Immunotherapy Will Be the Norm in Bladder Cancer Care

Immunotherapy agents that are moving through the pipeline are eventually going to change the treatment paradigms for bladder cancer, says Jonathan E. Rosenberg, M.D.

The impact of immunotherapy began with the May 2016 accelerated approval of the PD-L1 inhibitor Tecentriq (atezolizumab), based on phase 2 results of the IMvigor 210 study that showed an overall response rate (ORR) of 14.8 percent with Tecentriq.

Next, Opdivo (nivolumab) was granted a priority review designation by the FDA in October 2016 as a treatment for patients with locally advanced unresectable or metastatic urothelial carcinoma following progression on a platinum-containing therapy. The decision is based on findings from the phase 2 CheckMate-275 trial, which showed an ORR of 19.6 percent in patients treated with Opdivo.

Finally, at the recent 2016 SITC Annual Meeting, findings were presented from the KEYNOTE-045 trial, which demonstrated a 27 percent reduction in the risk of progression or death with Keytruda (pembrolizumab) versus chemotherapy in patients with advanced urothelial carcinoma whose disease progressed after prior treatment.

What are some of the highlights of immunotherapy in bladder cancer?

In an interview with CURE, Rosenberg, a medical oncologist at Memorial Sloan Kettering Cancer Center, discussed Opdivo, Keytruda and other emerging immunotherapies in bladder cancer, and how oncologists will tackle sequencing challenges should multiple agents become available.We have seen a tremendous explosion in potential new treatments for bladder cancer over the last two years. We have multiple new drugs that are in advanced phase clinical trials and a new drug approved in the United States — Tecentriq — that is the first PD-L1 inhibitor to actually be approved. We are expecting, over the next year, two to three approvals for similar types of agents.

Recently, at the 2016 SITC Annual Meeting, there were data presented on Keytruda versus chemotherapy and it is said to be a positive study favoring Keytruda.

This must be very exciting for the field. What are your thoughts on how the treatment paradigm is evolving?

We have also seen recent data with Opdivo that is showing substantial activity in a large phase 2 study that was presented at the 2016 ESMO Congress. Between these two other agents, as well as drugs such as the PD-L1 inhibitors avelumab and durvalumab, we have a staple of really exciting new drugs that are being tested in this disease.It’s a sea change in bladder cancer treatment. We are seeing efforts now to look at it instead of chemotherapy in some patients. There are two clinical trials that have shown that patients who cannot get standard cisplatin — because of other health issues in terms of nerve damage, kidney function, or just overall status — that we actually see these drugs being quite active and survival seems to be just as good, if not better, in randomized trials. We don’t know for sure yet.

The current indication for Tecentriq is only in postchemotherapy, but the data are promising in showing that people live as long with Tecentriq as they would if they got cisplatin in patients who can’t get cisplatin. While that’s not perfect data, it is certainly a very encouraging first step.

As time goes on, we are going to see this possibly replace chemotherapy or push it back to a situation where, if immunotherapy fails, then they get chemotherapy. It is a lot of investigation going on; we are even looking at it earlier in preoperative therapy to see whether or not we can stimulate an immune response that may have long-lasting effects.

Do these immunotherapy agents have the potential to move into frontline?

Additionally, there are postoperative trials going on for patients who have high-risk disease. Those trials are accruing patients who have received chemotherapy before surgery and the cancer is still aggressive, as well as patients who have disease that is high risk and cannot get chemotherapy. Those are randomized trials that are accruing globally.For some patients, it is clearly going to be a first-choice therapy. We need to explore whether or not there are benefits to combining immunotherapy and chemotherapy. In a lot of diseases, it hasn’t been beneficial. However, in bladder cancer, we have chemotherapy that does actually work quite well for patients. There may be some synergistic effects and we need to explore that in multiple clinical trials.

Anecdotally, how have you seen Tecentriq have an impact on patient outcomes in the short time since its approval?

There are trials comparing chemotherapy with immunotherapy in patients with newly diagnosed patients with metastases and they are also adding it to chemotherapy with some of those trials. We will get those results in a few years.The toxicity for immunotherapy is dramatically less than with chemotherapy, although with some patients the side effects can be quite severe. However, it is fortunately relatively rare. Most of the side effects are around autoimmunity, where the body is attacking itself from the cancer or at the same time it is attacking the cancer. Usually, that can be suppressed from medicines such as corticosteroids and prednisone, and occasionally needs stronger medicines.

If Opdivo and Keytruda are approved, how will we choose one to give in the second-line setting versus another?

On average, patients feel much better and, when they talk about their quality of life, these immune drugs are essentially preserved throughout if it is working. There is now some data coming out quantifying that and showing that as the case.Some of that will come from the randomized phase 3 trials and get a sense of the activity of the drug, although it is always very difficult to compare between these trials. My feeling at the moment, based on the data I have seen, is they are not that different in terms of how well they work and their side effects. There are some advantages, theoretically, to one versus another but not necessarily real.

Scheduling is going to be an issue in that some drugs are given every two, three or four weeks. Convenience might come into it, cost is going to be an issue, and I also assume that certain insurance companies are going to pick one over another as their preferred regimen.

All of these factors remain unknown at the moment, but it is very hard for me to distinguish them all. The combinations with immune treatments are also very exciting and need to be tested very thoroughly because they usually come with increasing side effects. The likelihood of severe side effects with many of the combinations — particularly those involving CTLA-4 inhibitors — is often associated with more side effects as seen in melanoma.

Is there similar excitement with durvalumab and avelumab in this field?

What do you hope the field will accomplish in five years?

Also at the SITC meeting data were presented for the combination of Opdivo and Keytruda (ipilimumab), showing that there are substantially higher response rates when you combine the two, but the data is still relatively immature still.The experience to date seems relatively similar in my opinion, so there is no reason to be less enthusiastic about them. They seem to be highly active drugs in the patients for who they work in. Durvalumab has a response rate similar to the other drugs and it’s the same thing with avelumab. They are a little farther behind in their development, so that is why there is a little less data out there about them, but we look forward to hearing more.To try to understand who will respond and who will not respond. There has been a lot of exciting biomarker work coming out of many of these clinical trials with Tecentriq that I was fortunate enough to be involved with, with Opdivo, and we will see more coming out from these other large clinical trials trying to break down patients into subtypes. We will figure out which subtypes benefit the most and which subtypes don’t benefit.

We are also going to do this with chemotherapy as a field and trying to understand whether there are groups of patients for whom chemotherapy works really well. The goal in my mind would be eventually to direct patients toward the treatments that are likely to be the most effective for them. However, at the moment, this remains unrealized.