
06:10non muscle invasive bladder cancer space.
06:12Ideally a sensitive and specific marker
06:15that can identify non invasively when
06:18patients have recurred with bladder cancer.
06:21There are ones that we use currently.
06:23So cytology is a commonly used urinary
06:26biomarker and and again without
06:27sort of going too much into it,
06:29cytology has its own major limitations
06:32for for one it's it's quite,
06:34it's quite intensive,
06:35it requires A cytopathologist to
06:37review their significant inter reader
06:40variability between cytopathologists.
06:42And on top of that it's despite
06:44being labour intensive,
06:45the performance of cytology is quite lacking.
06:49Sensitivities have been reported
06:50in the 50s to 60 percents with with
06:54in all comers with bladder cancer
06:56and then obviously substratifying
06:58we had a little more granularity.
07:00There are other biomarkers that
07:01have been reported and I'm going
07:02to just sort of show you a list
07:04of what's been out there that are
07:05protein based biomarkers,
07:06cell based biomarkers and the sort of
07:08in the interest of time what I would
07:10say is none of them are recommended
07:12for routine use or certainly for
07:15replacement of cystoscopy because of
07:17poor performance of these relative
07:19to cystoscopies.
07:22One real Ave. that's come to light in
07:24the last several years especially with
07:27the advent of widespread next generation
07:29sequencing is the the question about urinary
07:32tumor associated DNA as a biomarker.
07:34And so I'm going to spend just a
07:36few minutes talking about this.
07:38This has been reported as a proof of
07:40principle and several, several reports.
07:41And so there are versions that have
07:44been tested in the past and the
07:47proof of principle does demonstrate
07:48that it's a useful tool.
07:50There are sensitivities
07:51sometimes in the high 80s,
07:52mid to high 80s for urinary DNA biomarkers,
07:55especially in a tumor
07:57informed mechanism for it.
07:59But ultimately,
07:59the sensitivities and specificities
08:01don't seem to to be good enough to
08:04replace cystoscopy with current with
08:06current DNA sequencing technologies.
08:09And one of the reasons for this
08:11is some inherent limitations
08:12with next generation sequencing.
08:14So I'm going to talk just a
08:15little bit about that.
08:16This is a paper,
08:17it's a little bit old now,
08:18but it's a nice paper because it
08:20reviews some various platforms.
08:21I'm not going to go through
08:22in detail all of this,
08:23but what you can see here in
08:25this column is actually just
08:27various sequencing platforms here
08:28and the error rates associated
08:30with polymerase amplifications.
08:32And what you can see is error
08:34rates just from the amplification
08:35process of next generation.
08:36Sequencing can vary based on
08:38the platform but it's can be
08:41somewhere between point O1 to 1%
08:44amplification error rates which is
08:47not significant if you're checking
08:50for somatic mutations or really
08:52high volume mutations in a tumor.
08:54But it can be a problem if you're
08:57looking for heterogeneous low,
09:00you know really infrequent mutations
09:04in in something like a dilute sample
09:07like urinary like a urine sample.
09:10And so one example of I think a
09:12helpful figure for me is if you look
09:14at this sort of hundred well image
09:16here and you could see that tumors
09:18are we know tumors are heterogeneous,
09:20they present different populate,
09:22they have different populations
09:24with different expressions
09:25of tumor associated DN as.
09:27And if you look at standard next generation
09:29sequencing with the known error rates,
09:31what you can see is that a lot
09:32of the heterogeneity is missed.
09:34There are certain subpopulations that
09:36can't be captured very effectively and
09:38there are tools to get around this.
09:39We can do micro dissection for example
09:41and then do next generation sequencing,
09:44which adds a little bit of Labor.
09:46It's has difficulty with scalability and
09:48maybe capture some of these populations.
09:50But again some of the heterogeneity
09:52is missed.
09:55What about single cell sequencing?
09:56And again single single cell next
09:58generation sequencing is really
09:59effective at capturing rare events,
10:01but scalability becomes an issue.
10:04And when 1 zooms out and thinks
10:06about the challenge that faces
10:08urinary detecting tumor DNA in the
10:10urine the the picture starts to look
10:11a little bit more like this where
10:13we're trying to capture very very,
10:15very rare events and quite,
10:17quite dilute solutions And and this,
10:20this really can limit the
10:22sensitivity and of an assay.
10:24And and I think that's what's been
10:26shown in in previous attempts at this.
10:28One thing we've been looking at that
10:30we looked at at the University of
10:32Washington and are trying to develop is
10:34using a tool called duplex sequencing
10:35which was new to me as a fellows
10:38developed in the lab in the labs at
10:40the University of Washington with
10:42Scott Kennedy and and colleagues.
10:44And this is a tool that's really
10:46helpful for the detection of ultra rare
10:48mutations with quite high accuracy.
10:51The reason this is helpful is
10:53because of a computational tool.
10:55Duplex sequencing is primarily A
10:58computational tool which starts off
10:59by using a sort of standard error
11:02corrected next generation sequencing tools.
11:04So you know DNA,
11:06the DNA from specimens are fragmented.
11:09We use a unique molecular identifier
11:11that's ligated to the fragments and
11:13then next generation sequencing is performed.
11:16And if you can see here in this panel,
11:18there's a true mutation demonstrated
11:20here in green.
11:20And then as amplification occurs,
11:23there are amplification errors
11:25that accumulate during the during
11:27in various amplicons.
11:29And sort of a standard pathway
11:31would be to perform single strand
11:34consensus so that if all of the
11:36amplicons don't have a demonstrated
11:38mutation that mutation is sort of
11:41assumed to be an amplification error.
11:43The technology here is using the
11:46inherent complementarity of DNA to
11:48identify double strand consensus
11:49so that even early mutations,
11:51even founder mutations in the
11:54amplification process can be
11:56identified and and sort of deleted
11:58out of the final analysis.
