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Sequencing Approaches in Metastatic Renal Cell Carcinoma

Panelists: Daniel George, MD, Duke Cancer Institute ; Robert J. Amato, MD, Memorial Hermann Cancer Center; Toni Choueiri, MD, Dana-Farber Cancer Institute; Richard W. Joseph, MD, Mayo Clinic; Walter Stadler, MD, University of Chicago
Published: Wednesday, Aug 15, 2018



Transcript: 

Daniel George, MD: We’re going to have different frontline therapies Walt. How are you going to select your second-line therapy? Does the frontline therapy influence that? Does the response or tolerance to the frontline therapy influence that? It used to be we’d go from VEGF-targeted therapy to VEGF-targeted therapy. Then we got I-O therapies. Now, it seems like more confusion and options. Can you give us some clarity on your treatment selection?

Walter Stadler, MD: The most clarifying thing is that, this is good for patients; we have options and we have choices. I think that the pharmacology that is most underrecognized is, a TKI after an I-O monoclonal antibody, is different than in some other kind of second-line therapy. It simply has to do with the fact that these antibodies have very long half-lives. Remember that we can give them every month successfully, and the half-life of these drugs means that the antibody is sticking around in the serum at reasonable levels, probably above the level where you need efficacy, up to 4 months after you’ve given the therapy.

There are studies that have suggested that the level of the antibody on circulating lymphocytes, is longer than anyone’s measured, which is at 6 months. We have no idea what’s going on in the tumor microenvironment. One of things that I’m paying attention to is whether the VEGF inhibitor after an I-O inhibitor may really be combination therapy. I think that where this comes up important clinically, is that we know certain combinations—for example, pazopanib with some of the I-O inhibitors—have not played well together in terms of toxicity, and that leads me to use things like axitinib or cabozantinib in the post-immunotherapy setting, because I know those combinations are safe.

Daniel George, MD: Toni, what are your thoughts on this?

Toni Choueiri, MD: What we know is that the TKI can have activity pre–I-O and post–I-O. We have reported on that extensively. Interestingly, they have a better activity, and if there’s better activity, it’s because the immune milieu, or tumor microenvironment is prepped, or because Walt is saying that there is still some antibody there acting up. One of the data sets we have that is interesting, a very small number of patients, that were exposed to prior I-O versus not; the progression-free hazard ratio was really much better in patient who had prior I-O. I think that begs the question of sequential therapies; starting with I-O, following it with another I-O, or I-O followed by VEGF, or the reverse sequence. I have a small problem in that; from a safety perspective it’s excellent. Let’s not forget the attrition rate. For whatever reason, a patient who doesn’t want anything anymore. And let’s not forget that in medical oncology we’re able to cure metastatic disease usually—forget about precision medicine now for a while­—with combination chemotherapy. Sometimes when you give 4 drugs, 3 drugs, it’s better than 2; we know that in testicular cancer.

So, are we missing an opportunity to make a CR or deep response and perhaps cure? I don’t like to use that word; better with 3 to 4 drugs, at the price of toxicity where if you start by 1, the patient has side effects or just doesn’t want any more treatment, and you lose that opportunity. There will be room for sequential trials, and there will be room for the most aggressive combination trials.

Robert J. Amato, DO: It’s essential, and we’re all at academic institutions that have the existing technology, that we learn how to work with our scientists who we need to teach the clinic, and what are our clinical problems, and study these cancers so they can help us understand how tumors are acquiring resistance; which I view differently than adapting. Acquired resistance, to me, is you give drug I-O and within 4 months the tumor’s already taken off. They didn’t adapt, they’ve just resisted. The same thing occurs with TKs or mTORs. Why is that and what do we need to learn from that? We have to learn from the good patients. How many of us in this room biopsy the good patient response to understand why they were good?

Daniel George, MD: Hard to justify.

Robert J. Amato, DO: Right. I might call the thoracic surgeon and say, “Hey, can you take this nodule out, I want to learn why it’s better.” That’s the reason; he knows when he sees the patient because the patient’s healthy. The patient says, “Why do you want this done?” “Because I want to understand why this person did well and why his 10 counterparts did not.”

Daniel George, MD: Rich, in terms of picking a TKI after I-O therapy, what are your thoughts on it? Walt brought up some issues around subsequent toxicity risks and what not. How do you decide which TKI to do next?

Richard W. Joseph, MD: That’s another great question that I struggle with honestly. Without the randomized data to help guide us, of course, you’re left trying to choose from the plethora of TKIs that are out there, and then if you even think about pazopanib is in the frontline, is it even approved in the second? So, there are all these other things; you have second-line approvals. It’s a tough decision but I think right now; based on METEOR, that was a second-line trial that had survival; that’s becoming my first TKI of choice—let’s say after if I do I-O in the frontline. But I can’t say that’s a really scientific-based answer.

