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Kidney Cancer and Immunotherapy with Dr. Saby George at the 2020 CRI Virtual Immunotherapy Patient Summit

January 11, 2021

Immunotherapy has tremendously changed the treatment landscape for kidney cancer—also called renal cell cancer—and improved the overall survival rate of patients with metastatic kidney cancer. Oncologists have seen positive results in combining immunotherapy with conventional treatments such as surgery, laparoscopy, ablation, and targeted therapy. At the 2020 CRI Virtual Immunotherapy Patient Summit, we hosted a special breakout session on kidney cancer and immunotherapy to educate and empower patients, caregivers, and advocates.

Saby George, M.D., FACP, an attending physician and professor of oncology within the Department of Medicine at Roswell Park Comprehensive Cancer Center, discussed what patients with kidney cancer need to know about immunotherapy and answered audience questions about side effects, length of treatment, and COVID-19, among other topics.

Dr. George opened the session with an overview of kidney cancer and immunotherapy. He described the characteristics of kidney cancer and why it is challenging to treat. He also reviewed the history of immunotherapy for kidney cancer, focusing on a rapid period of discovery (2015-2018) during which checkpoint inhibitors and combination therapies were first approved for kidney cancer. Dr. George then looked to the future of immunotherapy for kidney cancer, discussing immunotherapy combination clinical trials that show great promise.

KIDNEY CANCER AND IMMUNOTHERAPY SESSION TRANSCRIPT

Tamron Hall: Welcome back. Now I'm pleased to introduce Dr. Saby George, who is here to talk to us about kidney cancer immunotherapy. Dr. George joins us from the Roswell Park Comprehensive Cancer Center in Buffalo, New York, where he is an Associate Professor of Oncology. Brian Brewer, from the Cancer Research Institute, will be facilitating the Q&A, so please leave your questions in the chat throughout the session so that he can share them with Dr. George. Dr. George, thank you for joining us.

Dr. Saby George: Thank you for the kind introduction, and having me at this summit. I thank you to CRI, Brian, and everybody else involved, and I'm excited to be here. And I would go over a short presentation, and then now give you a high level overview of kidney cancer therapeutics and how immunotherapy is utilized in kidney cancer.

Kidney cancer, as most of you know, it's a very difficult cancer to treat. Most of my time is spent treating kidney, prostate, and bladder cancer, and kidney cancer is my biggest population of patients. And it's a very difficult disease. There are various reasons for that, and I would like to talk about some of the things that make it challenging. Most of the kidney cancers that I treat are advanced. Early disease is treated mostly using surgery, and advanced kidney cancer treated using systemic therapy.

So number one, the tumor. Kidney cancer is very heterogeneous, meaning different parts of the tumor express different types of genes or mutations. So that makes it kind of very complex cancer, it's not one type of cell. They have different kinds of cell in different parts of the tumor. Number two, kidney cancer can suppress, in the tumor, immunity of the body, so it basically turns off the immune machinery that fights the cancer. Number three, anatomic challenges caused by the tumors in the kidney. Sometimes they can go extend into the renal vein, the vein that comes out of the kidney into the inferior vena cava, the bigger vein that goes into the heart, and into the right atrium and right ventricle in some situations. And so that makes it anatomic challenge to treat with tumor in these dangerous areas. If surgery is not possible, it's really challenging to manage those.

And then a couple other important things about kidney cancer are they create a low oxygen environment, or hypoxia is induced by the kidney cancer. And also, most of these kidney tumors are highly vascular, or has a lot of abnormal blood vessels, so this very knowledge has led to the development of some other treatments. Next slide please.

And the high level overview of kidney cancer therapeutics, I'd like to talk about that. So before 2005, which is called Cytokine Era in kidney cancer, we had, basically, IL2 and Interferon for using advanced kidney cancer. And they were used for the benefit, particularly the benefit of you long lasting, or durable, responses. Keep that word in mind, durable, because I'll be coming back to that word quite a bit. Durable means long duration of benefit.

