Case 4: Considering Special Populations in Bladder Cancer

EXPERT PERSPECTIVE VIRTUAL TUMOR BOARD

Arlene O. Siefker-Radtke, MD:I’m curious though, we weren’t able to get a biopsy, and we have a therapy that can target if a mutation is found. And let’s assume you did the liquid biopsy and it was negative. He has an upper tract tumor,FGFalterations reported in about 35%. I’d like to ask Gordon, is there anything that you can do in the urology clinic that would get tissue on this type of patient? Let’s assume there’s still some tumor up there in the renal pelvis.

Gordon Brown, DO:Go for the tumor obviously in his bladder and resect that. The challenges, genetically, are whether that’s reflective of his original tumor or not. We have to kind of assume that it is. But certainly assuming from performance status, there’s a higher perspective that he was willing to undergo that procedure. I think it’s very reasonable to try and get tissue there to send. If you happen to have a target, then you can have that discussion with the caveat that it might not be exactly reflective of what his lung disease represents. Nonetheless, I think it’s reasonable, and may also mitigate any local symptoms he has, as his disease progresses.

Arlene O. Siefker-Radtke, MD:Do you think that tumor that occurred more recently in the bladder, could it be related to the upper tract tumor? Perhaps some type of implant in the bladder?

Gordon Brown, DO:Yes. The most common site obviously of upper tract recurrence is the bladder; that can occur in up to 50% of patients over time. That’s why we surveil our lower tracts routinely in this patient population. It could be; that’s why I would sample it. And you know, that would be the intellectual kind of connection that we would make, assuming this showed something that wasFGFRpositive, or PD-L1 [programmed death-ligand 1] positive, etcetera, to justify the use of different agents in this patient who has somewhat limited options.

Arlene O. Siefker-Radtke, MD:Let’s assume you couldn’t get enough tissue in the bladder, there wasn’t much left. What about going back and looking at the renal pelvis? Especially if we think this could be an implant to the bladder from the renal pelvis tumor, and somehow genetically linked. Do we think that could be causing the met [metastasis]?

Elizabeth R. Plimack, MD:I guess that would be down on my list of options, but certainly before saying, “There are no more options for you,” we would send that. I guess my thought is that the lung metastasis may grow further and become better amenable to biopsy. Again assuming the patient can go for a biopsy procedure or a TUR [transurethral resection] procedure to get additional tissue. Clearly the least risky procedure would be to pull that upper tract tumor from the bank and send that, so that’s something we could do. And then liquid biopsy is something we’ll do as well.

Arlene O. Siefker-Radtke, MD:I’d like to explore a slight twist on this case. What if this patient not only had congestive heart failure, but also had type 2 diabetes with poorly controlled hemoglobin after failing immune checkpoint inhibition? Would you have still used enfortumab vedotin in that patient?

Elizabeth R. Plimack, MD:Well that’s a great question and you touch upon 1 of the mysteries of enfortumab vedotin, which is that it’s an antibody drug conjugate. We think that the side effect of neuropathy is expected with MMAE [monomethyl auristatin E]. It’s a neurotoxin. But there have been issues with diabetic patients having fatal adverse effects, related, or unrelated, to treatment. And so the study was amended to limit enrollment of exactly the patient you described. So I think where we are with enfortumab vedotin right now is we have single-arm trial data. We hope and expect accelerated approvals to come within a year. But the randomized and larger trials I think will answer these questions around who is a candidate. For now I would play it safe, and the answer would be no, I don’t think I would have recommended the patient. And he wouldn’t have been eligible for the trial with that.

Tian Zhang, MD:There is an expanded access protocol now for enfortumab vedotin, and we are one of many sites in the United States that are opening the expanded access protocol. I do think it’s a very active agent for our refractory patients. And so short of the poorly controlled diabetic patient and other patients who have neuropathy, I would certainly consider it for patients who are progressing past the standard lines of therapy. I think it’s a good option until we have approval in this space.

Arlene O. Siefker-Radtke, MD:So, we have 2 promising drugs. We have erdafitinib approved. Let’s assume we have enfortumab approved. And again, both have about a 40% objective response rate, and then the median overall survival, which shouldn’t be compared but does seem comparable. Erdafitinib about 13.8 months and enfortumab about 11 months. You have the same patient failing immunotherapy who has anFGFR3mutation, which would you choose?

Tian Zhang, MD:It’s a hard question early, and I think that it requires a conversation that you have with the patient, right? When they have the driver mutations, that’s great, and then you have the options. Then do they want to do the targeted small molecule inhibitor first, or do they want do the enfortumab vedotin?

I think it’s hard to distinguish them from an efficacy standpoint. I think we can talk about them from a toxicity standpoint and see if there are any differentiating factors on adverse effect profiles. But it’s a good problem to have, right? Then we could potentially sequence these therapies and do 1 after another. The good news is that enfortumab is not selected for Nectin-4 positivity, and you do have these options to talk about.

Elizabeth R. Plimack, MD:Yes, and I think convenience is something that will come into play. A pill is a lot more convenient than almost weekly infusions, which enfortumab requires. So again, I think it’s such a fortunate position to be in to have these choices, and the decision isn’t either/or but what’s first hopefully. And hopefully a patient can have the opportunity to achieve benefit from all of these.

Arlene O. Siefker-Radtke, MD:I think that’s such a great point, Betsy. I’ve been asked, “So you have 2 options, which do you give, which option wins?” And the response is, the patient wins. Because while people still think about who wins second-line, who wins third-line, the truth is if you build better treatments and treatments that are more tolerable, patients will then be available to go on additional lines of therapy.

And you remember the old prostate cancer days before taxanes were approved. And once it was single-agent taxane, everyone said, “OK, we’re done with prostate cancer, there will never be anything following taxane,” because it will be just that toxic. But look at how many lines of treatment have evolved now for the therapy of prostate cancer.

We’re seeing the same thing evolving in bladder cancer with these new and better agents, and maybe even an ability to avoid the toxicity of chemotherapy altogether. So I think it’s certainly a very exciting time for the treatment of our bladder cancer patients who are really the winners in this scenario when we have multiple strategies and perhaps multiple combinations approved down the road.

Arlene O. Siefker-Radtke, MD:I would like to give a huge thank you to Betsy, Tian, and Gordon for their time, for their thoughtful case presentations, and lively and informative discussion. To our viewing audience, thank you for joining us for thisTargetedOncology™VirtualTumorBoard® presentation. We hope today’s discussion was a valuable use of your time, and that you acquired some practical knowledge that you can take back to your clinic.

Transcript edited for clarity.