Treatment Considerations for Patients With Cisplatin-Ineligible Bladder Cancer

A roundtable discussion, moderated by Vadim Koshkin, MD, of the University of California, San Francisco, focused on treatment selection for different patient populations with advanced bladder cancer, including a discussion of new data presented at ASCO 2023. Dr. Koshkin was joined by a panel that included Matthew Zibelman, MD; Cora Sternberg, MD; and Daniel Petrylak, MD.

In the next segment of the roundtable series, the panel discusses the approach to treating patients with cisplatin-ineligible bladder cancer.

Watch the next segment in this roundtable series.

—

Dr. Koshkin: I want to now transition to talking about cisplatin-ineligible patients. We’ve been talking about cisplatin-eligible, and some of the topics like switch maintenance actually crossover. Does everyone at the table still believe that there is this a significant difference between cisplatin-based treatment and carboplatin-based treatment, and that it’s important to make the distinction between cisplatin-eligible and cisplatin-ineligible patients?

Dr. Petrylak: I think now it is. With our current data, it’s important to make the distinction between cisplatin-eligible versus -ineligible because we don’t have randomized data that tells us any of these other regimens are superior to cisplatin. We may have that in the future at some time. But certainly, I’m a firm believer that cisplatin is a better drug than carboplatin. I will make every effort to give cisplatin to a patient either by splitting the platinum dose, giving extra hydration to make sure their kidney function is preserved. Right now, that is the standard of care for frontline treatment: cisplatin versus carboplatin; cisplatin, preferably.

Dr. Sternberg: I agree with you 100%. But again, we do give carboplatin to the patients with comorbidities, with lower creatinine clearance, with hearing problems, with performance status problems. We are selecting the patients who are worse, and they do have worse outcomes.

Dr. Zibelman: I agree. I definitely use cisplatin in patients that are eligible. I do think though too, it’s important to acknowledge, if you look at in IMvigor130, patients who got cisplatin versus carboplatin, there’s not clearly a difference in those groups. Now they’re very selected. There was no rules; they could select who they gave carboplatin to and who they gave cisplatin to. I think that’s a huge part of it. But I think there are some people who believe that there may not really be much of a difference in that. But I am on board. I give cisplatin to patients who are eligible.

Dr. Koshkin: Yeah. I think what motivates a lot of this preference to give cisplatin to a patient as long as they’re able to tolerate it, is that there are complete responses, right? And long-term significantly improved outcomes for a minority of patients, unfortunately. But that we do see with cisplatin that maybe we don’t see us consistently with carboplatin. Would that be fair to say?

Dr. Sternberg: Yeah.

Dr. Petrylak: Then, the European data showed a median survival, I believe, of 9.3 months of gemcitabine/carboplatin in the control arm of one of their studies…

Dr. Sternberg: Versus…

Dr. Petrylak: Versus…

Dr. Sternberg: …MCV [methotrexate, cisplatin, vinblastine].

Dr. Petrylak: MCV. It was the first MCV, right. I think that if you look at the data, in total, it looks like carboplatin is not equivalent to cisplatin.

Dr. Koshkin: Yeah. The data you’re alluding to, that’s from I think the DeSantis paper from…

Dr. Sternberg: The DeSantis paper … pretty old data.

Dr. Koshkin: Yeah.

Dr. Sternberg: But that was what we had as a standard for a very long time.

Dr. Koshkin: I only mention that because, as Matt alluded to, more contemporary trials, like IMvigor, and even KEYNOTE-361; well, in IMvigor in particular, the outcomes in the carboplatin-based chemotherapy arm were at least somewhat better than that. Again, there are all sorts of perhaps selection biases, and there weren’t specific rules for who had to be on cisplatin versus carboplatin. But I think that’s why there is at least some debate now that whether cisplatin versus carboplatin makes as big a difference. But, having said that, it sounds like at least expert consensus here is that we still would try to give cisplatin more so than carboplatin.

Dr. Zibelman: One thing I’ll mention, and I’ve thought about sometimes, is one of the nice advantages of gemcitabine and cisplatin is if patients do have a difficult time, you can swap out the cisplatin, and potentially switch to carboplatin, which is a little harder to do if you’re choosing an MVAC [methotrexate, vinblastine, doxorubicin, cisplatin] regimen to totally swap. Although we’ll talk about subsequent therapy later, one of the things I’ve always liked about MVAC or secondary things is the ability to use gemcitabine as a single agent later, which almost adds an extra line of therapy for those patients, in some ways.

Dr. Sternberg: I don’t think I use that anymore now that we have so many newer antibody-drug conjugates and other drugs.

Dr. Zibelman: I have rarely used it, but I’ve had 1 in the not-too-distant past who had not had gemcitabine and I got there. But yes, we don’t always get to that anymore.

Dr. Koshkin: That kind of brings us to the next points we want to discuss, which are some of the newer agents available. Particularly for patients who are perhaps cisplatin-ineligible, but carboplatin-eligible, there’s of course data from EV-103, and that’s a study that made huge waves at recent conferences. Again, there’s a big presentation at this conference as well. I just want to ask the panel, do you view this data as practice-informing, practice-changing? How do you see that EV-103 data?

Dr. Petrylak: I think this is practice-changing because I will use enfortumab vedotin (EV)/pembrolizumab preferably over carboplatin/gemcitabine. One of the reasons why I made that selection is if you look at some of the responses with enfortumab as a single agent in visceral disease, they’re quite impressive. You don’t see those types of responses in patients who are treated with carboplatin-based regimens. Again, this is phase 2 data. These are small numbers of patients, so we’re going to need the EV-302 trial to confirm this, but we’re seeing survivals in the mid-20s; I think 27 months for the last report of EV-103. Again, I don’t think I’ve seen anything like that in this disease to this point. I would not yet substitute it for cisplatin because we don’t have randomized data. But certainly I think it’s an acceptable option with discussion of all the different possibilities with the patient at this point.

