This May, the U.S. Food and Drug Administration (FDA) shook up the treatment paradigm of metastatic urothelial carcinoma (mUC) by approving Tecentriq (atezolizumab), a PD-L1 inhibitor for patients with locally advanced or metastatic disease.
The approval of Tecentriq was based on results of the phase 2 IMvigor 210 study, in which Tecentriq demonstrated a 14.8 percent overall response rate in this patient subgroup, regardless of PD-L1 expression.
Before this milestone, it had been decades since the last FDA approval in the field, explains Gary D. Steinberg, who discussed immunotherapy and refractory superficial bladder cancer in an interview with CURE.
Steinberg, the Bruce and Beth White Family Professor, director of Urologic Oncology, the University of Chicago Medicine, discusses the impact of Tecentriq on the treatment landscape, the resistance to finding effective therapies for the disease, and what potential role immunotherapy may have in the field going forward.
In refractory superficial bladder cancer, what is the biggest news taking place?
Bladder cancer is a heterogeneous disease, and the majority of patients — when they are initially diagnosed — have non-muscle invasive bladder cancer. When I see patients with non-muscle invasive bladder cancer, I try to categorize them as low-risk for disease recurrence and progression, intermediate-risk for disease recurrence and progression- and high-risk for recurrence and progression.
The vast majority of patients I see are in the high-risk patient population. The standard of care for the initial diagnosis and treatment for these patients is intravesical — that means medication we put inside the bladder — immunotherapy, and the most common form of therapy is something we call BCG, or bacillus Calmette-Guérin. It is a live-attenuated vaccine that we have been using for probably about 50 years. It was initially FDA-approved, I believe in 1985, and we really have not moved beyond that.
The greatest unmet need for patients with high-risk non-muscle invasive bladder cancer is for the patients who have received intravesical BCG, but their cancer is either not treated, is refractory, or it is still persistent. There are patients who have had initial responses, but then their diseases recurred. Those patients are at a very high risk for disease recurrence. However, disease progression becomes even more worrisome in cases where the cancer was not invasive into the muscle, becomes invasive into the muscle, and can also metastasize to the lymph nodes, lungs, liver, bones and cause death.
There is probably an excess 30 percent mortality for patients with non-muscle invasive bladder cancer because of the lack of standardization of treatment algorithms. That is something that was addressed in the new 2016 guidelines for non-muscle invasive bladder cancer released by the American Urology Association and the Society of Urologic Oncology. However, the patients who are commonly referred to me are individuals who have high-risk non-muscle invasive bladder cancer that is resistant, refractory or unresponsive to BCG.
What are the main risk factors for developing bladder cancer?
The most modifiable risk factor for bladder cancer today is cigarette smoking. A smoker has about a four to five times greater risk of developing bladder cancer over a nonsmoker. If an individual stops smoking, that risk decreases; however, it is still two to two-and-a-half times greater than a never-smoker. What is the lag time if one stops smoking for 20 or 25 years? That individual still has an increased risk over a never-smoker.
There are a number of other environmental carcinogens that are class 1 carcinogens for urothelial cancer. These include toxins in the petroleum industry, aromatic amines, hydrocarbons, nitrates and nitrosamines in an individual’s diet, and arsenic in well water and in the drinking supply. However, the most modifiable risk factor is smoking.
Following the 1985 approval, there was a lull in new treatments. What were some of the challenges to finding effective treatments for this disease?
That is a very interesting question. Bladder cancer has almost been an orphan disease, although it is the fourth most common cancer among men and the eighth most common cancer in women—it is the fifth most common cancer overall. However, there is just a relative reluctance. [Patients] all know about their prostate. They all know about lung cancer and colon cancer, but very few of them know anything about bladder cancer.
Many individuals do not necessarily share their experiences, even when they have had this disease. It can be life-threatening. All too often, patients will have blood in their urine and they will ignore it, or they will call their internist and get an antibiotic. They are told, “Oh, you must have passed a kidney stone.” There is just a huge lack of information surrounding the disease, and I spend a lot of time trying to educate family physicians and internists.
Bladder cancer is actually three to four times more common in men than women. Unfortunately, many non-neurologists understand that to mean that the disease only occurs in men and not women, when actually there are more women who die from bladder cancer every year than women who die from cervical cancer. All too often, women with blood in their urine are treated as if they have a urinary tract infection. By the time they are ultimately diagnosed, there can be 13 or 14 months of delay. Why that is, and why it persists, I do not know.
