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Defining Progression in Metastatic Kidney Cancer

Panelists: Robert A. Figlin, MD, Samuel Oschin Comprehensive Cancer Institute at Cedars-Sinai Medical Center; Eric Jonasch, MD, University of Texas MD Anderson Cancer Center; Toni K. Choueiri, MD, Dana-Farber Cancer Institute; Michael R. Harrison, MD, Duke Cancer Institute; David I. Quinn, MBBS, PhD, USC Norris Cancer Hospital
Published: Wednesday, Mar 29, 2017



Transcript:

Robert A. Figlin, MD:
Michael, give us a sense of how you’re approaching frontline therapy. Do you see patients who come to Duke who you think are undertreated and who maybe have not gotten their optimal therapeutic opportunity with a VEGF TKI? Do you ever go back to some of the things that they’ve received before because you thought that they didn’t get a fair dosing schedule and appropriate management of their toxicity? How are you approaching patients in the frontline setting?

Michael R. Harrison, MD: That’s a great point. I think in terms of patients that are referred from the community, sometimes it can be very frustrating if you see patients that, like Toni was saying, are treated willy-nilly through several different lines. You’re looking back through the notes, looking back through the radiology reports and wondering, did they really progress or were they really intolerant of these medicines with optimal supportive care? So, you’re right, a lot of times I try to understand what therapies they’ve been through and sometimes end up putting them back on the therapy that they’ve already been on. I’ve had some good successes with that. Again, it takes a lot of counseling of the patient, really telling them what side effects to expect, and coaching them through that. Like Eric said, basically letting them know that we’re going to get the best benefit if we can achieve the highest dose intensity. It’s a partnership; working with our advanced practice providers and our nurses to give them that approach of great supportive care.

Robert A. Figlin, MD: David, we’ve gotten a better understanding of the frontline approach. One of the things that we’ve struggled a bit with—and I think Toni mentioned—clearly is when we think about doing trials, we use very strict criteria for what we call “progression.” They have to meet RECIST criteria, they have to have a certain dimension. Those dimensions take them off study. And what we learn in the clinic is that there are many patients who very well may have RECIST progression, but clinically are doing quite well. One of the questions that comes up for you and then Eric is, what constitutes clinical progression? How do we help our colleagues in the clinics around the country decide how to evaluate imaging, especially when we see many imaging evaluations in their reports where very small amounts of tumor change are constituted tumor growth on a radiology report? But when we see the patient, they continue to tolerate what we do well and seem to be benefitting. So, how do you navigate that?

David I. Quinn, MBBS, PhD: I think before you look at the scan, you need to look at the patient. And if the patient is tolerating therapy well, that’s an important piece of information. Then, you need to actually look at the scan. Many times we’ve had patients that have come in and they’ve been switched off their first-line VEGF TKI, and there have been a couple of percentage points that change in a disease that was already there. The radiologist has said this is progression in the report, but no one has actually looked at it and said, “Well, yes, this is 20% growth,” which is what we use in RECIST. Even if a patient gets to 20% growth via RECIST, sometimes I’ll say, “Look, you’re doing well. If I switch you to another therapy, you may not tolerate it as well and have slow growth. You don’t have any new lesions that are in critical areas, why don’t we just do another scan in 8 to 12 weeks to see where we are?”. We’re talking about a disease that intrinsically also lights up on scan, and if you examine patients when we’re doing these intermittent schedules of different drugs, most particularly sunitinib, and they have palpable nodes, they go up and down if you see them a week apart. So, I think that we need to be aware that there’s an oscillation in the disease that should not be confused with progression. At the end of the day, we need to integrate the imaging into our clinical decision making.

And most patients, if you want to leave them on for an extra scan, are fine, and I think I’m fine with that. What can happen in the community where these are very compressed practices, the report is read sometimes now by the patient before it gets to the physician, and the patient says, “The radiologist says I have progression.” They’ve already researched the next line of therapy. We have the opportunity. In our practices, we’re usually very well supported. We have advanced nurse practitioners and PAs who help us and will say, “Well, I was looking at this and the report says progression, but it’s not a very big change. Mr or Mrs Smith are well, I’m thinking we should leave the patient on.” And usually, that’s the right decision. A community practice oncologist who has their 3 patients/year, who gets a report, is often pushed to move by a very small inflection in disease that may be part of a natural variation.