And so from 2005 onwards, we had the development of new treatments based on the knowledge about VHL mutation and abnormal blood vessels in these tumors. So blood vessel targeting treatment, and signal blocking of mTOR pathway were utilized and new treatments were developed, targeted therapies. Targeted therapies like sorafenib, sunitinib, temsirolimus, everolimus, axitinib, pazopanib, bevacizumab, plus interferon, these were the treatments which were used at that time. And these were developed based on the ability to shrink the tumor and increase the duration of activity of the drug, or called the progression-free survival. Some drugs were able to minimally increase overall survival in patients.

So cumulatively, all these drugs put together, patients started living longer. Historically speaking, in the aisle two interferon era, stage four kidney cancer patients lived to a median of 18 months or less. So that being said, let's move to the next slide.

From 2015 onwards, we started seeing newer drugs developed. They are called checkpoint inhibitors, or the targeted immunotherapy era. The first treatment, nivolumab, was approved in 2015, based on the CheckMate 025 clinical trial, where nivolumab was compared to everolimus in that trial, and nivolumab demonstrated that patients treated with nivolumab live longer and had better response rate, more tumor shrinkage, and live longer, compared to everolimus treated patients. So overall survival was emphatically proven in that trial, and it led to the approval of the first checkpoint inhibitor in 2015.

The first combination treatment approved for use was a combination of ipilimumab and nivolumab, which was approved in 2018, based on a clinical trial called CheckMate 214, which compared ipi and nivo against sunitinib, which was the then standard of care prior to that. And the trial proved that the combination immunotherapy treatment can prolong the survival significantly. And after four years of follow-up, we published the latest data, which showed that patients live close to four and a half, five years on that on that regimen if they were exposed to that treatment as a first-line treatment.

And then subsequently, in 2019, we had two more combination drugs approved, axitinib in combination with pembrolizumab, and axitinib in combination with avelumab. So those were approved in 2019, Axitinib, being a tyrosine kinase inhibitor, or our blood vessel targeting drug, and pembrolizumab and avelumab are checkpoint inhibitors. So GKI checkpoint inhibitor combination also started to get approved and started to show significant benefit. And now we're hoping to have a couple more of these approvals coming through in the near future. Next slide please.

And so what does this all mean? So we had many approvals, immunotherapy approvals, in the past five years, and we're hoping that we will have better combinations, and ultimately we can have better response rates and durable, complete responses, and even cure for these advanced kidney cancer patients. Essentially, we have a lot of patients who have gone into complete remission. I still have patients from the Checkmate 214 and Checkmate 025 trials in complete remission, after many years of starting those treatment. They did not require an additional treatment after that.

So it's really, really amazing and I'm hoping that the future will hold better treatment options and better cure rates for this tough to treat cancer. And that being said, thank you. I'm happy to answer questions.

Brian Brewer: Dr. George, thank you so much for joining us today. And I'd also like to thank the Roswell Park Comprehensive Cancer Center for being such a great host, institutional partner to help make today's program possible.

Before we get to the questions, I'd just like to remind everyone that if you have any for Dr. George, you can submit them in the Q&A box. We'll try to get to as many of them as possible. Also, just as a reminder, we do have free, confidential and one-on-one clinical trial navigator consultations available to you for which you can register at any time. And we will be sure to send you information on that following today's program.

So with that, Dr. George, let's jump right into the questions. One of our audience members asked, "What do you think are the most promising immunotherapies for kidney cancer today?"

Dr. Saby George: So thank you Brian, once again, and yeah, that's a very good question. As I mentioned, alluded to earlier in the introduction slides, the most promising immunotherapy drugs that we have now are belonging to the classical immune checkpoint inhibitor, or targeted immunotherapy, which target different parts of the T cells or immune machinery, and basically activates or modulates the immune system. And these cells are a little soldiers. I would call them your little soldiers. They go and fight the cancer after getting activated.

So the classes that are approved for use in kidney cancer are anti-PD-1 and anti-PD-L1, both are the same, slightly different antibodies, and also anti-CTLA-4 antibody. Anti PD-1, drugs like nivolumab and pembrolizumab, and CTLA-4 drugs, the one that we have approved, is called ipilimumab. Ipilimumab is approved for use in combination with nivolumab. So those are these targeted immunotherapy drugs.

