Podcast Discussion (MP4 34501 KB)

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Transcript


Podcast Attendees:

LA: Managing Editor  at Advances in Therapy.


PI: Hannover Medical School, Hannover, Germany.


VG: University Hospital Essen, Essen, Germany.


Lydia: Welcome to our Adis podcast episode, which was funded by an educational grant from Eisai. I’m delighted to say that we’re rejoined today by experts Dr. Philipp Ivanyi and Dr. Viktor Grünwald to discuss first-line treatment for metastatic renal cell carcinoma, where they'll draw on their experiences on how to manage patients safely and choose the best treatments for them. So, thank you again for your time here, but just for any listeners who may be new to our podcasts, could you briefly introduce yourselves?


Philipp: Yes, thanks Lydia. My name is Philipp Ivanyi. I'm working as a medical oncologist here in the Comprehensive Cancer Center in Hanover in northern Germany. And of course, one of our main focuses is genitourinary cancer, in particular kidney cancer.


Viktor: Yeah, and I'm Viktor Grünwald. I'm a medical oncologist by training. And I, I specialize in GU (genitourinary) cancer therapies for medical therapies in particular, and I'm happy to talk about kidney cancer. I think it's a great topic.


Philipp: Right, it is a great topic, and then we're diving already into the great topic. I'm referring to the other podcast which we did where we talked about different options [1]. Now let's focus, Viktor, on a different topic. Once we have reached effective therapies, overall survival benefit usually also involves toxicity, and management is mandatory. So, it's a general recommendation. Once a colleague, you know, is having a new clinical experience, how could you think about management, what issues do you have to be aware of? Do you have any scheme? What do you have to focus on?


Viktor: Yeah, you have to have some sort of management because with the advent of targeted therapies, we expose our patients to continued treatment and chronic toxicity, and I think that's different from chemotherapy. I think that's something that we have learned in the past 15 years or so. And I think something that is important is to counsel patients. So what can be awaited, what is important? What can be done as a preventive measure? And what are the stop signs? You know, where should I contact the site to get to get help? I think these are, I mean, in essence, there are a few things that are quite important for me when it comes to targeted therapies.


Philipp: Right, in particular when we discuss the topic of PD1 (programmed cell death protein-1) TKI (tyrosinkinase inhibitor) therapy. And there's a new phenomenon if you ask me. We are also concerned about the follow-up; in particular, we are using a new checkpoint inhibition. It requires the team and also the healthcare providers in general, as well as the patient, to focus in particular on the follow-up once the toxicity has occurred [2]. And there we are now focusing already on one of the main challenges which we have had to learn about in the recent past, which is how to deal with the toxicity of PD1, TKI combo therapies in particular; they do have a kind of overlap, and I think one smart approach, and I'm not sure about you Viktor, is dissecting the toxicity according to each substance, and would you agree, if I go to a concept, where I say, well, go forward to data from the TKIs. We also had the good congress data presentation  [ASCO (American Society of Clinical Oncology) GU data] [3]. And would it be fair if I describe TKI toxicity as being mainly characterized by diarrhea in particular for VEGF (vacascular endothelial growth factor) and highly potent inhibitors, including hypertension and liver toxicity in terms of AST elevation as well as fatigue. Would you follow and say well this is even, for you, (if you use a combination therapy), one of the most frequent AEs (adverse events) of those therapies [2]?


Viktor: Yes, indeed. I think, I mean, there are different types of toxicities. I mean, some of them end up being recognized for  patients, such as hypertension. You know, until you know that it's [hypertension] very high in patients, usually if you don't measure it, you don't know. And then there are some that are really bothering patients, which could be diarrhea or could be fatigue. And I think this is driven by mucocutaneous toxicities. So, anywhere in the mucosa and the skin that is really bothering patients. So, there could be hand-foot syndrome, for instance, and diarrhea [4, 5].


Philipp: Right. Yeah.


Viktor: But also stomatitis, I think these are things that are really impeding patients' quality of life.


Philipp Ivanyi: Right, and we have data on these things from some TKIs. And what about the occurrence over time of TKI toxicity? You very often see these kinds of toxicities early on; they are quite constant in each patient. And I think there's also a time pattern which is a little bit different from PD1, or checkpoint inhibition toxicity. Would you agree? Or do you think we should not, you know, over-judge the data we have?


