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Determining Initial Therapeutic Approach in Advanced RCC

Panelists:Robert A. Figlin, MD, FACP, Cedars-Sinai Medical Center;Daniel J. George, MD, Duke University Medical Center;Thomas Hutson, DO, PharmD, Baylor Charles A. Sammons Cancer Center;David F. McDermott, MD, Dana Farber Harvard Cancer Center;Elizabeth R. Plimack, MD, MS, Fox Chase Cancer Center;Nizar M. Tannir, MD, FACP, MD Anderson Cancer Center
Published: Wednesday, Jul 13, 2016


Transcript:

Robert A. Figlin, MD:
Nizar, when you think about risk, good-prognosis patients, and intermediate poor-prognosis patients—for example, using the MSKCC (Memorial Sloan Kettering Cancer Center) criteria—is the conversation different for those different populations?

Nizar M. Tannir, MD: I think we have many drugs, as you mentioned, but the impact of these therapies really differs based on the prognostic category the patient fits in. So, I think the most challenging patient is the patient with poor risk. And, obviously, those are patients who have compromised performance status, or anemia, or hypercalcemia—and those, obviously, are patients who present with advanced disease and primary in situ already—automatically, they’re in the immediate-risk group.

Those patients, there is no conversation when you’re talking about somebody—in my opinion—with intermediate-risk disease and poor-risk disease; the conversation about watchful waiting, active surveillance. This doesn’t come to that patient. So, the conversation about, “Well, we can watch the patient and talk about the role of therapy,” that applies more for the patient who had a nephrectomy many years ago, now has low-volume disease, and the laboratory parameters are all good, normal, and then you can tell that patient, “Well, you can be observed.”

But the patient who has compromised performed status, hypercalcemia, anemia, any number of these—obviously, the two models that we use most widely are the MSKCC and the IMDC. And they’re very similar in that both models have the clinical parameters of time, from initial diagnosis to injection therapy under 1 year, being the risk factor. Performance status is very important in many cancers if it’s compromised, whether you’re looking at ECOG scoring system 2 or worse, or the Karnofsky 70% or less; those patients are sick, they need to have therapy. Traditionally, for patients who have poor-risk disease, the NCCN guidelines based that on one phase III trial of temsirolimus versus interferon versus combination. That trial obviously led to the approval of temsirolimus, in that poor-intermediate setting, based on old interferon being the comparator.

This field is changing. Now, with the advent of these new therapies, immunotherapies, I think the prognosis hopefully will be better, and we’ll see patients—who have poor risk disease, who present with advanced stage disease and primary in situ—respond to some of these newer therapies we have, particularly the immuno-oncology products, the immune checkpoint inhibitors. So, I think while, traditionally, a patient with poor-risk disease was bad news to confront—the patient comes to the clinic in a wheelchair with hypercalcemia, anemia, etc. and newly diagnosed—hopefully, the prognosis now, there is some hope that those patients can have a future based on these therapies that we have.

And I think I’d like to add to what was said already. We have pre-surgical trials. There are now some trials that take patients who present with primary in situ and metastatic disease. So, rather than send them up front for cytoreductive nephrectomy—the paradigm of treating them—we are getting a biopsy. That’s where you really need to do a biopsy if a patient has advanced disease. And you’re not going to do the up-front nephrectomy, especially if their performance is 2 or Karnofsky 70%. And then, based on the histology, we have trials to offer them therapy, in the context of metastatic disease pre-surgical before they get to nephrectomy. And we’ve seen some really impressive results. We’re awaiting a trial at MD Anderson in this patient population with combining an immune therapy, particularly nivolumab and ipilimumab, and also combining a target agent directly against VEGF with bevacizumab.

And we’ve seen impressive results in patients who had a doomed prognosis; not too long ago for those patients, the average survival was 8 to 9 months if they had poor risk disease. So, there is hope for those patients now that it’s no longer going to be the 8, 9 months’ survival for those poor-risk patients—but there is hope.

Robert A. Figlin, MD: Elizabeth, you had some thoughts?

Elizabeth R. Plimack, MD, MS: I was just going to say, we try to teach our Fellows that risk is an indicator of how badly they’ll do with a prognostic indicator. And although performance status and general health status is part of that, it’s a little bit separate. You can have someone that’s very healthy with terrible disease, and they can tolerate anything you give them, and we should be aggressive with them, even though they’re a poor risk. And then you can have a patient who’s very frail, with a poor performance status, who may have indolent disease and maybe you want to do nothing for that patient, even though they’re poor performance status. So, that’s just a clarification of risk versus frailty, for instance.