12:00And so only true mutations,
12:01even very rare mutations are
12:03identified in this that has been
12:05reported on several times and and
12:07it moves the error rate from one in
12:09100 and to 1 to one in 1000 to one
12:11in 10,000 in some series of standard
12:13next generation sequencing to
12:15something like one in 10 to the 7th.
12:17So it really adds quite a significant amount
12:19of quite a significant amount of accuracy.
12:23So how would we use this?
12:24I think the next step for us was if
12:26we're going to try to apply this
12:29technology to a screen to a surveillance
12:31program for bladder cancer patients,
12:33what genes are we going to look for?
12:36Luckily there have been a couple of
12:38publicly available and published series
12:40that have sequenced very large number
12:41or not very large numbers but large
12:43numbers of bladder cancer tumors.
12:45So this is the TCGA which was
12:47published and updated several
12:49times most recently in 2018.
12:51This is a series from Memorial Sloan
12:54Kettering which has sequenced some
12:56non muscle invasive tumors and some
12:59of the frequently mutated genes were
13:03sort of analyzed from these data
13:05and we came up with a list of some
13:07pretty frequent genes and you all will
13:09recognize many of these genes here.
13:11So the the basic approach that we took
13:14to developing at least the preliminary
13:16data for our our surveillance study was
13:19patients present with a a mass or hematuria,
13:23they undergo transurethral resection
13:25of bladder tumor and then after
13:27the diagnosis is made,
13:28a urine sample is taken immediately or
13:31soon after surgery they receive therapy
13:34intravesically and then a urine sample
13:36is taken after their therapy and then
13:39patients undergo cystoscopic surveillance.
13:41And the goal of this was
13:43to just understand one,
13:44are we able to reliably detect
13:46tumor associated genes?
13:47And two,
13:48do the do the levels of these tumor
13:50associated genes relate to their
13:52risk of recurrence moving forward?
13:54So I'm going to show you some examples.
13:55This is quite early work,
13:57but I'd like to show you some examples
13:59that got us excited about this.
14:00This is,
14:01this is data from a 77 year old
14:03male who presented to us with high
14:06grade T1 bladder cancer with no CIS.
14:09And this is just an analysis of
14:12their their pre and post urine
14:14for the 10 genes that we analyzed.
14:17It's important to note here that
14:18this is a tumor naive approach.
14:19So we're not sequencing the initial
14:21tumor and then going on to try
14:24to detect these lesions.
14:25This is an off the shelf approach
14:28which I think is really useful for
14:30scalability in a setting like this.
14:33And what you can see is the blue is
14:35the levels of of the variants detected
14:37for the common genes that we're detecting.
14:40The blue is before and the orange which
14:43is really almost difficult to see,
14:46is the after treatment.
14:48And I'll just I'll just point get
14:50your attention here to the Y axis
14:52and you could see that these are
14:54very very rare events.
14:55These varying allele fractions
14:57are really quite low.
14:58You know a a common varying allele
15:01fraction for previously reported
15:03assays would be .3 to .5 and so.
15:07So we're detecting really low levels
15:08and what you can see here is that
15:11there's clearly some dynamics at
15:13play here and this is the total
15:15variolial fraction.
15:15And you can see that this patient had
15:18a significant reduction in the total
15:21amount of detectable tumor associated
15:23DNA and they're now 18 months out,
15:26no, no recurrence.
15:27And you can sort of contrast
15:29that with this patient who had
15:31quite low levels at the beginning
15:33after surveillance or excuse me,
15:35after therapy,
15:36we were able to detect low levels
15:39of of stack two ERD 1A and quite
15:41significant levels of PIC three CA.
15:43And this is sort of demonstrated here
15:46really driven by this PIC three CA mutation.
15:49And ultimately the patient in
15:51about 6 1/2 months later
15:53was found to have a detectable
15:56recurrence on cystoscopy.
15:57Obviously these are specific examples that
15:59sort of just demonstrated this was feasible.
16:02And so we have now collected a total of 50
16:04patients and are working through the data.
16:07Now this is just a a heat map showing
16:09some of their some of their demographic
16:12and and pathologic data and approximately
16:1520 of them have experienced recurrences.
16:17And the the future of this is we're now
16:22working through their their clinical
16:24outcomes and trying to understand
16:26if we can reliably identify a lead
16:29time for identifying these patients.
16:30And so the the future of this is
16:33we're working through the data now
16:34trying to develop a a reliable way
16:37to detect treatment response,
16:38identify recurrences before they're
16:40grossly visible and maybe identify
16:43patients for whom early switching
16:45of therapy before a visible tumours
16:47identified and maybe be able to spare
16:50those patients subsequent surgery
16:51for example if we switch early.
16:53And I just wanted to highlight Jonathan
16:55Wright who's a a bladder cancer surgeon
16:57and researcher at the University
16:59of Washington who's my mentor and
17:01and and developed this project with
17:02me and Scott Kennedy of course,
17:04who was part of the development
17:07of this technology.
17:08And Doctor Blaha is a biostatistician
17:10here at Yale who as soon as I got here,
17:12I was lucky enough to get to meet
17:14him and and recruited him to work
17:15on this project with us.
17:16So have been really looking forward
17:19to this And as we analyze this data,
17:21the goal will be to develop a a larger
17:24study where we can collect ongoing
17:26urines with every cystoscopy and
17:29hopefully be able to follow and monitor
17:32these patients more longitudinally.
17:35I think that data will be richer.
17:36So we're preparing these,
17:38we're preparing this analysis
17:39now for hopefully some extramural
17:41funding in the spring.
17:43The thing that we're all trying to
17:45prevent is progression of these
17:47patients because progressing to
17:48muscle invasive bladder cancer is,
17:50is almost,
17:50it's an entirely really a different
17:52kind of clinical entity and it's
17:55it's has significantly poor outcomes
17:57associated with it.
17:58So this is that same paper that
18:00I showed you earlier,
18:00those same 400 patients and this is
18:03now progression rather than recurrence
18:05and you can see that low risk patients
18:06have a pretty low risk of progression,
18:08but high risk patients especially
18:11do progress significantly and many
18:13of them will progress to like I
18:15say this muscle invasive bladder
18:17cancer phase in invading the muscle
18:20or fat or or or onward.
