Challenges in Immunotherapy for Bladder Cancer- Maria De Santis

Maria De Santis discusses challenges in immunotherapy approaches for urothelial cancer with Alicia Morgans.  One of the key challenges is understanding if the clinical trial data is translatable in daily practice due to the fact that most patients presenting with urothelial cancer are elderly.  These patients tend to be over 70 years of age, have impaired renal function and decreased performance status. While it seems reasonable to treat these patients with immunotherapy, these patients have generally been excluded from clinical trials making it a challenge to translate clinical outcomes and toxicity to the greater population. 

The SAUL study attempts to answer these questions with atezolizumab in a real world setting by including patients that would be typically excluded from other clinical trials. The data so far demonstrates that the toxicity is similar to what was seen in the pivotal study but efficacy is a little worse, which is not unexpected.   

Biographies:
Maria De Santis is a medical oncologist and Chair of Section for Interdisciplinary Genito-Urinary Cancer Medicine at the Charité Medical University Hospital, Berlin, Germany. She has been Associate Professor of Medicine at Paracelsus Medizinische Privatuniversität in Salzburg, Austria, since 2008, and working as a senior consultant at the 3rd Medical Department – Center of Oncology and Hematology at Kaiser Franz Josef-Spital in Vienna for 18 years, where she has also lead the Genito-Urinary Oncology Service for 11 years. From 2015 until April 2018 she was appointed Associate Clinical Professor for Oncology at the University of Warwick, Coventry, and working clinically in genitourinary oncology at the Queen Elizabeth Hospital, Cancer Center, in Birmingham, UK. Also, she has been appointed Adjunct Professor at the Department of Urology at the Medical University of Vienna, Austria, in 2016.

Alicia Morgans, MD, MPH

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Alicia Morgans: Hi. I'm delighted to have here with me today Dr. Maria De Santis, who's a Medical Oncologist at the Charite Hospital in Berlin. Thank you so much for coming to speak with me today. 

Maria De Santis: Pleasure. 

Alicia Morgans: Wonderful. I always appreciate hearing your insights. Today I wanted to talk with you about challenges in immunotherapy, thinking about the data, also thinking about how the data in clinical trials may be somewhat different from what we see in real-world data, which I know is coming out. I'd love to hear your thoughts on this. 

Maria De Santis: Alicia, I think this is a very timely and very important question because we are always wondering if the trial data really are translatable into daily practice and into those patients that we see in our clinics every day. 

With bladder cancer, urothelial cancer in general, and, for example, immunotherapy, the issue is that those patients are frequently elderly. They are 70 plus very often. They tend to have impaired renal function. For those patients, actually, the immunotherapy seems to be an ideal treatment because you can give it with low renal function in general, but some say, "Well, those patients have not been included in the trials," because in the trials higher and better renal function was required and the performance status in the pivotal trials had to be zero or one. Many of our patients are performance status two or even three. The question is, can we apply, can we give them immunotherapy, and is it safe and it is working?

Most importantly, we need real-world data. Some of these data were presented at this EAU meeting, one of which is the SAUL study, which is atezolizumab in patients that progressed on prior chemotherapy, and in this trial actually patients with performance status two were also included, patients with impaired renal function with GFR down to fifteen mL/minute were included, and other patients, patients with stable brain metastases that were excluded from other trials, and patients with other histologists were included. Patients with autoimmune disease, or on dialysis were included. So, really very interesting patient populations where we did not have any data so far. And this is a huge trial as our trial is more than 1,000 patient trial, and we now see some of the data.

So, we see that actually, the tolerance is pretty good. So, the whole population seems to be pretty similar concerning toxicity to the pivotal data in the IMVIGOR 211 study for example. So, I would not have too many concerns concerning toxicity in elderly patients or patients with performance status 2. Besides efficacy is, of course, important, and here we see that real-world data is a little bit worse than the trial data. This is not unexpected. This is what see in all the trial actually and in all real-world data that our patients that have worse performance status actually don't live that long. The question is if they derive a benefit, and I have the impression that they do. So, those patients who responded, so the response rate in a SAUL patient response rate was a little bit lower than in IMVIGOR 211 trial for example, but those patients who responded also had longer-term response.

So, this is also reassuring because toxicity is low, lower than with chemotherapy, and it seems to work in those patients who are responding, and the others you would stop treatment anyway at a point. So, I found this data very reassuring and really important also to look into those patients who are on steroids, patients with autoimmune diseases, et cetera.

Alicia Morgans: And these patients didn't seem to have high levels of toxicity, and seem to have similar response rates as the rest of the patients?

Maria De Santis: Well as a toxicity was pretty similar, the response rates were a little bit lower than in the patient population of IMVIGOR 211 for example.

Alicia Morgans: For the autoimmune patients I mean?

