FormalPara Key Points

Platinum-based chemotherapy has been a standard treatment for patients with advanced urothelial carcinoma for decades based on its proven efficacy, and criteria to assess eligibility for treatment are well established; in cisplatin- or carboplatin-treated patients who have a response or stable disease, avelumab first-line maintenance has been shown to prolong overall survival and is a recommended treatment approach.

Enfortumab vedotin plus pembrolizumab has recently shown superior efficacy compared with platinum-based chemotherapy in patients with advanced urothelial carcinoma; however, the distinct toxicity profile of enfortumab vedotin plus pembrolizumab may make it less suitable for some patients and may limit the potential for receiving subsequent treatment.

In a phase 3 substudy in cisplatin-eligible patients, nivolumab added to cisplatin and gemcitabine treatment showed improved efficacy compared with cisplatin and gemcitabine alone.

SG: Hello everyone, I’m Dr. Shilpa Gupta. I’m a genitourinary (GU) medical oncologist and the leader of the GU Medical Oncology program at the Cleveland Clinic in Ohio, USA. It is an honor for me to be joined by my colleagues and friends Dr. Helen Moon and Dr. Srikala Sridhar to record this podcast on platinum eligibility and treatment sequencing in platinum-eligible patients with locally advanced or metastatic urothelial cancer. Dr. Moon, Dr. Sridhar, would you like to introduce yourself?

HM: Thank you. I’m Helen Moon. I’m a medical oncologist based out of Southern California. I’m with Kaiser Permanente, and currently I am the GU lead for the country and the research lead for GU in Southern California.

SS: Thank you, Shilpa. My name is Kala Sridhar. I’m a medical oncologist at the Princess Margaret Cancer Centre in Toronto. I’m the lead of the GU Medical Oncology site group and lead of the GU Medical Oncologists of Canada. Thanks for having me.

SG: This is really going to be a very interactive session. We want to talk about defining platinum eligibility for patients with locally advanced or metastatic urothelial cancer and treatment sequencing in these patients. As you know, the landscape has changed so rapidly. I want to highlight here that the treatment options will vary in different countries, depending on what treatment options are available there, so it can be affected by local considerations.

SS: Yes, that’s a really good point. I think we are more and more aware of what’s happening on an international stage and how things are different across different countries. So I’ll start with the first question, and this is why it is important to discuss platinum eligibility and treatment sequencing in patients with locally advanced or metastatic urothelial carcinoma. I’ll ask Helen to address that.

HM: Yes, absolutely. As you two have both alluded to, this area is changing so quickly that sometimes I wonder if a year from now we will be having the same conversation. But we do know that locally advanced and metastatic urothelial carcinoma, which we’ll talk about as advanced urothelial carcinoma, has a really poor prognosis; the 5-year survival for decades has been around a little bit less than 10%, about 8% [1]. We also know that this type of cancer is extremely sensitive to platinum-based chemotherapy, which has been our standard of care certainly in the US and I would say probably globally for over 2 decades, probably going on 3 decades [2,3,4], but the issue has been eligibility. For eligible patients with advanced urothelial carcinoma, they have a much better outcome than patients who are determined to not be eligible. So that determination of platinum eligibility really helps identify those potential treatment options.

Recently though, just to talk about what an exciting time it is in bladder cancer, EV-302 [phase 3 trial] reported out [5]. First-line treatment with a non-platinum agent, in this case enfortumab vedotin (EV) plus pembrolizumab, resulted in considerable improvement in progression-free survival and overall survival [5]. I think all three of us were really taken back by the data [presented] at European Society for Medical Oncology (ESMO) just last year, and this is compared to the gold standard now for decades, which is platinum chemotherapy [5]. We should see [EV plus pembrolizumab] more and more coming through as a first-line option, and this was given [Food and Drug Administration (FDA)] approval just a few months ago, and it’s certainly a new standard of care in the US [2]. But, as you’ve talked about, we’re talking about the rest of the world also. I believe the Europeans are meeting in the summer of 2024 to discuss this; I’m not sure what the situation is in Canada, maybe you can let us know that.

However, even with these really impressive overall survival and progression-free survival numbers, EV plus pembrolizumab has got toxicity. It’s got a very distinct toxicity profile, which includes things that we don’t normally see in bladder cancer, such as skin reactions, hyperglycemia, and the big thing that we all talk about, which is neuropathy [5,6,7,8,9]. In this patient population, who tend to be older [2, 10], they may be vasculopathic; they may have all the risk factors for neuropathy. Peripheral neuropathy is a very common treatment-related adverse event [with EV plus pembrolizumab] that can be cumulative, and what we see more and more [is that] they’re permanent [5,6,7]. [Patients] may never regain those “pretreatment nerves.” Because of this, the patient’s ability to keep receiving the same drug, if it’s working, or subsequent lines, could be compromised. So even as EV plays a larger role in the treatment of locally advanced and metastatic bladder cancer, we cannot forget platinum because it still has a very important role. Because of this, a lot of us are discussing sequencing EV plus pembrolizumab upfront versus a platinum, depending on the toxicity for patients, and I think it’s a worthwhile conversation.

