Treatment Sequencing and Use of Biomarkers to Guide Treatment Selection in 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 addresses treatment sequencing decisions following disease relapse, as well as the use of biomarkers to guide treatment decisions.

Watch the next segment in this roundtable series.

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Dr. Koshkin: Switching gears completely, we’ve discussed how most patients as their first, probably, and second line of therapy receive platinum-based chemotherapy and then, usually, a checkpoint inhibitor. Then, of course, now we’re introducing enfortumab [vedotin (EV)] and pembrolizumab. Upon progression on any of those regimens, how do you select the next option to give them, and what are your general approaches?

Dr. Sternberg: We try to sequence patients. First of all, we try to look for FGFR mutations to see if they’re eligible for erdafitinib, and if they’re not eligible for erdafitinib, we go to sacituzumab govitecan, which as you said is also approved for triple-negative breast cancer. It’s another antibody-drug conjugate with completely different toxicities than EV. It doesn’t have neuropathy or hyperglycemia. It does lower the blood counts, and patients get diarrhea so the side effects are a little different, but we’ve seen responses in those patients after enfortumab vedotin in patients where I can’t give erdafitinib. I would prefer to give erdafitinib if I could, but it’s 1 in 10 patients that are really FGFR mutated.

Dr. Koshkin: Dan, is that your approach?

Dr. Petrylak: Yeah, that’s my approach. I think it’s important to get the testing for FGFR early, especially at the beginning of the process when you’re treating a patient with metastatic disease because you want that information available if the patient does progress, rather than waiting the time to get the test done; it’s just simply better for the treatment decision to have that at hand. We look for FGFR mutations. That’s 1 thing.

Of course, clinical trials are important in the situation as well. I think now we’re seeing, it’s almost like the deck is being reshuffled. We’re seeing some of the later-line treatments being moved up earlier, and then how is that going to affect the sequencing later on? We don’t have any good answers as to whether something is better or not, whether you should select sacituzumab or if they are FGFR positive, sacituzumab over erdafitinib or erdafitinib over sacituzumab.

There is some data that’s being presented at this year’s ASCO meeting called THOR, and this looks at erdafitinib. It’s a randomized trial versus standard of care chemotherapy docetaxel, vinflunine in Europe, or paclitaxel, and found that, in this trial, that there was about a 5-month improvement in overall median survival and an improvement in progression-free survival. The objective response rate of erdafitinib was very similar to what was seen in the phase 2 study. It’s a viable option for these patients and certainly should be considered, but the problem is it’s only about 10% overall, but we need to look for it.

Dr. Sternberg: We don’t really know the right sequence either to give erdafitinib before EV or if we’re going to give it before. But if I find that they’re FGFR-mutated, I think that from the little data I’ve seen in phase 2 that I give the erdafitinib before EV even.

Dr. Petrylak: Well, there are a lot of subtleties to this because there may be a difference between the FGFR2 fusions versus the FGFR3 mutations. That’s one thing I think that’s important for us to look at in the future. The other issue too is, is there a change in the immunogenicity in somebody who’s being treated with erdafitinib? There actually maybe more of an immune effect, and we’re going to see a presentation at this meeting from Arlene Siefker-Radtke, MD, looking at the combination of erdafitinib with a checkpoint. We all thought that this meant that these were resistant to checkpoint therapy, but it may actually be that there may be a biological change that the erdafitinib is having in terms of the tumor microenvironment that may make them more susceptible to immune treatment.

Dr. Koshkin: Yeah, absolutely. What you’re referring to is, of course, the NORSE study that Arlene is presenting. There, I believe, its response rate is around like 70%. If I recall correctly, to the combination of checkpoint inhibitor and erdafitinib.

Dr. Sternberg: In platinum-ineligible…

Dr. Koshkin: In platinum-ineligible frontline patients. But again, very comparable to what we see with pembrolizumab/enfortumab, the population we were extensively talking about just now. Certainly, higher than erdafitinib alone, which is again is around low 40s. Certainly, exciting data and another way to sort of individualize treatment for patients.

