Managing Bladder Cancer in the Era of Cancer Immunotherapy

Advances in cancer treatment, such as immunotherapy, are helping to evolve the field of kidney cancer. Although immunotherapies show promise for patients, there are still challenges ahead.

During an interview with OncLive, a sister publication of CURE, Arjun Balar, M.D., an associate professor of medicine and director of the genitourinary medical oncology program at NYU Langone Health, discussed approved immunotherapies and what they are showing in clinical trials.

Please provide an overview of the immunotherapy agents for bladder cancer.

In the second-line setting, we have five different agents that have been approved. They are Keytruda (pembrolizumab), Tecentriq (atezolizumab), Imfinzi (durvalumab), Bavencio (avelumab) and Opdivo (nivolumab). These drugs all target the PD-1 pathway. Three of them are PD-L1 antibodies and two are PD-1 antibodies. Response rates are in range of 15 to 20 percent. We know from intent-to-treat analyses of two randomized phase 3 trials that it benefits patients in terms of survival versus standard of care chemotherapy.

We also have approvals of two of these agents, specifically Keytruda and Tecentriq, in the first-line setting for patients who are ineligible for cisplatin-based therapy. Right now, we know that patients who have low levels of PD-L1 expression may have shorter survival if they are treated first with immunotherapy and, perhaps, if platinum-based chemotherapy is an option for them they probably should receive that first. However, for patients who are still entirely chemo-ineligible, I think immunotherapy still represents really the only promising option that they have.

Are there specific clinical trials that you can expand on?

The bulk of my talk (during the Society for Immunotherapy of Cancer Annual Meeting) I focus(ed) on novel combinations. CTLA-4 plus PD-1 blockade I think is a very important pathway that needs to be tested further in bladder cancer. There are two randomized studies that are currently ongoing. This is the DANUBE study as well as CheckMate 901 that is testing CTLA-4 plus PD-1 access inhibition compared to chemotherapy. Those will be very important studies to look out for.

Similarly, we are looking at IMvigor 130 and KEYNOTE-361, which are two very large phase 3 trials testing the combination of platinum-based chemotherapy plus immunotherapy versus chemotherapy alone versus immunotherapy alone. Both are three-arm randomized trials. Those will likely lead to practice changing data, which will hopefully be available in the next year or so.

How do you see immunotherapy evolving going forward?

In bladder cancer, another major area of research interest of mine and others is to focus on the use of immunotherapy in earlier stage disease. We have studies ongoing now that are testing immunotherapy in stage 2 bladder cancer either in the perioperative setting in combination with chemotherapy prior to radical cystectomy; in the adjuvant setting for patients who have had surgery but have high risk pathology; or in combination with chemotherapy and radiation to treat bladder cancer definitively in lieu of surgery. This latter approach I think is the most exciting because many of our patients are either poor surgical candidates and can’t tolerate a radical cystectomy and many more are simply not willing to undergo a radical cystectomy, which is understandable given the impact that this surgery can have both on morbidity and subsequent quality of life after surgery.

We are also testing it in non-muscle invasive bladder cancer. Recently, there is some very exciting data from KEYNOTE-057 that was presented at the European Society for Medical Oncology 2018 Congress showing that for patients with (carcinoma in situ), 38 percent of patients achieved a complete response at 3 months. These are specifically patients who have failed BCG (Bacillus Calmette-Guerin — the main immunotherapy for treating early-stage bladder cancer). So, to have response rates in that range is quite promising. Obviously, we need to know how durable these responses are, but long-term follow-up will hopefully demonstrate that.