Some centers still use the old drugs, high-dose IL-2, but most centers stopped using those drugs with the introduction of these novel drugs, which can be given in the clinic rather than getting patients admitted for a week. So those are basically the drugs that we have for use in kidney cancer.

Brian Brewer: Well, thank you. Another question coming in from our audience right now is, "I'm currently on treatment. It's not an immunotherapy. Do I need to stop in order to receive immunotherapy?"

Dr. Saby George: Well, that's a good question, a common question that we face when new drugs are approved, actually.

So for you, if a treatment is working, make use of the treatment completely. So I would squeeze everything out of the treatment before stopping it, meaning if it's working, don't change it. If it's not broken, don't fix it. Because kidney cancer, there are a couple different types of phenotypes based on the genetic signature. So some type of kidney cancers respond well to targeted tyrosine kinase inhibitors, like sunitinib, pazopanib, and cabozantinib, et cetera. So if they work for five, six years, you don't need to change that. And if they don't work, then switch to the next treatment. Most likely it's going to be an immunotherapy.

The other phenotype is the one which can be targeted and which will respond well to immune checkpoint inhibitors. So again, in summary, if your treatment is working, there is no need to change it.

Brian Brewer: So that is prompting quite a number of questions to ask. Let's say, so someone, their treatment no longer is working and they switch to immunotherapy, how long does it take to know if it's working?

Dr. Saby George: So based on the studies that we've done so far, most of the response from immunotherapy occurs within the first scan, especially the combination immunotherapies like ipilimumab, nivolumab, or xitinib pembrolizumab or xitinib nivolumab combination, the response will occur within the first scan in most patients.

In select situations, some patients have a response after many months of having a stable disease or a tumor not changing at all for many months. That's a delayed response. And when we were using single agent nivolumab a lot, we saw a lot of what's called a pseudo-progression initially in some patients, meaning tumor would look a little worse radiographically initially, and then later they will shrink. So that's not real progression, but they will shrink in future in, and again, not a hundred percent of patients, but a significant percentage of patients benefited from continuing treatment beyond that pseudo-progression.

So a response could be of different patterns, like early response, delayed response, or initial worsening, then response.

Brian Brewer: So scans will make it look like the treatment's not working, the cancer's growing, but then actually something is happening. What is the cause of that? What is the cause of pseudo-progression?

Dr. Saby George: Right. Yeah. So I have studied that phenomenon and many others have done a lot of studies. A matter of fact, we have a paper in submission at this time as we speak.

So what happens is, as I mentioned earlier, the immunotherapies modulate your immune system, meaning activate your T cells and other cells, which will come and invade the tumor first. We want them to invade, and they will take time, sometimes many weeks or a few months to shrink down. So that's what's going on. So on a scan, if we do a scan right after or around the time that the immune infiltrate occurs, tumor could

You look a little bigger on a scan, but we don't know unless we biopsy it. And so how do we make a determination as to whether or not to continue treatment? Well, so typically it's guided by clinical expertise. If patients are doing well, despite tumor getting worse and they're tolerating the treatment well, then we tend to continue. If they are not doing well when tumor is getting worse, well, we know the answer. That's how the trials were done, and we've published extensively on this topic. It's less of an issue with the combination immunotherapies. It was more of a problem when we had a single agent nivolumab approved in 2015 and we started seeing those effects on the clinical trials itself. And it's a well-known phenomenon.

Brian Brewer: So your scans might show the tumor seems to be growing, but you ask the patient, "How are you feeling?

"Doc, I feel better. I feel much better." And that you're saying is actually a signal that something is happening.

Dr. Saby George: Right, and matter of fact, that's very true, actually. I have a patient right now. He comes from three hours away. See, he has a very aggressive disease. His cancer spread, metastatic renal cell cancer with sarcomatoid features, his tumor spread to lungs and heart muscle within three months of the removal of the kidney. So we started treating him with the dual combination, meaning immunotherapy, ipilimumab and nivolumab. The first scan after three months showed that pretty much all the lung tumors have shrunk significantly and some of them have gone away. And the tumor in the middle of the heart, the interventricular septum, got a little bigger, but this person is very athletically active and doing great, no worsening symptoms and was feeling great.