Viktor: I think TKI gives you chronic toxicity because you have to take the pill every day basically. I mean some of them may have some breaks in between, but at the end of the day it's chronic exposure. And when you look into the data, what you do see is that thir reporting becomes less frequent over time. So, you know, over time there's a decrease in grade 3, 4 or grade 2 diarrhea, for instance, and I think that relates to therapy management. That also includes dose adjustments and things that we do to keep patients on therapy. Honestly, I mean, the best patients (those that have the highest impact from treatment having the best results), they're being exposed, you know, even longer than others. So, you really have to find a way to deal with the chronic toxicity that comes from tyrosine kinase inhibitors [4, 5].


Philipp: Also, the checkpoint inhibitors are mostly given for a long time (once that works very well from the oncological side). Do you think there are, according to the kinetics we have, data from melanoma, in particular PD1, showing that it pops up around week 12 of therapy? Are these relevant data which you see in clinical day life [6, 7]?


Viktor: Well, I think with any therapy for kidney cancer the first 3 months are key to get patients on treatment to see what the toxicity is. You know, what does it look like? How does it impact patient's quality of life? Do we have to reduce the dose? And I think that's quite important, and that's also true for immunotherapies. You know, it comes in delayed, and it has a gap, and after a couple of weeks, you will see the full spectrum of toxicity. But, generally speaking, I think the first 3 or 4 months are also the relevant bounds for immunotherapy when it comes to toxicity. So, we speak about early acute toxicity, but how do you feel about immune-related toxicities that are coming in late? I mean, is that something of concern?


Philipp: Good question, really good question. I mean, if you look to the story of checkpoint inhibition, which all starts up also in cardiomyocytes in mice, and mouse models, there are some concerns from the cardiology side about cardiac toxicity. But if you look at the data, I didn't follow the topic at all recently, but I'm not really concerned about long-term toxicity, right? The probability, once the patient is on treatment, I guess what we can see from the data in the long run after they manage the first period, the probability of AEs is always nearly the same, but I don't think there are any data, correct me if I'm wrong, on really long-term toxicity itself, right? Accumulative toxicity.


Viktor: Yeah, What I had in mind is that, let's say you start off with treatment and a patient is on treatment 1 year and did not have any side effects, you know, it does not prevent the occurrence of grade 4 adverse events (according to CTCAE).


Philipp: Exactly. Yeah. Very important, right?


Viktor: It is a small chance, you know; it's less than 10% certainly, but it still may occur. You are on therapy 18 months, and then you have grade 3 diarrhea that comes from treatment. So it's something that needs to be considered and that is different from the tablets.


Philipp: Absolutely. Yeah. This is a very important point: even though it runs very well, (and recently this also happened to one of my patients) for let's say 1½ years, all of a sudden (nothing happened before) he really had a severe adverse event, and you need to be patient about this, right? So, now we have summarized the toxicity of each pattern a little bit. I guess this is key once you are aware (of each of the patterns when using the therapy, and this helps you to see things a little bit by chance in clinical day life), if you're using combinations, from which agent the toxicity comes. Would you agree? If you know a lot about each of them?


Viktor: Yes, basically there are some that are very distinctive and that are very specific for a given therapy, and then there is the group where it's overlapped. So, I think like pruritus or hypertension, I mean they relate to immunotherapy or TKIs, and then fatigue is a problem. Diarrhea is a problem. What about hepatitis if you use TKI/IO (immunooncological) therapies? Both components may contribute to the type of toxicity that we see.


Philipp: Right. So, and would you agree, the first thing I'm really concerned about is when I'm using a PD1/TKI combination which reaches at least a level of CTC (common toxicity criteria), grade 2 toxicity, then I'm pausing both substances. Would you agree with this general approach as a rule of thumb? Or would you use a different approach?


Viktor: Oh, it depends on the toxicity that you see.


Philipp: Okay. Yeah.


Viktor: We just recently had a patient who had grade 4 toxicity, so grade 4 hepatitis, within a trial. So we had to stop therapy with both agents. If it has that magnitude I also consider steroids at the same time as the occurrence, if it is grade 2, I mean that gives you some time to play around. That means only liver enzymes are elevated without any bilirubin. I think it is fair to say that you don't necessarily have to stop both agents. On top of that, the immunoagents have a very long half-life. So even if you don't do the infusion, there's still sufficient antibody in the system to maintain the immune response. I'm less convinced that you necessarily have to withhold both agents every time, but it helps to understand, you know, what the driving force behind the toxicity is.


