Immunotherapy’s Roles in Treating Metastatic Urothelial Carcinoma

Considerations for the role of immunotherapy in metastatic urothelial carcinoma as maintenance or switch therapy.


Ignacio Durán, MD, PhD: There’s no doubt that immunotherapy has changed the landscape of bladder cancer in the last 7 to 10 years. It started with the first study with atezolizumab [Tecentriq] in patients who had been heavily pretreated. In that context we observed some responses in which the drug was stimulating their immune system. That family of drugs, called checkpoint inhibitors, started its development in bladder cancer. We came to the conclusion that a number of compounds were very active in advanced bladder cancer. Two of them, atezolizumab [Tecentriq] and pembrolizumab [Keytruda], made it to the top of that list because of 2 randomized phase 3 trials. Pembrolizumab [Keytruda] was the 1 with the highest level of evidence, and it became the standard of care in patients who have progressed after receiving chemotherapy. That was the first hit of immunotherapy in bladder cancer, becoming the preferred second line.

What’s happened there since? What we’ve seen is the switch of chemotherapy from advanced stages to more initial stages of bladder cancer in the metastatic context. What I mean by more initial stages is that we went from second or third line to patients in the first line of treatment. Those attempts had different outcomes. Let me explain. One thing we tried was to introduce immunotherapy in the first line as a single agent. The results were relatively disappointing. We didn’t have a lot of data to support the use of immunotherapy single agent as a first-line approach. That would be strictly recommended in a very small portion of patients: those whom we consider unfit for any kind of platinum-based therapy and who have a high PD-L1 expression. That was a relative success.

The second attempt to move immunotherapy to earlier stages combined chemotherapy and immunotherapy in the first line. That was a failure. There were 2 studies, IMvigor130 and KEYNOTE-361, that failed to demonstrate an improvement in overall survival combined in chemotherapy plus immunotherapy in the first line. We should not use that strategy. Then came the third attempt, which has been quite successful: incorporating an immunotherapy after receiving first-line chemotherapy, not as a rescue treatment but as a maintenance treatment. There are different ways of doing maintenance strategy. After receiving some kind of therapy you can drop 1 of the compounds and maintain the other 1. That’s called a continuation maintenance therapy. Or you can do what we call a switch strategy. Let’s say you start with 1 treatment and, at 1 point, if there’s benefit, then you switch to a different 1. This is the strategy we’ve used with immunotherapy in the first line of bladder cancer. Patients are treated with 4 to 6 cycles of chemotherapy. If there’s any benefit—partial response, complete response, or stable disease—then we continue with avelumab [Bavencio]. This is what we call a switch maintenance. This is exactly where immunotherapy has a major place right now.

What about the second line? Where is immunotherapy in that context? If a patient doesn’t respond to chemotherapy, there’s no benefit to that treatment. Then we could use immunotherapy, most commonly pembrolizumab [Keytruda], as an alternative rescue treatment. Last, where is immunotherapy trying to go right now? Immunotherapy is developing in combination with different immunotherapies. We’ve got combinations of 2 checkpoint inhibitors. There are ongoing studies that haven’t been concluded. We’re also combining immunotherapy with a new class of drugs called antibody-drug conjugates. Avelumab [Bavencio] plus pembrolizumab [Keytruda] is 1 of these combinations with very appealing results.

Transcript edited for clarity.

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