So, my hunch was to continue and continue. And then every month we were doing echocardiogram to track this tumor, and we see that the tumor is shrinking now. That particular tumor is shrinking now and the lung tumors are going away. So we're anticipating another scan soon. So that's an example. I've had many examples and I published extensively on this topic, at least three manuscripts on this topic. So, that's how powerful it is. It would be a shame if I call it off for pseudoprogression, right?

Brian Brewer: Don't call it off too early. Well, what happens... This is a question coming in. What happens if my immunotherapy treatment isn't working and I have to stop? Is it possible that it might work later or can I go on a different one?

Dr. Saby George: Yeah. So that's another question. So what is the value of applying immunotherapy again if it had stopped working in the vein? So we actually had a couple studies answering that question at ASCO this year, Tony Showery, and our group actually published from a study using ipilimumab and nivolumab application, after the patients are being treated with nivolumab or similar drugs and progressed in the past. In that group of patients, this study showed that at least 15%, one out of six, will have a response, meaning even if you had a checkpoint inhibitor in the past or immunotherapy in the past, then reapplication after a few other lines of treatment may work. So that's basically what it shows. And I think it's something to do with the immune system or the tumor being hot or cold, or things like that. It's really hard to say what is behind it, but I'm hoping that we'll have clarity in the coming years as to how to select the best treatment at a particular time.

Brian Brewer: Can you just explain to our audience what you meant by hot and cold?

Dr. Saby George: So, some tumors, I think some of you may have heard that pancreatic cancer may not respond to immunotherapy, prostate cancer may not respond to immunotherapy, but in select situations they will respond. So it's something to do with the tumor infiltrate, tumor infiltrating lymphocytes. So for an immunotherapy to work, we modulate these immune cells. They have to go and invade and they have to work against the cancer. The cancer should have certain features like, say for example, PD-L1 or the PD-1 modulating pathway or neoantigens, multiple mutations, heavy mutation burden. There are a lot of features which makes it susceptible to immunotherapy. If you need to have some of these elements present for the immunotherapy to work. So that's basically what I meant, hot or cold. There was no good definition. At any time, we cannot really say if a tumor is hot or cold before applying an immunotherapy, I'm hoping that novel imaging modalities will shed light into identifying those things, and also helping us select the best treatment, if it is immunotherapy or not at a particular time.

Brian Brewer: Another question coming in from our audience, from a patient. "I'm receiving checkpoint blockade immunotherapy. I've had a complete response. How long am I supposed to stay on treatment?"

So first let's explain what a complete response is and then please answer the question.

Dr. Saby George: Right. That's a common question also that we face in the clinics. So a complete response is the best response. If you treat somebody with the anti-cancer drug, the disappearance of all the tumors is called a complete response. So now in the chemotherapy era, even if you have complete response, you stop it, the tumor starts growing in most situations, but in the immunotherapy era, it's different. We have durable responses. So some of them may not grow back, even if we stopped the treatment at that time. But the practice now is based on how the clinical trials were done. So the clinical trials were done in order to continue the treatment, as long as the patients benefit, meaning until the tumor progresses, or if they are benefiting, continuing until the patient has intolerance. If they develop a serious adverse effect, then we have to stop it and treat the adverse effect. So, that's basically how we approach it.

answer that question of stopping the treatment for a complete response, it's not really easy to say if it's going to grow back, or is it going to be a durable, complete response. And most patients are uncomfortable stopping the treatment which is working. So it's really unnerving to think about stopping a treatment which works.

But also on the other side we have seen from studies like CheckMate 214 that when patients had to discontinue treatment for serious adverse events, like serious a lung toxicity or a kidney toxicity or a cardiac ... Excuse me. When they had to come off for toxicity and if they had developed a response, even despite using steroid for managing the toxicity, most of the patients have maintained their response. So from the CheckMate 214, patients who had to discontinue treatment for serious adverse event, vast majority of them have not required a second treatment, meaning vast majority of them have not progressed after stopping the immunotherapy. So I hope I answered that question.

Brian Brewer: Yeah. By toxicity or adverse event, you're talking about side effects really?

Dr. Saby George:  Yes. Correct.