18:22And for those patients therapy really
18:24does transition standard of care therapy
18:27really transitions from the bladder,
18:29you know the the less invasive
18:32endoscopic approaches to therapy too
18:34often much more involved therapy.
18:36So I'll I'll talk briefly about that.
18:38The management of muscle invasive
18:40bladder cancer generally falls into two
18:42broad categories for patients who are
18:44candidates for for radical treatment.
18:46The 1st is radical surgery,
18:49radical cystectomy with lymph
18:51node dissection preceded by
18:53neoadjuvant chemotherapy.
18:54And the other is what we call
18:55trimodal therapy, which is the
18:57first mode is maximal endoscopic
19:00resection followed by chemo radiation.
19:02So those are the three modes outcomes
19:04are significantly poorer for patients
19:06with muscle invasive bladder cancer.
19:08This is a study that looked at data
19:10from from the VA of all places.
19:12These are Vinci data from the University
19:14of California in San Diego and these
19:16are multiple thousands of patients.
19:18And you could see overall survival
19:20plots for radical cystectomy with chemo,
19:22radical cystectomy without neoadjuvant
19:24chemotherapy are demonstrated here in
19:27the in the dashed orange and the dark
19:29blue line and trimodal therapy with
19:31preferred chemotherapy regimens up here.
19:34And you can see that survival is at
19:36at best at least from these real world
19:39data and admittedly somewhat sicker
19:41patients are somewhere in the 40 to
19:435545 to 55% range in the five year
19:46survival data that they report here.
19:47This varies a little bit based on
19:49you know some other factors,
19:50but that's what's reported here.
19:53One thing to note is that trimodal
19:55therapy with non preferred regimens
19:56in these data show a significantly
19:59poorer outcome that they were able to
20:01detect a statistically significant.
20:03So for for many decades now management of
20:05muscle invasive bladder cancer has this this.
20:08The central feature of it in the United
20:10States at least has been radical
20:11cystectomy with lymph node dissection.
20:14We have learned in the last several
20:16decades that chemotherapy prior to radical
20:18surgery doesn't prove overall survival.
20:21This was first shown in with level
20:23one evidence in a study in 2003 which
20:25administered M VAC prior to radical
20:28cystectomy and locally advanced muscle
20:31invasive bladder cancer and demonstrated
20:33about a 5% overall survival benefit.
20:35So you can see that's that top line
20:38here and and the the charts separate.
20:41Despite these data,
20:42they're good real world data that
20:44we do not use chemotherapy in the
20:47neoadjuvant setting very frequently
20:49or as frequently as we should.
20:51So this is a study looking at SEER data,
20:53It's now a little bit old 'cause it stops in.
20:55It stopped in 2011 and we could see
20:57sort of a trend upwards in the use
20:59of neoadjuvant chemotherapy with
21:01muscle invasive bladder cancer,
21:02but it peaks at around in this
21:04data here about around 23 to 25%.
21:08More recent data using the National
21:11Cancer Database reported that while
21:13again it's still increasing the
21:14use of neoadjuvant chemotherapy,
21:16the highest that they were able
21:17to detect was in the 35% range.
21:19And and so we're not using it nearly
21:23as frequently as as we could be.
21:26And this is a potential real
21:29opportunity for improving survival
21:30without major new interventions,
21:32without major new,
21:34you know all of the new fancy drugs
21:36that we have.
21:37This is tried and true and and we're just
21:40are not very effective at implementing it.
21:42What about radiation?
21:44And similarly there is high quality
21:46data that suggests that chemotherapy
21:49with radiation does improve outcomes
21:52for muscle invasive bladder cancer.
21:54This is the study out of
21:55from 2012 James ET al.
21:57But there's several others that have
21:59also demonstrated that chemotherapy
22:01administered with radiotherapy improves
22:03at least local regional control.
22:05And this is an overall survival plot
22:07that wasn't statistically significant.
22:08But you could see that chemoradiotherapy
22:10out outperforms radiotherapy alone
22:12at least in local regional control,
22:14if not both.
22:16Are we doing better with administering
22:18chemotherapy with radiation?
22:20We're doing better.
22:22We looked at this at using the SEER,
22:25the SEER Medicare data set.
22:27We looked at a cohort of about
22:292200 patients and sort of the
22:32kind of summary of this data,
22:34of the data that we found is that
22:35in 2200 patients with muscle
22:37invasive bladder cancer with
22:39undergoing curative intent radiation,
22:41approximately 40% of patients do not
22:43receive any radiotherapy in in the
22:46time that they're receiving radiation.
22:48So again a significant opportunity
22:50for improving,
22:51improving care for these folks.
22:53Similarly many about 20 to 25% of
22:57patients are receiving what we would
22:59call non preferred chemotherapeutic
23:01regimens like carboplatin or dosataxel alone.
23:04And these are therapies that that we
23:07there are good data that they do not
23:09perform quite as well as cisplatin
23:11for example in in the setting and so.
23:14So again these are this is just an
23:16opportunity for for improvement in
23:18patients undergoing radiation therapy.
23:20This is a chart over time.
23:22We're not.
23:22We're getting better at
23:24administering therapy,
23:24but it's not significantly better
23:26in terms of preferred regimens and
23:28we did detect the difference in
23:30overall survival in these patients,
23:31although we should note that I should
23:33note that level one evidence doesn't
23:35demonstrate a clear survival benefit,
23:37mostly local, regional,
23:38but we did see an overall survival
23:40benefit in these retrospective data
23:44for patients undergoing bladder
23:45sparing therapy or radical cystectomy
23:47for muscle invasive bladder cancer.
23:49The goal would be to also expand the
23:51the idea of does urinary DNA play a role
23:54in these for these patients as well,
23:56establishing the utility of urinary
23:58DNA as a biomarker in muscle invasive
24:00bladder cancer could play a role
24:02in predicting complete response
24:04after neoadjuvant chemotherapy,
24:05which I didn't show you data for,
24:07but is known to be a good marker for
24:09a good outcome for these patients.
