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Ashish Kamat: Hello everyone and welcome to UroToday's Bladder Cancer Center of Excellence. I'm Ashish Kamat, Professor of Urologic Oncology at MD Anderson Cancer Center. And it's a distinct pleasure to welcome one of my colleagues, Omar Alhalabi, who is a medical oncologist right across the hall actually from me. And we actually share a clinic and we share bladder cancer patients. And it's a great privilege and pleasure to have you on the forum, Omar. Welcome to the forum.

Omar Alhalabi: Thank you, Ashish.

Ashish Kamat: And we're going to have you share with us first one of your works that was highlighted and presented at ASCO on the prognostic factors of relapse in surgically resected small cell neuroendocrine carcinoma of the urinary tract. So Omar, take it away.

Omar Alhalabi: Thank you, Ashish. Thank you so much. It's my distinct pleasure to be on the UroToday platform joining you at the Bladder Cancer Center of Excellence. I appreciate this collaborative work that's been done in collaboration between medical oncology, pathology, and urology to name a few.

This is a piece of work where we looked at patients that have the rare variant histology or subtype histology of small cell neuroendocrine carcinoma in the bladder or upper tract disease. We looked at specimens from TURBTs, or transurethral resections, cystectomies, as well as at the time of relapse with metastatic disease. And this was presented at ASCO this year as a poster by our postdoc fellow, Dr. Moussa.

So as an overview for this talk, I will cover why we study small cell neuroendocrine carcinoma. And how is it different from conventional urethral cancer? We'll cover the neoadjuvant chemotherapy and the data that's been known so far for localized disease. And then the histological patterns of relapse in this disease as well as risk factors. And this is the new part from our work and then the next research directions.

So as it is probably known to the audience, small cell neuroendocrine carcinoma is different than conventional urethral cancer in terms of being often diagnosed at later stages. As you can see on the left side from this review article published in 2006, the majority of patients are diagnosed in stage two, three, or four. And their survivals compare inferiorly to on the right side the data that we gathered from the cancer.gov website for conventional urethral cancer where the majority get diagnosed in localized stage and have a better long-term survival. And so, small cell urethral cancer or the variant of small cell neuroendocrine carcinoma in the urinary tract represents an area of unmet need.

We had previously shown in a comparative effectiveness analysis that was published in European Urology late last year, the different ways of treating patients in the perioperative space. In this work, we looked at different neoadjuvant chemotherapy regimens that have been given historically at our site. And we looked at the differences in terms of achieving a pathological response at the time of cystectomy in patients that neoadjuvant chemotherapy versus not.

As you can see in the top figure, the dot plot, patients that receive neoadjuvant chemotherapy have a significantly less likelihood of having remaining neuroendocrine carcinoma component and a higher rate of achieving a YPT0, YPTIS, or what we refer to as pathological complete response. The different regimens, whether they were cisplatin etoposide or adriamycin had slight differences in their performance. But overall, the benefit that was derived was consistent across these different regimens. And we make the case in this paper to prefer small-cell-based regimens that are based on etoposide cisplatin.

We looked at survival and patients that received neoadjuvant chemotherapy in this effort showed a significantly improved overall survival, as you can see in Graph G1. The different chemotherapy regimens, again, it was difficult to show or discern preference between them. But when we grouped them as small-cell regimens, etoposide or adriamycin alternating with cis-etoposide, they showed a slight benefit over MVAC or IGEMSYS, the conventional urothelial regimens. Of course, it's a retrospective analysis and it's subject to limitations such as selection bias, small sample size, etc. We did an exploratory analysis in that previous effort and found a preliminary signal of association between BRCA1 and BRCA2 mutations, as you can see on the left side, with achieving a pathological complete response, as compared to the group that did not achieve this response.

Now leading on to this current new effort where we looked at the prognostic factors of relapse in the surgically-resected small-cell neuroendocrine carcinomas of the urothelial tract. And this is a picture of our stellar fellow Dr. MJ Moussa, who highlighted this work at ASCO. We basically had the methods of looking at a historical cohort of two-hundred-and-sixteen patients who underwent surgical resection for T1 to T4 disease with either node-positive or node-negative disease with no metastatic disease at our center, spanning across more than 30 years' experience. And then we captured the relapse events after surgery in a time-to-event outcome and looked at computing risk in a non-parametric method.