I am the chairman of the Scientific Advisory Board for the Bladder Cancer Advocacy Network, where we do everything we can to raise awareness. However, last year — for example — we had a bladder cancer walk, and we had maybe 200 people there. We raised, in Chicago, maybe $20,000. The same day, there was a multiple sclerosis (MS) walk. Not as many people have MS as they have bladder cancer, but there were thousands of people at that event. They were on the local TV stations and in the newspaper, and they raised millions of dollars. We need to adopt the practices of the breast cancer organizations and all of the other advocacy groups to get the word out, so that it is not a disease that has all this mystery.
One of the very fascinating things is that Cardinal Francis George passed away from bladder cancer, and he was extremely popular in Chicago. However, I suspect that if you polled the Catholic archdiocese, the rank and file, very few people would know that he had bladder cancer, had his bladder removed for his cancer, and then recurred with his urothelial cancer in his upper tract and ultimately died of the disease. He was clearly a very busy man. He had a lot of other issues to take care of, but he never really spoke much about his bladder cancer. I think that was a missed opportunity for the bladder cancer community. However, I understand, because there is just this reticence to talk about urinary function, I believe.
What can you share about the immunotherapy research being conducted in the field?
I graduated from medical school a generation ago already. I actually finished my residency 25 years ago, but I spend all of my time reading immunology. I have a number of vaccine trials that are ongoing that I am the principal investigator for at the University of Chicago, as well as nationwide, and I just find it to be fascinating. I was involved in immunotherapy trials for kidney cancer in the early 1990s, although we did not make very much progress. It kind of disappeared, and there has been a rebirth of immunotherapy treatments, especially with the checkpoint inhibitors that are available. We have got some of the largest drug companies in the world that are actively involved in immunotherapy research using various checkpoint inhibitors.
I have a number of vaccine trials going on in development. I probably have about 12 companies right now that I am actively working with, designing protocols, and looking at new immune mechanisms to treat bladder cancer. I just find this to be a fascinating time, and I really am very hopeful because the immunotherapies are extremely well tolerated.
Yes, there are some patients who could have some really serious, life-threatening conditions. Many times, they can be treated with high-dose steroids. However, the patients who respond tend to have fantastic, long-term durable responses. The toxicity is less than chemotherapy.
While there has been some tremendous success in this field, the key is to continue to do the basic science research and the translation research to continue to understand the mechanisms of how to best stimulate and inhibit the immune system to fight cancer.
Tecentriq was recently approved by the FDA for the treatment of patients with mUC. Can you talk about the significance of this approval and how it will impact the landscape?
It is common knowledge that the last FDA-approved combination for bladder cancer was in the 1980s. There really has been a dearth of new drug development, and most of the work has been in the chemotherapy realm. This is just a game changer. This is for patients; the FDA approval is based upon treating patients who had failed chemotherapy, who had very locally advanced and systemic diseases with metastases in lungs, liver, bones, and so forth.
While this is a Roche/Genentech drug, there are a number of other large companies with similar and slightly different molecules. We are looking at PD-1 and PD-L1. There are also. There is just a whole list of targets — immunotherapeutic targets — that we can begin to hit.
We are going to be starting a trial very shortly with Tecentriq, which was approved for treatment of metastatic disease in the non-muscle invasive setting for patients who are unresponsive to BCG. Dr. Peter O’Donnell of University of Chicago and I are doing a study [with Tecentriq] as an adjuvant therapy for patients who, prior to metastatic disease, had bladder cancer that has a high likelihood of recurrence or progression based on their pathology, based on their lack of response to cisplatin and chemotherapy, and we are seeing some wonderful responses.
Anecdotally, what have you seen thus far with immunotherapy?
I saw a patient whose daughter is an endocrine surgical fellow at the University of Chicago Medicine, and she called me up in tears on Christmas. Her father has just been diagnosed with advanced bladder cancer. He had been receiving treatment for non-muscle invasive disease and now had muscle invasive disease and metastatic disease, and he has been on our checkpoint inhibitor trials. He had a fantastic response with almost complete resolution of his metastatic disease.
Now, the question becomes, “What next? Should he have surgery? How long should we keep him on the immunotherapy?” We are in uncharted waters. Clearly, he would have passed away because his kidney function — due to his bladder cancer — was not good enough to receive cisplatin-based chemotherapy. We are seeing some great things. It is anecdotal in some instances, but we are seeing real data that are very encouraging.