Dr. Petrylak: It’s interesting to see the differences between urothelial cancer and clear cell carcinoma of the kidney where you have these great combinations with tyrosine kinase inhibitors (TKIs) such as lenvatinib and pembrolizumab, which really failed pretty miserably in platinum-ineligible patients with metastatic bladder cancer. But here, I think this may be the change that we’re seeing that the targeted therapy combined with immune therapy may actually have a role now in urothelial carcinoma.

Dr. Koshkin: Yeah, absolutely.

Dr. Zibelman: I think, to your point, it also shows the difference with lung cancer where combinations with chemotherapy and immunotherapy have been effective, and they’re really now dicing up lung cancer into so many different mutations, and we’re not unfortunately quite there yet in bladder cancer. I think FGFR in that population is the one that we have, at least for now. I think the other exciting thing is there are future next-generation FGFR-targeted drugs that are along the way that hopefully will offer even better responses as well as decreased toxicity because erdafitinib certainly has toxicities. Patients don’t love being on it. They’re fatigued, anorexic. Hyperphosphatemia is an issue. It’s not the easiest drug to give or take, and so hopefully future drugs will improve on that.

Dr. Sternberg: Dan and I worked on a study with rogaratinib. It was an interesting drug, but there was a problem with validating the marker, and they were using mRNA, and there was a problem with the marker. They stopped the trial because it wasn’t positive, I think in breast cancer. The whole trial was stopped in the beginning. They have to validate a marker better of what we’re looking at for the mutations.

Dr. Petrylak: It also lends to the question, what’s the best test to look at FGFR? That study, it was something, there was a response difference seen in the FGFR2 to FGFR3 DNA mutations. But when you looked at the RNA for all the FGFR subtypes, you didn’t see the difference. As Cora was saying, the test that we used to select may be actually very, very important to the outcome we have.

Dr. Sternberg: Originally, it was done with immunohistochemistry. Then when they redid it with another company, it was different. Then when they did it with, which wasn’t part of the study, with next-generation sequencing with the DNA mutations. Those patients really did have a benefit, but that wasn’t the plan of this study.

Dr. Koshkin: The correct biomarker is key, and it seems that erdafitinib…

Dr. Sternberg: Biomarker is key and validation of the biomarker is key. Companion biomarkers with our drugs is key. That’s part of the reason we’ve had so much problem with all these markers looking at PD-L1 and different companies having results 1 way 1 day and 1 way a different day. I find it also difficult, as you do, that in lung cancer patients a combination of chemotherapy and immunotherapy works, but it doesn’t work in urothelial cancer. I think it just has to do with the design of the trials and getting unlucky with all those, the way the trials were designed.

Dr. Petrylak: It could be related to the biology. If you look at the positive trials in urothelial carcinoma that were randomized, we have the nivolumab trial as adjuvant where the benefit seems to be in those patients had prior chemotherapy, the neoadjuvant treatment. Then we look at switch maintenance. These are a selected group of patients that, whether the chemotherapy is changing, the biology is not clear. Then, finally, the Merck study that looked at pembrolizumab and got it approved compared to chemotherapy. None of the other trials were positive. Is that because there’re different checkpoints that were used or is that because something biologically is going on different with this tumor type that pretreating with chemotherapy changes the microenvironment that makes it more susceptible to immune treatment? A lot of great questions to ask from this.

Dr. Zibelman: To that point, does the chemotherapy matter? We’ve done all of these studies in urothelial cancer with gemcitabine/platinum-based combinations, which is not the drugs that have shown benefit in combination of lung cancer, does that have something to do with it? We don’t know the answer to that.

Dr. Petrylak: I think this is really an important question. If you look at the data with cholangiocarcinoma where they’ve given gemcitabine/cisplatin plus a checkpoint and shown superiority of that combination, yet you don’t see that with your urothelial carcinoma. That’s again pointing to the biology.