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Durable Immunotherapy Benefits Foster Excitement in Bladder Cancer, Despite Low Response Rates

Shannon Connelly
Published Online:3:04 PM, Mon August 7, 2017

Arlene Siefker-Radtke, MD
While immunotherapy agents have only demonstrated a clinical benefit for approximately 15% to 20% of patients with urothelial carcinoma, it’s the durable responses observed in these patients that have doctors excited, says Arlene Siefker-Radtke, MD.

“It's the durability of the responses to immunotherapy that are creating all of the excitement and are giving us a threshold to build on to hopefully make bladder cancer a more chronic disease that no longer kills people,” she said.

In an interview with Targeted Oncology, Siefker-Radtke, associate professor, Department of Genitourinary Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, discussed the current status of biomarker research in bladder cancer, and the impact immunotherapy has had in the field.

TARGETED ONCOLOGY:  With all the recent approvals in bladder cancer, what is the best way for oncologists to decide which immunotherapy to give their patients?

Siefker-Radtke: The difficulty is that we currently cannot tell that 1 drug is definitively better than the other. The response rates appear similar amongst all 5 checkpoint inhibitors. They appear to have similar activity and similar survival. There have been some slight differences in the data that have been reported, but we know there can be differences in responses depending upon the population of patients that are treated on a trial. At the moment, we don't see any difference in outcomes based on response rates. Based upon effectiveness, they all appear to have fairly similar toxicity profiles as well. Perhaps the 1 notable exception is avelumab (Bavencio), where they have a 20% infusion reaction, and that's probably related to how that drug was developed. They were looking for some antibody-direct cytotoxicity, so perhaps that accounts for the increased transfusion reaction rate. Otherwise, they all appear to have similar toxicity profiles. 

TARGETED ONCOLOGY:  Looking at durvalumab (Imfinzi), are there certain patients that do better or worse with this agent? Can elderly patients tolerate this agent?

Siefker-Radtke: The response rates with these agents seem to be better in patients with node-only disease, however, we still see activity even in liver metastases and bone metastases. I've been impressed by these agents and how they do impact patients with bone metastases, where I haven't seen as much benefit with systemic chemotherapy. There might be something to the use of these agents in that patient population that it might make a difference.
As far as older patients, for the majority of patients, their tolerance of these agents, like durvalumab, is certainly much better than they would tolerate aggressive chemotherapy regimens. It's been a good option for patients who have poor kidney function and can't tolerate cisplatin-based chemotherapy, but also for patients who are more frail or elderly and have had difficulty tolerating the standard-of-care chemotherapy. I would estimate that more of the patients I've treated have been able to tolerate their immunotherapy and find it much easier compared to the chemotherapy they had previously received.

TARGETED ONCOLOGY:  What impact has durvalumab's approval had in the field of bladder cancer, and what areas are still being investigated with the agent?

Siefker-Radtke: The field has currently approved single-agent therapy, and it's definitely a benefit, but unfortunately, it's still only impacting about 15% to 20% of our patients. There may be more patients who have slowing of their disease or where it may extend their survival, but it's a small number that have those durable responses that have the potential to last for years.
Clearly, we need to do better, and we need to find better ways of modulating the immune system to improve on the activity of these drugs. One way we're looking at improving the activity of immunotherapy is looking at combinations of immune checkpoint inhibitors.
There is a frontline trial of durvalumab with tremelimumab that is currently ongoing (NCT02516241). Durvalumab is a PD-L1 inhibitor and tremelimumab is a CTLA-4 antibody. Early data with CTLA-4 and PD-1 combination therapy suggest a higher response rate with this combination, although there is the potential for more immune-related side effects. We're all eagerly anticipating the results of this trial, trying to see if there's any hint of early frontline activity with the combination that may be better than we would see with traditional chemotherapy. 

There's also another trial that is currently ongoing with durvalumab and it's called the BISCAY trial, where they're combining it with an FGFR inhibitor (NCT02546661). This combination might work in those more immunologically frozen tumors. There's some growing preclinical data suggesting that tumors that have FGFR3 mutations appear more cold to the immune system. They lack the immune infiltrate and an immune signal in their tumor. This may inhibit the ability of an immune checkpoint inhibitor to work in that group of patients. There are several companies looking at combinations of FGFR inhibitors with immunotherapy. The BISCAY trial is currently enrolling patients looking at a combination of an FGFR inhibitor with durvalumab to see if this could work on those cold tumors and restore the immune system to them and generate a better immune response.