24:11And there's more and more interest in
24:13trying to avoid radical surgery in
24:15patients that respond to neoadjuvant
24:17chemotherapy.
24:17For those that are not responding well,
24:19there's a question of would they
24:21benefit from expedited surgery or
24:23switching therapy and we don't know
24:24the answer to that because we've not
24:26had a good marker for assessing it.
24:29Currently we just use cross-sectional imaging
24:31which has a lot of limitations unfortunately.
24:34And then of course for those
24:36who retain their bladder,
24:36there's a question of whether or not
24:38a highly sensitive marker could be
24:40useful for monitoring and surveilling
24:42patients that underwent trimodal therapy.
24:44And so these are questions that we
24:46hope to interrogate in the future.
24:48We have about 20 patients that
24:50have muscle invasive bladder cancer
24:51before and after chemotherapy that
24:53have undergone radical cystectomy.
24:55So we're hoping to look into that at
24:57a small scale in the near future.
25:00And ultimately muscle that urinary
25:02DNA biomarker has to be integrated
25:05with broader with other biomarkers
25:07that are in development.
25:09So that would be another goal is
25:11to understand how it relates to
25:13other biomarkers.
25:14So I did want to talk about one other
25:16biomarker which was not probably new
25:17to to most of you as it's made-up quite
25:19a splash in a lot of different cancers.
25:21But I'm going to talk about its role
25:24in bladder cancer is circulating
25:25tumor DNA in in bladder cancer.
25:28This is also a very exciting area of
25:31our in this field in bladder cancer
25:34and it sort of started at least
25:36has come to the forefront in the
25:38setting of another clinical trial.
25:39This was a trial published in 2021,
25:42the use of adjuvant A tezalizumab
25:44for folks who have bladder cancer
25:47to try to reduce basically increased
25:50disease free survival in these folks.
25:52So these are high risk folks that
25:54had disease on final pathology after
25:56cystectomy and they were randomized
25:58to receipt the receipt of a checkpoint
26:01inhibitor at tesolizumab and the
26:03this trial unfortunately ultimately
26:04was a negative trial didn't show an
26:07improvement in disease free survival.
26:09But one subsequent study that resulted
26:12from analysis of these data was re
26:15analyzing the clinical data based
26:17on substrata for circulating tumor
26:19DNA positivity.
26:20And so I'm going to show you some of
26:22the data from this paper published
26:23in in in Nature 2021, May 2021.
26:27You can see here that the data are
26:31stratified by observation in the
26:33orange versus the blue receipt of
26:35a tesolizumab
26:36in the adjuvant setting and circulating
26:38tumor DNA negative up top and
26:41circulating tumor DNA positive below.
26:43And one thing that's clear is that
26:45CT DNA this is a tumor informed
26:46biomarker in this setting is
26:48quite prognostic if nothing else.
26:50It clearly distinguishes patients
26:51who have poorer outcomes from
26:53those who do better and it reflect,
26:55it seems to reflect some residual disease
26:59after cystectomy which is pretty intuitive.
27:01But one of the signals that's really
27:04important here is that the folks who
27:06received atesalizumab with CTDNA
27:08positivity clearly experienced the
27:10benefit in disease free survival
27:12based on this reanalysis and this
27:14is an overall survival reanalysis.
27:15Again, this is not a randomized trial.
27:17This is, this is a reinterpretation
27:20from this invigor 10 study.
27:23And what you can see here again is
27:25that is that adjuvant therapy for folks
27:28who have detectable circulating tumor
27:31DNA is is really seems to reflect
27:34a benefit for adjuvant therapy.
27:36It's pretty exciting because we know
27:39that with adjuvant therapy we are
27:41we're delivering a lot of therapy to
27:44some patients who don't have any cancer.
27:46These are all these patients have
27:47no evidence of disease at the time,
27:49they just have a risk of recurrence.
27:51And so the idea of being able to parse
27:54out residual disease and hopefully
27:56make sort of the idea of adjuvant
27:59therapy a little bit to move past
28:01that would is a really exciting
28:02thing I think for patients,
28:03hopefully minimizing over
28:05treatment of patients.
28:07These results have led to the
28:09development of a new study of Vigor 11,
28:11which is a a biomarker driven randomized
28:14trial to administer atizolizumab
28:16for CT DNA positive patients.
28:19So to try to validate these
28:21in a prospective fashion,
28:22I mean this is not,
28:23I know this is a busy slide,
28:24but this is not meant to be read just as
28:27a reference for anyone who's interested.
28:29So this is this trial's ongoing and it's,
28:30it's very exciting and many of
28:32you who treat other cancers will
28:34know that they're really good data
28:36for similar biomarkers,
28:37circulating tumor biomarkers now
28:39in colorectal cancer and lung
28:42cancer and several other cancers.
28:43This trial has a disease free survival
28:46primary endpoint and I I do want to
28:48touch on that a little bit because
28:51the right way to answer this question
28:53is a is a prospective clinical trial
28:56that is the gold standard therapy
28:58and excuse me gold standard approach
28:59to answering a question like a
29:02therapeutic intervention like this.
29:03But clinical trials as many of you
29:05know have significant challenges
29:06and are difficult to conduct.
29:08They're quite resource intensive
29:10and they do face challenges for
29:13accrual of patients and and and
29:16completion within certain time points.
29:19And so I did want to talk about one
29:22particular challenge with these is
29:24endpoint selection and clinical trials.
29:26So surrogate endpoints have been a
29:28a bit of a topic in clinical trial
29:31design and implementation science over
29:33the last 10-15 years or so at least.
29:36And and just to define the term,
29:38surrogate endpoints are are outcomes
29:40that themselves are not known to
29:43have a clinical benefit but are
29:45thought or known to predict an
29:47outcome that has a clinical benefit.
29:49So they do not themselves carry
29:52a lot of meaning.
29:54They carry meaning because we think they're
29:56related to something that carries meaning,
29:57does that pretty, pretty reasonable.
