First-Line Treatment Options for Patients With Metastatic Urothelial Carcinoma

Transcript:
Shilpa Gupta, MD: That was really a beautiful discussion. Thank you all. Now we’ll switch gears to the metastatic setting which, like most of you said, is what you see a majority of the time in your practice. I’ll start with Petros. Can you briefly go over cisplatin ineligibility, and are you following the traditional ... criteria or are you more lenient with the creatinine clearance in your real-world practice?

Petros Grivas, MD, PhD: A great question, Shilpa. So as ... and colleagues said in a 2011 article published in the Journal of Clinical Oncology, the ... criteria is lying in the sand. It’s a consensus-based criterion that included creatinine clearance 60 or higher, ECOG PS [performance score] of 0 to 1, absence of significant hearing loss or neuropathy grade 2 or higher, and absence of symptomatic heart failure NYHA [New York Heart Association] class 3 or higher. I think this has been a great effort. It helped us a lot as a field in standardizing definitions and helping both academic and community oncologists in clinical practice how to select patients for cisplatin. I think there’s definitely some variation in different clinics based on the degree of comfort.

Partially, in the absence of a clinical trial, if a patient meets otherwise criteria to give cisplatin, I have been comfortable let’s say reducing my threshold of GFR [glomerular filtration rate] to 50 ml/minute or higher. We have some retrospective data that we published with Vadim Koshkin, MD, and others looking at that cohort. We had about 30 patients with GFR below 60, and 20 of them had between 50 and 60, and they did OK. These are the patients whom I may speed this cisplatin dose but, of course, it's small data sets. We cannot definitively make strong statements. It’s an artistic approach based on the level of comfort. I know some colleagues of mine who go even below 50 ml. I’m not that brave. I usually use 50 ml as my cutoff. But again, I don’t think that is a right or wrong answer. It depends on the patient and the providers’ ability and comfort.

In terms of hearing, it is a discussion with the patient. It also depends on the degree of hearing; the patient’s preference, which is important; and the curative version or curative intent setting, neoadjuvant curative intent, more stakes here. Patients may opt to go for it when palliative intent may have more reservations but the discussion with the patient also about the hearing and of course, following up with audiology can be very helpful. I think someone who has significant neuropathy grade 2 or higher or symptomatic heart failure or ECOG PS of 2, for me these are clear contraindications to cisplatin, and we have discussed other options in metastatic urothelial cancer. If I cannot use cisplatin, which is my preferred agent, I use carboplatin in either case with gemcitabine. And, in either scenario, I switch maintenance avelumab [Bavencio] for those with responsive stable disease.

Shilpa Gupta, MD: Thank you. Petros and Mamta, is that your cutoff also? What is your go-to regimen? Do you ever use dose-dense MVAC [methotrexate, vinblastine sulfate, doxorubicin hydrochloride (Adriamycin), cisplatin] in frontline cisplatin-eligible patients?

Mamta Parikh, MD, MS: Yeah, thanks. I do use dose-dense MVAC for some patients that are fit with metastatic disease but, as I said, are young and fit patients. I do still consider dose-dense MVAC for those patients. I use similar criteria to what Petros mentioned. I think though, as you mentioned, there is some room for flexibility with the creatinine cutoff if patients are otherwise quite fit. There is some data for using split-dose cisplatin, so I do sometimes use that when I’m using gemcitabine plus cisplatin. That’s another approach that can be taken.

Shilpa Gupta, MD: Thank you, Mamta. Andrea, is that your experience? Also, in your experience are your patients willing to take the risk for hearing loss, especially in a neoadjuvant setting? A lot of my patients would say, “If it’s curative, I don’t mind if my hearing becomes worse.” What’s your experience in the metastatic setting? Are patients willing to take that risk or do you lean towards carboplatin?

Andrea B. Apolo, MD: If there are hearing issues, I do discuss that it could get worse, and if I think cis-platinum and we think cis-platinum is the best option and the patient is otherwise eligible. We do get audiology and get an ENT [ear, nose, and throat] consult and we discuss it because there are different types of hearing losses and some particularly do get worse with platinum-based chemotherapy. But I have also seen hearing issues with carboplatin. It's less common, but it can happen too. In terms of kidney function, my cutoff is I go below 50 ml if I think cis-platinum is the best option and the patient is otherwise fit, I can go as low as 45 ml for creatinine clearance and I split the dose of the cis-platinum. That’s something that I do.

For patients that are not cis-platinum-eligible, my go-to is gemcitabine and carboplatin. This is generally well tolerated, and we can play around with the AUC [area under the curve] of carboplatin if needed. The responses are pretty good. I think that in the main phase 3 data on gemcitabine and carboplatin, the overall survival is low, but it does include patients that have poor performance status. So that’s something to think about, which I think really does affect the outcome in the patients when you group them all together and they have a low-performance status.

One thing that I wanted to mention, and I think this is important, is that we used to use pembrolizumab [Keytruda] and atezolizumab [Tecentriq] in the first-line study for patients that were cisplatin-ineligible and were PD-L1 high. Those labels have been removed. There was an ODAC [Oncologic Drugs Advisory Committee] meeting run through the FDA asking the question now that the KEYNOTE-361 study was negative, and this was the first-line study of pembrolizumab monotherapy or pembrolizumab plus platinum vs. just platinum-based chemotherapy. Now that that study is negative and didn’t show a survival benefit for the patients that were receiving monotherapy pembrolizumab, and the biomarker did not select out the patients, what is the rationale for keeping pembrolizumab in the first-line setting? I was part of the ODAC meeting, and we did discuss that there’s a small group of patients that can’t get any platinum-based chemotherapy.

Shilpa, you have led this effort in terms of really trying to get a consensus as to who are these patients because these are a very heterogeneous group of patients, as most of the patients we can treat with carboplatin-based chemotherapy if they’re not cis-platinum-eligible. So who are these patients? The FDA removed the label for the first-line treatment of cis-platinum-ineligible patients that are PD-L1 high for pembrolizumab but left it for patients that are platinum-eligible. Just recently due to the IMvigor130 study that was presented at ASCO GU [American Society of Clinical Oncology Genitourinary Cancers Symposium], the atezolizumab labeled for the first-line setting in cisplatin-ineligible PD-L1 high was voluntarily withdrawn.

When I looked at the IMvigor130 data—the IMvigor130 study is the phase 3 trial and the final overall survival was presented here at ASCO GU 2023. The study is a randomized phase 3 trial, a large study made up of 1200 patients with monotherapy atezolizumab in 1 arm, atezolizumab plus platinum-based chemotherapy vs. platinum-based chemotherapy plus placebo. In that study, if you look at the atezolizumab arm, and you specifically look at the patients that were cis-platinum-ineligible that were PD-L1 high using their assay, the VENTANA PD-L1 Assay, you saw those patients were selected out, and they did do better. I have some mixed feelings right now about the label being withdrawn in this population of patients. Although, I know that it’s very complicated to get patients tested for PD-L1 in the metastatic setting. You’ve seen the right assay is really important, the assay that was particularly used in that setting within that clinical trial.

Shilpa Gupta, MD: Thank you, Andrea, for highlighting that. That was a wonderful discussion. I was wondering the same thing. If anything, this label should have escaped for the PD-L1-positive subgroup of patients, but it is complicated how these things work and you would love to get more harmonization of biomarkers. As you mentioned, platinum-ineligibility is sometimes overcalled in the community and our efforts in being involved in the platinum-ineligibility work is to avoid that and design trials for those patients who otherwise get left out.

Transcript edited for clarity.