Checkpoint Inhibition Could Shift Standard of Care in Bladder Cancer


Immune checkpoint inhibitors have shown promising findings for patients with advanced bladder cancer, with data from phase II studies submitted to the FDA for consideration. The next question facing oncologists is how to optimally utilize these agents, according to James L. Gulley, MD, PhD.

In an interview withTargeted Oncology, Gulley, chief of the Genitourinary Malignancies Branch, director of Medical Oncology Service, National Cancer Institute, discussed immune checkpoint inhibitors and upcoming studies that may shift the treatment paradigm away from cystectomy.


What is the current state of immune checkpoint inhibitors in bladder cancer?


Currently, there is no approved immune checkpoint inhibitor for muscle-invasive bladder cancer, but there are a lot of us that feel like there could be possibilities in the future of having these checkpoints approved in this early disease state.

These checkpoints are actually very interesting. As you know, nivolumab and pembrolizumab have been approved in advanced cancers like melanoma and lung cancer. However, there are a wide range of phase III clinical studies ongoing looking at a variety of different cancers, including bladder cancer.

Data has suggested significant activity of atezolizumab and avelumab in patients with metastatic bladder cancer. Really, the question is "how can we best use that information now that we're seeing activity," and hopefully the phase III results will bear that out with those drugs. How can we take that earlier in the disease setting? Is it feasible to do, is it safe to, and is either treatment alone or in combination better than one another?


What is the hope with these ongoing trials?


The hope is that we’re going to see not only replication of the other work that has shown something that I think is remarkable, and that is that we’re seeing quick, deep, and durable responses in patients throughout a wide range of different cancers. We hope that that’s going to lead to approval in bladder cancer, as well as other cancers.

Also, what we’re seeing is that these results don’t happen with every patient. There are patients that have prolonged stable disease and there are patients that progress right through treatment. What we’re trying to figure out is who the patients that are responding are and how can we get a higher proportion of patients to respond.


With patients that progress right through treatment, what would be the next line of treatment?


In bladder cancer, most of the trials have been done in metastatic bladder cancer in the second-line setting. There is no standard third-line setting. Typically, you’d use either single agent chemotherapy or turn to clinical trials.

In the non-muscle invasive bladder cancer setting, there are trials that are going to be looking at using these treatments instead of BCG (Bacillus Calmette-Guerin) and there are trials that are looking at combining them with BCG. So you might see some of those trials showing effect.

One thing with the nonmuscle invasive bladder cancer setting is if you fail multiple treatments, typically one would eventually need to go to cystectomy. Obviously that’s a radical procedure where they take out the entire bladder, and that can lead to significant changes in the lifestyle of the patients. They can often make a neo-bladder for the patient, but it’s an involved process.

If you could find an immunotherapy that could prevent this very big surgery from going on that is well-tolerated, this would be a huge advance.


Would combination therapies be beneficial in the field of bladder cancer?


We’re just scratching the surface of combination immunotherapies with all this good data that we’re getting from anti—PD-1 and anti–PD-L1 agents. We’re seeing remarkable activity.

What we’re going to see in the future is likely a lot more — this is just the tip of the iceberg that we’re seeing right now. With combination therapies, we can get at T cell inflamed tumors and that will translate into the unleashing of those T cells with the immune checkpoints.

So this would potentially mean combining a vaccine with a checkpoint inhibitor, or radiation with a checkpoint inhibitor, or BCG that causes local inflammation with a checkpoint inhibitor. We could even combine them with therapies that can specifically bring in this immune response, and that can be further activated by immune checkpoint modulation.


What do you see as the future treatment paradigm in nonmuscle invasive bladder cancer?


The key thing is for nonmuscle invasive bladder cancer, it’s not ready for prime time yet to use these immune checkpoint inhibitors, but stay tuned. I think the future is really bright and I think that based on the activity in metastatic disease, we’re likely to see activity in localized disease, in nonmuscle invasive bladder cancer, and perhaps even in muscle invasive bladder cancer. That could translate into long-term disease control.

The community has lately been on trying to figure out the concept of functional cure. We’ve borrowed that from the HIV literature, where you’re now taking patients that have been HIV-positive for many years, yet their CD4 counts are normal and their viral loads are undetectable. We’re taking that terminology and applying it to these patients that have been treated with these immune checkpoint inhibitors where, after 36 months if they didn’t have disease progression by then, none of them had disease progression out to 10 years.

These are the types of things that we’re looking at and potentially, right around the corner, we’re going to see that we can take something superficial bladder cancer, or nonmuscle-invasive bladder cancer, and translate that into something where we can find more effective therapies other than just BCG that can lead to long-term, good outcomes for patients and perhaps having to go to the currently unavoidable cystectomy that unfortunately so many patients have to go through.

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