30:00So they're used as a substitute and
30:02they're thought to predict clinical
30:04endpoints and they're increasing in use,
30:08they're becoming more and more frequent.
30:09I really like this study from JAMA
30:11Oncology which tracks the proportion
30:13of randomized clinical trials and
30:15these are endpoints that are used in
30:18various clinical trials over time.
30:20And you could see that overall survival's
30:22the most common clinical endpoint.
30:24And then you could see that it's
30:25kind of become falling out of
30:27favour in randomized trials.
30:28While progression free survival for
30:30example in is becoming more and more
30:32popular in randomized clinical trials.
30:34And I I think not UN coincidentally
30:36industry funding is also significantly
30:38increasing in these in these studies and
30:40what the study concludes is that the use
30:42of progression free survival is increasing.
30:45Progression free survival is more likely
30:48to be a positive trial if you use PFS
30:50rather than OS in a clinical trial.
30:53And and and it's becoming like I say it's
30:57it's become the the major most common
31:00endpoint used in clinical trials now.
31:03So why should be should we be worried
31:06or cautious about this trend?
31:08Well,
31:08the assumption when a surrogate
31:11endpoint is used is that there's some
31:13cause for the patient's illness,
31:14you know their malignancy.
31:16We detect some surrogate endpoint like
31:19progression free survival and that in
31:21turn leads to a clinical endpoint like
31:24there's the patient's overall survival.
31:26But as we all know that 'cause
31:28this cause causality scheme,
31:30this causation scheme is not always
31:32quite as direct cause can be related to
31:35the endpoint in multiple different ways.
31:37And so we really have to be kind of
31:39cautious about assuming this level
31:41A and there are ways to validate
31:43surrogate endpoints.
31:44People have done this in the past
31:46where they we can look at clinical
31:48data and try to make sure to that
31:50the surrogate endpoint is truly
31:52causally linked or significantly
31:54predictive of a clinical endpoint.
31:55And the answer seems to be it kind
31:57of varies whether or not a surrogate
31:59endpoint is linked to a clinical endpoint.
32:02It varies on,
32:03it varies based on the cancer and
32:05the specific clinical details.
32:07So this is an another paper that looked
32:09at the meta analysis of surrogate
32:11endpoints in various trials and it's
32:13not always the case that they do
32:15predict the clinical endpoint with
32:18with reliability. This is a big table.
32:21We don't,
32:21I'm not going to go through all of that.
32:23This is not again not meant to be read,
32:24but just to say that this meta analysis
32:27looked at multiple various trials
32:28in the past in areas of medicine
32:30where we use the surrogate endpoint
32:32and we found that
32:33when the clinical endpoint was measured,
32:35we really did ultimately find that
32:37they were not predictive of each other.
32:40And I think one really telling
32:42example of this is the cast trials.
32:44This was a trial in cardiology which
32:46looked at patients who would experience
32:48myocardial infarctions in the past
32:50who had had ventric experienced
32:53intermittent ventricular arrhythmia.
32:54And the common thought prior to this
32:57publication of the study in 1991
32:59was medications anti arrhythmics
33:02that decrease ventricular arrhythmia
33:04would also decrease the risk of
33:06sudden cardiac death in patients.
33:07And so these were quite commonly
33:09used at the time until a a pretty
33:11heroic I think and really brave
33:13study was performed this CAST trial
33:15it was published in 1991 and what
33:18they found was pretty striking.
33:21Patients who received placebo
33:22did significantly better than
33:24patients who did who received anti
33:26arrhythmics in the post MI period.
33:28In fact mortality was was almost
33:30double in the patients who
33:32received the intervention arm.
33:34And in you know,
33:34as I was learning about this trial,
33:36I read an editorial by a cardiologist
33:38who was reflecting on this and said,
33:40you know most Americans can
33:41remember where they were when
33:43President Kennedy was assassinated.
33:44And every cardiologist can remember
33:46where they were when the cast trial
33:48was published because it was really
33:50striking and and and it sort of
33:52highlights I think the importance of
33:54validating any assumed benefit from
33:57clinical from surrogate endpoints.
33:59So people have tried to do this
34:00and like I say it kind of varies.
34:02So this is again a big trial is a big
34:04table not again not meant to be read here,
34:06but what you can see is that
34:08whether a surrogate endpoint is
34:10helpful depends on the setting.
34:11So this multiple studies have shown that
34:14progression free survival and advanced
34:16through metastatic colorectal cancer
34:17is a reasonable surrogate for overall
34:20survival in in many of these trials.
34:22Whereas in breast cancer it seems to
34:23not be a a good surrogate and and
34:26it has to be done on an individual
34:29basis for each cancer for each stage.
34:32It's really quite quite important work
34:34because we rely on them significantly.
34:36This is a paper demonstrating
34:37how much we rely on them.
34:38This is a paper published in JAMA in
34:412020 and what you what they demonstrate
34:43by evaluating FDA acceptance based
34:45on surrogate endpoints is that the
34:47use of surrogate endpoints is is
34:49increasing like we talked about
34:51and 61% of new medication of of
34:54medications that are approved based
34:56on surrogate endpoints are based
34:58on endpoints that have not been
35:00validated or lack correlation studies.
35:03So we really don't know if the surrogate
35:05is related to the endpoint we really
35:06care about which is making patients
35:08live longer or making patients live happier,
35:10healthier or you know lives that
35:12are have better quality of life.
35:14I guess 61% of the time we don't
35:17have a a link,
35:1916% of the time we use them
35:21despite data demonstrating
35:22a poor connect, a poor link between
35:24surrogate endpoints and overall survival.
35:26And only 5% of the time is there
35:29a established high correlation.
35:32There is a a post marketing requirement
35:35for medications that are approved based
35:37on surrogate endpoints and this paper
35:39demonstrates that upwards of 1/3 of them,
35:41third of trials don't report
35:43within the time period.
35:44So in bladder cancer,
35:45we do use surrogate endpoints quite a bit.
