Frontline Pembrolizumab Approval Leaves Questions for Later Lines in Bladder Cancer

Jorge Garcia, MD

With 5 checkpoint inhibitors approved for the second-line setting of urothelial carcinoma treatment, and 1 available for a frontline indication, how will researchers choose which drug to administer to patients?

The answer to that question remains in flux, explains Jorge Garcia, MD, because if pembrolizumab (Keytruda) is given as a frontline therapy and a patient’s disease progresses, it makes little sense to immediately administer another PD-1/PD-L1 inhibitor. The other newly approved PD-1/PD-L1 therapies include nivolumab (Opdivo), atezolizumab (Tecentriq), avelumab (Bavencio), and durvalumab (Imfinzi).

Researchers are aiming to answer these questions and also improve patient outcomes with other options, such as combination regimens, in a number of ongoing trials. One such combination is pembrolizumab plus chemotherapy—a regimen that was recently approved by the FDA for the frontline treatment of patients with non—small cell lung cancer.

OncLive: Can you provide an overview of your lecture on bladder cancer?

Pembrolizumab was recently granted approval by the FDA. What impact is this decision going to have?

In an interview during the 2017 OncLive^® State of the Science Summit^TM on Genitourinary Cancers, Garcia, a medical oncologist at Cleveland Clinic, discussed how the field of bladder cancer has transformed with the FDA approval of pembrolizumab, and how oncologists should choose between 5 checkpoint inhibitors now available for the second-line setting and beyond.Garcia: We discussed the standard of care that has existed in bladder cancer for the last 20 years or so. Then, I dove into immunotherapy and the emerging role of PD-1 inhibitors. Now, we have 5 agents that are FDA approved as of today. I briefly reviewed the data of each of those trials and put that data into context when you look for biomarkers and patient selection: What does the future hold for bladder cancer?That is a huge and important approval for us because, thus far, the approval and the registration of atezolizumab, avelumab, nivolumab, and durvalumab have all been in the context of phase I/II studies that are based upon response rates and durability of responses. However, none of the trials has had survival benefit. Pembrolizumab and the KEYNOTE-045 trial demonstrated, for the first time, that a checkpoint inhibitor in the second-line space against chemotherapy was able to lead to a survival benefit in patients in that context.

First, it is the only agent with survival data. Secondly, it indeed can be utilized in the frontline setting for patients with platinum-resistant disease to some extent. That will be the newer standard of care for patients in that context.

It has been more than 1 year now since the first checkpoint inhibitor was approved. What has it been like for you to see this invasion of immunotherapy unfold?

Now, how do you put that data into context with the IMvigor data from Genentech/Roche, that was in a press release, as a negative trial? It randomized patients to atezolizumab versus chemotherapy. That trial’s press release was negative for survival. We have to wait to see the data to put it into context.It has been great, because bladder cancer has been traditionally considered an orphan disease. There fully have not been any data supporting any treatment for the last 10 to 15 years outside of chemotherapy. That is rewarding for us and for our patients; it allows them to have options. The tricky part of getting 4 to 5 agents approved within 24 months is, which one are you going to use? Do we need to use all 5 treatments when roughly, biologically, they may be the same?

Most people will get 1 of them and then we will move on [to something else]. The biggest challenge for us in the field is what to do after you get a checkpoint inhibitor. Most patients who receive checkpoint inhibition won’t derive any benefit from immunotherapy. The people who really want to be on a PD-1 inhibitor are the ones we want to pick from the get-go—they are likely to respond, likely to have a durable response, and maybe possibly be cured.

But, the vast majority of patients do not have a benefit. The biggest question right now resides in biomarkers. Can we detect, or utilize a test, to tell us that patients should or should not be on a checkpoint inhibitor?

If you give a patient frontline pembrolizumab, which of these checkpoint inhibitors will you give in the second-line setting or beyond, if any?

There is emerging data in the bladder cancer space looking at mutational load and genomic signatures that will predict your response to platinum-based therapy. Remember, chemotherapy still works, but the “sex appeal” of checkpoint inhibition in the field coupled with the side-effect profile of these agents—especially when you compare this profile with chemotherapy—makes these [treatments] really attractive for most patients, across all diseases, for that matter.That is a great question. Thus far, my personal opinion with the data that we have is once you have failed a PD-1/PD-L1 inhibitor, that it is really not a great rationale for you to be rechallenged with another immediately after. I will use a sample of the analogy of renal cell carcinoma, which we have multiple TKIs for. Back in the days, we used to use a TKI followed by a TKI.

Now, immunotherapy followed by immunotherapy is not something that we’re at yet. If a patient were to get a [PD-1 inhibitor] and they progress, then maybe they could have a CTLA-4 agent. That may be different because, mechanistically, those agents are different. However, PD-1 followed by PD-L1 is not going to be how you move the field forward.

What ongoing clinical trials are interesting you now?

How do you progress on a PD-1/PD-L1 agent and then develop genomic signatures? You can use it to predict subsequent response; that is probably the most logical approach. Now, using a PD-1/PD-L1 inhibitor instead of chemotherapy when you are unfit to get cisplatin in the frontline setting, most people will then probably move back to chemotherapy or move to a clinical trial or a genomic-driven study.That is a good question. We are looking at a combination of CTLA-4/PD-1 inhibition, obviously with ipilimumab (Yervoy) and nivolumab. We are also looking at a durvalumab combination with CTLA-4 blocking agents, which is the attraction right now. The interest will be to see, if you add chemotherapy to a checkpoint inhibitor, what will be a likely benefit?

Will chemotherapy always have a role in this field?

What type of research are you working on?

We recently saw the results in lung cancer where pembrolizumab plus chemotherapy was superior to chemotherapy alone in the frontline setting. The question is, “Can we replicate that data in bladder cancer with the upcoming trials that we have?” We have to wait and see.I do think so. There are patients who are likely to benefit from chemotherapy and they are unlikely to benefit from checkpoint inhibition. The question is, “Who are those patients?” At this point, we don’t really know.We have a young, energetic program right now for bladder cancer. We are interested in looking at patients with atypical bladder cancer—not the traditional urothelial carcinoma—trying to identify genomic signatures for patients with small cell bladder cancer. We also are trying to identify the subsequent treatment patients are getting after PD-1 inhibition, which is a key point of interest for all of us.

What are the key takeaways of immunotherapy in bladder cancer that community oncologists should apply in clinical practice?

We are participating in most of the trials in the second-line space. There is a trial looking at genomic signatures for PD-1 plus an FGFR inhibitor or a PARP inhibitor, and so forth. We have a significant interest in trying to develop ideas and concepts for patients who have DNA repair mutation or changes, which is an area now gaining a lot of momentum for PARP inhibition data.The standard of care in the second-line space is PD-1 agents and it will be pembrolizumab, in my opinion. It is very important for people in the community to understand that we are talking about frontline PD-1 therapy in bladder cancer. We are not talking about patients who can’t get cisplatin-based therapy; we are talking about patients who are unfit to get cisplatin-based chemotherapy.

When you look at that data, even though it is not phase III data, it’s provocative in the sense that when you look at median survival, responses, and durability of response, the data for those who are unfit to get cisplatin is actually mathematically very similar to what we have seen in people who are able to get cisplatin-based chemotherapy.

Unless we have the data from the frontline trials, I am concerned that, because of the safety and tolerability of these agents, [physicians] will just simply see a patient with advanced bladder cancer and say, “You have to get a PD-1 inhibitor and not get chemotherapy.” We have to wait and see how the field plays into that.