Second-Line Treatment for Metastatic Urothelial Carcinoma


Second-line treatment approaches available for metastatic urothelial carcinoma and considerations for switching therapies vs re-challenging with prior therapy.

Neeraj Agarwal, MD: Petros, tell me about how you approach treatment of your patients with metastatic bladder cancer in the second-line therapy setting.

Petros Grivas, MD, PhD: This is a great question, and I agree that it’s been a great discussion. For platinum-refractory disease, the simple answer is that we have 3 options. Patients who have progression on platinum-based chemotherapy and are immunotherapy naïve can get pembrolizumab. We have phase 3 data from the KEYNOTE-045 trial with pembrolizumab vs salvage chemotherapy by Joaquim Bellmunt and colleagues published in the New England Journal of Medicine in 2017. This is the only phase 3 trial in the platinum-refractory setting that saw overall survival benefits as a primary end point. I tend to use pembrolizumab for those patients.

Another option is erdafitinib. We have data from a phase 2 single-arm study, BLC2001, that was published by Yohann Loriot also in the New England Journal of Medicine. It was not randomized. It saw a very impressive response rate with erdafitinib. About 40% with patients with FGFR2- or FGFR3-activating mutation or fusion. We have ongoing phase 3 trial called THOR comparing pembrolizumab with erdafitinib, as well as salvage chemotherapy with erdafitinib depending on prior chemotherapy. The THOR trial will define the best second-line therapy, pembrolizumab or erdafitinib, in patients with a positive status, FGFR2 or FGFR3 mutation, or fusion.

The third option is clinical trials. We have many clinical trials at our center looking at immunotherapy-based combinations to see whether we can improve upon pembrolizumab alone or atezolizumab in that platinum-refractory setting. Recently, the FDA has received withdrawal of 2 agents, durvalumab and atezolizumab, in platinum-refractory disease. Technically, 3 checkpoint inhibitors are available: pembrolizumab, avelumab, and nivolumab. However, of the 3, pembrolizumab has level 1 evidence for platinum-refractory immunotherapy-naïve disease. The options are pembrolizumab, erdafitinib, or clinical trial. Of course, we can talk a little later about antibody-drug conjugate. Do you do the same thing, Neeraj? Do you have any comments?

Neeraj Agarwal, MD: Yes. Before I answer your question, I have 2 quick questions for you. What is the utility of second-line immune checkpoint inhibitors, such as pembrolizumab, if patients have already received avelumab maintenance therapy based on the JAVELIN Bladder 100 trial data in the first-line setting? How do you approach this? The other question is, what’s the utility of erdafitinib in patients who don’t have FGFR mutations? And if there are FGFR2 and FGFR3 infusions, how do you approach that? I’m curious. I want to learn and hear from the expert.

Petros Grivas, MD, PhD: Thanks, Neeraj. I appreciate that. In simple words, if a patient has progression on available maintenance therapy, they can move on to the second-line therapy. I wouldn’t use a single-agent checkpoint inhibitor in that setting. The patient already had progression on avelumab. I would move on to antibody-drug conjugates, belantamab mafodotin or sacituzumab govitecan, or erdafitinib for mutation or fusion-positive patients. Obviously, we can think about immunotherapy-based combination trials. But if someone has progression on a checkpoint inhibitor, I wouldn’t use another 1 by itself. I would change the class of agents.

Patients who have FGFR2 -or FGFR3-activating mutation or fusion are candidates for erdafitinib based on the FDA label and approval. However, patients with amplification on FGFR don’t have that indication. I’ve used erdafitinib for either mutation or fusion, but it has to be on label. It has to be an activating mutation or fusion in FGFR2 or FGFR3. I’d stick with that and not extrapolate for any other, not FGFR2 or FGFR3 alterations or amplifications.

Neeraj Agarwal, MD: That’s very important. That’s what I was hoping to hear: that it’s not indicated for FGFR amplifications. This is not an uncommon report to see when we get the comprehensive genomic profiling results. And it’s probably 1 of the most commonly asked questions by trainees in the clinic, so thank you for answering that.

Transcript edited for clarity.

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