35:48We rely on them really heavily.
35:51Here's an example from bladder cancer,
35:52which we won't go into a whole lot,
35:54but this is a paper published in 2017,
35:56which is a single arm phase two
35:58trial that evaluated atezalizumab
36:00in a very difficult population.
36:02This is cisplatin ineligible
36:04patients in the second line setting.
36:06This was about 119 patients were enrolled,
36:09102 of them discontinued therapy
36:11because of progression and objective
36:13response rates were in 23% or so at a
36:15median follow up of about 17 months.
36:17So this wasn't a home run thing,
36:19This wasn't, this was,
36:20this was a a signal and a difficult
36:23population and it resulted in
36:25accelerated approval by the FDA
36:27for atizalizumab in this setting.
36:29And this is just as an aside,
36:31multiple cost effectiveness analysis
36:33of this drug show that it it's
36:36really quite costly to administer,
36:38you know,
36:39upwards of $400,000 per quality adjusted
36:42life here for a tesolizumab in this setting.
36:45And we learned about five years
36:47later that it was withdrawn.
36:49And it was withdrawn because the final
36:51data reported out that overall survival
36:53benefits were not detected in this setting.
36:56Now some might say,
36:56all right, well that's,
36:57that's, that's showbiz.
36:58That's the cost of it.
36:59You know sometimes you approve drugs
37:01and you give patients drugs that
37:03don't do that much benefit for them,
37:05but at least they get them faster.
37:07You know and what I would say is
37:09that the the effect is can often be
37:11more widespread than than we really
37:13think about at least than than I
37:14think about this is a a paper that
37:19was published by the folks at the
37:21University of Pennsylvania which
37:22evaluated the Flatiron database.
37:24So a kind of a,
37:25a large national database for patients
37:28who are exposed to cancer medications
37:32that were then ultimately withdrawn.
37:34And what they find is that it takes
37:37about 46 months from accelerated
37:39approval to withdrawal.
37:40So we don't get, it's not a huge,
37:42huge time period,
37:43but it does result in approximately
37:451/4 of patients with cancer in
37:47the United States getting exposure
37:49to therapy that ultimately is
37:51demonstrated to not be beneficial.
37:53And in bladder cancer, it's about 22%.
37:56So it's a significant number of patients.
37:58And this is an interesting editorial.
38:00This is an editorial.
38:01It's it's a letter that talks about
38:04what the global impact of this
38:06practice is for other countries,
38:09especially low and middle income countries.
38:12And here the the group Bashal Gawali's
38:16a medical oncologist who writes and
38:18thinks a lot about this problem.
38:20And he highlights that often times
38:23other countries,
38:24especially low and middle income countries,
38:26will approve medications
38:28based on FDA recommendations.
38:30And so the FDA approves these
38:32medications conditionally,
38:33they're accepted as FDA approved
38:35medications in other countries and then
38:38if they're withdrawn in the United States,
38:39they continue to be approved in these
38:41other countries and in fact are often
38:44continue to be marketed in these other
38:46countries for the indications for which
38:48they're withdrawn here in the United States.
38:51And that's a really striking
38:53fact that I'm gonna,
38:54these are long quotes,
38:55but I think it's worth just
38:57looking at this is from the paper.
38:58Thus once a drug is approved by the FDA
39:00via the accelerated approval pathway,
39:03the drug can be marketed and
39:04promoted in low middle income
39:06countries as an FDA approved drug.
39:09And then confirmatory trials confirm
39:10they're negative and these are not
39:12communicated to those same countries.
39:14And this is an example,
39:16example again from in this
39:17case a tezalizumab,
39:18which I've highlighted multiple Times Now,
39:21but immediately after the
39:23drugs withdraw from the market,
39:24the company issued letters in this
39:26case to India stating that the
39:28Tezalism A tezalizumab would continue
39:30to be marketed in that country.
39:32And it's not just this country or
39:34this medication or this company,
39:35but this is they show nine other
39:37examples in this in this paper.
39:39So my point in all of this is that this
39:41is a practice that has some real downsides,
39:44should be really thought about
39:45carefully and and of course many people
39:47are thinking about it carefully,
39:49but has does have global implications.
39:51We wanted to look at what some
39:53of these surrogate endpoints,
39:54how they behave in bladder cancer because
39:56again that's that's been my main interest.
39:59And so we took a look at this.
40:02We looked at the relationship
40:04between commonly used surrogate
40:05endpoints and overall survival
40:06in metastatic bladder cancer.
40:08And the methods were pretty straightforward.
40:10We just did a review of clinical
40:12trials in bladder cancer.
40:14We looked at progression free survival
40:16and response rate and some other
40:18information and determined determined how
40:21effectively it predicts overall survival.
40:24So this is a big table.
40:26We looked at all trials which were
40:2762 trials and split them up into
40:30immune checkpoint inhibitors and
40:32non immune checkpoint inhibitors and
40:34we can skip through some of this.
40:35But you can see that the immune checkpoint
40:38inhibition trials were performed,
40:39the median year of publication was
40:42later than the than the chemotherapy
40:44trials and and tended to have much
40:46larger ends compared to checkpoint
40:48non checkpoint inhibitor trials,
40:50which we can talk about why that matters
40:53and we reported this earlier this year.
40:55The first thing you can do to try to
40:58understand sort of how well these two,
40:59a surrogate endpoint and a clinical
41:02endpoint relate is you can ask well
41:04what is the R-squared coefficient for
41:06the hazard ratio for progression free
41:09survival compared to overall survival.
41:11And you you can see here that
41:12in this case
41:13it was pretty reasonable,
41:14it was about .6.
41:15So it's not a strong predictor,
41:17but it's not a strongly correlated,
41:20but it's it's I would say
41:22moderately correlated.
41:221 can ask a second question,
41:24which is what it's a metric called
41:28surrogate threshold effect.
41:29And what surrogate threshold effect is,
41:31is what result from the hazard
41:36ratio of progression free survival
41:37do you need to see to give you
41:4095% confidence that it's going to
41:42reflect an overall survival benefit.
