Panel Discusses Treatment Selection After Progression on EV/Pembrolizumab

A roundtable discussion, moderated by Vadim Koshkin, MD, discussed the post-EV-302 world for metastatic urothelial carcinoma, as well as recent trial data from the American Society of Clinical Oncology Genitourinary Cancers Symposium 2024. Dr. Koshkin was joined by Petros Grivas, MD, PhD; Karine Tawagi, MD; Terence Friedlander, MD; and Guru Sonpavde, MD.

In the third segment of the roundtable series, the panel weighed in on treatment selection after patient progression on EV/pembrolizumab.

Watch the next segment in this series.

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Dr. Koshkin: I believe this is a good segue to our next topic. So, post-protocol therapy on EV-302 would be interesting. It will reveal what patients received after progressing on the EV-302 regimen. Currently, with EV/pembro, which is adopted for many and most patients where it is available, unfortunately, patients will progress on this regimen. What would be your therapy of choice?

Dr. Sonpavde: In this setting, I think the community standard would be gemcitabine platinum or another preferred platinum-based combination. Erdafitinib, of course, comes to mind for patients with FGFR3 mutations. Personally, I would lean towards erdafitinib before gemcitabine-platinum in that subgroup of patients. However, the community standard remains gemcitabine-platinum. Sacituzumab govitecan is available but now approved only post-platinum. So, it is uncertain if it would be allowed post EV/pembro in clinical practice.

Dr. Friedlander: It is interesting that sacituzumab is approved in triple-negative breast cancer and is commonly used there. In bladder cancer, its activity is noted, although not as pronounced as EV monotherapy, showing about a 23% response rate. Dr. Grivas recently published a study on its combination with immunotherapy. Maybe you can share about that shortly. With a 23% response rate in the TROPHY-U-01 trial, it is active. However, I agree with you. I am uncertain about jumping to sacituzumab. We lack data on the activity of platinum in the second line post EV/pembro space. Considering patients will be progressing despite immunotherapy, they will have more aggressive disease. Platinum should likely be given, but better datasets are needed, hopefully emerging soon.

Dr. Grivas: I completely agree. At the Uromigos meeting, Dr. Tawagi and I discussed an excellent idea about a trial in this space. Could you share more about your thoughts on that?

Dr. Tawagi: Indeed, we were considering this question precisely. How will chemotherapy perform in the second-line setting post EV/pembro? Additionally, a concern we share is the potential neuropathy from EV/pembro affecting the eligibility for cisplatin. Would we still expect a response rate around 40% in the second-line setting of chemo post EV/pembro? As discussed, sacituzumab generally falls in the 20% range. There are no trials comparing the 2 in that setting, though ongoing trials, such as TROPHY-U-01, are evaluating sacituzumab with or without immunotherapy. This also raises the question of repeating immunotherapy. While in kidney cancer, repeat immunotherapy has not shown benefit, will the same hold true for bladder cancer?

Dr. Grivas: That is an excellent question. Returning to your point, we recently published data on sacituzumab plus pembrolizumab combination in platinum-refractory patients, immunotherapy-naïve in the second-line setting. The trial met its primary endpoint with an overall response rate of 41%, including a 20% complete response rate. The median duration of response was about a year, and median progression-free survival was a little over 5 months. We’re actively designing the ECOG-ACRIN 8231 phase 3 trial, comparing sacituzumab plus pembrolizumab versus sacituzumab alone after prior immunotherapy. The entry points could vary, including after adjuvant nivolumab or pembrolizumab, post-developmental maintenance, or post EV/pembro. This trial will provide crucial insights into the efficacy of immunotherapy in challenging cases.

Dr. Koshkin: I agree; it is a crucial question. If patients progress on this immunotherapy-containing regimen, EV/pembrolizumab, will there still be activity with another checkpoint inhibitor-based regimen? What are everyone’s thoughts?

Dr. Friedlander: I am not overly optimistic that if a patient has been treated with a checkpoint inhibitor and progressed despite it, we will see responses with another checkpoint inhibitor. Smaller series show rare responses when switching PD-1 inhibitors, and in RCC, switching PD-1 inhibitors has not proven beneficial. However, in cases where patients received adjuvant nivolumab, completed treatment, and then relapsed, there might be a role for giving another PD-1 inhibitor after the completion of therapy. We need more studies to confirm this, but I am skeptical that we will see significant responses to checkpoint inhibitors despite progression.