Bladder Cancer Treatment Algorithm Discussion with Drs. Karine Tawagi and Sia Daneshmand

Intro Hello everyone I am Rahul Gosain. Speaker 2 And I'm Rohit Gosain. Speaker 1 And we are the oncology brothers. Today, we're excited to have a fellow Canadian who's also a friend and famously known as one of the two docs, Doctor Karine Tuaji, a medical oncologist and then a nationally renowned researcher and a urologist, Dr. Sia Danishman, from Southern California, to discuss their approach in treating bladder cancer using an algorithm and to reiterate the current standard of care treatment options. Karine and Sia, thank you so much for joining us. Speaker 3 Thank you and pleasure to be here. Speaker 2 So as you were starting off with just covering the entire bladder cancer, you have to teach us in 15 minutes. Early stage bladder cancer So starting off CEA with non muscle invasive bladder cancer, urologist here play a huge role where we have BCG which we have been utilizing for years now. Recently we have data on pembrolizumab and a vaccine CEA if you don't mind going over your approach here in early stage or non al invasive. Speaker 3 Yeah, thanks. It's a a large topic to cover, but I'll I'll try to do it some just this year. So yeah, as you have it right there, I think the most important is, is categorizing this between low grade and high grade or you know the what we call the AUA risk categories. Typically the, the low grade tumors are not once we are concerned about progression, but we're certainly concerned by recurrence. And so for the most part they're undergoing cystoscopic surveillance. Occasionally we do use some intravascal chemotherapy. We try to not to use BCG in this setting because of the national shortage and the fact that low grade tumors are really not all that responsive to BCG anyway. So if anything intravascal chemotherapy for bladder for the low grade tumors, if they're recurrent then they become this intermediate risk category. And we do have a number of clinical trials right now investigating a number of agents that hopefully will reduce the recurrence rates. And again we're not so concerned about progression in those patients because that tends to be less than 10%. Usually the high grade ones are the ones that are that are worrisome, right. Those, those are the ones we are concerned about not just recurrence but also progression to higher stages and potentially even muscle invasive disease as 20 to 25% of these can progress to muscle invasive disease. So that the mainstay of therapy for that would be PCG still after 40 years, but things may change a little bit in the future. Again, we're having a major national shortage right now of intravesical PCG. So other agents are being tested in this setting to to see if we can replace BCG or at least alternate and be able to use some other form of intravascular therapy. So I like your, I like how you have this represented here. I think this is sort of from a sort of 30,000 foot square a view of this this would be how we manage it. I I see up there you have Nada Ferragen Ferragenovac, which is the newest agent that was approved for BC2 refractory CIS plus minus papillary disease. That was just approved actually last year, but became available first to a select few centers in the US in October and then and then widely available as of January 17th. So that is in our armamentarium right now that's known as etstilotran. Again that affairs unit fared on effect. First gene therapy to be used for bladder cancer, Pembrolizumab does have a role for BCG refractory CIS as well. That was the first agent that was approved in 2020 and that is again used for BCG refractory CIS plus minus papillary disease. The only issue is you guys are very familiar with pembro obviously you use it in so many different disease states, cancerous and and the issue is you know we're we are dealing with a a non muscle invasive bladder cancer and the use of checkpoint inhibitors in this setting does give us a little bit of a pause given the potential for life threatening side effects or you know life altering at least side effects where you know as urologists we're used to just keep treating with patients with with intravascal therapy. So radical systemically always remains as the sort of gold standard option for BCG refractory disease, but that's being utilized less and less as we have more and more options for patients who are have not progressed to invasive disease. Speaker 1 Absolutely. Thank you, Sia. A few things to reiterate that the bulk of our patients when diagnosed with bladder cancer indeed have an early stage cancer and it's also important to appreciate the extent of the disease. It is important for us to have adequate sample or biopsy to make that decision saying is this indeed muscle invasive or non muscle invasive? If not, then Corrine's going to jump on and would remind that the board exam answer here is to repeat the biopsy. I mean since 2020 Sia alluded to this pembrolizumab has been approved for high risk non muscle invasive bladder cancer that's not responsive to BCG. We have other options available as well. Have you noted a lot more referral to medical oncologists in the community or in academic centers because of disapproval? Yes. Speaker 4 Definitely I think but SIA brought up some good points. You know first of all it's two years of therapy, not just one year. And then second of all, the toxicities that could be lifelong from immunotherapy are not to be discarded. So I think there were about 10:00-ish percent or so of patients that got pembrolizumab that had grade 3 or 4 toxicity from immunotherapy. So I think that's definitely something to consider, but I do think we are seeing more of these non muscle invasives in our medical oncology clinic and you