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Future of Bladder Cancer Likely to Be Combination Immunotherapy

Danielle Bucco
Published: Thursday, Dec 21, 2017

Arjun V. Balar, MD
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%.

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.

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

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.

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.

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

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. 

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. 

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

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. 


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Online CME Activities
TitleExpiration DateCME Credits
Clinical Interchange™: Translating Research to Inform Changing Paradigms: Assessment of Emerging Immuno-Oncology Strategies and Combinations across Lung, Head and Neck, and Bladder CancersOct 31, 20182.0
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