From Science to Clinical Utility: Cxbladder Monitor - Bladder Cancer Surveillance for Patients with Urothelial Carcinoma - Tamer Aboushwareb, Neal Shore & Josh Meeks

December 1, 2022

Tamer Aboushwareb, Vice President of Medical Affairs, Pacific Edge, Ltd provides an overview of the Cxbladder Monitor urine-based cancer surveillance test and is joined by Neal Shore and Josh Meeks for a discussion on the clinical implications of the use of this test. Several supportive publications are highlighted and Drs Shore, Meeks, and Aboushwareb discuss the Cxbladder Monitor algorithm, its ability to outperform current FDA-approved urine-based monitoring tests as well as cytology in a larger representative population undergoing surveillance for recurrent carcinoma, and its use as a confirmatory negative to justify postponing cystoscopic investigations in select patients.


Tamer Aboushwareb, MD, PhD, Vice President of Medical Affairs, Pacific Edge, Ltd. USA, Winston-Salem, NC

Joshua Meeks, MD, PhD, Edward M. Schaeffer, Professor of Urology, Associate Professor of Urology and Biochemistry and Molecular Genetics, Northwestern University, Chicago, IL

Neal Shore, MD, FACS, Director, CPI (Certified Principal Investigator by the Association of Clinical Research Professionals), Medical Director for the Carolina Urologic Research Center and practices with Atlantic Urology Clinics in Myrtle Beach, South Carolina

Read the Full Video Transcript

Tamer Aboushwareb: Good evening everyone. I'm here with Dr. Neal Shore and Dr. Josh Meeks to present our data on the Cxbladder Monitor Test as part of our discussion today. My name is Tamer Aboushwareb. I am the VP of medical affairs at Pacific Edge and I will be showing you data around our test today. As we discussed before, the hematuria evaluation of bladder cancer management presents a significant clinical challenge. Seven million patients present with hematuria every year, and 81,000 of those are diagnosed with urothelial cancer every year. The overall cost of urothelial cancer detection and management in the US is almost five billion, which makes it one of the most costly cancers to handle. Pacific Edge Diagnostics was started in New Zealand in 2001 with a main goal to deliver actionable results that can contribute to a clinically meaningful difference in cancer diagnosis and treatment. Through the development of state-of-the-art cancer diagnostics and prognostics, our US headquarters and proprietary CLIA/CAP accredited laboratory was established in Hershey, Pennsylvania. In 2011.

We commercially launched our urine based genomic messenger RNA biomarker test for bladder cancer, the Cxbladder test in 2013, and got approval from the New York Department of Health in 2017. Since then, we have validated our test in over 20 peer reviewed publications for bladder cancer detection and surveillance. And since launch, over 85,000 Cxbladder tests have been performed for more than 2000 clinicians in the US. We also launched the bladder cancer in-home sampling kit in 2020. Our test consists of five biomarkers and very briefly, I will go over these biomarkers with you. The top four biomarkers, as you can see, are involved in the varying aspects of cell growth, division and proliferation and show differential expression in the cancers of the urinary tract. That's why those markers were identified and used. The fifth biomarker, on the other hand, the CXCR2, the high expression of the fifth biomarker is indicative of inflammation of the bladder tissue.

The importance of adding this marker to our test was to differentiate between just pure inflammation versus the cancer that can also cause some inflammation. The Cxbladder Monitor test has shown to be validated in multiple publications over the years. Our first publication, the Performance Characteristics of a Multi gene Urine Biomarker Test for Monitoring for recurrent urothelial carcinoma in multicenter study was published in The Journal of Urology in 2017. And showed a sensitivity of 93%, 95 for high grade or late stage disease, and 86 for low grade TA and a negative predictive value of 97%. The second publication was a clinical comparison of non-invasive urine tests for ruling out recurrent carcinoma, which was published in urologic oncology in 2017 and showed a sensitivity of 91% negative predictive value of 96% and that the Cxbladder outperformed cytology and FISH independently and combined in detecting these tumors. The final study that was published in 2019 in European neurology was titled Evaluation of Cxbladder and Adjudication of Atypical Cytology and Equivocal Cystoscopy.

In this study, we showed that Cxbladder correctly adjudicated all urothelial carcinoma patients with atypical cytology and or equivocal cystoscopy, and ruled out 35% of patients with sensitivity of 91.5% and negative predictive value of 97.4%. Our first study for the validation of the test was the Kavalieris study that was published in 2017, and it was aimed to validate the multi gene messenger RNA biomarker test with sufficiently high sensitivity and negative predictive valve. To rule out the urothelial carcinoma patients with a prior history of urothelial cancer, thereby reducing invasive diagnostic evaluations without compromising patient care. In this study, we had 763 patients. They were all treated for bladder cancer, within the last two years, 1,036 samples were collected. All patients received cystoscopy and histopathology to confirm or rule out disease. The overall sensitivity in this study was 93% and the overall negative predictive value was 97% of importance here.