Robert A. Figlin, MD: So, Eric, there’s a phenomenon taking place in our clinics and across the country using either next-generation sequencing, circulating tumor cells, or some other noninvasive biomarker often obtained in the blood. Do we have any insight into whether or not we’re going to be able to use that to identify how and when people are progressing?

Eric Jonasch, MD: In 2017, the answer is no, but is it what we have to move towards? Absolutely. We have an increasingly large number of drugs. We do not have enough patients or time to do 2-drug combinations of 50 drugs to be able to actually determine whether they’re good for renal cell carcinoma in general or for a patient in specific. So, we have to develop biomarkers, and these biomarkers could be imaging-based. The holy grail would be can you actually image a tumor and look at the ratio of T cells to tumor cells? And not only that, are the T cells healthy or not, for example? We don’t have that, but this is the moonshot idea that we should be working towards from an imaging perspective. From a circulating microenvironment perspective, clearly the tumor is shedding DNA, it’s shedding cytokines, chemokines, and a variety of other things that are giving us an idea of what that organ, that we call a cancer, is doing. And that’s the organ made up of the cancer cells and the various immune cells.

Monty Pal has an abstract at ASCO GU this year looking at a circulating tumor DNA using the Guardant platform. This is a platform that looks at mutational analysis of 71 genes, asking the question of, a) are they there and b) have they changed? And this study demonstrated a couple of interesting things. One is that p53 mutations, which is not something we usually ascribe as being a common mutation in renal cell carcinoma, a) was at a relatively high rate, higher than we would expect looking at TCGA and other things, and b) at the time of progression, went up. VHL, NF1, several other things were not changed as much. Now the downside of Guardant is that it does not have some of the most important via renal cell carcinoma genes. It does not have BAP1, PBRM1, SETD2. Therefore, it’s an inadequate platform for renal cell carcinoma as it stands. We need to develop customized panels like this. What will it mean from a therapy perspective? Can we actually drug a target p53 mutation at this point in time? No, but I think it’s things like this, as well as circulating cytokines and angiogenesis factors that if we do our work and we can link that back to real defined tumor biology, that’s going to make a big difference.

Transcript Edited for Clarity

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Transcript:

Robert A. Figlin, MD:
Michael, give us a sense of how you’re approaching frontline therapy. Do you see patients who come to Duke who you think are undertreated and who maybe have not gotten their optimal therapeutic opportunity with a VEGF TKI? Do you ever go back to some of the things that they’ve received before because you thought that they didn’t get a fair dosing schedule and appropriate management of their toxicity? How are you approaching patients in the frontline setting?

Michael R. Harrison, MD: That’s a great point. I think in terms of patients that are referred from the community, sometimes it can be very frustrating if you see patients that, like Toni was saying, are treated willy-nilly through several different lines. You’re looking back through the notes, looking back through the radiology reports and wondering, did they really progress or were they really intolerant of these medicines with optimal supportive care? So, you’re right, a lot of times I try to understand what therapies they’ve been through and sometimes end up putting them back on the therapy that they’ve already been on. I’ve had some good successes with that. Again, it takes a lot of counseling of the patient, really telling them what side effects to expect, and coaching them through that. Like Eric said, basically letting them know that we’re going to get the best benefit if we can achieve the highest dose intensity. It’s a partnership; working with our advanced practice providers and our nurses to give them that approach of great supportive care.

Robert A. Figlin, MD: David, we’ve gotten a better understanding of the frontline approach. One of the things that we’ve struggled a bit with—and I think Toni mentioned—clearly is when we think about doing trials, we use very strict criteria for what we call “progression.” They have to meet RECIST criteria, they have to have a certain dimension. Those dimensions take them off study. And what we learn in the clinic is that there are many patients who very well may have RECIST progression, but clinically are doing quite well. One of the questions that comes up for you and then Eric is, what constitutes clinical progression? How do we help our colleagues in the clinics around the country decide how to evaluate imaging, especially when we see many imaging evaluations in their reports where very small amounts of tumor change are constituted tumor growth on a radiology report? But when we see the patient, they continue to tolerate what we do well and seem to be benefitting. So, how do you navigate that?

