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Future Directions for RCC Research

Insights From: Brian Rini,MD, Cleveland Clinic Main Campus; David F. McDermott, MD, Harvard Cancer Center
Published: Monday, Dec 17, 2018



Transcript: 

Brian Rini, MD: I think moving forward, kidney cancer treatment is very quickly going to be that every patient is going to get an I-O [immune-oncology]–based combination in the front line. It might be I/O plus I/O, it might be I/O plus TKI [tyrosine kinase inhibitor], or it might be I/O plus bevacizumab. Sorting out those differences, we’ll obviously await comparative clinical data and other factors that determine which patient gets which drug. But I think very few patients are going to get TKI monotherapy once all these are presumably approved and we have full data.

The next steps would then be figuring out what to do with patients who are refractory to these combinations because you’re using both mechanisms upfront, potentially. Are combinations active in sequence? Do you get combination 1, then combination 2, then combination 3? Can you get away with giving monotherapy and then adding in the second drug only if necessary? There are a lot of different ways. In drug development, for kidney cancer and every cancer, a lot of times there are just these big phase III trials where things are put together and they work. But then we go back and figure out how to actually use them: timing, dosing, sequence. Those questions aren’t often asked in the initial drug development, they come later, and I think that’s what the next few years are going to bring.

David F. McDermott, MD: I think the most promising thing on the immediate horizon is the application of immune checkpoint blockade in the earlier stage III setting. These agents have shown effectiveness in melanoma when applied to patients with stage III disease. We know that they’re active in melanoma. We know that they’re active as single agents in kidney cancer now. The hope is that it translates into kidney cancer with meaningful improvements in disease-free survival and, importantly, overall survival in those adjuvant settings. That would be truly exciting for our patients. Preventing stage IV disease from developing will lead patients to having a much longer life with improved survival. To me, that’s the thing I’m looking forward to over the next 5 years. How do those adjuvant therapy trials with immune checkpoint blockade read out?

It’s an exciting time for our patients, with new options that are meaningfully prolonging their lives, and in some cases, leading to complete responses. But it’s hard to keep track. I would try to put things into different buckets. Most of what you’re seeing in 2019 is the combination of VEGF and PD-1 [programmed cell death protein 1] blockade, 2 great tastes that work reasonably well together, and they improve outcomes compared to sunitinib. I’m not sure there are major distinguishing characteristics between them.

Eventually, people are going to pick the one that they are most comfortable with and apply it. We won’t be using all 5 in our patients, but they’ll be preferred in many patients because they combine 2 approaches that many oncologists are comfortable with and have been using for over a decade, in the case of VEGF, or over the last 3 or so years with PD-1.
             
I think people will find those regimens easier to apply than they may think. In the case of PD-1 and CTLA-4 [cytotoxic T-lymphocyte–associated protein 4], CTLA-4 has carried a somewhat intimidating reputation because of the immune-related adverse effects. I think we’re getting much more effective in managing those adverse effects. I think to me, that’s the important take-home point. Ten years ago, with ipilimumab, we didn’t always intervene aggressively or quickly regarding adverse effects. We let things smolder, trying to see if they would improve.

Now we’re very quick to act with immunosuppressive regimens that are much more effective than they were 10 years ago. If you can educate yourself and your team about how to recognize those adverse effects and how to manage them, we’re doing much better than we were. What’s exciting about those I-O/I-O combinations is the chance for the complete response, which might lead to remissions of disease. I think that’s the goal that most patients have: the chance to be treated, for the treatment to work, for it to stop, and for them to live off treatment for a while.

I do think it’s worth it for the average oncologist, the average nurse practitioner or nurse in oncology, to learn about these new treatments because it’s really rewarding for me to occasionally present a patient with that opportunity. It makes you feel good about what you’re doing, to actually see an outcome like that. It’s good for both patient and clinician. We need to produce more of those remissions for patients with advanced kidney cancer.

Brian Rini, MD: I think the next questions are, How do we cure patients? Can we get away with monotherapy in some patients? Can we go the other direction and give triplets? Are triplets going to be viable? Are they going to be more curative? I think for the first time in kidney cancer the message I’d like to get across is that I’ve shifted my thinking from, “Gee, I want to control this patient’s disease as long as possible” to, “I want to cure this patient’s disease.” Certainly, that’s in in the frontline setting. I’m not so sure in the second or the later line setting, but in the frontline setting, I want to give them the regimen that has the highest chance of cure. I’ll worry about the rest after that. That’s a different way of looking at patients rather than a sequence of monotherapies, and we’re trying to control and minimize toxicity, which is still important of course. But for me, fundamentally, I think the field has shifted a little bit towards a more curative paradigm.