know with some of the new treatments that are coming out, you know we may continue to see more of these patients as well. Speaker 2 Another option that CA you did mention was cystectomy, though a lot of our patients don't tend to rely on that because of the quality of life issues associated with it. Now we also in the era of BCG refractory or BCG shortage, we have the option of gemcitabine, Erdafetanib intravesticles. CAU have been very much involved with the phase one trials of it. We'll have to see how it all pans out, but certainly an option for future itself. Now looking at muscle invasive bladder cancer where medical oncologist plays a huge role here, Corrine your approach here particularly for cisplatin eligible versus cisplatin ineligible patients? Muscle Invasive Bladder Cancer Yeah, absolutely. So I think most of the time these patients are of course seen by urology first and they'll have you know a resection of the bladder tumor and then if there's bound to be muscle invasion, then it will be properly staged. And then referred to medical oncology for consideration of chemotherapy prior to cystectomy if they're eligible or consideration of chemo radiation if they're also a candidate for that. So I think the categories that you have here, so cystectomy eligible, you can go into cisplatin eligible versus cisplatin ineligible. And so for cisplatin eligible, we know that there is a defined role for neoadjuvant chemotherapy and those options are gemcitabine, cisplatin as well as dose stents and back. And so I think in the community and at academic centers, I think gemcitabine cisplatin is the most commonly used regimen and that's given every three weeks, usually for four cycles. But if there are positive lymph nodes, maybe providers will choose to go up to six cycles for younger fit patients, you can consider Dosanth MVAC, The Vesper trial released its final overall survival a few months ago and there was a benefit of using this regimen. It does include an anthracycline, so you have to be more wary of cardiotoxicity and things like that. And that's given every two weeks up to six cycles as well. And then for those patients that qualify for cisplatin, then they can get the new adjuvant chemotherapy then go to for cystectomy. Even for patients that are suspectingly eligible, you can consider bladder preservation if they meet the criteria. So I think that if a patient meets the criteria for bladder preservation, they really should still be offered both options. And so criteria for bladder preservation or concurrent chemo radiation include smaller tumors usually under 5 centimeters. Although some radiation oncologists may be more comfortable at a higher size if they can have maximal resection by the urologist of the primary tumor if they have adequate bladder function and no hydronephrosis as well as no CIS. And so often times when we see those patients after the referred from urology, we consider if they're eligible for both options or not. Another thing I wanted to mention for cisplatin eligibility is noting if they have hearing loss, if they have pre-existing neuropathy, if they have renal dysfunction, usually a GFR cut off with 50 or so is our cut off for cisplatin whether they have heart issues and what their performance status is. And so for some more elderly patients, they may not be eligible based on frailty. And then for SIS button ineligible, we know that there is no defined role for neoadjuvant chemotherapy and so that's where patients go to cystectomy right away. So I think if you're looking at this algorithm here for cystectomy eligible that are CIS plan ineligible, then you can fall into the secondary category of cystectomy and then we'll finish for the cystectomy eligible for those patients. We know that if they have residual disease after the cystectomy and they've had new adjuvant chemotherapy meaning they were CIS plan eligible. There is a role for nivolumab immunotherapy for one year after the cystectomy if there is still a residual muscle invasive disease at the time of surgery and so that's T2 or greater or if they have positive lymph nodes that's based on the Checkmate 274. We don't have overall survival survival data for nivolumab. So I think again it's a risk benefit discussion. There can be some long term toxicities from immunotherapy that we need to be aware of. There also was the AMBASSADOR trial that presented recently pembrolizumab in the adjuvant setting, which also didn't have overall survival benefits. It's not FDA approved. So I think we can leave nivolumab on there for the point of this discussion. And then for patients that did not receive neoadjuvant chemotherapy going to the second arm here that undergoes cystectomy, you can consider giving them adjuvant chemo if they're eligible for cisplatin. But really those patients that are eligible for cisplatin should have received it in the neoadjuvant setting and then if they were not eligible, you can consider adjuvant involvement. So in the second arm of muscle invasive for patients that are cystectomy ineligible or the caveat that I would add is patients that are cystectomy eligible but prefer to keep their bladder, you can do chemotherapy with concurrent radiation and I mentioned some of the eligibility criteria. Those regimens are often 5 if you with mitomycin C, it's about a five week regimen. You can also consider gemcitabine alone, you can consider cisplatin alone. There have also been some especially in COVID times providers that gave capacitabine as a sensitizer to have an oral option. But I think that for patients that want to keep their bladder, we know that there is a quality of life benefit for patients that do keep their bladder. And so that should be considered for patients that are eligible. The caveat