Even though this is primarily a medical conversation, I think cost is also significant [for EV plus pembrolizumab] [9, 11]. These are very expensive drugs, and they work, and so the cost piece is more and more figuring into the conversation. We’re here in the US where patients may be asked to cost share if there are significant infusion copays that they may be responsible for, and [costs] may limit usage in other parts of the world, whereas a more centralized healthcare system makes the decision whether or not they can afford these drugs.

So, having said all of that, we are still talking about platinum-based chemotherapy because it’s expected to remain a very important treatment option, even as EV plus pembrolizumab comes into play—also later lines of therapy, later lines of options. What if [EV plus pembrolizumab] is just not available in your country? Those are the reasons why we may still be talking about [platinum-based chemotherapy]. Platinum-based chemotherapy is also a second-line treatment [2, 4, 5]. So if you’ve received EV plus pembrolizumab upfront, you may have this conversation again a few months to a year from now, although the other thing that we’ve seen, certainly during the summer of 2023, is platinum shortages [12]. And this speaks to a bigger problem that if medications, which are life-saving, are generic they’re more susceptible to the vagaries of production and of marketplace access. All of these things play into why this conversation today is still relevant.

SS: Yes, I think you’ve made some really important points relating to access to these treatments. To your question, in Canada, we’re hoping for maybe the beginning of the fall [2024] to see access to EV plus pembrolizumab, but again, we really don’t know exact timelines, and then the next piece, of course, in Canada, will be the funding. Certainly, there will be differences around the world in terms of when access comes into play, and things like platinum have been around a long time, which means that there’s a lot of familiarity with these drugs. So I agree with you, I think [platinum-based chemotherapy] will be around for a little bit of time yet to come.

HM: Yes, I also think that we know that we’re still going to have to be playing with platinum for many years to come. So, for that patient with advanced urothelial carcinoma, what criteria do you, Shilpa, or do you, Kala, use when you’re determining eligibility for platinum chemotherapy?

SG: That was a great start and discussion. I agree with you that platinum [agents] are here to stay. Even in patients [whose disease] progressed on EV plus pembrolizumab, platinum is what they often received as second-line [treatment] [5]. We don’t have any other data for what [patients should receive] right after EV plus pembrolizumab.

I would say that the choice of treatment was informed by, historically, cisplatin eligibility [2,3,4], so whether a patient is eligible for cisplatin or not, but if a patient is ineligible for cisplatin, whether they are eligible for carboplatin-based therapy. Around 50% of our patients are ineligible for cisplatin [3, 13]. Then, there’s this category of [patients who] are ineligible for even carboplatin-based chemotherapy or unsuitable for any treatment whatsoever. The whole category of platinum ineligibility stemmed from the FDA restriction of labels for single-agent pembrolizumab and atezolizumab for frontline treatment of cisplatin-ineligible patients, [which] later on became restricted to platinum-ineligible patients [14]. On average, our patients [with advanced urothelial carcinoma] are older than patients with other cancers [2, 10] and have several comorbidities, and when considering platinum-based chemotherapy, [these characteristics] become very relevant.

The criteria for cisplatin eligibility have been defined since 2011 by Galsky et al., which was from an international survey of bladder cancer experts [15]. This criteria uses the benchmarks of Eastern Cooperative Oncology Group (ECOG) performance status 2 or higher, creatinine clearance less than 60 mL/min, grade 2 or higher [peripheral] neuropathy, significant heart failure (class III or worse per New York Heart Association), and [audiometric] hearing loss grade 2 [or higher] [15, 16]. Any one of these criteria deems a patient ineligible to receive cisplatin. Based on clinical experience with cisplatin-based chemotherapy in the real world, creatinine clearance of 50 [mL/min] is more practically used and not really 60 [mL/min] [17], and then there are strategies we can use like split dosing of cisplatin [2, 18,19,20], so I think, for the modern world, [the creatinine clearance threshold] is 50 [mL/min] and not really 60 [mL/min]. Patient perspectives on potential positive and negative effects of treatment can also affect [choice of chemotherapy]. This is what we’ve been doing for cisplatin-ineligible patients for a long time now.

[Considering] whether a patient is eligible to receive carboplatin or not, we did a survey with around 60 medical oncologists in the US who treat bladder cancer and came up with consensus criteria for very frail patients—the bar was really low—for example, [ECOG] performance status of 3 or higher, creatinine clearance less than 30 [mL/min], peripheral neuropathy grade 2 or higher, and significant heart failure (class III or worse per New York Heart Association) [also ECOG performance status of 2 with a creatinine clearance of less than 30 mL/min] [21]. So I would say that those are the patients you have to really evaluate whether they are fit for anything, but in our practice, it’s only 10% of patients who are totally unfit for any platinum.

