Future of Bladder Cancer Likely to Be Combination Immunotherapy

Arjun V. Balar, MD

Immunotherapy has been shown to have an additional benefit when combined with other regimens for the treatment of patients with bladder cancer, according to Arjun Balar, MD.

For example, if the combination of pembrolizumab (Keytruda) and the IDO-inhibitor epacadostat is positive in a phase III study, it could become a preferred frontline regimen for patients with bladder cancer. Pembrolizumab is currently FDA approved for the treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy, or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. The PD-1 inhibitor is also approved in the frontline setting for patients with locally advanced or metastatic disease who are not eligible for cisplatin-containing chemotherapy.

In the phase I/II KEYNOTE-037/ECHO-202 study, the combination of pembrolizumab and epacadostat is being evaluated for safety, tolerability, and efficacy in patients with select malignancies, including bladder cancer. Responses were seen in 35% of patients with urothelial carcinoma with a median duration of response being 30.6 weeks. Among patients who received 0 or 1 prior line(s) of treatment, the overall response was 38%.

OncLive: What is the status of immunotherapies and what are we looking forward to in the future?

In an interview with OncLive, Balar, an assistant professor in the Department of Medicine, and director, Genitourinary Medical Oncology Program, NYU Langone’s Perlmutter Cancer Center, discussed novel immunotherapy combinations for the treatment of patients with bladder cancer.Balar: There are several different ways of addressing the immune system in bladder cancer that are being tested in multiple clinical trials. One of the important pathways is the CTLA-4 pathway. There are early phase studies suggesting that the combination may lead to higher response rates and perhaps these responses might be durable.

There are large experiences that are soon to be published. There is the phase I dose-expansion cohort of patients treated with durvalumab (Imfinzi) and tremelimumab. That data will hopefully be presented soon for patients with metastatic bladder cancer in the second-line setting. In the first-line setting, there are 2 large randomized phase III trials of PD-1 plus CTLA-4 that are currently ongoing but data for those 2 studies will not be available for a couple of years.

What do you predict the treatment field of bladder cancer will look like in 5 or 10 years?

The IDO pathway is also interesting. IDO1 seems to be a key enzyme that regulates T-cell function, especially in PD-1 blockade tumors. The combination seems to be very well tolerated in terms of IDO plus PD-1. There are now phase I studies showing that the response rate of epacadostat, which is an IDO1 inhibitor, plus pembrolizumab seems to achieve a higher response rate. That has led Merck [the developer of pembrolizumab] to partner in 2 randomized phase III trials. One is in the first-line setting, whereas the other is in the second-line setting testing pembrolizumab with or without epacadostat.In 5 or 10 years, I believe that patients with metastatic bladder cancer will be receiving some form of combination immunotherapy. What is unknown at this point is what that combination might be. It is possible that a subset of patients will be treated with CTLA-4—based combinations. The other could be IDO plus PD-1 combinations but that certainly would be a significant contribution in terms of a new standard of care.

Currently, how do you determine the sequencing of treatments for patients?

In the muscle-invasive setting, patients with localized bladder cancer who may not be candidates for cystectomy or are refusing cystectomy may be treated with chemoradiation in addition to PD-1 blockade. We are seeing that there may be synergy between the combination of those treatment options. Now there are trials testing those combinations which may be a new standard of care in muscle-invasive disease, as well. That is a tough question. I do not know if we have an answer of exactly how we should sequence therapies for patients with metastatic bladder cancer. We have 2 approvals in terms of disease settings. First, we have second-line metastatic bladder cancer after failure with platinum-based chemotherapy. It is clear that, for any patient who had previously received platinum-based chemotherapy and has now progressed, immunotherapy should be an option for them.

Will chemotherapy be a mainstay in the treatment of patients with bladder cancer?

As we continue to see advances in the field of metastatic bladder cancer, what advice do you have for community oncologists to decipher the new information?

The bigger question is for patients in the first-line setting who may be cisplatin ineligible; is immunotherapy the best treatment for the patient or is chemotherapy still an option? The majority of patients who are not eligible for chemotherapy should be treated with immunotherapy, and then perhaps with chemotherapy after. However, there is clearly a subset of patients who have a very extensive disease burden who are symptomatic and may benefit from chemotherapy first and followed by immunotherapy. That represents about 10% of all patients with bladder cancer.Absolutely; I do not think we are ready to give up on chemotherapy. Chemotherapy is still here to stay. It may represent the best option for a proportion of patients. It is still effective and can lead to durable responses in a minority of patients. Certainly, there may be ways of leveraging the effects of chemotherapy along with immunotherapy, perhaps in combination, as well. Certainly, chemotherapy will still be a part of the standard of care for some patients with metastatic bladder cancer.It is tough when there are data coming out almost every other week at another medical meeting. [It is often challenging] to keep up with this information. Participating and continuing medical education activities, trying to attend meetings, and keeping up to date is one of the best ways of doing it. Are we looking at Bacillus Calmette-Guerin (BCG) in combination with systemic therapies? In non-muscle invasive bladder cancer that is intermediate or high risk, patients are often treated with intravesical immunotherapy with BCG. We know that a substantial proportion of these patients, even though they respond to intravesical BCG, will ultimately progress and have refractory/recurrent disease. For those patients, we often treat them with cystectomy, meaning that their bladder must come out. This is after multiple courses of BCG.

Obviously, the challenge is that many of these patients do not want their bladder out. It is a morbid surgery where 60% of patients will have some form of a perioperative complication. This is a pressing need in terms of a novel therapy. There are now trials of systemic immunotherapy agents, such as PD-1 blockade, that is being tested in patients with non-muscle invasive bladder cancer focusing on several subgroups. One of them are patients who had prior BCG and have no other options. They are being treated with PD-1 blockade.

There are also other trials looking at BCG plus PD-1 as primary therapy in patients who have high-risk muscle-invasive disease. We do not have any data yet from any of these trials to know how much PD-1 adds to this disease population. Ultimately, if we see that there are some durable benefits to these patients, then we may envision a future where systemic immunotherapy, such as PD-1 agents, may become standard of care for high-risk non-muscle invasive bladder cancer.

Smith DC, Gajewski T, Hamid O, et al. Epacadostat plus pembrolizumab in patients with advanced urothelial carcinoma: preliminary phase I/II results of ECHO-202/KEYNOTE-037. J Clin Oncol 2017;35 (suppl; abstr 4503).