Bladder Cancer Treatments Continue to Evolve

The ever-changing treatment paradigm of bladder cancer shows no signs of slowing down as novel immunotherapy agents continue to move through the pipeline.

In May 2016, the field saw the accelerated approval of the PD-L1 inhibitor Tecentriq (atezolizumab), which was based on positive results from the phase 2 IMvigor 210 study.

Then, in October 2016, the FDA granted a priority review designation to Opdivo (nivolumab) as a treatment for patients with locally advanced unresectable or metastatic urothelial carcinoma following progression on a platinum-based therapy.

Most recently, findings from the KEYNOTE-045 trial demonstrated a 27 percent reduction in the risk of progression or death when patients with advanced urothelial carcinoma who had progressed after prior treatment were treated with Keytruda (pembrolizumab).

Now that these agents have established their place in the second-line setting, Daniel P. Petrylak, M.D., is confident that they could demonstrate equivalent efficacy in the frontline.

“If we see confirmation of the data from IMVIGOR 210, where platinum-ineligible patients had a 15-month median survival, it’s very likely that these will move upfront,” he said.

Please give an overview of where we are in bladder cancer right now.

In an interview with CURE, Petrylak, professor of Medicine and Urology, Yale Cancer Center, provided a summary of his presentation on advances in bladder cancer from the recent 2016 Chemotherapy Foundation Symposium. He shed light on the emerging roles of both immunotherapy and targeted agents in the treatment of this disease.In the past, bladder cancer did not have a standard second-line treatment. We know that, with gemcitabine and cisplatin, about a third of patients respond completely, about a third of patients have a partial response and the last third don’t respond at all. The median survival is about 15 months. And in the past, chemotherapy was toxic and ineffective in this situation. At best, we were seeing survivals of approximately nine months.

In 2013, a phase 1 trial was opened of Tecentriq in bladder cancer. More than 90 patients were treated on that study. About a quarter of the patients had a partial or complete response, and some of those patients are still durable today from that original trial. The exciting results we saw in this phase I trial went on to a phase II trial, which looked at Tecentriq at the same dosage in more than 300 patients with metastatic bladder cancer that failed platinum therapy. A very similar response rate was seen, and this led to the FDA approval of Tecentriq for metastatic bladder cancer.

As part of that IMvigor 210 trial, there was also a subsection that looked at patients who are not eligible for platinum-based therapy. This study included about 110 patients. They received Tecentriq, and they had a very similar survival to what we would see with gemcitabine/cisplatin for platinum-eligible patients. So this is very exciting, and this is moving forward in other clinical trials. And it’s also showing that checkpoint inhibition therapy is active in this disease.

There are other checkpoint inhibitors as well that are being evaluated. Durvalumab has about a 25 percent response rate. Keytruda has recently been evaluated in a randomized trial compared with dealer’s choice of chemotherapy. And although we don’t know the data just yet, there was a recent press release that said that there was an advantage to Keytruda. So we would hope to see that that drug gets approved sometime this year for bladder cancer as well.

Say Opdivo and Keytruda also get approved. How will oncologists choose which agents to use?

What are the factors to take into consideration when choosing a patient's therapy?

What's the likelihood of any of these agents moving into the frontline?

Is it worthwhile to look at targeted agents in this space?

Five years ago, nobody was interested in doing bladder cancer research. Now, with Tecentriq, there’s a lot of excitement surrounding all the checkpoint inhibitors. There are a variety of first- and second-line trials that are evaluating these agents in bladder cancer.That’s a great question. We don’t have any comparative data between the two different treatments. Unfortunately, the marker studies that we have are also not really adequate in telling us whether a patient should go on one drug versus another. The other thing is, we don’t have any sequential trials. So I don’t know if a patient who’s failed Tecentriq is going to respond to Keytruda, or vice versa. Does PD-L1 have activity after PD-1? We really don’t know the answer to that particular question. To my knowledge, there are no sequential trials at this point.I look at a patient’s age and their performance status. Obviously, if a patient has had an autoimmune disease, that factor eliminates them from going on a checkpoint inhibitor. Unfortunately, we don’t have any FDA approved drugs right now as frontline agents, so if someone is elderly and may not tolerate chemotherapy, it’s not standard care as of yet to treat them with a checkpoint inhibitor.I think it’s very likely. If we see confirmation of the data from IMvigor 210, where platinum-ineligible patients had a 15-month median survival, it’s very likely that these will move upfront.Keep in mind that only about a quarter of patients have responses [to these checkpoint inhibitors], so the majority of patients don’t respond to these treatments.

We’ve been working with two targeted monoclonal antibodies. I’m leading a trial with the AGS-15E antibody, which is targeting something called SLITRK4, which is a neuroendocrine marker on bladder cancer cells. This antibody is linked to a chemotherapeutic agent, MME, which is an antitubulin agent. Dr. Jonathan Rosenberg is also working with an antinectin antibody called the 22CE antibody. We’re doing these trials in parallel, and it’s all linked to the same payload.

We found that there’s about a 50 percent overall response rate in patients who failed previous therapy. There’s about a 30 percent response rate in liver, and about a 35 percent to 40 percent response rate for patients who failed prior checkpoint inhibition therapy. Now, there are preclinical studies suggesting that there may be synergy between these targeted antibody-drug conjugates and checkpoint inhibition. So, we’re moving forward, and we’re seeing a lot of new targets.

We’re also leading a trial looking at Cyramza (ramucirumab) combined with docetaxel, compared with docetaxel alone in patients who failed prior first-line chemotherapy and also those who have been on prior checkpoint therapy.

We’re all excited about the survival data from some of these trials, and the randomized phase 2 study, although that was not powered for survival benefit. The randomized phase 2 study was published earlier this year in the Journal of Clinical Oncology, and it showed about a 12-month survival for patients treated with Cyramza and docetaxel. So that’s in the ballpark, and I think we’ll start seeing very interesting sequencing of these particular agents together.