Expert Discusses Impact of Atezolizumab in Advanced Bladder Cancer

David Nanus, MD

The PD-L1 inhibitor atezolizumab (Tecentriq) has been found to be non-toxic and has demonstrated a major survival advantage in patients with metastatic urothelial bladder cancer, according to David Nanus, MD.

In May of this year, the FDA granted atezolizumab an accelerated approval for patients with locally advanced or metastatic urothelial carcinoma whose disease progressed during or after platinum-based chemotherapy, or within 12 months of receiving platinum-based chemotherapy, either before or after surgery.

The accelerated approval is contingent on results from an ongoing confirmatory phase III study, IMvigor 211 (NCT02302807), which is comparing atezolizumab with chemotherapy in patients with locally advanced or metastatic urothelial bladder cancer who have progressed on at least 1 prior platinum-containing regimen.

OncLive: What is the impact of atezolizumab in bladder cancer?

In an interview with OncLive, Nanus, medical oncologist, Weill Cornell Medicine, discusses the recent FDA approval and its impact on the malignancy and the disparity between patients who do well on the treatment versus those who don't, as well as what to expect in the future for upcoming treatments in this setting.Nanus: Atezolizumab and the immunotherapy have already had, and will continue to have, a major impact on the treatment of patients with advanced urothelial bladder cancer. The problems today that we face are numerous. One is that the best drug is cisplatinum, and many of our patients can't get cisplatinum. Many patients today present at an older age because bladder cancer is a disease that a patient can have for many years before it becomes metastatic. I see patients that are 70 and 80 years old who really can't tolerate combination chemotherapy. I guess what's more important is, even if they respond to chemotherapy, virtually everyone relapses, and the median survival with chemotherapy is a little bit over a year for most patients.

The idea that we can have an immunotherapy that is less toxic is very exciting. What was interesting about one of the recent analyses of the study is that they showed approximately 30% to 40% of patients had virtually no toxicity. Now we have a drug where the majority of the patients have none, and those that do have toxicity, it's quite minimal. So that's exciting.

Then, I think what's probably the most beneficial to patients is the durability of some of the responses. It's not different than most of the immunotherapies. Patients either don't respond, and in this disease, it's about 40% to 50% that do, and it's unfortunate. But if they do respond, then they usually respond for a while, and it can be for years. I have patients that have literally been responding for years to immunotherapy. I think that's really exciting because we suddenly have a disease that becomes a chronic illness; perhaps we're going to cure some people.

Although, I think it's too premature to say that. We do see patients that have come off therapy that have prolonged remissions—we've seen that in melanoma and other diseases, so whether or not that will be true in bladder cancer is unclear. It likely will be true, though.

Atezolizumab will have a major impact on how we treat patients. The other interesting, recent abstract was one in which patients were treated prior to getting cisplatinum with atezolizumab, for a variety of reasons. They weren't eligible for cisplatinum, they had other potential facts that would prevent them from getting chemotherapy, and we saw very high response rates—higher than expected in that group of patients, with a median survival of around 14 or 15 months. The median survivals are misleading, because that takes everybody into account. As I said before, if a patient responds, he responds for a long time. So the median survival underestimates the benefit to the patients who do respond and can live for many years.

What are the biggest unanswered questions with atezolizumab?

That's also extremely exciting because, again, these are elderly patients who have metastatic disease, who can’t tolerate chemotherapy, and they suddenly have a non-toxic (for most patients) immunotherapy that has generated amazing responses. So for this disease, it's a very exciting time.Obviously with any new drug that costs a lot of money, it's all about developing a biomarker. Right now, it doesn't seem like there is going to be one simple biomarker that's going to say either "treat" or "don't treat." So that's obviously an unanswered question. The other question is going to ask how long we have to treat patients. If we stop treatment, can patients be re-treated and get a response? For example, a patient could stop after 6 months or a year, and say 2 years later, he relapses and goes back to the same drug—will he respond again? Those are the big questions.

Are there any immunotherapy clinical trials in bladder cancer that you're excited about?

Obviously, because of the price of the drug, those are the things we need to figure out. That's a problem in all of today’s targeted therapies and immunotherapies. When can we safely stop a drug and still get the continued, persistent benefit of the agent?The first exciting aspect of what's going to happen in immunotherapy is the combination immunotherapy agents, which we've seen, in melanoma, are much better with a PD-1 inhibitor, plus a CTLA-4 inhibitor. We're participating in a study now where patients are randomized to chemotherapy, a PD-1 inhibitor, and a combination PD-1/CTLA-4 inhibitor. Those are some of the questions that need to be answered.

I think the other interesting area is neoadjuvant, or adjuvant, space. There have been two prospective randomized trials of patients with muscle-invasive bladder cancer receiving chemotherapy, and that translates to survival advantage and even mortality in patients receiving chemotherapy. If immunotherapy will be doing the same thing, or if we select patients that can get neoadjuvant immuntherapy downstage, or perhaps surgery with muscle-invasive disease and post-operative immunotherapy, then that will be a step forward.

The other space is superficial bladder cancer. We know Bacillus Calmette-Guérin (BCG) is an immunotherapy, and it can be put into the bladder and it works, but many patients relapse. Will we be able to use some of these checkpoint inhibitors and other immunotherapy agents to treat really early-stage bladder cancer?

The good thing is that urothelial cancer is responding to immunotherapies. I think bladder cancer, outside of melanoma, is the biggest solid tumor where this has the most benefit to patients. It's a new era, and there are a lot of patients with urothelial cancer out there each year.