Immunotherapy Continues to Be Integrated in Metastatic Bladder Cancer

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.

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

In an interview during the 2018 OncLive® State of the Science Summit^TM 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.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.

Can these agents be compared?

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. 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.

Is PD-L1 testing now required?

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. 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.

What are the challenges with PD-L1 testing?

What clinical trials are you looking forward to reading out?

If I'm concerned about my patient’s chemotherapy fitness, then the label would suggest I could just give that patient immunotherapy. I find myself wanting to test the PD-L1 status in those patients who are on the border. I might be able to give them gemcitabine/carboplatin, but they might do better with immunotherapy. Those are the patients who we need to know the PD-L1 status of. If they're PD-L1 positive, I'll recommend pushing toward immunotherapy, but if they're PD-L1 negative, I'm going to try to improve that patient's performance status to be able to receive gemcitabine/carboplatin. The big difficulty is that we have 2 diagnostic assays that are now FDA approved. They both have different cut points in how they define what a positive patient is. They also have different algorithms on how to calculate the percentage of positive cells. Both are linked to an individual drug. One assay is linked to pembrolizumab use, and the other is linked to atezolizumab use. It is very confusing to follow. If you're thinking about using one of these drugs, you have to order a certain assay and know how to do the proper scoring. We're waiting to see whether dual immunotherapy is going to be a difference maker in this disease. There are 2 frontline trials where dual immunotherapy is being examined against chemotherapy as a standard backbone or single-agent immunotherapy. In other diseases, we've seen that dual immunotherapy may have an added benefit. There is an older trial of gemcitabine/cisplatin and bevacizumab (Avastin), [so there may be] a role for a VEGF-targeted drug in urothelial cancer.

Then, there are these frontline trials that are influencing the recent FDA guidance. Could 3 drugs do better than just a chemotherapy doublet alone? That question will be very interesting to read out and could change the standard of care in the frontline setting. Those combinations are on the near horizon, and we haven't even talked about targeted drugs or agents with different mechanisms that are in the pipeline.

Is immunotherapy's path forward in combination with chemotherapy?

Is there anything else you would like to emphasize?

There are now 2 drugs that have FDA breakthrough designations. One is erdafitinib, which is an FGFR3 inhibitor, which have shown very promising data. We are all interested to see where that fits in the armamentarium if it's approved. Then, there is enfortumab vedotin, which is an antibody-drug conjugate that has shown very impressive data in its early-phase testing. It has a very interesting signal in patients with liver metastases. Traditionally, that is a terrible prognostic factor, but this drug is showing impressive response rates in that population. Perhaps. There is an assumption that those frontline trials will be positive, but there may still be patients where the 3-drug regimen, even if it was approved, may not be tolerable for some patients in the frontline setting. Perhaps then you're going to sequence. We don't know whether there is a different sequence of these treatments that is better or not. Is there something to when the chemotherapy is introduced relative to immunotherapy that changes outcomes? Some sequencing trials are ongoing. I don't necessarily think it will be all 3 drugs at once. There may be some patients who are still sequenced.We can't stop here. The future is in molecular subsets of metastatic urothelial cancer. In my practice, I offer all patients with metastatic disease genomic tumor sequencing when they hit that metastatic frontline setting. While they're receiving their platinum-based chemotherapy, I do genomic molecular testing from one of many various laboratories. I use that information to identify genomic targets that we now have clinical trials for.

Is genomic testing done more than once?

For example, patients with HER2 or ERBB family alterations may be eligible for clinical trials. Data have been published that shown promise for those patients. There are now PARP inhibitors that can target DNA repair mutations. Trials are ongoing looking at those segments. It may have a direct role in setting a patient up for FGFR3 inhibitor therapy if that drug is approved. In the past, patients with FGFR alterations have been eligible for those trials. In my experience, it's been a very effective tool to genomically sequence patients. It has allowed patients to be eligible for trials that will help us move the field forward. I generally do genomic testing once, but you're bringing up an interesting point. Perhaps the tumor is changing over time. There's certainly evidence that suggests that the mutation pattern changes over time. Should we be testing a metastatic site versus an archival bladder specimen? These are really relevant questions.

FDA limits the use of Tecentriq and Keytruda for some urothelial cancer patients. FDA. Published July 5, 2018. Accessed September 24, 2018. https://bit.ly/2mggoOu.