41:44So you observe the surrogate and
41:46it give and it gives you with
41:4895% confidence an OS benefit.
41:50And So what would that number be?
41:51And so that turns out to be pretty,
41:53again, pretty straightforward
41:54to actually calculate.
41:55The first thing you do is you get 95%
41:57predictive sort of confidence interval
42:01around your correlation line and
42:03then you want a value that is below 1.
42:06And so you see what hazard ratio
42:09that for progression free survival
42:11that number intersects at.
42:13And for bladder cancer,
42:14we found that that R-squared was .6 and
42:17the surrogate threshold effect was .41,
42:19which means if you want 95% confidence that
42:22the OS is improved without observing it,
42:25you should,
42:26you should see APFS of .41.
42:28It doesn't mean that you need to have
42:31a .41 PFS to have an OS benefit.
42:34It just means that if you're not
42:35going to measure OS directly and
42:37you want that confidence you that's
42:39that's the value you need to get.
42:41We did the same for objective
42:43response rate here.
42:44And what you can see is that
42:46for for hazard ratio,
42:47for objective response rate,
42:48it actually never hits that
42:5095% confidence interval line.
42:51So for that our R-squared was .03 and
42:55our surrogate threshold effect was not,
42:57was not actually not reached,
42:59it's it wasn't calculable.
43:00And so from this study we sort of
43:03conclude that you know surrogate
43:05surrogate endpoints are poorly
43:07characterized in bladder cancer and
43:08there's sort of a weak to moderate
43:10correlation for progression free survival,
43:12but really quite a poor correlation
43:14for response rate or tumor shrinkage
43:17on cross-sectional imaging.
43:18And so we really should be
43:21deemphasizing response rate we
43:23conclude as a primary endpoint when
43:25possible in metastatic bladder
43:26cancer clinical trials more broadly
43:30I think outside of bladder cancer
43:31sort of zooming out again you know
43:33the question of clinical trials,
43:35we've seen this trend of clinical
43:36trials changing pretty significantly
43:38and there it's responding to a
43:39lot of pressures and you know I'm
43:40not under the impression that this
43:42is an easy thing to do.
43:44But when you think about the major
43:46stakeholders in clinical trials
43:47that are involved in bringing a
43:48new medication to patients,
43:50you know you think about the FDA,
43:53you think about the Pharmaceutical industry,
43:55you think about the patients
43:56themselves and and patient advocacy
43:58groups and then physicians.
44:01And you know I'm happy to have
44:02a longer discussion about this
44:03if people are interested.
44:05But I think that if you look at each of
44:07these factors individually,
44:08I think that the onus really is and
44:11has to be on physicians to protect the
44:14scientific integrity of clinical trials
44:16and make sure that we're we're really
44:18cautious about some of these things.
44:20I think I think while all of these
44:24other factors are key players in
44:26in bringing medications to patients
44:29really we're we're we are the ones
44:30who really are I think best equipped
44:32and and the onus really falls on us to
44:34think about how to do this and protect
44:36patient clinical trial integrity.
44:38So this is the thing I'm interested
44:40in and I'd love to you know many,
44:42many of you have have thought about this
44:44of course and and and a lot of academic
44:46scholarship about this here at Yale.
44:47One of the first things I did when
44:49coming here is I connected with the
44:51copper Center and contacted Mike Leapin
44:53and Carrie Gross and reached out to
44:55him because Carrie Gross has of course
44:56written quite a bit about this and
44:58thought deeply about a lot of these problems.
45:00And so we have started to work
45:02together a little bit on,
45:03on some projects that look at
45:06topics related to this.
45:07And I also wanted to highlight one other
45:09organization with many of the folks
45:11that I referenced in these other papers,
45:13Christopher Booth and Bishal
45:14who's who's also a part of this.
45:16And this isn't not an organization
45:19I'm I'm a part of,
45:20but they did start up a program
45:22called Common Sense Oncology and
45:24it's for physicians primarily who
45:26are interested in taking on the the,
45:29the role of thinking about this
45:32and and moving, moving.
45:34I would say the conversation to
45:37talking about endpoint design,
45:38the appropriateness of crossover and
45:41clinical trials and and some of the
45:44sort of some of the implementation
45:46signs around clinical trials.
45:48So just wanted to make people aware of that.
45:51So in conclusion,
45:52there's a lot of important work
45:53to be done in bladder cancer as I
45:56hope I've highlighted,
45:56there's a lot of room to
45:58continue to improve patient care.
46:00I think that urinary DNA has has
46:02a potential role in that future.
46:04We have very early data and there's
46:06some more robust data out there and
46:08we're hoping to continue to work and
46:10validate this as a biomarker in in
46:11both early and late bladder cancer.
46:14We need to be giving more chemotherapy
46:16and bladder cancer.
46:17We need to be giving more chemotherapy
46:19in for patients undergoing surgery
46:21and for folks undergoing radiation.
46:23And I hope I I showed you some
46:24data to convince you of that.
46:26And finally clinical trials are key,
46:29they're really important for patients
46:30and and especially in bladder cancer.
46:32We've seen tremendous,
46:33tremendous work and really
46:35exciting data of late especially.
46:37But I think it is the role of
46:40physicians really to ensure the
46:42integrity of the of the scientific
46:43endeavour that is a clinical trial
46:45and design answers that really focus
46:47on questions that are meaningful
46:49for patients making them live
46:50longer, improving their quality of life.
46:54Thank you very much for your attention.
46:55I'm happy to to chat a bit
46:57and answer some questions.
47:04Thank you Doctor Gatley.
47:07Any questions audience?
47:09The Internet very good,
47:12maybe I will set up for questions.
47:14So it's very beautiful
47:15talk about the urine DNA,
47:16how it's being used for non most
47:18invasive bladder cancer and some work
47:19you did in in terms of visibility
47:21and you also mentioned about the the
47:23low sensitivity and the low yield,
47:25you know where it sort of makes sense
47:26because it's really superficial disease,
47:28very low volume of disease.