Transcript Edited for Clarity 
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Transcript: 

Brian Rini, MD: I think moving forward, kidney cancer treatment is very quickly going to be that every patient is going to get an I-O [immune-oncology]–based combination in the front line. It might be I/O plus I/O, it might be I/O plus TKI [tyrosine kinase inhibitor], or it might be I/O plus bevacizumab. Sorting out those differences, we’ll obviously await comparative clinical data and other factors that determine which patient gets which drug. But I think very few patients are going to get TKI monotherapy once all these are presumably approved and we have full data.

The next steps would then be figuring out what to do with patients who are refractory to these combinations because you’re using both mechanisms upfront, potentially. Are combinations active in sequence? Do you get combination 1, then combination 2, then combination 3? Can you get away with giving monotherapy and then adding in the second drug only if necessary? There are a lot of different ways. In drug development, for kidney cancer and every cancer, a lot of times there are just these big phase III trials where things are put together and they work. But then we go back and figure out how to actually use them: timing, dosing, sequence. Those questions aren’t often asked in the initial drug development, they come later, and I think that’s what the next few years are going to bring.

David F. McDermott, MD: I think the most promising thing on the immediate horizon is the application of immune checkpoint blockade in the earlier stage III setting. These agents have shown effectiveness in melanoma when applied to patients with stage III disease. We know that they’re active in melanoma. We know that they’re active as single agents in kidney cancer now. The hope is that it translates into kidney cancer with meaningful improvements in disease-free survival and, importantly, overall survival in those adjuvant settings. That would be truly exciting for our patients. Preventing stage IV disease from developing will lead patients to having a much longer life with improved survival. To me, that’s the thing I’m looking forward to over the next 5 years. How do those adjuvant therapy trials with immune checkpoint blockade read out?

It’s an exciting time for our patients, with new options that are meaningfully prolonging their lives, and in some cases, leading to complete responses. But it’s hard to keep track. I would try to put things into different buckets. Most of what you’re seeing in 2019 is the combination of VEGF and PD-1 [programmed cell death protein 1] blockade, 2 great tastes that work reasonably well together, and they improve outcomes compared to sunitinib. I’m not sure there are major distinguishing characteristics between them.

Eventually, people are going to pick the one that they are most comfortable with and apply it. We won’t be using all 5 in our patients, but they’ll be preferred in many patients because they combine 2 approaches that many oncologists are comfortable with and have been using for over a decade, in the case of VEGF, or over the last 3 or so years with PD-1.
             
I think people will find those regimens easier to apply than they may think. In the case of PD-1 and CTLA-4 [cytotoxic T-lymphocyte–associated protein 4], CTLA-4 has carried a somewhat intimidating reputation because of the immune-related adverse effects. I think we’re getting much more effective in managing those adverse effects. I think to me, that’s the important take-home point. Ten years ago, with ipilimumab, we didn’t always intervene aggressively or quickly regarding adverse effects. We let things smolder, trying to see if they would improve.

Now we’re very quick to act with immunosuppressive regimens that are much more effective than they were 10 years ago. If you can educate yourself and your team about how to recognize those adverse effects and how to manage them, we’re doing much better than we were. What’s exciting about those I-O/I-O combinations is the chance for the complete response, which might lead to remissions of disease. I think that’s the goal that most patients have: the chance to be treated, for the treatment to work, for it to stop, and for them to live off treatment for a while.

I do think it’s worth it for the average oncologist, the average nurse practitioner or nurse in oncology, to learn about these new treatments because it’s really rewarding for me to occasionally present a patient with that opportunity. It makes you feel good about what you’re doing, to actually see an outcome like that. It’s good for both patient and clinician. We need to produce more of those remissions for patients with advanced kidney cancer.

Brian Rini, MD: I think the next questions are, How do we cure patients? Can we get away with monotherapy in some patients? Can we go the other direction and give triplets? Are triplets going to be viable? Are they going to be more curative? I think for the first time in kidney cancer the message I’d like to get across is that I’ve shifted my thinking from, “Gee, I want to control this patient’s disease as long as possible” to, “I want to cure this patient’s disease.” Certainly, that’s in in the frontline setting. I’m not so sure in the second or the later line setting, but in the frontline setting, I want to give them the regimen that has the highest chance of cure. I’ll worry about the rest after that. That’s a different way of looking at patients rather than a sequence of monotherapies, and we’re trying to control and minimize toxicity, which is still important of course. But for me, fundamentally, I think the field has shifted a little bit towards a more curative paradigm.

Transcript Edited for Clarity 
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