During a Targeted Oncology case-based roundtable event, Pedro Barata, MD, MSc, discussed with participants their approaches to therapy for a patient whose bladder cancer progresses after receiving chemotherapy and immunotherapy.
A 72-year-old man presented with dizziness and hematuria. He had a medical history of hypercholesterolemia controlled with medication as well as cataracts and mild chronic obstructive pulmonary disease. He was a current smoker with 20 pack-years. A CT of his chest, abdomen, and pelvis revealed a 3.5-cm mass in the bladder and multiple lung metastases. A lung biopsy and pathology confirmed stage IV urothelial carcinoma. He had an ECOG performance status of 1 and estimated glomerular filtration rate (eGFR) of over 60 mL/min.
The patient received gemcitabine plus cisplatin for 6 cycles and had a partial response at completion of chemotherapy. No maintenance therapy was given, although it was discussed with the patient. Seven months later, disease progression was discovered on routine follow-up imaging. The patient received pembrolizumab (Keytruda). A partial response was achieved at 6 cycles. Molecular testing showed no FGFR2/3 mutation or fusion.
RESKE: I would probably, as a third-line option, use enfortumab vedotin [Padcev] to see whether that might get some response.
BARATA: So your go-to post-platinum and post-immunotherapy option is usually enfortumab?
RESKE: Yes. I haven’t treated a lot of patients [with enfortumab], but the ones I’ve treated, I’ve seen some pretty good responses.
GILL: I agree about enfortumab vedotin. The investigators specifically mentioned FGFR2/3 testing there to guide you a certain way. It is very useful to get, and if it was positive, I would go ahead and consider the patient for erdafitinib [Balversa].
I think out of the options that we have, I would go with enfortumab. If you look at the NCCN [National Comprehensive Cancer Network] guidelines, you have other options available as well.1 But I wouldn’t jump to them. He’d already received gemcitabine. There’s paclitaxel or docetaxel. Out of those, I would try enfortumab before them.
BARATA: At what time points do you perform molecular testing?
BALDEO: Usually, on diagnosis of metastatic disease, I’d do both liquid and tumor molecular testing, so I’ll have options. But I agree, I’d use enfortumab for this patient.
HAMMOUD: Based on the NCCN guidelines, after failing cisplatin plus gemcitabine and pembrolizumab, I would do enfortumab as well. For the molecular testing with metastatic disease, we do it up front at diagnosis. So we test them early on.
BARATA: Some physicians would consider other therapies, like sacituzumab govitecan [Trodelvy] for example, assuming this patient does not have FGFR when you do genetic testing. Have you tried anything else besides enfortumab?
GALLAGHER: My thoughts are with everyone else’s. That would be the go-to, enfortumab vedotin. I would save sacituzumab for after. That would be fourth-line therapy. Molecular testing is upon diagnosis of metastatic disease. It is very helpful because if I found a FGFR3 mutation, then I could use erdafitinib in the third-line setting.
BARATA: If this patient had an FGFR2 or FGFR3 mutation, would you decide differently, or would you still go with enfortumab, which I’m assuming is the go-to? Anyone who would do erdafitinib before doing enfortumab in the post-platinum, post-pembrolizumab, FGFR-mutated scenario?
GALLAGHER: Yes, I would.
BARATA: Can you expand on that? What would make you do the targeted therapy first?
GALLAGHER: I would think they’re more fit at that point and less worn down by other treatments. So they would just be the best candidate for the targeted therapy.
BARATA: Would everybody else go with the antibody-drug conjugate first?
BALDEO: I haven’t used these yet, but I would talk to the patients about the adverse events [AEs] like the retinopathy with the FGFR inhibitor vs neuropathies. So it depends on the patient and what their comorbidities are, too.
BARATA: So you’ll have that discussion with the patient. But basically, you would consider those 2 options in your discussion? It would be either enfortumab or erdafitinib? You wouldn’t bring other options, like sacituzumab govitecan or even a taxane?
BALDEO: Not yet.
GALLAGHER: I have very limited experience with enfortumab. But I know it’s weight-based and it has a cutoff, so you must monitor the patient’s weight so you don’t go over a certain dose. For hyperglycemia, I believe you do the glucose check before you give it because there’s a cutoff there; you don’t want to have a rapid increase in the serum glucose. Those things I’ve paid attention to. Unfortunately, the skin issues are real, and I may have seen Stevens-Johnson syndrome that had developed from this. It can be quite toxic. Then again, it could be not very toxic [for every patient], but you must use care and monitoring and try to intervene as soon as you feel like something’s going on.