SS: I think this assessment of cisplatin eligibility is important and has been important for years because platinum, of course, has been our standard frontline treatment for a long time. I think we’re much better at giving cisplatin now than we were maybe 20 years ago or maybe even when the Galsky criteria were first created. We do things like added hydration, we check the magnesium levels, and then we can also adjust the dose a little bit. Split-dose [cisplatin], for example, makes it easier for patients; day[s] 1 and 8 are the same, [and] especially their antiemetic regimens remain the same as well. So I think there’s a number of factors involved in terms of addressing their eligibility for cisplatin or carboplatin, which you recently also gave us some criteria around as well, which helps us to determine who should be getting cisplatin, who should be getting carboplatin, and who should maybe not be getting any platinum-based chemotherapy.

SG: Thank you. That’s a really great discussion. Helen, do you have anything to add to that?

HM: I think you guys all make a great point. Before we had EV, we wanted to give platinum and [determine] how we are able to give it. There [was] certainly the thought, for many years, that cisplatin is more potent [and] has more activity in this space, and just like what Kala said [about] hydration and cisplatin, I’ve given it [to patients with] creatinine clearance closer to 40 [mL/min] back when there was no other option. So I think we’ve gotten much better at doing this.

SG: Our next question is a natural follow-up of this discussion. For patients who are eligible for platinum, how do you decide which platinum to offer and what regimen? There is this whole thing about gemcitabine plus cisplatin or dose-dense [methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC)], and a lot of people have switched to gemcitabine plus cisplatin in the metastatic setting. I would love to hear what your thought process is for these platinum-eligible patients.

SS: For my patients I tend to be somewhat of a gemcitabine plus cisplatin person. I’ve used a lot of gemcitabine plus cisplatin. I feel very comfortable using gemcitabine plus cisplatin. My feeling is, if the disease is going to respond to platinum, I don’t think there’s going to be a big difference between gemcitabine plus cisplatin and dose-dense MVAC, and both are recommended as per level 1 evidence [2,3,4, 22, 23]. Of course, for those who are cisplatin ineligible, and the criteria is a little bit more liberal than it used to be, I too use a creatinine clearance of 50 [mL/min] in most of my patients, [and] something like gemcitabine and carboplatin would be a choice [2,3,4, 24]. Those who have a response go on to receive maintenance avelumab as per the JAVELIN [Bladder 100 phase 3] study [2,3,4, 25,26,27].

We know that real-world studies and surveys have reported that use of cisplatin in clinical practice is actually lower than predictions based on eligibility, with eligible patients sometimes receiving carboplatin or immunotherapy (IO), indicating that some of these treatment guidelines are not universally followed [28,29,30,31,32]. I think some of this comes down to the experience of the physicians. Are they treating many [patients with] bladder cancers in a year, or are they just treating a few here and there? What’s the comfort level? And certainly they’re concerned about tolerability. It may also depend on what other cancers they treat and what drugs they are used to using in those other settings. Patient comorbidities are important. Patient preferences are important, and, as well, access to affordable healthcare [28].

Cisplatin-based chemotherapy is generally considered more efficacious than carboplatin-based chemotherapy for patients with advanced urothelial carcinoma. If you take a look at all of the studies, you tend to see those who are treated with cisplatin tend to do just a little bit better [33, 34], even if they’re not directly compared head-to-head. But patients who are ineligible for cisplatin typically have a worse performance status and worse prognostic characteristics associated with their shorter survival [15, 35], so there’s some confounding factors as well.

We know, in some countries, an alternative option for cisplatin-ineligible patients with PD-L1-positive tumors is immune checkpoint inhibitors—monotherapy with, for example, pembrolizumab or atezolizumab [3, 4], although these are no longer approved in this setting in the US [14, 36]. I think we have to be careful because platinum-based chemotherapy, despite all its problems, has fairly respectable response rates, and some of those response rates are coming in higher than single-agent IO [37, 38]. I know there’s a lot of pressure to use IO, and some of that is coming from our patients, but I think it’s important that we stay true to the data we have around platinum-based chemotherapy.

In the US, EV plus pembrolizumab is recommended and already approved, initially in the cisplatin-ineligible group, and more recently in the cisplatin-eligible group as well [2, 5,6,7, 39]. Also, in the frontline setting, we’ve seen the results from the substudy of the CheckMate-901 [phase 3] trial [40]. This is a really interesting trial that only enrolled patients who were cisplatin eligible. The thinking here was that combining cisplatin and immunotherapy may do better or have better outcomes than combining carboplatin and immunotherapy, so that formed the basis for this trial. This is first-line treatment with nivolumab plus cisplatin-based chemotherapy followed by nivolumab monotherapy, and this resulted in significantly longer progression-free survival and overall survival compared with cisplatin-based chemotherapy alone [40]. Nivolumab plus cisplatin-based chemotherapy has a potential to become an additional first-line treatment option, and it just got FDA approval in the US as well [41]. The efficacy of this combination has not directly been compared with cisplatin-based chemotherapy followed by avelumab maintenance; however, there were some patients who did go on to receive, in the standard arm, avelumab maintenance [40, 42]. [Nivolumab plus cisplatin-based chemotherapy’s] role in countries where EV plus pembrolizumab is available is really less clear. Shilpa, did you want to comment?