Carcinoma in situ had a sensitivity point 97%. The T1 tumors had a 100% and high grade tumors was 97%. All of that to show that our test almost never misses high grade tumors, the only misses sometimes that happen will happen in low grade tumors. The Cx Monitor algorithm offers high sensitivity and high negative predictive value combined for ruling out urothelial cancer. The second study I want to show you today was the Lotan study that was published in Urologic Oncology in 2017. And again, this study goal was to really compare the sensitivity and negative predictive value of the Cxbladder Monitor test compared to cytology and other tests that are FDA approved. The population was 803 patients treated for bladder cancer within the last two years. The results showed that UroVysion FISH exhibited the sensitivity of 33% and negative predictive value of 92%. Cytology and UroVysion when performed sequentially had an observed sensitivity of 38% and observed negative predictive value of 93% while in the same exact patient population Cxbladder had a sensitivity of 91% and a negative predictive value of 96%.

In conclusion of this study, the Cxbladder Monitor algorithm significantly outperformed current FDA-approved urine based monitoring tests as well as cytology in a larger representative population undergoing surveillance for recurrent carcinoma. We feel that this supports the use of the Cxbladder as a confirmatory negative to justify postponing cystoscopic investigations in select patients. Again, I wanted to mention that during the pandemic, we had introduced our in-home sampling kit, which made it much better for patients to have for the non-muscle invasive patient monitoring and recurrence. And the in-home sampling kit improved a clinic and procedure workflow through the identification of low probability patients, which you can delay action versus the standard clinical protocol patients. And the patient in home sampling to clarify equivocal hematuria workers, the presence of this kit I'm sure helped a lot of physicians to deal with their patients during a time where patients could not come to the office. Thank you very much for your time and listening and I'm happy to take questions and hear your point of view.

Neal Shore: So thanks, Tamer. That was a great overview of an enormous body of work, thousands of patients, hundreds of sites both in the US and outside the US. So I was great. The early slide, I mean 800,000 patients with non-muscle invasive bladder cancer in the US alone, the prevalence getting cystoscopy three to four times a year. And that nearly four, five billion dollar price tag. And so if we can use a test like Cx Monitor and cut down not only on that frequency of unnecessary cystoscopies, it's been my experience that most patients, the vast majority will say, "Oh, can we skip this cystoscopy?" They're happy to do it. Maybe it's one a year rather than for a year. And then as you point out during a pandemic where it was really hard bringing in patients who were both well, who were either elderly and frail or immunocompromised or had geographical barriers to be able to get a test that gives you, such as the Cx Monitor to give you the confidence to say, "It's okay, you don't have to come in and get the cystoscopy."

I mean the implications of for value based care, convenience to patient, most importantly safety, that we're not missing high grade cancer is a very compelling argument. And I think these are the types of strategies and Cx Monitor and the work that your team has done. And I know Josh and I have been proud to be part of some of the trials and ongoing trials is really important for our colleagues, especially those who are just still very busy, overwhelmed with a lot of throughput in their practice. And if you can cut down on the number of cystoscopies, frankly it opens your schedule to seeing more new patients. And so I think you did a great presentation. I hope our colleagues who are unfamiliar or haven't had experience with this biomarker look into it.

Joshua Meeks: I would agree with you, Neal. I mean, I think that my real experience with Monitor came during the pandemic and it was... Every patient sort of had a question, we'd go through every single case and say, "How much risk does a patient have? Is a worth it for them to come to our hospital?" And when you have to make a decision on every single case and you kind of have to risk stratify them, there's a lot of folks that were on their own, were asking for other alternatives. And that's where really we started looking at "Is there a way to do this?" And then the fact that it's a home test, the fact that you can put an order in and then very quickly get the results back, I think that just made this very easy to use. Patients were satisfied with it, even when it was positive, they had a justification to come into the office for a procedure.

So I think it really starts opening the question up for patients about how often do we need to do cystoscopy? And a good way to begin is folks who are at the end of their surveillance, they're not getting intra-vesical therapy, they're past that window and you're following them and they're asking you, "How often do we do this?" And again, for folks that I think can move on to stopping cystoscopy, which is often very hard to do for many folks who want that reassurance is saying, "Well tell you what, in six months we'll send this to your house." And that works really well as an implementation, you can use it for anybody. But I think that's where we've really started to apply it, is to deintensify some of the burden for folks. And again, if it's positive with the numbers you showed, I mean that in a very low false positive rate and a very high negative prediction value. I mean, I think that's really where we said, "Okay, this is positive. You need to come in."

Tamer Aboushwareb: That's great to hear. Thank you very much both of you for your confidence, number one, and of course for the feedback. So I do have a question for you because let me say first, our data indicate that our best time to start using the test is about nine month post original diagnosis, which usually I would say, again, I'm not going to say how you practice, but generally speaking, I assume most urologists would like to do after the first diagnosis, would like to do the first cystoscopy to make sure that there're no recurrences.

Since these are the most common recurrence time by nine months, that's maybe when you might start to see or want to use a test. If you start using it nine months or later, whatever, what is the cadence that you would think about this? If it's early on would you do one time the test and if it's negative you can skip and then do cystoscopy? Or would you do the test every single time and the longer you are after the diagnosis, how would you change that if the case? So I would like to hear your opinions on that.