47:29I wonder if we can share any
47:31data or any insights on using
47:32that in most invasive disease,
47:34maybe this is better setting
47:35to use that in most invasive
47:37setting how we can monitor,
47:38you know,
47:39treatment response from your agent chemo
47:40or even chemo radiotherapy as well.
47:42Yeah,
47:44yeah, there's a couple of questions.
47:46I think when when asking what its
47:49role would what a marker like this,
47:51what role it would play in
47:53muscle invasive bladder cancer,
47:54I think the first obvious thing
47:56for me would be to ask for folks
47:58who receive chemotherapy and
47:59have a really strong response.
48:02Can we identify patients who are
48:05completely responded to chemotherapy
48:07and we can maybe de escalate their
48:09therapy and identify them for
48:11not having radical cystectomy.
48:13Right now people try to do this
48:16with cytology or bladder biopsies
48:18and it has reasonable sensitivities
48:20again somewhere in the 80% or so.
48:23But if you're going to forego cystectomy,
48:26you would want to be really,
48:27really sure that there is no residual
48:30cancer because being wrong about that
48:32has a real high cost I think for patients.
48:35And so I think that that's one real
48:37exciting place and I don't have any
48:39data here to show you except to say
48:41that we can definitely detect tumor
48:43associated DNA before chemotherapy,
48:45you know after resection but
48:48before chemotherapy.
48:49So those dynamics are at play and
48:51we have seen decreases in that
48:53number with chemotherapy,
48:54but we've only,
48:55I've only looked at about 10 patients or so.
48:57So not enough to be able to say
49:00yeah we can start eliminating
49:01cystectomy in some of those,
49:03but that I think that that
49:04would be a key question.
49:06Thank
49:06you. We should definitely
49:07do this study here as well.
49:09Any other questions,
49:12questions, so maybe I can ask
49:14another question about this.
49:15So with that design,
49:17what would be the adequate endpoints?
49:20You know you talked about
49:21endpoints in metastatic setting.
49:23You know we talked about the endpoints
49:24in non most invasive disease,
49:26most invasive disease.
49:27With the introduction of
49:29this novel biomarkers,
49:30What do you think will be adequate
49:32endpoints in studies like that?
49:35To start a study like that would have to,
49:37would have to be an I think a
49:39prospective observational study.
49:41I think I would start with urine
49:43collections data analysis and then
49:45undergoing radical cystectomy.
49:47And the main endpoint I'd look for
49:48is pathologic complete response
49:50and the reason I choose that is
49:51because I didn't share it here,
49:53but from that 2003 paper with Grossman ET al.
49:56That first showed us the benefit of M
49:58Vac and muscle invasive bladder cancer.
50:01But multiple other papers have shown that
50:04patients who have pathologic complete
50:06response on surgery do significantly,
50:08significantly better.
50:09It's a really nice surrogate.
50:11So this is and this kind of ties
50:13back to how we ended the talk is
50:16that surrogates aren't all bad,
50:17it just has to be a a validated useful
50:20surrogate and I think pathologic
50:22complete response is one of those.
50:24So that's how I would do it to start.
50:26And then ultimately I think that
50:28the goal would be a prospective
50:30study where you identify patients
50:32who sort of are positive and then
50:34become negative after chemotherapy.
50:36So you biomarker select them into a
50:38study and then you would randomize
50:39those patients or at least you know
50:41it's that's a tough thing to randomize
50:43too but you would as much as you
50:46can offer patients multiple arms to
50:48treatment or no treatment and and and
50:51then you know observe quite carefully
50:54afterwards but you we would need,
50:56I I think we'd need pretty good data
50:58before we would you know withhold
51:00surgery for patients in this setting.
51:02I should say there's a study out
51:04of Fox Chase that is doing this.
51:05There's the retain study that's
51:07looking at de escalating therapy and
51:09you know it'll be exciting to see
51:11the results but we got we we have
51:13to be really careful I think in in
51:15these patients because it's it's
51:16a bad disease if we miss a window
51:19very life changing treatment too
51:20especially with the cystectomy as well.
51:22Thank you. Any other questions,
51:25questions, any questions from the online
51:31do new therapies replace
51:33chemotherapy, give up chemotherapy.
51:38So yeah that's a that's a good question.
51:42I think the so bladder cancer has
51:44seen I think like a lot of solid
51:46organ malignancies has really seen
51:48kind of a revolution and how we
51:49treat it in the last 1015 years.
51:51We've seen the importance
51:53of checkpoint inhibitors.
51:54We have antibody drug conjugates and
51:57several other important classes.
51:59And I have seen you know a lot of
52:01these medications move earlier and
52:03earlier in the treatment paradigm.
52:05Cisplatin is really quite a useful drug
52:06I think in bladder cancer and Doctor
52:08Kim of course could probably speak
52:10about this much more than I could.
52:11But I don't think that we'll ever
52:13be at a phase where or at least
52:15not anytime soon that I can think
52:17of where chemotherapy has no role,
52:18but no doubt checkpoint inhibitors
52:20and these other therapies are
52:22definitely moving earlier.
52:23I think they're going to play
52:24a bigger and bigger role in,
52:25in bladder cancer patients.
52:26We just I think for the first time saw
52:29data that there's an overall survival
52:31benefit in the frontline setting to
52:33a regimen that isn't cisplatin based.
52:35So we've we beat cisplatin in the
52:37first line setting for the first
52:39time with a combination of inforimab
52:41Vidotin which is antibody drug
52:43conjugate coupled with pembrolizumab,
52:45A checkpoint inhibitor.
52:45So those two agents you know
52:47and that's a that's a big deal.
52:48We've been using cisplatin for for
52:50decades now and and and so it's
52:53proven a really resilient regimen.
52:54So big,
52:55big news, they had a standing
52:56ovation at the ASIMO meeting.
52:58Yeah. All right, good again.
53:01Thanks Doctor Kelly,
53:02you have fantastic talk. Thank you.
53:15That's a
53:19funny one.