SG: You summed it up very well, and in the real world we actually looked at this and published it—that unnecessarily patients are deemed platinum ineligible when they could easily receive gemcitabine plus carboplatin followed by avelumab maintenance [43], which is the recommended standard of care, or has been. And patients with single-agent immunotherapy don’t do well [37, 38] when they can actually get gemcitabine plus carboplatin. So it’s very important to recognize that only about 10% of patients are those who won’t be able to get carboplatin [43, 44] because it’s not more than that.

SS: So then, leading into our next question. What criteria do clinicians use to determine if patients are ineligible for platinum-based chemotherapy? And this really highlights some of the work that you’ve done recently, Shilpa.

SG: Yes, and just to build on what we were discussing, that the platinum-ineligibility space stems back from when the FDA restricted the label of immunotherapy for frontline settings. We did a survey, and updated it in 2022, where we included different criteria, including age, creatinine clearance, performance status, peripheral neuropathy, hearing loss, and anything else that people had, finetuned it, and then added data with maintenance avelumab to see what [clinicians] were actually using. Based on the consensus, with[in] the limitations of that, the conclusion was that anybody with an [ECOG] performance status of 3 or higher, creatinine clearance less than 30 [mL/min], grade 2 or higher peripheral neuropathy, class III or worse [New York Heart Association] heart failure, [or] a combination of [ECOG] performance status [of 2] and creatinine clearance of less than 30 [mL/min would be platinum ineligible] [21]. We asked this particular question (about combined performance status and creatinine clearance) because, in the EORTC 30986 study, [patients] with ECOG performance status 2 who got [gemcitabine plus] carboplatin and had creatinine clearance less than 60 [mL/min] did really poorly [24]. But when we asked that question, instead of 60 [mL/min], 30 [mL/min] was still the cutoff. [These criteria] are just guidance for people to use at the point of care and also to develop clinical trials for this patient population. One such trial (that is enrolling platinum-ineligible or -refractory patients) that is ongoing is building on an atezolizumab backbone [45]. Similar criteria are also included in the European Association of Urology (EAU) guidelines [3]. So I think there’s uniform agreement, on the most part, for when not to use any platinum.

SS: Helen, any comments?

HM: In this space, no, but you guys brought up this really great point, which is patients with bladder cancer tend to be older, tend to be more frail, [and] sometimes sicker. What we see [as] the biggest barrier is that the first team that evaluates [the patient], whether that’s a hospital internist or urologist, has deemed that they are not healthy enough to even consider more therapy. So it’s the people [who] don’t walk through the door that I actually worry about more than people who do walk through the door. Because if you truly look at the definition—what’s both published and will be commonly used—a good amount of people could get treatment and could get platinum chemotherapy. Yet, when we look at the real-world correlation, we know that probably just a little bit more than half are offered [treatment] [46], whereas it probably should be much more in the majority. So those [issues] are what I worry more about.

When I think about patients who are truly not eligible for platinum chemotherapy, [in] those patients, obviously the kidney function you think about; that’s a very black and white type of scenario. But you also think about their functional status if they’re really just too frail to come and go through the rigor of chemotherapy. In that very limited space, and I have to say I can only think of maybe 10–20% [of patients], even though the real-world data suggest something like 40% of these patients are offered immunotherapy as monotherapy [47]. What we know is that—and there are country-to-country differences—pembrolizumab and atezolizumab have been potential options [2]. This [was based on] two fairly modest phase 2 trials [48, 49], and subgroup analyses show that there is benefit [50], and the FDA has given that approval [for pembrolizumab monotherapy] and have not removed it, so we are still able to do this in the US.

Presumably, if [patients] cannot get platinum, things like EV [plus pembrolizumab] could be thought about, but I would say that, if functional status is the reason that they cannot get platinum, I cannot imagine that they would be eligible for EV, which is an equally potent though different type of toxic drug [5,6,7]. But, if you go by label, EV plus pembrolizumab is also as an option. I would really reserve [EV plus pembrolizumab] for patients who are somewhat borderline primarily on the kidney function and not because of a functional issue. Patients who are really ineligible for any platinum chemotherapy overall tend to be more frail, and a lot of the time those conversations, rightly so, talk about goals of care, palliative care, and so on.

