Immunotherapy Combo Regimens Next Step in Bladder Cancer

Danielle Bucco
Published: Wednesday, Nov 29, 2017

Elizabeth Plimack, MD
Elizabeth Plimack, MD
There has been excitement in the bladder cancer community following the FDA approvals of 5 PD-1/PD-L1 inhibitors, including nivolumab (Opdivo), durvalumab (Imfinzi), avelumab (Bavencio), atezolizumab (Tecentriq), and pembrolizumab (Keytruda).

Now, ongoing trials are looking to push the field forward by investigating immunotherapy combination regimens.

For example, preliminary results of the phase I/II ECHO-202/KEYNOTE-037 study (NCT02178722) demonstrated that pembrolizumab plus epacadostat was generally well tolerated and was associated with an increased response compared with anti–PD-1 monotherapy in patients with advanced urothelial carcinoma.

The study investigated 40 patients with prior platinum therapy and no prior checkpoint inhibitor therapy. The overall response rate (ORR) was 35% (n = 13) among 37 efficacy evaluable patients. The median duration of response was 30.6 weeks (range, 9.7-93.1). Among patients who had received 0 or 1 prior lines of treatment, the ORR was 38%. A phase III study is scheduled to further investigate the combination for this patient population.

In an interview with OncLive at the 2017 Society of Urologic Oncology Annual Meeting, Elizabeth Plimack, MD, chief of the Division of Genitourinary Medical Oncology at Fox Chase Cancer Center, discussed the impact of the immunotherapy approvals in the first- and second-line setting for bladder cancer and the future of combinations for these patients.

OncLive: This has been a big year for bladder cancer. Can you comment on the immunotherapy approvals?

Plimack: It has been a huge year in bladder cancer. As I was putting together my talk, all the references were from 2017. In my talk, I will be going over the data that led to the approval of 5 new immunotherapies in bladder cancer. They are all checkpoint inhibitors. Five of the regimens are approved in the second-line space and 2 of those 5 are approved in the first-line space. I will be going through the data that supports those approvals. 

Can you discuss the first-line agents pembrolizumab and atezolizumab?

In the frontline space for patients who are not eligible for cisplatin but have metastatic disease, there are approvals for both pembrolizumab and atezolizumab. Those were accelerated approvals based on single-arm phase II studies. They were approved because they are generally easier on patients who are cisplatin ineligible. The results can be durable, meaning when patients respond, they tend to respond very well.

However, with these early-data, single-arm studies, we do not have long-term follow-up but we hope to see durability. This is what we have seen in older trials of these agents in other settings.

Unfortunately, only 20% to 30% of patients will respond to these agents. We need new treatments in this space.

In the second-line setting, how do you determine which checkpoint inhibitor to give to patients?

There are 5 checkpoint inhibitors approved in the second-line setting in bladder cancer. By second-line, we mean patients with metastatic disease who previously had platinum-based treatment either as part of their neoadjuvant therapy within the year or just recently as part of their care for metastatic disease. It is hard to differentiate between the 5 regimens. We do not have randomized trials comparing each of them.

Pembrolizumab and atezolizumab have phase III trials that have reported out. The pembrolizumab trial was positive and published. The atezolizumab study has not been published but was presented at a European meeting earlier this year. Unfortunately, the study was negative for its primary endpoint. There are some nuances into the study design that led to the negative results but both agents continue to hold on to their approval in the front-line space. 

In terms of guideline recommendations, since pembrolizumab has a positive phase III trial that has been published and peer reviewed, there is level 1 evidence. Atezolizumab remains a 2B level in the NCCN guidelines, simply because it is a single-arm trial. 

What challenges are we still facing with immunotherapy regimens for this patient population?

One of the challenges that clinicians face is determining which of the 5 options they should use. There is no right answer; however, there are a few things that most of us will look at. The first is the scheduled administration. Atezolizumab and pembrolizumab are given every 3 weeks, whereas the remaining 3 are given ever 2 weeks. For patient convenience, every 3 weeks seems preferable. That is a minor reason but when you are choosing between 5 regimens without hard data, that is something to consider.

Having a positive phase III study is the reason why many people would choose pembrolizumab but atezolizumab maintains its approval based on the single-arm data. It should be noted that it preformed similarly in the phase III trial. There were issues with the design that led it to be negative.

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