Immunotherapy Combo Regimens Next Step in Bladder Cancer

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.

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

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

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.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. 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.

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

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

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

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. 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.

Are there any combinations that are looking promising?

One of the main challenges with checkpoint inhibitors is that they do not work for everyone. There is a lot of excitement because when they do work, they work well. The fact remains that 70% to 80% of our patients do not respond to them and will not achieve benefit. What we are now looking at in clinical trials are ways to improve the activity of immunotherapy. For example, novel agents in combination with these checkpoint inhibitors, such as IDO inhibitors, are on the forefront of investigation. These are agents that are not immunotherapeutic for patients who either cannot tolerate immunotherapy or quickly progressed through them. In terms of checkpoint combinations, there are a couple of trials that are in development. One is with an IDO inhibitor epacadostat with pembrolizumab. There is also an IDO inhibitor in combination with nivolumab being tested by Bristol-Myers Squibb. The early phase I data with epacadostat and pembrolizumab was encouraging in terms of efficacy in patients with previously treated bladder cancer. That will be explored going forward.

Another combination is ipilimumab (Yervoy) and nivolumab. Again, we have seen the phase I basket data for that combination but based on the efficacy and the durability of response in those patients, it has been investigated in a phase III trial, as well. There are immunotherapy combinations, immunotherapy novel combinations and immunotherapy chemotherapy combinations, which all need to be investigated further. Hopefully, we will be smarter about them this time next year. Looking back on this year, how would you describe the growth of immunotherapy in bladder cancer?

The last approval prior to May 2016 in bladder cancer was cisplatin in 1978. It has been a long drought in bladder cancer, but now there is an explosion of approvals and interest in bladder cancer. There are more trials for patients with bladder cancer than ever before, which is wonderful for our patients and the community of us who treat bladder cancer. This was a huge year for publications and for many of these early data that we saw in meetings in 2016.

Is there anything else you would like to add?

Again, we are going to be seeing a lot of new data at upcoming meetings that are going to advance the field forward. The standard of care today might not be the standard for very long.Helping clinicians choose therapies in the metastatic space is important because it is more confusing now for good reasons. There are good clinical trials available now with agents that have demonstrated efficacy in early phase trials and early phase designs involving rational testing of novel biologic agents. It has never been a better time to consider a clinical trial.

Smith DC, Gajewski T, Hamid O, et al. Epacadostat plus pembrolizumab in patients with advanced urothelial carcinoma: Preliminary phase I/II results of ECHO-202/KEYNOTE-037. J Clin Oncol. 35 2017 (suppl; abstr 4503).