My last point will be that [in patients with bladder cancer], there are frequent infections. I’ve seen patients in the hospital looking terrible because they’re dealing with urosepsis or pain or difficulty from not being able to sleep because of bladder irritation, and if the right antibiotics, the right supportive care, [are] given sometimes a week or two later, they look pretty darn good with [the use of] nephrostomy tubes and so on. So, if with full supportive care they’re still really looking frail, I think it’s incumbent upon us to discuss goals of care. I think there should be an effort to try to “right the ship,” if you will. As always, this is an area [where] we don’t have that many great options, so prospective trials focusing on these patients are truly warranted and desired in this group.

SG: Thank you, Helen, that was a great segue to the next question. For patients not eligible for any platinum chemotherapy, what would you recommend? You alluded to the fact that pembrolizumab and atezolizumab [monotherapy] are options, although in the US, atezolizumab has been withdrawn [2, 51,52,53], and you also mentioned about supportive care. Any other thoughts in your practice? What percentage [of patients] are you offering single-agent immunotherapy to? Sometimes it’s just the eyeball test [of] this patient can’t really tolerate even platinum. I agree with you; in that patient I would be very hesitant to offer EV plus pembrolizumab because, if they can’t tolerate carboplatin, I think [they would be unlikely to] tolerate EV, unless they [have] an ECOG performance status [of] 0 and, just because of the disease, [their condition] has rapidly deteriorated. Anything else you want to add to these options for patients who are truly platinum ineligible?

HM: Thank you for asking this question. I think I pre-answered it [with] a lot of the points that I made. But [to address] that last bit, and this was particularly brought home to me the last time I [was] on call, there was a patient newly diagnosed with bladder cancer [with] lymph node blockage who looked very ill. At the time that I was called in to consult, the hospital urologists indicated that the best option was hospice. Yet with percutaneous tubes [and] antibiotics, 2 weeks later he looked pretty darn good. I think we just have to really respect the fact that [patients] can turn around quickly and do our due diligence so that the first look is not the only look we give when we’re talking about the eyeball test.

SG: Helen, in your experience like you said, [most] patients who show up at our door can get something, so how often do you offer hospice to these patients who are coming to your doorstep? Because I don’t think I’ve seen any such patients—maybe one or two a year where they’re not even [well] enough for single-agent IO.

HM: If they make it through my doorstep, my experience is very similar. It’s rare [that I offer hospice], and usually it’s because they are either at the extremes of age or there was something that because of the healthcare system they didn’t get to my door in time. But overall that’s really rare. In the hospital, if you take [an] inpatient call, which probably we all do, you do see it here and there, but just like you, I’ve got to be talking about one to two cases a year at most. So when I see numbers in the real world that deem a good swatch of our patients as platinum ineligible, I really wonder if [patients are] getting that type of care that we want for them.

Jumping onto that, so let’s say you have a patient walking through the door. You think, “Okay, I can offer you treatment,” and you [have gone] ahead and offered platinum-based treatment because again that’s what we were doing for so many years, and they have disease control at that point. What is the recommended approach that you currently do? So you gave your platinum—usually we give 4–6 doses. You scan. You have disease control. What is the conversation like at this point?

SS: So, we know a large proportion of patients do have a response to upfront platinum-based chemotherapy [5, 37, 38], and I think that’s an awfully good place to be and an important thing for our patients. Once they have a response, then we think about maintenance avelumab, which is based on the JAVELIN [Bladder 100] study. And when I say response, I mean the patient had complete response, partial response, or stable disease after 4–6 cycles of treatment [26, 27]. I’ll be honest, I’m tending to give a little bit more 4 cycles than 6 cycles because I worry about the cumulative neuropathy that can happen not only with platinum but also with subsequent treatments, like, for example, EV that we currently use in the third-line setting [2,3,4]. In patients with an upfront response to treatment, I do follow up with maintenance avelumab, and there’s about 70% or so of patients [who] do respond to chemotherapy, [and] about 30% don’t [37, 38, 54]. In those 30% who don’t respond, I go on to give second-line pembrolizumab [2,3,4].

[The use of avelumab maintenance] is based on the JAVELIN Bladder 100 phase 3 trial, which has given us level 1 evidence in this area [2, 4, 26, 27]. I think that it has been good for patients and good for us because, when a patient has responded [to platinum-based chemotherapy], it’s nice to say we’re not just waiting for disease progression; we’re actually doing something actively to try to limit or prevent disease progression as much as possible. The one thing about this trial that was nice was benefits [with avelumab maintenance] were seen regardless of whether patients got gemcitabine and cisplatin or gemcitabine and carboplatin; in patients who received 4, 5, or 6 cycles of [platinum-based chemotherapy]; in older patients; and regardless of the treatment-free interval from the end of chemotherapy to the beginning of avelumab [within] the 4−10 week period that was outlined in the trial [26, 27, 55, 56]. Also, importantly, avelumab did not have any detrimental impact on quality of life [57], and, again, when we think about our patient population tending to be a little bit older—average age about 72 [years]—often hav[ing] comorbidities, often [being] smokers or ex-smokers [2, 10], that quality of life is a really important consideration. We’ve seen long-term results from this study that continue to show that there were benefits observed regardless of the type of response they had, whether they had a complete [response], partial [response], or stable disease with frontline chemotherapy [27, 58].

