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Spotlight

This roundtable series considers treatment options in the metastatic bladder cancer setting, as discussed by key opinion leaders and participants at virtual live events.

Using Targeted Treatments in Patients With Metastatic Urothelial Cancer

Have you had experience with sacituzumab govitecan (Trodelvy) in urothelial cancer? ​

For which patients are you using it? ​

How are you sequencing it with other lines of therapy in bladder cancer?​

 Have you used sacituzumab govitecan? How do you see the data that supported accelerated approval of the compound?

 I have not used it in bladder cancer. I use it a lot in breast cancer so I’m very familiar with it. Initially, it was a learning curve; the neutropenia and the diarrhea were a little bit surprising when we are using an antibody-drug conjugate, but we learned how to take it more seriously. With growth factors routinely [used], it’s very well tolerated.

I have a younger patient who failed chemotherapy, then failed immunotherapy, so we added enfortumab vedotin [EV; Padcev] but we continued the immunotherapy. I don’t know if that’s legitimate or completely off the books here.

 That’s a great question. We do certainly lack data to show a benefit of EV/pembrolizumab [Keytruda] post immunotherapy. We don’t have that data. The data are not clear. That doesn’t mean it might not work to, when you progress on pembrolizumab, add EV. I think we’re figuring out the synergistic effect.

By the way, your experience with sacituzumab in breast cancer, to your point, you think it’s manageable, especially if you do G-CSF [granulocyte colony-stimulating factor].

Oh, absolutely. Nowadays, it’s a very well-tolerated agent. We have learned how to use it.

 No. But I believe that sacituzumab will be efficacious and I like its AE profile a little better than that of EV. I also know that sacituzumab is effective across a lot of cancers, [and is in] phase 2 trials right now, including small cell lung cancer [NCT05633667]. I am happy to use it once we get to the third line. I have a few patients that start [treatment for metastatic urothelial cancer] and most of them don’t make it beyond the second line.

 Based on the data that you’ve seen, it sounds to me that the data were enough to impress you. Is that a situation where you’re going to be thinking EV or sacituzumab?

 I wanted to ask you earlier: There was a significant fatality rate on the phase 2 trial with EV.

 Do you know if that got better in the phase 3 trial?

 I cannot recall the number of deaths on the phase 3 trial…. That’s certainly a learning curve with EV. It’s not a walk in the park for some patients. What I can tell that from the efficacy perspective is I’ve seen patients that EV didn’t touch the disease and sacituzumab was able to control it, which is quite interesting.

I don’t know if others have that experience or not, but they’re definitely different compounds and it’s interesting to see. I don’t know if that has to do with the expression of Trop-2 or Nectin-4 because we don’t [test for] it in clinical practice. But that is the experience I have with it and I’ve used it, so I agree with you that the data, to me at least, was compelling to offer it to patients for sure. I do it routinely—let me put it that way.

How should neutropenia be monitored/managed?​

What about diarrhea associated with sacituzumab govitecan?​

How do you/should you counsel patients regarding potential toxicities with this agent?​

Dr Nidhiry, have you used sacituzumab? If so, neutropenia can occur and in addition to that, you can see some diarrhea.

 What do you do for that, if you’ve used it?

 I’ve used it in 1 patient after the progression on EV, and the neutropenia was a major issue for that patient. Diarrhea wasn’t as much of a problem. I used diphenoxylate/atropine [Lomotil] to manage the diarrhea and it seemed to work.

 Did [sacituzumab] work for your patient?

 The patient seemed to benefit for a few months and then he progressed, but he got a few months out of it.

 Since you’ve used it, how did you counsel the patient regarding what you might expect with the profile of sacituzumab?

 I told them this is [like] some of the chemotherapy-based treatments and he could experience AEs similar to chemotherapy, including risk of infections and diarrhea, and we discussed that. He was already through EV and EV is a similar drug, not with the same AEs but it’s an antibody-drug conjugate, so he was familiar. He was open to trying it. His performance status was still pretty good, and he was open to keep going, and that is why I decided to pursue this.

 I did use both agents in urothelial cancer. I also used sacituzumab in the breast cancer population. The skin toxicity for EV is definitely there, I’ve seen it, and I typically counsel the patient about that. With sacituzumab, myelosuppression and fatigue are very noticeable.

But we always counsel the patients that unfortunately, when urothelial cancer comes back, there are 2 points I like to stress. One, this is an incurable cancer. The second thing is that if they get to second line, there is a good chance they will not get to a third-line setting because the percentage of patients who can move from 1 line to the other drops with subsequent lines of therapy. You might want to use your most efficacious drugs up front because the chance of them being able to receive subsequent line of therapy dwindles down the line.

There is skin toxicity with EV, but I think the recent approval of EV with pembrolizumab

 will make us use that combination more up front because of the amazing 70% objective response rates that we’ve seen in the phase 2 data,

 and I hope to see this pans out in the phase 3 study and translates into overall survival benefit.

 So you consider the antibody-drug conjugates very active options. Do you think they’re both better than the platinum-based chemotherapy? Is that something you will see in the future doing EV and sacituzumab for a patient who has not received a platinum-containing regimen, for example?

 Yes, I started using that a few months ago, even before the FDA accelerated approval [of EV plus pembrolizumab].

1. Yu EY, Petrylak DP, O'Donnell PH, et al. Enfortumab vedotin after PD-1 or PD-L1 inhibitors in cisplatin-ineligible patients with advanced urothelial carcinoma (EV‑201): a multicentre, single-arm, phase 2 trial. 