Daniel George, MD: I think it’s an area we need more data for sure.

Transcript Edited for Clarity 

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Transcript: 

Daniel George, MD: We’re going to have different frontline therapies Walt. How are you going to select your second-line therapy? Does the frontline therapy influence that? Does the response or tolerance to the frontline therapy influence that? It used to be we’d go from VEGF-targeted therapy to VEGF-targeted therapy. Then we got I-O therapies. Now, it seems like more confusion and options. Can you give us some clarity on your treatment selection?

Walter Stadler, MD: The most clarifying thing is that, this is good for patients; we have options and we have choices. I think that the pharmacology that is most underrecognized is, a TKI after an I-O monoclonal antibody, is different than in some other kind of second-line therapy. It simply has to do with the fact that these antibodies have very long half-lives. Remember that we can give them every month successfully, and the half-life of these drugs means that the antibody is sticking around in the serum at reasonable levels, probably above the level where you need efficacy, up to 4 months after you’ve given the therapy.

There are studies that have suggested that the level of the antibody on circulating lymphocytes, is longer than anyone’s measured, which is at 6 months. We have no idea what’s going on in the tumor microenvironment. One of things that I’m paying attention to is whether the VEGF inhibitor after an I-O inhibitor may really be combination therapy. I think that where this comes up important clinically, is that we know certain combinations—for example, pazopanib with some of the I-O inhibitors—have not played well together in terms of toxicity, and that leads me to use things like axitinib or cabozantinib in the post-immunotherapy setting, because I know those combinations are safe.

Daniel George, MD: Toni, what are your thoughts on this?

Toni Choueiri, MD: What we know is that the TKI can have activity pre–I-O and post–I-O. We have reported on that extensively. Interestingly, they have a better activity, and if there’s better activity, it’s because the immune milieu, or tumor microenvironment is prepped, or because Walt is saying that there is still some antibody there acting up. One of the data sets we have that is interesting, a very small number of patients, that were exposed to prior I-O versus not; the progression-free hazard ratio was really much better in patient who had prior I-O. I think that begs the question of sequential therapies; starting with I-O, following it with another I-O, or I-O followed by VEGF, or the reverse sequence. I have a small problem in that; from a safety perspective it’s excellent. Let’s not forget the attrition rate. For whatever reason, a patient who doesn’t want anything anymore. And let’s not forget that in medical oncology we’re able to cure metastatic disease usually—forget about precision medicine now for a while­—with combination chemotherapy. Sometimes when you give 4 drugs, 3 drugs, it’s better than 2; we know that in testicular cancer.

So, are we missing an opportunity to make a CR or deep response and perhaps cure? I don’t like to use that word; better with 3 to 4 drugs, at the price of toxicity where if you start by 1, the patient has side effects or just doesn’t want any more treatment, and you lose that opportunity. There will be room for sequential trials, and there will be room for the most aggressive combination trials.

Robert J. Amato, DO: It’s essential, and we’re all at academic institutions that have the existing technology, that we learn how to work with our scientists who we need to teach the clinic, and what are our clinical problems, and study these cancers so they can help us understand how tumors are acquiring resistance; which I view differently than adapting. Acquired resistance, to me, is you give drug I-O and within 4 months the tumor’s already taken off. They didn’t adapt, they’ve just resisted. The same thing occurs with TKs or mTORs. Why is that and what do we need to learn from that? We have to learn from the good patients. How many of us in this room biopsy the good patient response to understand why they were good?

Daniel George, MD: Hard to justify.

Robert J. Amato, DO: Right. I might call the thoracic surgeon and say, “Hey, can you take this nodule out, I want to learn why it’s better.” That’s the reason; he knows when he sees the patient because the patient’s healthy. The patient says, “Why do you want this done?” “Because I want to understand why this person did well and why his 10 counterparts did not.”

Daniel George, MD: Rich, in terms of picking a TKI after I-O therapy, what are your thoughts on it? Walt brought up some issues around subsequent toxicity risks and what not. How do you decide which TKI to do next?

Richard W. Joseph, MD: That’s another great question that I struggle with honestly. Without the randomized data to help guide us, of course, you’re left trying to choose from the plethora of TKIs that are out there, and then if you even think about pazopanib is in the frontline, is it even approved in the second? So, there are all these other things; you have second-line approvals. It’s a tough decision but I think right now; based on METEOR, that was a second-line trial that had survival; that’s becoming my first TKI of choice—let’s say after if I do I-O in the frontline. But I can’t say that’s a really scientific-based answer.

Daniel George, MD: I think it’s an area we need more data for sure.

Transcript Edited for Clarity 
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