Robert A. Figlin, MD: Dan, just summarize for us your thoughts about what therapies you offer patients newly diagnosed. We have now a larger number that are commercially available, including IL-2, which goes back over a decade. How do you make that decision?

Daniel J. George, MD: Yes. I think this is very much a changing time in the field. And I think what Nizar brought up is really exciting and hopeful in terms of the newer immunotherapies in untreated metastatic disease. But we don’t have any data there yet. Just to be clear, that’s still clinical trial information, and those patients need to go on studies, and these are absolutely the studies we should be doing and accruing to. But out there in practice, I don’t think we’re ready to now start first line with our immune oncology therapies, except for the case of high-dose IL-2.

High-dose IL-2 has been around for 30-plus years now and has proven—in selected patients, mind you—a subset of patients that get a partial or complete response that’s very durable. And we’re careful, at least at our institution at Duke, about who we select for that. People under 70, people with good performance status—as Elizabeth said, good functional status. Low/intermediate risk, people that we want to treat. The goal here is a little bit different than what Tom laid out. It is to get that durable response—hopefully, that complete response—for these patients. We recognize that goal is unlikely, and we set our patients up to recognize that this very well may not work, but they can afford to do that because their disease is asymptomatic enough, minimal disease–burden enough, that we can afford some progression and still get on to what we consider to be some really active and exciting second-line therapies. So, that’s a population of patients we still treat with high dose IL-2 therapy.

When it comes to our systemic tyrosine kinase inhibitors—really, our other standard of care in the front-line setting—the conversation’s a little bit different. We’re not necessarily talking about a drug that’s going to get them to a potential durable CR, although there are circumstances—though they are rare—of patients with oligometastatic disease where we can get disease control and then complement that with either the surgeries or radiations to get to a CR. So, it’s not completely off the table for those patients. But for the majority of patients out there that have disease that is of intermediate risk, or poor risk, or good risk—but we want to treat them because they’re young and healthy, and we’re concerned about the pace of that disease burden—that’s the population patients will treat with a VEGF TKI.

Now, what comes with that is two things. One, here’s the conversation we have about progression-free survival, what we like to call “cancer control.” Our goals for these patients is to control that disease as long as possible. And the secondary to that is maintaining a good toxicity profile, maybe manipulating the dosing regimen, the dosing level, or even an intermittent approach, at times, in order to get the best balance there is between quality of life and disease control. So, it’s a different conversation. That’s the majority of our patients. The high-dose IL-2 for others, and then observation for others. Rarely, but still occasionally, we’ll use temsirolimus for those poor-risk patients, particularly the poor performance status, poor-risk patients. That’s our spectrum right now. That may change in a year or two. But for right now, that’s where we are.

Transcript Edited for Clarity
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Transcript:

Robert A. Figlin, MD:
Nizar, when you think about risk, good-prognosis patients, and intermediate poor-prognosis patients—for example, using the MSKCC (Memorial Sloan Kettering Cancer Center) criteria—is the conversation different for those different populations?

Nizar M. Tannir, MD: I think we have many drugs, as you mentioned, but the impact of these therapies really differs based on the prognostic category the patient fits in. So, I think the most challenging patient is the patient with poor risk. And, obviously, those are patients who have compromised performance status, or anemia, or hypercalcemia—and those, obviously, are patients who present with advanced disease and primary in situ already—automatically, they’re in the immediate-risk group.

Those patients, there is no conversation when you’re talking about somebody—in my opinion—with intermediate-risk disease and poor-risk disease; the conversation about watchful waiting, active surveillance. This doesn’t come to that patient. So, the conversation about, “Well, we can watch the patient and talk about the role of therapy,” that applies more for the patient who had a nephrectomy many years ago, now has low-volume disease, and the laboratory parameters are all good, normal, and then you can tell that patient, “Well, you can be observed.”

But the patient who has compromised performed status, hypercalcemia, anemia, any number of these—obviously, the two models that we use most widely are the MSKCC and the IMDC. And they’re very similar in that both models have the clinical parameters of time, from initial diagnosis to injection therapy under 1 year, being the risk factor. Performance status is very important in many cancers if it’s compromised, whether you’re looking at ECOG scoring system 2 or worse, or the Karnofsky 70% or less; those patients are sick, they need to have therapy. Traditionally, for patients who have poor-risk disease, the NCCN guidelines based that on one phase III trial of temsirolimus versus interferon versus combination. That trial obviously led to the approval of temsirolimus, in that poor-intermediate setting, based on old interferon being the comparator.

