Exploring Response and Resistance to Checkpoint Inhibitor Therapy in Bladder, Other GU Cancers

Padmanee Sharma, MD, PhD

Padmanee Sharma, MD, PhD

A major challenge in the field of immunotherapy currently lies in resistance to checkpoint inhibitors. However, in cancers such as urothelial or renal cell carcinoma (RCC), these agents are showing a great deal of promise and are being tested in combination regimens.

PD-1 and PD-L1 inhibitors have already been approved in certain patient populations of bladder cancer and metastatic kidney cancer. Trials are currently ongoing for the use of these inhibitors in combination with CTLA-4 inhibitors in hopes of finding even better responses for these patients.

There are over 2000 different clinical trials currently looking at the use of checkpoint inhibitors in various settings. Many of these trials are investigating the combination of checkpoint inhibitors in bladder and kidney cancer.

In an interview withTargeted Oncology,Padmanee Sharma, MD, PhD, professor of Immunology in the Department of Genitourinary Medical Oncology at The University of Texas MD Anderson Cancer Center, discussed the development of checkpoint inhibitors in several cancers, including urothelial carcinoma, RCC, and prostate cancer. She addressed the challenges in resistance to these agents and where some clinical trials are moving forward in the field.

TARGETED ONCOLOGY:Can you discuss some of the challenges with resistance to checkpoint therapy?

Sharma: I think there are many resistance mechanisms, we just need to identify them. Unfortunately, I think if we are just using clinical endpoint for the readout as to whether immune checkpoint therapy will work in some patients, tumor types, or those kinds of things, the clinical endpoint itself is not going to give us the answer. It may say yes, you did not reach your clinical endpoint with statistical significance, but it doesn’t tell you why.

We have to really delve into longitudinal tumor biopsy samples and blood samples in order to really look at what’s happening to the immune response over time to see what those resistance mechanisms may be. It may be that there are other immune checkpoint pathways that are being expressed, and so you didn’t block those, you only blocked CTLA-4 or PD-1/PD-L1, and there are others that we need to think about that might be important as well. There might be other things going on as well, like the tumor cells have these mutations within them that allow them to escape the immune response.

There are things we need to understand, and then we can try to overcome those different resistance mechanisms. I don’t think it’s going to be 1 thing. I think it’s going to be different things in different tumor types and maybe even different patients.

TARGETED ONCOLOGY:What is important for clinicians to understand about the response and resistance to checkpoint inhibition at this point?

I would like them to know that obviously there are a lot of responses, so please consider immune checkpoint therapy in those areas that we have seen responses, like bladder cancer, lung cancer, kidney cancer, and melanoma. With all local oncologists, since academic centers are aware of this [already], I think there is a big community of local oncologists that need to know that these are agents their patients could be treated with and they have good responses that can be seen. I think that’s something we need to keep in mind.

I think in the rest of the field, it’s about this idea that we can’t just keep throwing agent A and agent B together and hope that they work. We have to start thinking in a rational way to try and guide what clinical trials we are developing. If you look at clinicaltrials.gov, there’s over 2000 clinical trials with immune checkpoint agents. I don’t even think we have enough patients to fill all those clinical trials, so we need to be a little bit smarter.

I understand that while we are doing all of those trials, there are patients dying. We need to come up with treatments fast. Doing laboratory studies where it could take years before you actually identify a mechanism is not the most efficient way in doing it. We need both avenues. I understand you need to run clinical trials quickly because you have patients you want to treat, but I hope that we can see the point to doing a laboratory research which may take some years, but then hopefully will come back to the clinic to give us the rational combination therapies.

TARGETED ONCOLOGY: What are some of the most recent developments in cancers that are showing a lot of promise with checkpoint therapy, like urothelial carcinoma and RCC?

Sharma: Right now, we have approved monotherapy, PD-1 therapies and PD-L1 therapies, in bladder cancer. I think in order to increase the response rates and look at the things we could do in combination therapies, there are many trials that will address that now in bladder cancer, so we’ll have an anti—CTLA-4 plus an anti–PD-1 or PD-L1. Those are things we have to think about for bladder cancer. Clearly, it’s still addressing the immune response because those agents don’t target the tumor cells. That combination has actually already shown promise in other tumors.

In kidney cancer, clearly that combination is now approved in metastatic kidney cancer for patients with disease that has poor-risk outcomes. It’s important to also consider how we would combine other agents and take that into even earlier disease settings, not just the metastatic disease setting. Can we take that into patients who are undergoing nephrectomy, because in metastatic kidney cancer, you can have a nephrectomy even though you have metastatic disease. Can we do it in that sort of setting where you already give therapy, you do surgery, and you can see that benefit from the combination of immunotherapy and surgery.

The other thing in kidney cancer, I think of angiogenesis as a big part of that field, so can we combine antigenic agents or tyrosine kinase inhibitors with the immune checkpoint therapies? I think there are many ways of addressing these types of cancers.

I think the other thing I want to think about is how do we get prostate cancer to become a tumor type that immune checkpoint therapies will work [in]? I think we are trying to make progress there. The anti—CTLA-4 monotherapies didn’t do it and the anti–PD-L1 therapies didn’t do it, but now we’ve looked at the combination of the 2 and we will present that data soon.

TARGETED ONCOLOGY:Could you touch on some of the research currently ongoing in prostate cancer?

Sharma: I published a paper inNature Medicinemaybe a year or 2 ago now. We showed that when we gave anti—CTLA-4 in a presurgical trial, which is what I love doing because you can do these trials where you have access to all the tumor samples. It’s easier for these patients that are scheduled for surgery. We gave them anti–CTLA-4. We had all of these prostate cancer tumors to look at and what we saw was that even though at baseline, prior to any treatment, there’s really not a lot of PD-1 and PD-L1 expression in prostate cancer. It’s pretty negative. After we gave anti–CTLA-4, these patients saw a lot of PD-1 and PD-L1. It gave us an inkling that it’s not there at baseline, but it evolved over time, which is what we should have expected because the immune responses are evolving in a dynamic thing. It’s not metastatic. We should not have expected that 1 biopsy can tell us everything we need to do and what’s processing in the prostate cancer microtumor environment.

Now that we saw that, we did propose to Bristol-Myers Squibb and they accepted to run the trial with us on this anti—CTLA-4 trial plus anti–PD-1 combination. I can just tell you from my own clinic, we have had patients who did phenomenally well on that clinical trial. That’s going to see a new surge of interest in how to do those kinds of studies and maybe combining with other agents, so combination therapy and combining with other agents to hopefully try and get prostate cancer to where we are in terms of melanoma and other cancers where immunotherapy is working.