So we’re sort of building on that now. There are a few trials, such as the MAIN-CAV trial and the JAVELIN Bladder Medley trial, that are trying to build on the backbone of maintenance avelumab and trying to see if we can do even better [59, 60]. As well, the DISCUS trial is a really interesting trial that’s looking at 3 versus 6 cycles of platinum-based chemotherapy [prior to avelumab maintenance], and the primary endpoint here, really interestingly, is quality of life [61]. So there’s a lot going on in this space, and I think we’re really doing better in terms of outcomes for our patients. So, we can follow up with another question, and I’ll ask Shilpa: for patients who have disease progression with first-line platinum-based chemotherapy, what’s your recommended approach?

SG: Ever since immunotherapy came on board, we’ve been fortunate to have several immunotherapy options for patients who progress on platinum, whether it’s cisplatin- or carboplatin-based chemotherapy [2,3,4]. Based on level 1 evidence, pembrolizumab is our treatment of choice based on the phase 3 KEYNOTE-045 study where second-line pembrolizumab was better and improved overall survival significantly compared to investigators’ choice of chemotherapy after platinum [2, 62, 63]. In the US now, durvalumab and atezolizumab are withdrawn from this indication, but the other two immunotherapy options are avelumab or nivolumab based on phase [1/]2 trials [2, 64,65,66]. But, like I said, [because of] level 1 evidence, pembrolizumab is our go-to choice.

I want to bring up the targeted therapy erdafitinib [a fibroblast growth factor receptor (FGFR) inhibitor]. For select patients who have FGFR alterations, fusions, or mutations, that’s a very valid option [2,3,4, 67, 68]. More recently, we did answer the question about sequencing, and we found that pembrolizumab should be offered before offering erdafitinib based on the THOR [phase 3] trial [69], but [erdafitinib] is a very valid option after immunotherapy [67]. In practice, we like to do genetic testing [for FGFR status] for patients at the time they develop metastatic disease—the sooner, the better—but that is at least [when] we should get it so we’re not scrambling at the last minute. I’ll also add sacituzumab govitecan (a Trop-2–directed antibody-drug conjugate)—we have access to that in the US based on the accelerated approval for patients who [have had] prior platinum [and] immunotherapy and prior EV [2, 70]. That brings me to EV, which is approved [in the US] for monotherapy for [cisplatin-ineligible] patients who had one prior line of therapy [2, 71]. In the past, we were using [EV] for patients who had prior platinum and immunotherapy, but now the [updated US] label [means that cisplatin-ineligible patients with] any one line of prior therapy can get EV [2]. But in the changing landscape, it’s a moot point if more and more patients will get EV and pembrolizumab frontline.

SS: Yes, certainly a lot of options now on the table, very different than a few years ago when we didn’t have a whole lot going on. And I think this speaks to a lot of collaborations between us, industry, patient groups, [and] scientists; really a multidisciplinary approach to drug development I think is what we’ve been seeing. Helen, comments?

HM: Yes, I was just kind of thinking out loud. You have the platinum 4–6 cycles. Just like you I’m veering more toward the 4 [cycles] to save those nerves for a later line. Let’s say [patients] do well. We talked about maintenance avelumab. They don’t do well, they progress, and Shilpa just took us through a really nice list of the subsequent [options]. What if a patient had the platinum, had the maintenance avelumab, or were deemed maybe too ill for platinum and got IO, but the immediate prior line of exposure is an IO [monotherapy] and now they progress? What are you offering these particular patients?

SS: So current treatment guidelines include several subsequent options in patients who have received both platinum-based chemotherapy and an immune checkpoint inhibitor, such as avelumab maintenance or second-line pembrolizumab [2,3,4]. EV monotherapy is recommended treatment based on the EV-301 phase 3 trial of EV versus chemotherapy [2,3,4, 72]. Another option in this setting is erdafitinib, and this is a later-line option, but it’s for those who have FGFR2 or [FGFR]3 genetic alterations or mutations [2,3,4, 68]; it’s really important that we have the testing in place so we know the status of the patient. We recently saw results from the THOR phase 3 trial that provided level 1 evidence for erdafitinib treatment in patients with prior immune checkpoint inhibitor treatment [67]. A long time ago we were doing a lot of platinum rechallenge. I don’t tend to do that as much, but sometimes [for] someone who hasn’t had platinum in a long time and they’ve exhausted all their other options, I may go back to it; of course, we have to watch for neuropathy. When we look at the exploratory analysis from the JAVELIN Bladder 100 trial, we found that 60% of patients who received avelumab first-line maintenance went on to receive second-line treatment, with most receiving rechallenge with platinum-based chemotherapy or treatment with non-platinum-based chemotherapy reflecting treatments available at the time the study was conducted [73]. So there’s really been a movement in terms of what’s been available and what is available now compared to even a few years ago.