is that of course keeping your bladder you have a higher chance of local recurrence. For some patients, they may not be eligible and if they if they have to be compliant with cystoscopies as part of the surveillance moving forward. Speaker 3 I just add to that, approximately 30% of patients are ideal candidates for chemoradiation. So it's not for everyone. You do have to consider that if they fail about 15 to 20% will move on to cystectomy as a salvage option and they may not be eligible for a neo bladder at that point having had radiation in the pelvis. So things to consider that there is a 1520% failure rate with chemo radiation and as Karine mentioned that there are a lot of non muscle invasive recurrences which means more intravesical treatments in a radiated bladder that may be poorly tolerated. So she, I I think Corinne mentioned the beginning good bladder function that's I can't stress the importance of that because if you've got a bad bladder already that's low capacity, low compliance irradiating it, it's is going to make it even worse so. Speaker 1 Yeah, there's a lot that's happening here. So, Corinne, thank you for walking us through so elegantly. One thing I want to mention that in the community the usage of cisplatin has been a lot lower than what it is in academic centers. Split cisplatin dosing And the reason why I want to bring that up is carboplatin in neoadjuvant settings is subpar and we can consider split cisplatin dosing in certain patients if need be. If we are doing that Karine, what does split cisplatin look like? Like what does that infusion regimen looks like in your clinic today? Speaker 4 So then you get this sysplatin instead of on just day one of the 21 day cycle, you get it on day one and day eight at a lower dose of 37.5. And I actually consider that for a lot of patients that you know maybe have more of the border lines plan eligibility features. But I think to your point, yes, carboplatin in the new adjuvant setting is inferior and we really need to advocate for patients to be considered for new adjuvant treatment if they qualify in the community. Speaker 3 Yeah, I can't stress this enough myself that CARBO really has very limited role in non metastatic disease. In bladder cancer, I would say not even limited has no role and so it should not be used in the neoadjuvant or adjuvant space in bladder cancer. The only indication for it would be a ineligible patient and that now with EV pembro, I think that's been supplanted as well. So I see a lot of people sort of starting out with CIS and going to to Carbo after. They're not interchangeable. They should not be used in that setting as as Kareem said. Speaker 1 Thank you. Speaker 2 Now talking about metastatic disease based on ASMO 2023, we saw the standard of care change. Metastatic disease In fact where we used to be using cisplatin if patient is cisplatin eligible and or relying on carboplatin based regimen. Now after EV3O2 showing doubling of overall survival with EV pembro rightly so. Doctor Powell's got standing ovation for this. Karine, your approach in this setting here. Speaker 4 Yeah, I think that was really exciting. It completely changed the landscape of advanced metastatic bladder cancer. And so I think based on EV3O2 data from ESMO, I think everyone's first line standard really should be in fortumab pembrolizumab. As you mentioned, there was doubling of the overall survival and doubling of the progression free survival. About 30% of patients had a complete response, which is amazing and 70% of total patients had a response. And so I think most patients are going to be candidates for in fortumab and pembrolizumab. A few caveats are if you have uncontrolled diabetes, if you have cirrhosis or child pure B or greater, there's maybe a bit more concern for toxicity if you have pre-existing neuropathy which would in fortumap can worsen neuropathy, but of course cisplatin can also worsen neuropathy. So in general, I think that this is our new really exciting standard of care in the first line setting. I think that maybe in the community also there is less of a defined roles of how to manage toxicities from antibody drug conjugates. And this is going to be really an evolving paradigm that we're going to have to be really conscientious of because we had that with immunotherapy where there was all these new toxicities that we have to learn how to manage. And I think the same now is true for these antibody drug conjugates. We do want patients to get what is now considered to be the best standard of care both at academic centers and in the community, but also to be comfortable with managing these toxicities. And as a group, we have to do better in terms of defining these managements or these toxicities. And so I think that for most patients that would definitely be the standard. I think what to do in the second line setting after EV pembro is a very big question mark. What to do in the second line setting after EV-Pembro So they're in the protocol. We don't have the full paper out from EV3O2, but there were some patients that got chemo after EV pembro. So I think you can consider platinum based chemotherapy. I think one of the concerns again is if they have neuropathy from the infortumab, are they going to be eligible for cisplatin, are they going to be eligible for chemo at all after progression or toxicity on EB pembro? I don't know that there's going to be a huge role for docents MVAC in the second line setting. And then if they do qualify for chemo, what are the response rates going to be? Are we going to expect the same kind of response rates as we saw in the first line setting which was in the 40% range? And then if they do get chemo, is there a role for maintenance evelumab or immunotherapy? And so I know