RAZAQ: I haven’t used enfortumab, but I have heard about it. Some of these skin reactions make me uncomfortable, so I wanted somebody to share their experience. The skin toxicities are normally graded based on how much skin is involved. So do we wait until it is grade 2 or grade 3 before we interrupt it? What’s the point where you want to stop treatment for the skin toxicities, and how do you treat? If somebody could share their experience, I would like to hear that.
RESKE: One of the things patients I treat complain about is alopecia, and there is a vague fatigue that you get a lot. It’s unclear where it might originate from. It might have multiple reasons. It’s not that I treat a lot of patients, but those are the main complaints.
BARATA: You can grade rash. That’s what they do in the clinical trials. There’s a tool called CTCAE [Common Terminology Criteria for Adverse Events], and if you type CTCAE.pdf, you have access to it; it’s version 5.0 right now. If you find the skin rash, you can grade the toxicity. It must be not only the amount of skin involved, but also the severity of the lesions. Do you have blisters, peeling? How deep are the lesions? Do you need to have medication to control them? Basically, that’s how you grade them. You go from no rash at all to sometimes grade 4 rash that requires hospitalization. So it’s a good question.
Does anyone else have experience with enfortumab that you want to share?
HAMMOUD: I haven’t used it myself, but I covered for a colleague who used it, and the patient had a bad skin reaction.
BARATA: What happened to that patient? Did they have to discontinue the drug or were they able to stop for a little bit and go back on it?
HAMMOUD: It was held for some time and was restarted with a dose reduction.
Paying attention to the skin makes a big difference because you can act on it sooner rather than later, which is helpful.
GILL: I haven’t used enfortumab myself. I have heard from some patients that have been on it in the past, and it’s hard to say whether it’s the patients themselves or the drug, but they had a rough time with it and would tell me frequently that they’re very happy they’re not on that anymore.
BARATA: The same with neuropathy. It tends to be sensitive in nature. It can be a limiting factor. We’re talking about a relatively significant treatment-related AE of 46%, so it’s almost half of the patients who are going to encounter that.2
About the glucose levels, it’s not as frequent, but we do need to check it, and I believe the cutoff is 250 mg/dL. In other words, if you get a patient in clinic to get treatment, or at the infusion to get treatment, and their glucose is higher than 250 mg/dL, you cannot do treatment.
Alopecia is observed in almost half of the patients at 45.3%.2 It’s something that I think we are less effective in controlling. So that’s as far as it goes, in terms of AEs. How do you counsel patients regarding potential toxicities with this agent?
GALLAGHER: Usually, generally speaking, I always highlight the AEs that are common and that we encounter.
BARATA: Have you had experience with sacituzumab govitecan in urothelial cancer or other cancers? Do any of you feel engaged or motivated to use it? Is there anything in the data that would make you want to use this drug?
CHARBONNET: Based on the data, it seems like this might have less toxicity than enfortumab. We’re familiar with irinotecan. The other thing is after 3 lines of treatment, these patients progress in less than 3 months and the median progression-free survival of sacituzumab is over 5 months. To me, it shouldn’t wait till the fourth line of therapy.3
BARATA: Those are great comments. I’m with you. I’ve used it and it has a different safety profile from enfortumab. I use the example of irinotecan as a way for us to think of the topoisomerase inhibitor, but I should say the payload is SN-38. But you’re right, the safety profile is different and it does play a role in the management of urothelial carcinoma. To your point, the natural next step could be moving it earlier in the course of the disease.
THEODOSSIOU: My experience has been in the stage IV breast cancer setting, and the toxicity there is consistent with what you described. I have not used it in bladder cancer, but if I did use it, I would use it per the package insert, which is essentially once you fail platinum therapy and an immune checkpoint inhibitor, so I would use it as third-line therapy. The familiarity in the breast cancer arena makes me more willing to try it.
BARATA: So you would consider it for third-line therapy? What in the data makes you think that this is an option?
THEODOSSIOU: Familiarity is important, and being primarily a breast cancer physician, I do have familiarity with the drug. So I’m not afraid to use it.
BARATA: Can you share some tips about things like the safety profile that you encounter? Do you have a different experience with the drug?
THEODOSSIOU: Primarily, diarrhea and leukopenia. In the breast cancer arena, this is a third- and fourth-line agent, so those are heavily pretreated patients.
BARATA: That’s the experience for other colleagues and my own experience, too. You mentioned the neutropenia. Do you dose reduce, or do you add GCSF [granulocyte colony-stimulating factor]? Do you do it from the get-go?