Monotherapy with the antibody-drug conjugate sacituzumab govitecan, which is a Trop-2–directed antibody and a topoisomerase inhibitor, is also an option for patients in some countries [70]; we don’t have access to this in Canada. [Sacituzumab govitecan] is a different antibody-drug conjugate than EV, so the thinking is there’s going to be no cross-resistance and not necessarily overlapping toxicities. Some of the data for sacituzumab govitecan comes from the TROPHY-U-01 [phase 2] trial [70]. Finally, in some countries, treatment with non-platinum-based chemotherapy, such as paclitaxel, docetaxel, or vinflunine, can be considered, although there’s a lower level of evidence [2,3,4, 74]. Certainly for us, when we get through EV and they don’t have any FGFR mutations, I do end up going back to a taxane from time to time, and I do get some responses in that context. So I think it’s really showing that there [are] a lot of options, [and] a lot of movement in the disease. I think biomarker testing is going to be increasingly important over time.

So this brings me to the next question, which I think is really relevant to us today, and that is: does neoadjuvant or adjuvant treatment affect the treatment approach for patients with advanced urothelial carcinoma? I’ll ask Helen this question.

HM: I was just listening to you answering the last question, [and] my head is whirling. Remember the days of just platinum and taxane? [There were] two options, so we flipped back and forth, and now there’s just so much different sequencing, [and] so many different moving parts. Just to add yet another moving part to this is the idea of neoadjuvant or adjuvant treatment in a little bit of a different population. So far we’ve been talking about patients who [have] locally advanced or metastatic [disease]; in other words, we’re not talking so much [about] surgery for a cure. But let’s back up a little bit and have that patient that you’re seeing, you think you can cure their bladder cancer by offering them a cystectomy. Generally, what would be considered the standard of care is neoadjuvant [cisplatin-based] chemotherapy [2, 4], if they’re eligible for it, and the same conversations we have about cisplatin ineligibility apply here. Within the last few years, [we are] talking about these patients [who] receive a year, generally, of adjuvant immunotherapy [with nivolumab] [2, 4]. Let’s say, if [disease recurs in] that patient in a metastatic fashion within a year, so in the middle of the IO exposure or shortly thereafter or a long time thereafter, how does that play into the selection of treatment beyond that? The honest answer is I don’t think we 100% know, but it is a scenario that we find ourselves in more and more. So if I look at that patient, and they now have advanced disease, they [will need] systemic therapy. In some ways, this is well defined in the [gynecological] world—the idea of platinum resistance—whether that’s [after] 6 months or 12 months; I’ve seen different numbers. We are well aware of this in the chemotherapy world—that if you progress within 6 or 12 months of having received platinum, it may not be your best option to rechallenge with the same drug. Does that same idea apply for immunotherapy? What’s the optimum amount of time afterwards? What if there is progression that happened in the middle of immunotherapy? And how much progression is progression? What if it’s one nodule? What if it’s a lot?

So neoadjuvant treatment with cisplatin-based chemotherapy would be our standard [2, 4], but that confounds subsequent treatment selection. Nivolumab is approved in some countries for patients with a high risk of recurrence and is sometimes limited to patients with PD-L1-positive tumors [2, 4]. This approval of nivolumab was based on the primary endpoint, which was disease-free survival, in the CheckMate 274 [phase 3] trial, and that’s what gave us the level 1 evidence [75]; however, the overall survival data [are] not yet mature or available or presented. Just a few months ago, at [the American Society of Clinical Oncology Genitourinary Cancers Symposium 2024], we saw the third immunotherapy in this space, which is pembrolizumab, in a large US-led cooperative trial by Alliance [AMBASSADOR Alliance A031501; phase 3 trial of pembrolizumab versus observation], which showed similar efficacy [to CheckMate 274] in disease-free survival but with no positive overall survival data yet [76]. So, now, while we’re still waiting for regulatory approval in that space, how do we sequence immunotherapy [including adjuvant treatment]? No prospective trials have assessed the impact of treatment in earlier stage on the treatment of advanced disease. In other words, what you pick upfront by deciding to give neoadjuvant [treatment], by giving that 1 year of IO, how does that affect your second, third, [or] fourth line? Of course the hope is that you don’t need to make that second or third or fourth line, because that patient’s cured, but we do not have high-level prospective data in that space. In clinical practice, we see this “1 year” talked about quite a bit; some people will say 6 months. But if there is that 1-year gap between treatment, so the last [intravenous (IV)] infusion and no [further] treatment within a year, you see this defined in clinical trials and in practice—that the patient can be essentially treated as if they’ve been newly diagnosed with metastatic disease and everything we’ve talked about [previously] applies. However, if they relapse within that 1 year from the end of neoadjuvant or adjuvant treatment, I think a lot of us think of them more as second line and that the cancer is really resistant or refractory to what you were treating them with, and we should really move on to a different mechanism of action in terms of drug selection. This has been the approach currently, in a lot of our clinical trials, and I’m sure, as more and more drugs [become available] and sequencing alters, it’s going to be a much more complicated space.

