Gary D. Steinberg, MD
The treatment paradigm of metastatic urothelial carcinoma (mUC) was shaken up in May 2016 when the FDA approved the PD-L1 inhibitor atezolizumab (Tecentriq) for the treatment of patients with locally advanced or metastatic disease.
The approval of atezolizumab was based on results of the phase II IMvigor 210 study, in which atezolizumab demonstrated a 14.8% 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, MD, who discussed immunotherapy and refractory superficial bladder cancer during the 2016 OncLive State of the Science Summit on GU and Prostate Cancer.
In an interview with OncLive
during the meeting, Steinberg, the Bruce and Beth White Family Professor, director of Urologic Oncology, the University of Chicago Medicine, discusses the impact of atezolizumab 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.
OncLive: 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% 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 4 to 5 times greater risk of developing bladder cancer over a nonsmoker. If an individual stops smoking, that risk decreases; however, it is still 2 to 2.5 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.