THEODOSSIOU: In the breast cancer setting, those are patients on third-line therapy. Typically, I dose reduce rather than add GCSF.
BARATA: When you are counseling your patients about this drug—and I know it’s not bladder cancer, but let’s use that as an example for your breast cancer population—what do you tell the patients about the potential toxicities?
THEODOSSIOU: Neutropenic precautions and diarrhea are the main ones that I caution them and counsel them about.
BARATA: Does anyone have a question about this because the experience is limited with this molecule?
GILL: Based on the sacituzumab study, I am more inclined to use this agent than enfortumab. Do you have a paradigm that you use? I know we haven’t compared these agents head to head, so we don’t have those data. In the absence of that, is there a way that we can choose a particular agent?
BARATA: You raised fantastic points. We don’t have head-to-head studies in the later-line setting, so we cannot make any definitive statements about which one is better. They’re both active; we can say that. It’s true that enfortumab has survival data, but it’s also true that the safety profile of sacituzumab is very different, and perhaps some of us would find it more favorable. We are more used to dealing with the cytopenia and the GI [gastrointestinal] issues than perhaps the neuropathy, which is tough, and that tends to be a limiting factor of enfortumab. That’s one of the aspects that I look at. When I have a patient, I like to think of the safety profile of the different agents and pick one or the other.
I use both, and not necessarily in the standard-of-care setting, because we have trials for them. I believe they play a role in the management of metastatic HER2 carcinoma, too. I don’t think you can go right or wrong with 1 sequence vs the other. The important message here is I think it’s obsolete to think of a taxane monotherapy or gemcitabine monotherapy without using an antibody-drug conjugate. That’s an important message based on these data.
HAMMOUD: If someone has diabetes or ocular issues, for example, I will try to avoid enfortumab and go more to sacituzumab. Mostly, this is what I would be looking for. It seems enfortumab has more neuropathy than sacituzumab, so that’s another thing we can consider [From the Data2,3].
BALDEO: I’ll say the same thing. It depends on the comorbidities and what the patient is willing to risk having. If they have neuropathy already, I’ll avoid enfortumab. Mostly comorbidity and the tolerance are what we discuss with them.
GILL: The diabetes is a good point, and preexisting neuropathy, too. I would go more toward sacituzumab. Maybe if they’ve had a rough go previously, in terms of cytopenia, that would lean me more toward enfortumab. Just looking at the patient’s clinical status in general and seeing what they would be able to tolerate is how I would make my decision.
CHARBONNET: About 20% of my patients [are] diabetic, and if I give 6 cycles of gemcitabine plus cisplatin, the neuropathy is already there. So I would avoid the enfortumab as third-line therapy. For me, it’s a little bit easier just to give growth factors, Lomotil [diphenoxylate and atropine], extra fluids, and manage the diarrhea rather than [manage] neuropathy, which I don’t know how to address, especially in a diabetic patient after cisplatin therapy. It just seems like sacituzumab is going to be less toxic than enfortumab. Or, if it’s not, I know how to manage its toxicities a little bit better.
GALLAGHER: Sacituzumab has compelling evidence so it may be a better choice in the third-line setting. I mentioned reserving it for fourth-line therapy, but the problem is, who gets to fourth-line therapy? It’s not common in metastatic bladder cancers. Would they even be well enough to receive that in the fourth line? So move it up to the third line. I can see that being the discussion. I don’t usually give patients choices. I try to narrow it down myself, and then present the AEs of the one I’m thinking.
THEODOSSIOU: Inflammatory bowel disease would be a contraindication for me to give sacituzumab. The choice [of which therapy] is made primarily based on the AE profile. So if I have a diabetic patient or someone with bad neuropathy, that would be a red flag for enfortumab. If I have someone with inflammatory bowel, that would be a red flag for sacituzumab.
1. NCCN. Clinical Practice Guidelines in Oncology. Bladder cancer, version 2.2022. Accessed October 4, 2022. https://bit.ly/3IIkLe3
2. Powles T, Rosenberg JE, Sonpavde GP, et al. Enfortumab vedotin in previously treated advanced urothelial carcinoma. N Engl J Med. 2021;384(12):1125-1135. doi:10.1056/NEJMoa2035807
3. Tagawa ST, Balar AV, Petrylak DP, et al. TROPHY-U-01: a phase II open-label study of sacituzumab govitecan in patients with metastatic urothelial carcinoma progressing after platinum-based chemotherapy and checkpoint inhibitors. J Clin Oncol. 2021;39(22):2474-2485. doi:10.1200/JCO.20.03489