SG: Yes, that was a really good discussion. The landscape has changed so much, and it’s really good to discuss this and share our thoughts. Now to summarize, the treatment landscape for advanced urothelial cancer is evolving and will continue to evolve. The big question is: how will the rest of the world be able to catch up with this new treatment regimen of EV plus pembrolizumab, which is now the standard in the US already [2, 5], [and] hopefully soon in Canada and Europe but the cost and toxicity really need to be weighed in. Kala, you mentioned before that the DISCUS trial is even taking a step further to see if 3 cycles of platinum are enough versus 6 [cycles before avelumab maintenance] [61], and we’ve already more or less adopted our practice to 4 cycles; I do that too. The big question remains: how many cycles of EV and pembrolizumab do you need before just doing maintenance pembrolizumab? I think that’s a big challenge, and in my opinion, indefinite EV plus pembrolizumab is just not feasible for the majority of patients. Then, the [next] big question is “what is the optimal second-line treatment after EV plus pembrolizumab?” and that's a data-free zone. We know platinum will have a role there, and whether sacituzumab govitecan will have a role after platinum or before platinum, we really don’t know.

Consequently, first-line platinum-based chemotherapy still remains an important option, at least, I think, in the rest of the world. In the US, determining platinum eligibility has been a key consideration so far, and when platinum is used more and more in second line, I think we [will] still refer to these criteria of eligibility, especially after EV, if people are even eligible because [more than half of patients] do get neuropathy [5,6,7]. As we discussed, cisplatin- and carboplatin-based chemotherapy are standard of care followed by avelumab maintenance for patients [whose disease does not] progress, and nivolumab and cisplatin-based chemotherapy just became approved in the frontline setting in the US [2,3,4]. We’ll see what the rest of the world adoption will be. Split-dose cisplatin is a very valid, very widely used option for patients who can’t get the regular doses [19, 20], and EV and erdafitinib are next-line options for patients who [have received] prior platinum and immunotherapy [2,3,4]. Sacituzumab govitecan, for now, has availability in the US [2, 70], but the phase 3 trial for overall survival has still not read out. I would love to hear from you, Kala, and then Helen any parting thoughts to add.

SS: No, I think you covered it really nicely. Really great summary. All these new options are available to us, [and] I think we’re going to need to really answer these questions about how best to sequence these new treatments and, as well, [whether there are] biomarkers out there that can help us to guide what we do next. I think the other thing to keep an open mind [about] in the metastatic setting is can we target oligometastatic disease or oligoprogressive disease. Do we need to look at things like radiation or stereotactic body radiation therapy (SBRT), for that matter, that allow us to maybe extend the life of our current systemic treatments a little bit longer? So I think some of those questions are before us right now, as we wait for some of the newer trials to report. I think the changes in the landscape sometimes are going to make it tricky for ongoing trials where the current standard of care may not be the real standard of care at this time based on all the developments. So how we adjust our clinical trial design will also be important. These are good problems to have, I’d reiterate, because I think we have so much we can do for our patients right now, and it’s a very positive time. Helen?

HM: Yes, I absolutely agree and, you know, in terms of options always amazing. I think there [are] still unanswered questions like you’ve alluded to. Sometimes I’m a little concerned that we have such an embarrassment of riches and so many options it becomes overwhelming and that there’s an education gap there, which is probably why we’re doing this podcast so that out in the community there’s not the sense that things are changing so fast that we don’t know what we're doing. I dare to make a few strong statements. I think EV plus pembrolizumab—that survival data, [and] that response data—is such that it deserves that spot as one of, if not the, standard of care in the US. I think that, unless you have a contraindication to immunotherapy, the days of just chemotherapy without immune exposure are probably behind us, whether that’s EV plus pembrolizumab, [cisplatin] plus nivolumab, or platinum with maintenance avelumab. Somehow an immunotherapy probably needs to make its way to your frontline treatment, and while head-to-head trials [have not been] done, the idea that you would just be offered platinum alone, if you can tolerate immunotherapy, should probably be reconsidered. Then, just like you were saying—this is not just in bladder cancer but in a lot of cancers—what does progression mean? If there is cancer going out of control over your body, that’s a totally different scenario than if there are one or two spots. Should it be SBRT [that is used]? Should other novel therapies be considered? Also, I know Shilpa alluded to FGFR as kind of a fruit of a lot of molecular work that we’ve done, but for patients with, let’s say, [low] ERCC1—there’s not that many of those patients—should platinum still stay because we know they have exquisite sensitivity to platinum [77]? So a lot of questions that I’m looking forward to working on the answers [for] in the coming years.

SG: Thank you. This was really a great discussion.