Philipp: Well exactly, it helps to understand the situation most of the time. Let's go to the last point. We have plenty of reviews on how to manage IO combinations, right? And they focus, only, of course, on the IO. They are not focusing on TKI. Do you think we always call them also stoplight systems in Germany? Because they give you green, red, and yellow, and some hints on what you should do by continuing the therapy and initiating either diagnostics or steroids. And do you think we simply can follow the guidelines according to checkpoint inhibition also for the PD1/TKI combinations?


Viktor: With some deviations, I would say. Because I think the toxicity that comes from the immunocomponent is probably more dangerous, you know. It has more impact, and if you miss the time point to treat it properly (so meaning using corticosteroids) that becomes more challenging, and it could be lethal to patients. So, I think that that's the critical point about the immunocomponent. That's why we are so keen to recommend all teose adverse event managements, isn't it?


Philipp: Yeah it is. But I mean, you have to be fair, you said it could be lethal. We have to be honest, also TKI is not an easygoing substance. We have meta-analyses which underlined that they also increase the mortality and morbidity by themselves, right [8]? So, it's also not an easygoing targeted agent like imatinib in CML (chronic myeloid leukemia), for example. They are also potent and toxic drugs, which can cause harm. For instance, cardiotoxicity. But let's go back to one last question from my side: When I'm looking at all the reviews and expert opinions, right, and following the protocol guidelines and we don't have fairly randomised prospective trials in the majority of cases about toxicity management. My personal experience is whenever a situation, in particular for IO, is really unclear, don't waste too much time with diagnostics; start treatment, right? In particular with steroids. When you’re thinking about consulting the endocrinologist, which you definitely need in some situations. In the beginning I was always lost in differential diagnostics, and this means, first of all, start treating any concern with steroids, would you agree? Second of all, I also learned sometimes it's only worse or getting worse, a cancer, the underlying disease, which is causing weird situations. And once we are following those guidelines, we are always losing this point.


Viktor: Yeah, you are absolutely right. It's not always toxicity. It could be the disease itself, and you’re just not successful with your treatment. I mean, that's one thing to consider. The second thing is, as you said, if you're in doubt you should use steroids because many times immunotherapy can give you adverse events that are not captured by this side effect or supportive guidelines, and, you know, you may miss the point and just miss the window of opportunity to treat the patient. I mean a very good example is one of my patients, and he had an immunocomponent, it wasn’t even a single agent immuno, and he was hospitalized for a stroke actually, which he did not have. But he was being treated accordingly, and one day it was the right side, and then, 2 days after was, you know, the right side improved and the left side started to have hemiplegia. So, you know, we started doing corticosteroids, and it improved by the end of the day. But you can spend a lot of time doing diagnostics, and some of them need to be done. You have to be certain that it's not a different disease that you just don't capture but you should not wait because, you know, for some of the rare adverse events patients are just having poor outcomes because they are not being treated properly with corticosteroids and there are also data, I mean, I just start talking and talking, don't I? But there's data for, let’s say, in the beginning: hepatitis has been a subject for biopsies (liver biopsies), which is okay. I mean, you need to understand what the driving force is here. But there was a paper suggesting that if you go for diagnostic procedures, and you go for biopsies, you just delay the appropriate treatment, and you will have poorer outcomes with that. I mean, you know, then after, I don't know, a couple of weeks’ time, what is the cause of this? But you miss the point, which is treatment.


Philipp: Right. But then it's too late, right?


Viktor: You know, I think that that's the danger of having weird side effects from the immunotherapy.


Philipp: Right so we can summarize this point as, let's say, “If in doubt, steroid it out,” right? If it makes sense to say it like this and now. Thanks again for this nice talk. So, I think what we can summarize what we both learned with evolution of the therapy: every potent therapy nowadays, unfortunately, still has potential to do harm. It might be toxic, but we have to learn about the toxicity, we have to learn how to discover, and we have to try to memorize and to analyze the characteristics of each of the toxicities and how to carry out the appropriate management. And sometimes, in particular when we're using IO, don't lose too much time with diagnostics [9]. Steroids are not that harmful, at least in the short run, and also you can stop them if in doubt. And so thank you again for having you here and having this great discussion with you, Viktor.


Viktor: Thank you Philipp, it was a great topic.


Lydia: Thank you both; that was fantastic.