Maria De Santis: For the autoimmune patients, well we have very low numbers. The response rates seem to be similar, but it is a little bit difficult to really draw final conclusions here because with the low numbers it might of course be, you might be criticized in saying, "Yes, autoimmune patients have the same response rates." With the low numbers we have, we have the impression it is still early days, but it's the first time that those patients were included, and I think the toxicity data is somewhat valid in this respect.

Alicia Morgans: And that's what's most important I think. When we first started using these medications, and the reason that these patients were excluded from the clinical trials was really a concern about the potential toxicity in patients who already have an autoimmune disorder, so very reassuring as you said I think to see that they were able to tolerate it at least reasonably well. Whether they responded or didn't respond may be more based on the tumor or other characteristics that we don't yet understand, but they at least didn't have severe toxicities that would preclude us from considering utilization of things like an atezolizumab in the real world which is very helpful.

Maria De Santis: Yeah, that's true. And what we see here is that discontinuation rate because of toxicity was not significantly higher in those special subgroups of patients with autoimmune disease or patients on dialysis, so I think this is a pretty good indicator.

Alicia Morgans: Yes, that's very good. Well, what about elderly patients? Because as you said sometimes the performance status and elderly status kind of go hand in hand, and these are patients who may not have access to things like chemotherapy, and in this study, it sounds like all of these patients had already received chemotherapy. This was used really in a second line setting but did these patients, the elderly patients, and frail patients seem to have reasonable toxicity profiles and potential response rates?

Maria De Santis: Well, actually yes, but here I could also refer to the pembrolizumab data that we have, so there are subgroup analysis now are for elderly patients, those seventy-five plus, and the same patients have a performance status of two, and then looking into the subgroup with respect to toxicity and response rate. It's really interesting seeing for example of the KEYNOTE 52 data, and this elderly subgroup performance data two, had actually the same response rate as the whole population of the study, so I found this really interesting and important because these are the patients that are discussed a lot in our MDT's and many say, "Well, this patient is elderly and maybe it does not make sense to give them treatment and maybe they should go for best supportive care, but on the contrary I think they should receive the immunotherapy, because we have the indication even from the pivotal studies from the subgroups that they derive a benefit.

Alicia Morgans: Absolutely, and we all know chronologic age and physiologic age can be very different things. So, the number of your years and the fitness of your body may actually be somewhat different. So, precluding people based on just their age is not a great idea and this data supports that, and so does your practice clearly. But that's very helpful to know because it's not just the clinicians that sometimes ask those questions. Patients and their families ask the question, too. Is it worth it for my grandmother to go through this? And if the toxicity data is supportive and the response rates seem reasonable and they are, then we can have those conversations with the data in hand to say yes, I think this is a good option for you to at least consider.

Maria De Santis: Yeah, definitely. So age should not preclude patients from getting immunotherapy these days. Performance status is important for example in patients with performance status 3, I think we need to think twice.

Alicia Morgans: Yes.

Maria De Santis: Because we don't have a lot of data here, and they might not derive the same benefit as patients with performance status 0-2, irrespective of their age I think.

Alicia Morgans: Well, maybe the next real-world study, Maria. We should do as in patients with a higher performance status even comorbidities. I look forward to, maybe we can work with you on that study to see what the best practices are. Finding the data and learning is always the best way. So, any other updates that you have for us? Thinking about use of immunotherapy in the real world and your clinical practice?

Maria De Santis: Well, I think we have now more data in hand in patients with low renal function, and I think these were the patients that have always been discussed and actually precluded from chemotherapy, and also from immunotherapy so far, and I think this is the very new indication that also those patients can receive immunotherapy. I think this is a real most important part of the real world data we are seeing now. Otherwise, patients that are on dialysis for example, not only patients with urothelial cancer, but also with renal cell carcinoma could receive treatment with immunotherapy, and we don't have a lot of data here. The numbers are pretty low, but still, it is important to have at least a few case reports collected prospectively collected to give us information.

Alicia Morgans: So, Maria, do clinicians need to think about the timing of infusion of these immunotherapies with their dialysis? Is this something that's a problem, or is this not dialyzed?

Maria De Santis: It is not dialyzed, and with this respect, it is no problem, so it is pretty easy going with combining dialysis and immunotherapy.

Alicia Morgans: That's very important to know. Thank you. So, if you had to send or have one take-home message for the end of this, what would you love for our listeners to take home from this real-world data?

Maria De Santis: Well, immunotherapy is safe for patients with low renal function, and it is also pretty safe for those patients with autoimmune diseases and for those patients who are on longer-term corticosteroids, and for those with stable brain mets. Don't exclude them from treatment.

Alicia Morgans: Okay, well thank you so much, and thank you so much for talking with me today.

Maria De Santis: Thank you, Alicia.
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