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Immunotherapy Continues to Be Integrated in Metastatic Bladder Cancer

Caroline Seymour
Published: Thursday, Oct 04, 2018

Peter O’Donnell, MD

Peter O’Donnell, MD

An FDA safety warning suggests that the role of immunotherapy in the treatment of patients with metastatic bladder cancer may need altering, explained Peter O’Donnell, MD, an associate professor of medicine at the University of Chicago Medicine.

In May 2018, the FDA released a warning against the frontline use of single-agent immunotherapy, specifically pembrolizumab (Keytruda) or atezolizumab (Tecentriq), in PD-L1–low expressing platinum-eligible patients with advanced urothelial carcinoma.

The warning was announced following an analysis of the phase III KEYNOTE-361 and IMvigor130 trials. Both studies investigated the use of immunotherapy with or without chemotherapy versus chemotherapy or immunotherapy alone. The assessment indicated a decreased overall survival (OS) in the single-agent immunotherapy arms compared with chemotherapy in patients with PD-L1–low status.

“We're trying to solve how to integrate [immunotherapy] in terms of where we use it and at what sequence we use it along with chemotherapy which has been our standard for many years,” said O’Donnell.

As these efforts evolve, he noted that the landscape is likely to change again in the near future with the addition of targeted agents, as both erdafitinib and enfortumab vedotin received FDA breakthrough designations in 2018.

In an interview during the 2018 OncLive® State of the Science SummitTM on Renal Cell Carcinoma and Bladder Cancer, O’Donnell discussed the integration of immunotherapy in the treatment paradigm of advanced bladder cancer and its potential role as combination therapy.

OncLive®: How has the landscape of advanced bladder cancer changed?

O'Donnell: It's an exciting time in metastatic bladder cancer, in the sense that over the past several years we've had the introduction of 5 new FDA-approved immunotherapies. When the immunotherapies first came to market, they were approved in the platinum-refractory setting. Essentially, every patient was getting those therapies.

Then, there was also the interest in using them in the frontline setting. A year ago, I was using them a lot more in this setting. It's changed dramatically just in the last couple of months, with the FDA announcements, that we’re restricted in our use of frontline immunotherapies if the patient hasn't received platinum yet. Certainly, cisplatin-based therapy is still the gold standard in that frontline setting. If your patient is cisplatin-eligible, you're going to be offering them a cisplatin-based combination.

There are also patients who are cisplatin-ineligible. Those are the patients who, 1 year ago, we were pushing immunotherapy for. With the FDA announcement, it seems that those patients should be receiving gemcitabine/carboplatin rather than immunotherapy monotherapy unless we know that the patient is PD-L1 positive. Now, we're doing PD-L1 testing in the frontline setting to try and identify patients in whom we still might use immunotherapy.

Then, of course there's that small segment of patients who are not chemotherapy-eligible at all. They're not fit for any type of chemotherapy, even carboplatin-based treatment. According to the new FDA guidance, those patients would be eligible to receive immunotherapy as opposed to no treatment at all. 

Can these agents be compared?

Only by extrapolation; they haven't been compared head-to-head. In the platinum-refractory setting, we have Level 1 data for pembrolizumab. The randomized phase III trial showed an OS benefit against taxane-based chemotherapy. Unfortunately, the randomized phase III trial of atezolizumab was negative in that same comparison. In the platinum-refractory setting, I find myself using pembrolizumab as the first choice because of its Level 1 designation.

I don't think we know as much about the other 3 immunotherapies. They certainly are valid options in that setting, we just don't know the survival benefit of those therapies yet. 

Is PD-L1 testing now required?

  It's now required if you have a cisplatin-ineligible patient in the frontline setting in whom you're thinking about using immunotherapy. If a patient can't receive chemotherapy, you're going to want to think about PD-L1 testing. It's also required if you're going to use an immunotherapy in a patient who is chemotherapy-eligible, but if a patient could receive gemcitabine/carboplatin, I'm generally going to choose that.

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Community Practice Connections™: New Directions in Advanced Cutaneous Squamous Cell Carcinoma: Emerging Evidence of ImmunotherapyAug 13, 20191.5
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