Dr. Sternberg: I mean, we’re going to hear at this conference an update of the EV-103 data in the cohort A with the EV and pembrolizumab in the platinum-ineligible patients by Dr. [Shilpa] Gupta, and showing overall response rate of 73%. That’s like we were talking about with MVAC, that kind of response rate and overall survival of 26 months. I think that that’s very important data that we’re going to be hearing, and it’s a great combination. It’s not without its toxicities. We talk about MVAC having toxicities, but EV and pembrolizumab, if you give it long enough, you’re going to have toxicities as well.

Dr. Zibelman: Yeah. I think that’s the only word of caution, I guess I would say, is because I do think people are going to use it, and with those response rates, it’s very enticing and hard to, even without randomized data yet, to make a case over gemcitabine/carboplatin. But I do think the toxicity of EV as something that’s important to know and understand. The neuropathy as patients are on this earlier in the disease and on it potentially longer, can be really problematic. I think being able to adjust dose and schedule and understanding that better is going to be really important. The rash is certainly an issue that we see, and I know something that we’ve started doing, and are hoping to publish our experience in the not-too-distant future, is using steroids around it carefully as a prophylactic, like you used to do with docetaxel or other drugs. In patients who’ve had rash, using it day before, day of, and day after at low doses, being very cautious about hyperglycemia, which is another side effect, and obviously steroids can worsen, so you have to watch that carefully. As we start to use this earlier in more patients and they’re getting it longer, I think being able to manage the toxicities is going to be really important.

Dr. Sternberg: But I think if people are on long enough on EV, they all will get neuropathy. They don’t want to get off of it either. Even if they can’t drive their car, if they’re falling, they will not stop it because they’re doing so well.

Dr. Petrylak: This is, I think, one combination that requires a tremendous amount of attention from health care providers who are taking care of these patients, either the physician or the nurse practitioner seeing the patients. I draw the analogy with EV/pembrolizumab to marathon running. In other words, you don’t want to sprint at the beginning. You really want to save everything for the long term. We know from the data that most patients respond by 2 months with their first evaluation, so you have an idea as to how they’re doing. You also can get very, very rapid responses to pain, particularly in bone. If a patient develops neuropathy early, it’s important you counsel that patient to be sure that they know that we’re doing this for the long term, especially if they’re responding.

The neuropathy seems to be 2 different types. One, of course, there can be a rapid one that develops initially. Then there’s the long term neuropathy, in somebody who’s been on the drug combination for a long time. The early one can resolve if you stop the drug for a period of time or if you dose-reduce. The late one’s a little bit more difficult to manage. But I’ve had patients off treatment for 3 months with stable disease. After an initial response, we’ve been able to resume them again at that particular point. I think that it’s very, very important that you evaluate the patient at each treatment and determine whether the neuropathy is worsening.

Dr. Sternberg: Some of our patients come in with neuropathy to start with from the cisplatin that they had before.

Dr. Zibelman: Or comorbidity is an underlying thing.

Dr. Sternberg: Yeah, diabetes comorbidities, yeah.

Dr. Zibelman: Yeah. In my mind, I’ve compared this to using FOLFOX in colon cancer where patients will go on everything, and then maybe stop the oxaliplatin, and continue on 5FU, and I almost potentially see an approach like that with this combination where patients maybe stop the EV at some point, continue potentially on the pembrolizumab, and maybe there’s an option for adding it back later depending on how the neuropathy is and what their disease is doing.

Dr. Sternberg: Usually with the rash, if it’s not that bad, we start off with topical corticosteroids, but then if it gets worse, we’ll go to systemic corticosteroids as you do.

Dr. Koshkin: This is all really fascinating how different centers manage the various toxicities of enfortumab, which I think we all agree is a very active drug, but takes, I think, experience to know how to use it correctly, and knowing when to dose-reduce and knowing that dose-reducing, even upon dose reduction, you still get continued responses. That’s something where, this is a drug where I think a lot of academic centers have had a pretty rapid uptake and are using it. It’s less familiar to a lot of community oncologists because it’s only approved for bladder cancer, unlike say, sacituzumab, which is also approved for breast cancer and is another targeted agent we use for bladder.

Dr. Petrylak: At this meeting I believe there’ll be a presentation of enfortumab in head and neck cancer. I’m very interested to see what those results will be. That may actually help to broaden the use of the drug in this disease state.

Dr. Koshkin: I also wanted to ask, we’ve been talking about this patient population that really is a cisplatin-ineligible patient population, for which we agree there is data from EV-103 of the pretty good activity of enfortumab and pembrolizumab. But we were also discussing earlier how certain patients maybe are borderline cisplatin-eligible, but we’re nervous about maybe getting them through cisplatin and using various strategies like split-dosing and others. But do you see maybe more of those patients being shifted into the cisplatin-ineligible category and then getting enfortumab and pembrolizumab as a result?

Dr. Petrylak:  Yeah, because that was included in this trial. Those types of patients, based upon the creatinine clearance, based upon other factors that were involved with platinum ineligibility, neuropathy is a little bit more problematic because that’s something you have to worry about with this particular combination. But hearing loss or cardiovascular issues, certainly I think that EV would be an acceptable approach in these patients. Again, particularly if they’ve got visceral disease.