This is a summary schema of the timelines where initially here, patients had a transurethral resection and had a TUR where they basically had broken down between having small cell neuroendocrine carcinoma alone or predominant histology or having it as a minority. A majority of patients at our center received neoadjuvant chemotherapy, 72%. And then at the definitive surgery, we found that the receipt of a neoadjuvant chemotherapy alters or makes it more likely to not see residual small cell at the time of definitive surgery, as compared to the patients that did not receive neoadjuvant chemotherapy. And then this seems to correlate with the risk of relapse. We had 41% relapse on long-term follow-up, 55 did not relapse, and 4% were lost to follow-up.

When we looked at the cognitive incidence function for relapse, it seemed to be that patients that had the highest percentage of small cell remaining after neoadjuvant chemotherapy at the time of cystectomy, carried the highest risk of relapse with a five-year cognitive incidence of almost more than 80% in terms of relapse. And then the risk of relapse was decreasing the less small cell was captured in the time of cystectomy reaching the best group that had achieved PCR after neoadjuvant chemotherapy with a cognitive incidence function of less than 20% over five years.

On the other hand, pathological stage also correlated with the risk of relapse with the patients that had node-positive disease carrying the highest risk of relapse of 80% plus. And then neoadjuvant chemotherapy also carried an improved or reduced risk of relapse long-term. The primary site of cancer, whether it was lower tract or upper tract, did not really correlate with the relapse function.

This is a breakdown with a numeric breakdown of the events that we called failed events, which indicates relapse, competing events, which is dying from a reason that wasn't cancerous, and then censored, which were the patients that did not have a relapse. And again, this is just a summary of the figures showing that the histology at risk section did carry a predictive role in terms of predicting relapse.

When we looked at the univariable and the multivariable analysis for relapse, we do see that the hazard ratio for having any small cell residual at the time of cystectomy, 87 patients compared to 40 that had residual histology but it was not a small cell, the hazard ratio of increased relapse was 3.4. Receipt of neoadjuvant chemotherapy carried a protective impact from relapse with the hazard ratio of 0.45. The stage of diagnosis having locally advanced disease with T3 T4, or node metastasis carried a higher risk of relapse with a ratio of two. And then the same for the stage of resection.

Now in a multivariable analysis, the factors that remain significant were having any small cell at the time of cystectomy the ratio of 3.7. As well as the known factors, which include having a higher clinical stage of diagnosis with a local advanced disease or having residual lymph node metastasis at the time of cystectomy.

In terms of future research directions for this effort, we believe or our hypothesis is that small cell differentiation in bladder cancer drives a distinctive tumor immune microenvironment, and confers an early metastatic potential. It produces unique surface antigens and provides biological vulnerabilities that can be effectively targeted with combination therapies.

We aim to define the oncogenic and immunologic effects of small cell differentiation in bladder cancer using our clinical specimens, the baseline transurethral sections. Determine the evolving oncogenic and immunologic drivers of the relapsing clones as compared to the primary tumor using our clinical specimens as well. And then hopefully, this will lead to developing novel and biology-informed preclinical combination therapies for small cell bladder cancer that can hopefully translate into the clinic and help our patients with this aggressive variant.

In summary, small cell neuroendocrine carcinoma of the urinary tract benefits from neoadjuvant systemic therapy. The persistence of small cell neuroendocrine carcinoma at surgery is associated with a high risk of relapse. Our findings highlight the need for neoadjuvant or adjuvant approaches that target the small cell carcinoma in a better or more specific way to decrease the risk of relapse in these patients. Thank you.

Ashish Kamat: Thanks, Omar. Thanks for that summary of the work that you've done so far. And congratulations, once again.

So you presented the factors that are associated with the relapse and clearly we always look for factors that we can modify and factors that we can't modify. When you look at the presence of persistent small cell neuroendocrine component on the final pathologic specimen, in some ways, that appears to be a modifiable component, but it also could be non-modifiable. What's your sense, based on the work that you've done so far? Is it something that we could actually modify maybe more cycles of neoadjuvant chemotherapy? What are some of the clues that you came up with in this work?

Omar Alhalabi: That's an excellent question, Ashish. Thank you. At the moment, I have to be honest that it does seem maybe non-modifiable. However, the hope is with some work that we're doing to characterize unique surface antigens that are more so seen in the small cell differentiation as compared to the urothelial differentiation. And we learn from the small cell lung cancer experience, for example, Nectin-4 expression is not really seen that much in these variants from our experience, as compared to the conventional urothelial cancer. However, on the other hand, there are more unique antigens such as B7-H3 and others that are being explored in the small neuroendocrine carcinoma world that we believe could represent an avenue to explore in the adjuvant space.

