Immunotherapy Emerges as Alternative to Surgery in BCG-Refractory Bladder Cancer

Kevin Chan, MD

Surgical treatment of patients with non-muscle invasive bladder cancer can be considered a curative option, but the associated risk in comorbid patients is leading researchers to further explore the option of immunotherapy.

Kevin Chan, MD, an associate clinical professor in the division of Urology and Urologic Oncology, Department of Surgery, City of Hope, explains that for patients who are refractory to the immunotherapy bacillus Calmette-Guérin (BCG), are elderly, and have several comorbidities, receiving another immunotherapy—even if it has a lower response rate—may be a more effective choice.

Currently, the PD-L1 inhibitor atezolizumab (Tecentriq) is FDA approved for the treatment of patients with locally advanced or metastatic disease, based on results from the phase II IMvigor 210 study that showed an overall response rate (ORR) of 14.8% in patients with locally advanced or metastatic disease, regardless of PD-L1 expression. Among patients with PD-L1 expression ≥5%, the ORR was 26%.

In June 2016, nivolumab (Opdivo) was granted a breakthrough therapy designation as a potential therapy for patients with unresectable locally advanced or metastatic urothelial carcinoma who have progressed on a platinum-containing regimen.

OncLive: What are we seeing in the space of BCG-refractory non-muscle invasive bladder cancer?

In an interview with OncLive during the 2016 OncLive State of the Science Summit on GU Cancer, Chan discussed the latest updates in BCG-refractory non-muscle invasive bladder cancer and how to decide between surgery and an alternative approach.Chan: This is a common and kind of historically big problem. This is a group of patients who can be cured with surgery, but the surgery is pretty morbid and carries a lot of risks. In general, this population is elderly and has a lot of comorbidities. We are always kind of searching for alternative treatments—something simpler that doesn’t require surgery that can hopefully at least prolong life.

If surgery is curative, why isn’t it the optimal option?

How do you determine if someone is a good candidate for surgery?

There’s a lot of risk for surgery. At what point do these risks outweigh the fact that a patient may be cured of bladder cancer?

However, the big dilemma is that we know that surgery is curative. With these other kind of alternative therapies that are not as effective, you’re risking progression of disease. Ultimately, you can lose that window of curability as you go down this alternative treatment road.It carries about a 60% to 70% complication rate. The average age of patients with a muscle invasive bladder cancer, a high-risk bladder cancer, is about 73. This is an elderly population. Many of them have heart disease and these are big operations that make this surgery somewhat risky. There are people who are not candidates for surgery, but you want to be able to offer them something. Then, there’s the group of patients who adamantly refuse surgery. They don’t want to lose their bladder, they’re scared of the surgery, and they’ll do anything else—even if it means a suboptimal treatment.I don’t think there are a lot of things stopping us from doing surgery on these patients. It really is just informing patients of what the risks are. Many times, when they have these comorbidities, they will hear that and may not want to proceed. I don’t think there’s a lot of hesitation on the clinician’s side to recommend surgery. It is just kind of weighing risks and benefits. If a patient is at a high risk for surgery and has a high chance of dying on the table, then maybe these alternative therapies that can buy you 1, 2, or 3 years of time may be worth engaging in.[Patients undergo] a radical cystectomy and urinary diversion, which is taking out the bladder and making a new way to urinate using a piece of intestine. That carries with it typically anywhere from a 50% to 80% complication rate. These complications commonly include infection and bowel obstruction.

You mentioned other therapies are being explored. Are there other promising treatment options available or perhaps will be in a decade or 2?

What do you see the treatment landscape of non-muscle invasive bladder cancer looking like in the future?

There are also a lot of metabolic changes that happen when the urine is absorbed by intestine. Any of these things can stress an elderly patients’ body; it’s not so much that they would die of the infection, but they can die from the stress of responding to an infection. Sepsis itself may not kill the patient, but they may get a heart attack in the process because of the stress and the tax on their body.This is definitely a big area for research. Right now, we are better off than we were 10 years ago. There are a lot of these intravesical therapies, in which we can put medicine into the bladder and instill it for a couple of hours. Then, there are the immunotherapy agents that can go into the bladder and spare their bladder. Most of them are well tolerated and don’t have a lot of side effects. The biggest issue is whether they’re going to work, and all of them carry with it an approximate 20% to 30% durable response rate. Those aren’t great numbers, especially when you’re talking about [how] the alternative is curable disease versus trying something that has about a 30% chance of success. However, there are new agents out there and new modalities that are trying to increase this durable response rate. There are some promising ideas.Right now, we use chemotherapy in the bladder. There are actually a number of trials looking at multiple chemotherapies at the same time, capitalizing on the complementary modes of action of each of these agents. That’s promising. There’s nanoparticles where albumen-bound chemotherapy agents have better solubility and can lead to a better delivery to the actual target cancer cells. That is an area of study and promise. There’s also work being done with these immune checkpoint inhibitors.

Interestingly, PD-L1 is highly expressed and correlates with tumor stage in bladder cancer. In particular, there’s a 15-to-20-fold higher expression of PD-L1 in the BCG-refractory patients than is expressed prior to BCG. Therefore, there is certainly an activity with the cancer that is potentially making them essentially susceptible to PD-L1 or checkpoint inhibition. That is actually a big area of promise that’s being used in advanced bladder cancer, but we think that it may also have a role in more early-stage disease.