Neal Shore: Well, it's a good question. I think that there's a lot of variability here and I actually enjoy the variability to the answer. And I, God help us if we can stop having the art of medicine. And at the same time, we like to have an algorithm. A lot of our colleagues will say, "Well, if you just tell me, give me a cadence, a schedule." But it really depends. As I think as Josh said earlier, what was the original stage? Was it TAG3? Certainly for CIS and T1 patients, we're going to be scoping them and they're going to be receiving intra-vesical therapies. But for those patients who have not had any recurrence after their intra-vesical treatment, whether it was approved therapy or clinical trial and they've been free of disease and we want to relinquish them from the burden of Q3 months cystoscopy.

And then the other group of patients who have really low grade disease who we are pretty confident they're not going to recur, and yet we don't want to do unnecessary, repetitive cystoscopies, there's that spectrum. And so how old are they? What are their travel dynamics? Is there a pandemic going on or not? And some of it can be... What's their healthcare coverage? So I try to be as precision based as possible. I have to say in my career, if I can avoid unnecessary endoscopic procedures and feel comfortable and explain to the patient that I have a simple urine based test like Cx Monitor. I find that 95 plus percent of patients are very happy to have that explanation and avoid a cystoscopy

Joshua Meeks: I'd say, you live in a very different climate than I do, Neal, as far as the temperature. And I have a lot of folks that leave Chicago in the wintertime and when they're away and rather than return all the way back to the city, this gives them an opportunity to do a test. And it's not that you're, again, you're never going to come back to the office, but if you're thinking instead of coming back in January for cystoscopy, you could be risking all of that. It could even just delay that some, because you're confident that everything looks good. So I think with our population, oftentimes the winner is a very appropriate time to release, considering people that are in the right, again, they're probably not receiving intra-vesical therapy, but again, it's a discussion with every patient. And I just think it's another tool to use with folks to think about following their cancer and doing the best to give them the best care you can.

Tamer Aboushwareb: So if I understand correctly, I guess maybe the best way to describe it is really personalized medicine, really, where every single patient is going to be personalized depending on their own situation. Your assessment of risk and so forth, but you still feel that there's going to be a pathway to use the test in almost all patients, but just in different timeframes and different time points and different cadences.

Neal Shore: Yeah, I think that's fair. I think it's clearly patients who have high grade NMIBC who are undergoing active treatment, invariably it's going to be an intra-vesical therapy, could be systemic therapy with a checkpoint inhibitor. But outside of that group, I think you have those, you can frame it, bookend it for the less aggressive, and those who were more high grade in NMIBC who are now free of disease after a comfortable period of time.

Tamer Aboushwareb: Sounds good. Perfect. And how would you maybe suggest, what would be the next step for a test like this? We already know that our test has a very high negative predictive value. We already know that we provide a really solid negative for this test. What else can we do to maybe enhance our products, enhance the offering that we have for the patients? Is there anything that we can do more for upper tract tumors or a different type of problem that you can have in these patients?

Neal Shore: Well, I'll defer that to Josh because he's doing some pretty cutting edge work in both upper tract and lower tract in terms of where we are in terms of the therapeutics. But I love your comment though, Tamer on, it is about precision based care and individualizing to patients and patients are getting that now. That's an overarching theme across virtually all cancer types.

Joshua Meeks: Yeah, I mean think the two things I would really take with that would be thinking about it as an outcome of minimal residual disease. You report on five genes and the tests come back to us, it's not quite black and white, but there is a threshold and above the threshold we tend to have more concern than others. But we don't really know qualitatively what the threshold means. And I think tailoring that to the patient through therapy, I think that would be a very intriguing question. As far as during therapy, "Is the number going down and how much does that represent mineral residual disease?" I think that's a pretty important question for disease response. And I think from a patient perspective, receiving information about what the result shows and what that means. And I think, again, any kind of patient forward kind of results that is really meant for them to understand because we're going to talk to them about it. But I think if they have some of that information already and are kind of armed with it, I think that can only really add to the benefit of the test.

Tamer Aboushwareb: That's perfect. Great. Thank you. That's actually very good advice. And that's also one of the things that we consider regularly as a company and how to improve, facilitate the understanding of our test results to patients, obviously to physicians, but certainly physicians are much easier to explain to, but how to make it as easy as possible for a patient to understand what that result means and what the risks are and so forth. So, that's certainly something we can work on with you all. Would either of you have any questions for me?

Neal Shore: Well, I know you guys are doing some additional trial work, you've been enormously proactive in that over the last decade. So I would say we thank you for that. And I know we're an ongoing trial right now, so I think this is how we continue to make advances and this is a field that needs advances for all the reasons that we've talked about.

Joshua Meeks: Yeah, I mean, again, I think working with patients and patient advocates is only going to often result in greater strides, right? Because they're the ones at risk, but they're also the ones who have to balance procedures with molecular testing. So I think they're likely, from our experience with patients who've received the test, they're going to be an advocate for it.

Tamer Aboushwareb: Well, again, thank you very much for your time and thank you very much for your feedback. I appreciate it. And until we meet again, thank you.