This field is changing. Now, with the advent of these new therapies, immunotherapies, I think the prognosis hopefully will be better, and we’ll see patients—who have poor risk disease, who present with advanced stage disease and primary in situ—respond to some of these newer therapies we have, particularly the immuno-oncology products, the immune checkpoint inhibitors. So, I think while, traditionally, a patient with poor-risk disease was bad news to confront—the patient comes to the clinic in a wheelchair with hypercalcemia, anemia, etc. and newly diagnosed—hopefully, the prognosis now, there is some hope that those patients can have a future based on these therapies that we have.

And I think I’d like to add to what was said already. We have pre-surgical trials. There are now some trials that take patients who present with primary in situ and metastatic disease. So, rather than send them up front for cytoreductive nephrectomy—the paradigm of treating them—we are getting a biopsy. That’s where you really need to do a biopsy if a patient has advanced disease. And you’re not going to do the up-front nephrectomy, especially if their performance is 2 or Karnofsky 70%. And then, based on the histology, we have trials to offer them therapy, in the context of metastatic disease pre-surgical before they get to nephrectomy. And we’ve seen some really impressive results. We’re awaiting a trial at MD Anderson in this patient population with combining an immune therapy, particularly nivolumab and ipilimumab, and also combining a target agent directly against VEGF with bevacizumab.

And we’ve seen impressive results in patients who had a doomed prognosis; not too long ago for those patients, the average survival was 8 to 9 months if they had poor risk disease. So, there is hope for those patients now that it’s no longer going to be the 8, 9 months’ survival for those poor-risk patients—but there is hope.

Robert A. Figlin, MD: Elizabeth, you had some thoughts?

Elizabeth R. Plimack, MD, MS: I was just going to say, we try to teach our Fellows that risk is an indicator of how badly they’ll do with a prognostic indicator. And although performance status and general health status is part of that, it’s a little bit separate. You can have someone that’s very healthy with terrible disease, and they can tolerate anything you give them, and we should be aggressive with them, even though they’re a poor risk. And then you can have a patient who’s very frail, with a poor performance status, who may have indolent disease and maybe you want to do nothing for that patient, even though they’re poor performance status. So, that’s just a clarification of risk versus frailty, for instance.

Robert A. Figlin, MD: Dan, just summarize for us your thoughts about what therapies you offer patients newly diagnosed. We have now a larger number that are commercially available, including IL-2, which goes back over a decade. How do you make that decision?

Daniel J. George, MD: Yes. I think this is very much a changing time in the field. And I think what Nizar brought up is really exciting and hopeful in terms of the newer immunotherapies in untreated metastatic disease. But we don’t have any data there yet. Just to be clear, that’s still clinical trial information, and those patients need to go on studies, and these are absolutely the studies we should be doing and accruing to. But out there in practice, I don’t think we’re ready to now start first line with our immune oncology therapies, except for the case of high-dose IL-2.

High-dose IL-2 has been around for 30-plus years now and has proven—in selected patients, mind you—a subset of patients that get a partial or complete response that’s very durable. And we’re careful, at least at our institution at Duke, about who we select for that. People under 70, people with good performance status—as Elizabeth said, good functional status. Low/intermediate risk, people that we want to treat. The goal here is a little bit different than what Tom laid out. It is to get that durable response—hopefully, that complete response—for these patients. We recognize that goal is unlikely, and we set our patients up to recognize that this very well may not work, but they can afford to do that because their disease is asymptomatic enough, minimal disease–burden enough, that we can afford some progression and still get on to what we consider to be some really active and exciting second-line therapies. So, that’s a population of patients we still treat with high dose IL-2 therapy.

When it comes to our systemic tyrosine kinase inhibitors—really, our other standard of care in the front-line setting—the conversation’s a little bit different. We’re not necessarily talking about a drug that’s going to get them to a potential durable CR, although there are circumstances—though they are rare—of patients with oligometastatic disease where we can get disease control and then complement that with either the surgeries or radiations to get to a CR. So, it’s not completely off the table for those patients. But for the majority of patients out there that have disease that is of intermediate risk, or poor risk, or good risk—but we want to treat them because they’re young and healthy, and we’re concerned about the pace of that disease burden—that’s the population patients will treat with a VEGF TKI.

Now, what comes with that is two things. One, here’s the conversation we have about progression-free survival, what we like to call “cancer control.” Our goals for these patients is to control that disease as long as possible. And the secondary to that is maintaining a good toxicity profile, maybe manipulating the dosing regimen, the dosing level, or even an intermittent approach, at times, in order to get the best balance there is between quality of life and disease control. So, it’s a different conversation. That’s the majority of our patients. The high-dose IL-2 for others, and then observation for others. Rarely, but still occasionally, we’ll use temsirolimus for those poor-risk patients, particularly the poor performance status, poor-risk patients. That’s our spectrum right now. That may change in a year or two. But for right now, that’s where we are.

Transcript Edited for Clarity
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