. 2021;22(6):872-882. doi:10.1016/S1470-2045(21)00094-2

2. 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. 

 2021;39(22):2474-2485. doi:10.1200/JCO.20.03489

3. FDA grants accelerated approval to enfortumab vedotin-ejfv with pembrolizumab for locally advanced or metastatic urothelial carcinoma. News release FDA. April 3, 2023. Accessed June 14, 2023. https://bit.ly/4062b7b

4. Hoimes CJ, Flaig TW, Milowsky MI, et al. Enfortumab vedotin plus pembrolizumab in previously untreated advanced urothelial cancer. 

. 2023;41(1):22-31. doi:10.1200/JCO.22.01643

During a Targeted Oncology™ Case-Based Roundtable™ event, Pedro C. Barata, MD, MSc, and participants discussed when in sequence they would use sacituzumab govitecan for patients with metastatic urothelial cancer. This is the second of 2 articles based on this event. 

Physicians Discuss Sequencing of Sacituzumab Govitecan in Bladder Cancer

Targeted Oncology: What led to the use of sacituzumab govitecan (Trodelvy) in patients with metastatic urothelial cancer?

 Trop-2 happens to be highly expressed in urothelial carcinoma. It’s an epithelial cell surface. Sacituzumab govitecan is different from other antibody-drug conjugates. Here you have a Trop-2 target or Trop-2-directed therapy, and govitecan is the SN-38 which is we know is the active compound of irinotecan. It’s a topoisomerase inhibitor as the payload, tagged with an antibody towards Trop-2. The data across solid tumors is interesting, with overall response rates [ORR] over 30%, median progression-free survival [PFS] of 7.3%, and a very manageable safety profile.

 For that reason, it ended up getting accelerated approval for triple-negative breast cancer.

 It also got a fast-track designation and accelerated approval for metastatic urothelial carcinoma.

We are waiting for the phase 3 confirmatory trial regarding sacituzumab.

The TROPHY U-01 trial [NCT03547973] had 3 cohorts. There were more [cohorts but I will] talk about these 3. Cohort 1 included 100 patients with metastatic urothelial carcinoma progressing after a platinum-based chemotherapy and an immunotherapy. Cohort 2 included patients with advanced urothelial carcinoma who could not get platinum-based chemotherapy, but they did progress on immunotherapy. Cohort 3 included immunotherapy-naïve patients who progressed on platinum. We are talking about a 200-patient study on these 3 cohorts, 100 for Cohort 1 and then 40 or 60 in cohorts 2 and 3. ORR was the primary end point.

What were the results for patients who were enrolled after progressing on platinum-based therapy and immune checkpoint inhibitor therapy?

[Looking at the baseline characteristics] for Cohort 1, these patients were pretreated and half of them got 3 or more lines of treatment.

 A third had liver metastases. Everyone was exposed to platinum therapy. Two patients were exposed to erdafitinib [Balversa]. The median number of prior treatments was 3 for metastatic disease, and you do have a fair number of patients with 2 or 3 prognostic risk factors. I would argue that it's a heavily treated population.

In the Cohort 1, final results showed the ORR was 27%, including 5.3% complete responses, and the rest were partial responses, 22%. When patients responded, the duration of response was 7.2 months, which is similar to what we were seeing in other tumors. But the bottom line is the ORR was stable throughout and in different subsets of patients, including those who received enfortumab vedotin [Padcev]. Three patients out of 10 had enfortumab vedotin as prior therapy.

The median PFS was close to 6 months [5.4 months, 95% CI, 3.5-7.2]. Overall survival was closer to a year [10.9 months, 95% CI, 9.0-13.8].

What was the safety profile of sacituzumab in these patients?

[Looking at] the safety with treatment-related adverse events [AEs] of any grade and then significant grade 3 and 4 toxicities, neutropenia can occur [frequently (46% of any grade)]. Cytopenias like leukopenia, can occur, and there is some anemia and some diarrhea. What is remarkable to me is the number of AEs that have 0 grade 4 AEs. There are double digits for the hematologic AEs or the cytopenias. Everything else is in the single digits, even for grade 3. For most patients, they do well.

You can debate what to do about the neutropenia. I have to highlight the 30% who got G-CSF [granulocyte colony-stimulating factor] in this cohort, and 6% needed to discontinue treatment due to AEs, and that was commonly neutropenia. They had 1 treatment-related death, [which was because of] febrile neutropenia.

I think we’re very familiar with this [toxicity profile]. We use topoisomerase inhibitors. We use irinotecan and others, and so we know what topoisomerase inhibitors do. I do have the sense that this is somewhat familiar to [oncologists] because some of us are treating other cancers where we’re using topoisomerase inhibitors.



1. Tagawa ST, Faltas BM, Lam ET, et al. Sacituzumab govitecan (IMMU-132) in patients with previously treated metastatic urothelial cancer (mUC): Results from a phase I/II study. 

. 2019;37(7_suppl):354. doi:10.1200/JCO.2019.37.7_suppl.354

FDA grants accelerated approval to sacituzumab govitecan-hziy for metastatic triple negative breast cancer. FDA. Published April 22, 2020. Accessed June 13, 2023. https://bit.ly/3NarQav

3. FDA grants accelerated approval to sacituzumab govitecan for advanced urothelial cancer. FDA. April 13, 2021. Accessed June 13, 2023. https://bit.ly/2QoWumx

4. 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. 

During a Targeted Oncology™ Case-Based Roundtable™ event, Pedro C. Barata, MD, MSc, discussed data supporting the use of sacituzumab govitecan in advanced urothelial carcinoma. 