It's plausible that chemotherapy or trying to maximize the benefit of chemotherapy preoperatively could reduce the likelihood of seeing small cell at the time of resection. However, in our experience, there is still a population of patients that despite getting maximum chemotherapy preoperatively, they still had persistence of resistant clones of small cell. And those probably need a more novel therapy.

Ashish Kamat: Yeah. No, again, you are young and you have many years ahead of you, right? So you're looking at the long horizon, which I think is great. But for our global audience and for patients who are looking at right now, if you see a patient in front of you in the clinic today that has bulky disease in the bladder, knowing what you know now, considered a standard preoperative number of cycles? Or are you now tempted towards extending it? And maybe having your urologist, and I'm speaking for myself too, involved a little bit more in advising on the number of cycles based on the bulk of disease?

Omar Alhalabi: That's a great question. So, we believe that a specific number of cycles is... Obviously the patient's tolerance and their ability to handle toxicity is the top priority here. But in our experience with this variant, what we have done is to give two cycles beyond maximal clinical response. And so oftentimes, we will restage patients after every two cycles, so every six weeks, either with imaging which includes a CT urogram or an MRI, as well as a repeat cystoscopy or exam under anesthesia to assess the benefit.

And once we believe the patients had reached maximum benefit from the neoadjuvant phase, we give two cycles beyond maximum benefit. So sometimes this does end up exposing the patient to six cycles, maybe sometimes eight cycles. Obviously tolerance again, is key and making sure there's no accumulative toxicity. But we do see that in our data set, and this is an excellent question that we will definitely circle back and probably publish, the inferior number of cycles does lead to higher residual small cell at the time of cystectomy. So, thank you for that insight.

Ashish Kamat: Yeah, I think it's an important point to bring up. The other question I wanted to ask you is, and this might've been before your time at Anderson, but I'm sure you're aware. And I know you are aware that we used to offer prophylactic cranial radiation for patients that had bulky disease. And of course, we had a prospective trial that Dr. Choi was leading. And I keep asking him, he needs to publish at some time because it was a worthwhile publication.

But with this knowledge that you have now, with patients that start out maybe with bulky disease. Maybe we don't consider them for whole-brain radiation, but now they have residual disease after therapy. Are you incorporating ctDNA for these patients? Are you incorporating maybe consideration of whole-brain radiation? How are you counseling these patients in the post-operative setting?

Omar Alhalabi: That is a great, also excellent question. So, we are very soon going to explore a risk calculator for the development of brain mets in these patients that are long-term being followed. And we are testing in collaboration with Dr. Choi, the impact of prophylactic cranial radiation in preventing this whether they were on a clinical trial or in the standard of care.

As you may know, in small cell lung cancer, the enthusiasm toward prophylactic cranial radiation has been... it waxes and wanes. And so that does influence how we view this, given that our numbers are always going to be smaller. And it's going to be much more difficult for us in this rare subtype to make strong conclusions as our small cell lung colleagues. But it is a consideration. I discuss it with patients, especially if a patient, despite as much as we could give neoadjuvant chemotherapy, still at the time of cystectomy, had a T4 disease with several lymph node metastases and the histology was small cell, this does have more than 80% in our data, risk of relapse. Majority will relapse until proven otherwise.

And we are looking at the sites of relapse. It tends to be 15% are relapsing with local disease, with lymph nodes or in the surgical side. But 85% are relapsing in other sites, lung, liver, or brain. Actually, 20% is relapsing in the brain. And I'm sorry I didn't show that data, but that percentage makes it worth considering and discussing with the patient. But more to come on this.

And whether ctDNA can help us, we are pursuing efforts in collaboration with our industry collaborators in collecting specimens on these rare variants. And see if the experience that's transpiring in traditional or conventional urethral cancer can be also used in these rare variants.

Ashish Kamat: Yeah. Again, I've always said small cells should be considered a systemic disease that just happens to manifest first in the bladder. Because otherwise, we're doing a patient a disservice, right? Local consolidation, whether it's surgery or partial cystectomy or even radiation, is just a small part of this whole journey for small cell carcinoma of the bladder. So a very, very important point and important data that you presented.

Omar, thank you for taking the time. It was a pleasure seeing you virtually. And I'll see you in clinic shortly.

Omar Alhalabi: Thank you, Ashish. Thank you so much.