Brian Brewer: That's the question there. Of course, there were a lot of questions about what the side effects are, but you just ran through how different organs can become inflamed and there can be various problems. How are those side effects managed just quickly? I know we're almost out of time, and we still want to get to COVID because that is another big question we are having.

Dr. Saby George: Sure, sure. The side effects that I mentioned, they belong to the class called immune-mediated adverse event, or irAE. Basically that occurs, those kind of side effects, occur when the activated immune cells go and attack the normal tissue, like the skin, like your kidney, colon, liver, heart, lung, brain, thyroid, pituitary, brain, anything. Any organ can be affected by an over-activated immune system. So that leads to irAE. They have to be identified in a timely fashion and managed in a timely fashion, otherwise some of them could be fatal.

Most of them are treated using high-dose steroid, high-dose steroid for a week or two, and then it's tapered over roughly four weeks. During that time, excuse me, the patients also will require prophylactic antibiotics to prevent opportunistic infections as well. That's a standard way of managing it. Sometimes we have to use other drugs in addition to steroid.

Brian Brewer: Well, and when someone has that adverse event or that side effect that's immune-related and you're able to taper it down, are they able to continue their treatment than at that point with immunotherapy?

Dr. Saby George: Right. If you are on dual checkpoint inhibitor, meaning ipilimumab and nivolumab or axitinib and pembrolizumab, you may be able to continue one of those after successfully managing the side effect. But if it's a grade four, generally speaking grade four event or grade three liver toxicity or certain types of toxicities-

Brian Brewer: Those are the worst ones, right?

Dr. Saby George: Yes.

Brian Brewer: Higher the greater.

Dr. Saby George: Those are the more dangerous ones. They occur, we tend not to use those drugs. We try to go to the other safer drugs because it's not fun to have that re-elicited. Because, like I said, some of these could be very fatal. But when that occurs, when patients have these side effects, generally speaking, a lot of patients have significant tumor control also.

Brian Brewer: Let's get to COVID then really quickly. It's the top of everyone's mind right now. Are cancer patients more susceptible to infection? And how is COVID affecting treatment of cancer patients, especially those that are currently on immunotherapy?

Dr. Saby George: Right. So COVID, I don't think cancer patients are any more susceptible unless they are receiving high-dose steroid, unless they are post high-dose chemotherapy, etc. If they have normal cell counts and everything and if they are receiving these classes of immunotherapy drugs, generally speaking, they are safe.

But if somebody's needing high-dose steroid for the management of these side effects, then it's become very tricky. That's the time when they may be more susceptible to infections like this. It's really, really dangerous, so you have to wear a mask and follow the instructions.

Generally speaking, our cancer patients at our cancer ... Or my experience is that they're very smart. They try to stay away from trouble. Very few patients have become sick in the past year from COVID. So I hope all the patients are very careful, and they take care of themselves during this time, particularly till we have control over COVID.

Brian Brewer: We've heard actually from a lot of cancer patients saying, "This is how we live all the time already because with our compromised immune systems from treatment or whatever." So it's almost like we're stepping into their world now.

What about the vaccine? Are there any potential risks for kidney cancer patients receiving a COVID vaccine?

Dr. Saby George: COVID vaccine, we heard about a couple different candidates, but I did not see any data. Being a clinician investigator or a physician scientist who does these kind of trials for a living, I have to see the data to comment on it. I don't know the efficacy and safety. I don't go by what's in the newspaper. I would like you to all strictly look at the data, discuss it with your doctor, and see if it's safe.

Generally speaking, most of the vaccines are safe if there is no live virus involved. I guess that will be the case. But again, I can't comment on it till it's published and approved.

Brian Brewer: Well, thank you so much, Dr. George, for that wonderful discussion. Unfortunately, that's all the time we have. If we couldn't get to all of your questions, don't worry, Dr. George will be following up with those in a vlog post with the Cancer Research Institute. So please be on the lookout for that.

Brian Brewer: Once again, Dr. George from the Roswell Park Comprehensive Cancer Center, thank you so much for your time with us today.

Dr. Saby George: Thank you so much, Brian.

Tamron Hall: Dr. George, thank you so much for the informative discussion. Thank you all for joining us and participating in the Q&A.

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