David I. Quinn, MBBS, PhD: I think before you look at the scan, you need to look at the patient. And if the patient is tolerating therapy well, that’s an important piece of information. Then, you need to actually look at the scan. Many times we’ve had patients that have come in and they’ve been switched off their first-line VEGF TKI, and there have been a couple of percentage points that change in a disease that was already there. The radiologist has said this is progression in the report, but no one has actually looked at it and said, “Well, yes, this is 20% growth,” which is what we use in RECIST. Even if a patient gets to 20% growth via RECIST, sometimes I’ll say, “Look, you’re doing well. If I switch you to another therapy, you may not tolerate it as well and have slow growth. You don’t have any new lesions that are in critical areas, why don’t we just do another scan in 8 to 12 weeks to see where we are?”. We’re talking about a disease that intrinsically also lights up on scan, and if you examine patients when we’re doing these intermittent schedules of different drugs, most particularly sunitinib, and they have palpable nodes, they go up and down if you see them a week apart. So, I think that we need to be aware that there’s an oscillation in the disease that should not be confused with progression. At the end of the day, we need to integrate the imaging into our clinical decision making.

And most patients, if you want to leave them on for an extra scan, are fine, and I think I’m fine with that. What can happen in the community where these are very compressed practices, the report is read sometimes now by the patient before it gets to the physician, and the patient says, “The radiologist says I have progression.” They’ve already researched the next line of therapy. We have the opportunity. In our practices, we’re usually very well supported. We have advanced nurse practitioners and PAs who help us and will say, “Well, I was looking at this and the report says progression, but it’s not a very big change. Mr or Mrs Smith are well, I’m thinking we should leave the patient on.” And usually, that’s the right decision. A community practice oncologist who has their 3 patients/year, who gets a report, is often pushed to move by a very small inflection in disease that may be part of a natural variation.

Robert A. Figlin, MD: So, Eric, there’s a phenomenon taking place in our clinics and across the country using either next-generation sequencing, circulating tumor cells, or some other noninvasive biomarker often obtained in the blood. Do we have any insight into whether or not we’re going to be able to use that to identify how and when people are progressing?

Eric Jonasch, MD: In 2017, the answer is no, but is it what we have to move towards? Absolutely. We have an increasingly large number of drugs. We do not have enough patients or time to do 2-drug combinations of 50 drugs to be able to actually determine whether they’re good for renal cell carcinoma in general or for a patient in specific. So, we have to develop biomarkers, and these biomarkers could be imaging-based. The holy grail would be can you actually image a tumor and look at the ratio of T cells to tumor cells? And not only that, are the T cells healthy or not, for example? We don’t have that, but this is the moonshot idea that we should be working towards from an imaging perspective. From a circulating microenvironment perspective, clearly the tumor is shedding DNA, it’s shedding cytokines, chemokines, and a variety of other things that are giving us an idea of what that organ, that we call a cancer, is doing. And that’s the organ made up of the cancer cells and the various immune cells.

Monty Pal has an abstract at ASCO GU this year looking at a circulating tumor DNA using the Guardant platform. This is a platform that looks at mutational analysis of 71 genes, asking the question of, a) are they there and b) have they changed? And this study demonstrated a couple of interesting things. One is that p53 mutations, which is not something we usually ascribe as being a common mutation in renal cell carcinoma, a) was at a relatively high rate, higher than we would expect looking at TCGA and other things, and b) at the time of progression, went up. VHL, NF1, several other things were not changed as much. Now the downside of Guardant is that it does not have some of the most important via renal cell carcinoma genes. It does not have BAP1, PBRM1, SETD2. Therefore, it’s an inadequate platform for renal cell carcinoma as it stands. We need to develop customized panels like this. What will it mean from a therapy perspective? Can we actually drug a target p53 mutation at this point in time? No, but I think it’s things like this, as well as circulating cytokines and angiogenesis factors that if we do our work and we can link that back to real defined tumor biology, that’s going to make a big difference.

Transcript Edited for Clarity
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