The Future of Immunotherapy for Urothelial Carcinoma Treatment

Immunotherapy combination regimens may represent the future of urothelial carcinoma treatment, according to Evan Y. Yu, M.D., as it may be a novel approach to induce higher and more durable response rates in patients.
 
Additionally, while the success of immunotherapy has made a significant mark in the field, an unmet need still lies in the fact that these agents only provide a clinical benefit for approximately one out of every three patients, adds Yu, a professor in the Division of Oncology, Department of Medicine, University of Washington School of Medicine. Several ongoing clinical trials are examining immunotherapy agents in combination with other immune-based therapies, as well as with chemotherapy.
 
In an interview with CURE, Yu discussed the current treatment options for metastatic urothelial carcinoma, the unmet needs that still exist in this space and the possibilities for the future treatment landscape.
 

What are the current treatment options in metastatic urothelial carcinoma and what needs still have to be addressed with regard to treatment?

 
Yu: Right now, the first-line option for metastatic urothelial bladder cancer is still platinum-based chemotherapy — gemcitabine with cisplatin or gemcitabine with carboplatin. That may change in the near future as there are some frontline studies in patients who are cisplatin-ineligible and there are a couple agents that may get Food and Drug Administration (FDA) approval in that setting in the near future. But at this point in time, it’s still platinum-based chemotherapy for first-line.
 

Once you go into the second-line, most people are starting to use immuno-oncology (IO) agents. The FDA approved agents are the PD-L1 antibody, Tecentriq (atezolizumab), based on response rates and durability of response and the PD-1 antibody Opdivo (nivolumab), based on response rates and durability of response as well. Keytruda (pembrolizumab) is a PD-1 antibody that actually has the best level one evidence right now with survival benefit. However, Keytruda is still currently being evaluated by the FDA. We may see survival benefit in other studies in the near future, as Tecentriq has a randomized phase III trial that will probably read out reasonably soon.
 
That’s where we are in terms of FDA-approved agents. There are a lot of other exciting things being developed with fibroblast growth factor receptors (FGFR) antibodies, antiangiogenic agents and antibody drug conjugates.
 
There’s certainly an unmet need in the fact that there is no third-line approved therapy. There’s certainly an unmet need that the IO agents still only induce response rates in maybe 20 percent of patients and stable disease in up to another 15 percent. I generally tell patients that one out of three will have some sort of clinical benefit from an IO agent. How can we make it so that those patients who currently wouldn’t receive clinical benefit can respond in the future? Perhaps we need to do combination therapy. There certainly are combination trials that are ongoing that have promise for the future.
 

What impact has immunotherapy made in the field of urothelial carcinoma?

Immunotherapy has made a huge impact on the field. First off, we didn’t have any agents that induced an overall survival benefit and now we do. The first one was Keytruda. Second off, these agents are pretty low in toxicity. Other than the few patients who get immune-mediated side effects, they’re generally less toxic than cytotoxic chemotherapy. Thirdly, we see durable clinical benefit — people that respond or have stable disease resulting in long-term clinical benefit that may last one-to-two years or more. We just have not seen this with traditional chemotherapy. Last of all, we usually don’t see stable disease with chemotherapy. Either you respond or you progress, so stable disease is something new that has occurred with IO agents.
 

Where do you envision the treatment landscape for urothelial carcinoma will go in the next few years?

 
I think in the treatment landscape, IO agents will likely find their way as first-line therapy. First, they’ll get it in the first-line for patients who are cisplatin-ineligible, but there are trials underway that are comparing IO agents directly to chemotherapy. They may find themselves in first-line in combination with chemotherapy or as a single agent. However, we have to have some caution with single-agent IO therapy in the first-line, because there is a subset of patients that harbor rapidly progressive disease that could still be better served by chemotherapy since the response rates are initially higher with chemotherapy.
 
I would say that IO agents will likely move into the first-line eventually, but whether that’s as a single agent, or in combination with another immunotherapy agent or with chemotherapy, we will have to wait to see what pans out. Although, IO agents may not be right for everyone in the first-line, they will probably be administered for most patients in the first-line. As a result, I think it will lead to a shuffle to try to understand what’s best for second-line and third-line, but it leaves an opportunity to develop other drugs in other classes like I mentioned earlier; antiangiogenic agents, FGFR inhibitors and antibody drug conjugates are all very promising in this disease as well.
 
Finally, I think we will begin to better understand predictive biomarkers — who will respond and who won’t. At this point in time, I do not think the data is very compelling for prediction of response to therapy with PD-L1 immunohistochemistry, but hopefully in a few years we’ll have better markers to provide some predictive capability.
 

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