we've seen in in kidney cancer for example that re challenging with immunotherapy did not have good efficacies. So I think that it's quite possible that the same will be the case in bladder cancer and there are going to be trials looking at what to do in that second line setting post EB pembro. Unfortunately, I don't think we're going to have a comparative trial where it's going to be chemo versus sassituzumab versus these FGFR agents. So really we're going to be plagued with comparing individual trials to decide what to do in the post EV pembro setting. And so I think for patients that are chemo eligible, I would consider chemo in the post EV pembro setting. I would also send for next generation sequencing and if they have FGFR 3 mutations, I would consider erdafitinib in that in this setting. And then in terms of Fasta, Tuzumab, it has been approved in the post chemotherapy post immunotherapy setting. It had response rates in the 20% range. And so how is that going to perform after EV pembro, it's another antibody drug conjugate that has different toxicities from infortumab. So theoretically you know it could be well tolerated. There are ongoing trials looking at it in this setting and so I think that could also be an option, but I think this will be an evolving field for sure in the next few years. Speaker 1 OK. Radical Cystectomy in Selective Fit Patients Wow, there's a lot to unpack here. This is, this is great. Dialing this back a little to Evie Pembro. Corinne, you mentioned 30% complete response. I would love to see CTDNA playing a bigger role in defining complete response, but SIA? Any role of radical cystectomy in those selective fit patients that got complete response. Speaker 3 Yeah, it's a great question and and I I don't think we've quite, we don't we don't know the answer. You know there's some patients who go on to EV pembro for locally advanced disease that this includes pelvic lymph nodes. And so we're seeing some spectacular responses in those patients, but they may have some disease in the bladder. We've selectively taken patients to the OR and and seen some actual CRS with EV pembro where the imaging didn't quite show us what we thought was ACR. So I think it's an evolving field and and I'm not sure what the role of cystectomy will be in, in some of these patients, but certainly the the ones who have residual disease in the in the bladder have responded in the lymph node. I think there will be a role and to your point, I think CTDNA will will play an important role in determining whether now we should be taking these patients. If their CTDNA is positive, they probably have some element of systemic disease and maybe we shouldn't be doing localized either radiation or cystectomy, whereas the ones who are CTCTDNA negative, perhaps they're the best candidates for moving on to localized therapy. So. Speaker 1 Evolving field and again these we have new options in community. We need to start to get comfortable in managing some of these side effects. Screening for infotumab, you've mentioned peripheral neuropathy, diabetes. We have to keep an eye out for skin reactions with sassitizumab. We've used this in breast cancer as well. Something to be mindful about is diarrhoea, neutropenia and then I have a patient who's actively on Erdofutenib. Keeping phosphate abnormalities is important, creating any clinical pearls around these agents in managing their toxicity. Speaker 4 I think for infortumab, you know dose reductions are very common specifically for neuropathy or even for the skin toxicity. So that frequently happens. I think for patients that have a response, some providers are choosing to drop the infortumab if they get to that complete response, let's say there's not a defined period, but maybe you can use CTDNA to support, you know, let's say at six months or nine months or a year they're have a response. Maybe you just keep them on pembrolizumab, I think you know for the skin toxicity, you know topical steroids and antihistamines and things like that. I think for sassatusumab it's important to consider primary GCFGCSF prophylaxis. There was actually a retrospective study at ASCO that looked at patients that got GCSF prophylaxis with sassatusumab if you can get it approved by insurance and there was no severe neutropenia for those patients. And you know, I think for urdafitinib, to your point, you know the the phosphate binders is a big thing as well. And then having a good rapport with specialty services, you know there's rarely ocular toxicity within fortumab or even with purdefitinib. So it can be. Speaker 3 And the nail toxicity is it, that's quite unique. Speaker 2 Well, we've covered a lot here in last few minutes, covered the entire bladder cancer paradigm from medical oncologist and urologist standpoint. Outro CIA, Karine, thank you so much for going over this current standard of care options in bladder cancer for our listeners. Let us go over a quick recap. Speaker 1 In this discussion with Doctor Karim Tuwaji, a medical oncologist and Dr. Sia Danishment, A urologist, we've covered the current landscape of bladder cancer. We had a chance to focus on growing options in non muscle invasive space as our patients continue to ask for us to do better than just radical cystectomy. Speaker 2 Then we also had a chance to discuss localized muscle invasive bladder cancer and our options for including current role of immunotherapy in adjuvant settings. We then covered the new standard of care which is EV with pembro along with options such as hertafutinib and sastatusumab for metastatic disease. Thank you for joining us. Make sure to check out our renal cell cancer discussion with Doctor Monty Paul and prostate cancer discussion with Doctor Rayna McKay. We are the oncology brothers.