TARGETED ONCOLOGY:  What would you recommend that community urologists or oncologists should know about durvalumab?

Siefker-Radtke: The response rates are still low, on the range of 15% or 20% with immunotherapy, so if I have a patient with very rapidly progressive cancer, I might consider chemotherapy first in the hopes of cooling off the disease, and then follow that with immunotherapy in the second-line setting. But if the patient is not a candidate for cisplatin, certainly, giving an immune checkpoint inhibitor upfront would be very reasonable.

Immunotherapy is making the biggest impact in the durability of response. That's what is truly exciting about these agents. We're seeing responses that are lasting on the order of years, and we've never seen that with systemic chemotherapy. I have patients who have had an immune checkpoint inhibitor and [have an ongoing] complete or partial remission for more than 3 years. It's the durability of the responses to immunotherapy that are creating all the excitement and are giving us a threshold to build on to hopefully make bladder cancer a more chronic disease that no longer kills people.

TARGETED ONCOLOGY:  Where are we currently with biomarkers in bladder cancer research?

Siefker-Radtke: There have been a lot of studies trying to find biomarkers, which would help us pick which patients are going to respond to an immunotherapy. If these are successful, it would be a wonderful thing, as we could do more personalized medicine. The first biomarker that was studied is PD-L1 expression on the tumor. Unfortunately, the data has been all over the place with PD-L1 expression. Some studies suggest a response rate may be enhanced by looking at PD-L1 expression. However, other studies suggested that similar patients might respond even if they are PD-L1 negative.

I think the problem with PD-L1 in bladder cancer is that the marker is too dynamic. If the tissue was collected in the setting of Bacillus Calmette-Guérin therapy or the setting of chemotherapy, we know both of these agents can upregulate PD-L1 expression on the tumor. That might be why the data has been so variable. The tumors might have been collected under different conditions. We also know the different antibodies that have been studied have variable expression on the tumor. I've seen bladder slides that are taken from a single part of their tumor where 1 cut apart has 1 antibody staining dark, or grossly positive, and the other antibody appearing very light, or what we would consider negative. 

At the moment in bladder cancer, we don't have a good marker, and PD-L1 appears too dynamic and variable and hasn't had a tight correlation with response to an immune checkpoint inhibitor. There have been alternate markers that are being studied, and I would argue that we still need more data with these markers to determine how relevant they will be in the treatment of bladder cancer. One is looking at The Cancer Genome Atlas subtyping, so essentially, we look at the genes that are expressed by the tumor themselves to determine which cancers behave in a certain fashion. With gene expression profiling, we also call this molecular subtyping or molecular characterization. By doing this, we found that there are groups of tumors that appear immunologically cold and lack an immune marker and an immune infiltrate. There are other groups of tumors that appear warm. They have an immune signature and there appears to be greater responses with atezolizumab and nivolumab in those groups of warm tumors, compared to the cold tumors.

A similar profile has been seen using the interferon-gamma gene signature. This has been reported in the setting of melanoma tumors that can generate interferon-gamma—a gene that contributes to inflammation and drawing in immune cells. When the tumor expresses that, they're more likely to see activity with an immune checkpoint inhibitor, as compared to those immunologically cold tumors that lack an interferon-gamma gene signature. Looking at gene profiles, we're starting to gain a sense of which tumors respond. There are additional studies looking at tumor mutation burden, suggesting those tumors that have more mutations might be more likely to respond than others. At the moment, we truly lack a definitive biomarker that would absolutely tell us which patients should and should not receive immunotherapy. At the moment, I'm recommending immune checkpoint inhibition in all my patients.

TARGETED ONCOLOGY:  Is there anything else ongoing in the area of bladder cancer immunotherapy that you are particularly excited about? 

Siefker-Radtke: There are additional combinations that are being studied looking at alternate checkpoint inhibitors outside of CTLA-4. There is a new class of drugs called the IDO inhibitors which may impact the regulatory T cells that might block the response from immunotherapy, and those are being studied in combination with immune checkpoint inhibitors. There's truly a lot of new treatments on the horizon that are showing promise and will be studied in the future in phase II trials. I would encourage patients to look for phase II trials, they might get the next best treatment for bladder cancer.

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