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Metastatic RCC: Selecting Therapy at Recurrence

Panelists: Daniel George, MD, Duke Cancer Institute; Neeraj Agarwal, MD, Huntsman Cancer Institute; Robert Alter, MD, Hackensack University Medical Center; Bradley McGregor, MD, Dana-Farber Cancer Institute; Nicholas J. Vogelzang, MD, FASCO, FACP, Comprehensive Cancer Centers of Nevada
Published: Wednesday, Apr 25, 2018



Transcript: 

Daniel George, MD: Now we’re getting into the second-line space. Bob, when you’re looking at a patient who has progressed, what are the factors that you’re going through in your mind to judge what their prognosis is and what you’re going to give them for the next treatment?

Robert Alter, MD: Historically, we’ve always used a limited number of classes of drugs. We had TKIs and we had mTORs. I think when you deal with community oncologists where the bulk of their practices is colon cancer, lung cancer, or breast cancer, they’ve always been told to change mechanisms, so we used that: It was a TKI, mTOR, TKI, then mTOR, which is how we lived until 2012. Tom Hutson tells me stories from when he was back in Cleveland Clinic when they only had 2 drugs. You got sunitinib and you got sorafenib, and when you progressed you went back on sunitinib or you went back on sorafenib. They still had patients who responded. I think that was really the foundation of a TKI followed by a TKI.

The first thing I do when I have my patients is look at the response that they had, obviously, tolerability, how they handled the therapy, and the duration of the therapy that they received. I still believe, based upon the AXIS clinical trial and upon the METEOR clinical trial, that you can actually have a TKI followed by a TKI with significant success. If you have a patient who had good tolerability to the therapy, if you had significant success—I would consider that 6 to 9 months of no progression—I may still consider utilizing a TKI. Now we have nivolumab, and I think we have to respect the benefit that it can offer. When it comes to how we sequence next, I always like to look at patients’ functional quality of life. Obviously, you have to make sure that they are not only tolerating the medicines well but also if they have aged in front of us. I still think the duration of response is important. I don’t look as much for the partial response. I think that if you even looked at the temsirolimus data, you can have a partial response and then progression shortly thereafter. To me, that’s not a durable therapy. To me, the duration is much more important than the initial response itself.

I think the tumor burden is going to be important. Whether they’re progressing or what organs that they’re progressing in—I think you feel this panic if they’re progressing in an organ or if they’re getting very symptomatic—may make us react in a certain way. I use the example of Lenvima (lenvatinib)/everolimus, where the data were intriguing initially. I had a patient of mine who had a very good response to a TKI and then rapidly progressed, so I put him on that combination, and he had a remarkable response within a week. All his symptoms resolved and the tumor shrank. At the same time, too, I’ve had that response with nivolumab.

Again, sometimes you don’t know where you’re going, but you really have to recognize that it’s the patient, the tumor burden, and the duration of response. The generation has skipped already, but they still believe that IV therapy is the way to go: Pills don’t work; intravenous does work. They’ve taken a pill. They now have had negative reinforcement because their pill has not worked, and they feel compelled to go to an IV form. Prior to nivolumab, we had temsirolimus, which I don’t think was our best safety net. But now that we do have an IV therapy, patients feel a little bit more of a sense that they’re getting “real” therapy compared with a pill.

Nicholas J. Vogelzang, MD, FASCO, FACP: The television tells them to take that.

Robert Alter, MD: Yes, but not for that indication—for a different indication. I think it’s not just the tumor burden. It’s the symptoms, where the disease is, and how rapidly the disease is progressing. As we said before, it’s a multitude of everything that you have to piece together, and this is really the art of how we take care of our patients. It’s not as simple as you progress, and therefore your next therapy is a given sequence.

Nicholas J. Vogelzang, MD, FASCO, FACP: The issue is if you progressed on a TKI at first line, I still think that cabozantinib and nivolumab are equally appropriate but for separate subsets of patients. Monty Pal and I had a meeting for ASCO review, and I said that cabozantinib is like my Ghostbuster drug. Who do you go to? If you’ve got a really bad problem, I’m going to use cabozantinib right away. If I got a little bit more of a slow tempo, I’m going to use nivolumab. And then if they progress right through nivolumab—which, believe it or not, does happen—then I’ll have cabozantinib as a backup or I’ll use lenvatinib/everolimus. Those are more or less the issues. Now, from my perspective, I am eager to ask you guys this. If you’ve used cabozantinib up front, what do you do after an immune therapy? What do you do after Opdivo (nivolumab)?

Neeraj Agarwal, MD: After cabozantinib?

Nicholas J. Vogelzang, MD, FASCO, FACP: Yes. You used cabozantinib up front, and now you’ve used nivolumab second, I would imagine. What are you going to do?

Neeraj Agarwal, MD: I think a third-line option is still not very clear, even with ipilimumab/nivolumab coming on board. Let’s say the combination gets approved and you give it first line followed by cabozantinib second line, what do you do in the third line? I think the question about the best third-line option is completely unanswered right now. Nobody knows, in my view. If I give cabozantinib first, I will use nivolumab second, but I don’t really know what a third-line option is, because there has not been a serious, pure third-line trial that we have seen. In absence of high-level data, I think I will use axitinib or lenvatinib with everolimus.

Robert Alter, MD: I do like that lenvatinib/everolimus does offer a new mechanism because you’re now giving an mTOR in there, plus you already have the security of giving a TKI with that. Again, I’ve used it in a handful of patients—I could literally count them on 1 hand—but I’ve seen some patients have dramatic responses. But it is toxic, and that’s the problem. I’ve used lenvatinib when it came to thyroid cancer, as well. The toxicity to that initial dose requires reduction as we’ve had with Cometriq (cabozantinib), which was for thyroid cancer. But I think we’re learning that these TKIs are toxic, especially if you’re getting them third and fourth line. They are going to have a dose adjustment—there has to be one—yet they still give significant benefit to our patients. I think we should definitely believe that, as you say, moving forward is going to be interesting with axitinib working so well with I-O combination. We’re going to eventually use that down the line, too. But I think we can’t forget where we came from. I’m forgetting Nexavar (sorafenib). I’ve got that.

Nicholas J. Vogelzang, MD, FASCO, FACP: Interferon.

Robert Alter, MD: I totally forgot about that.

Neeraj Agarwal, MD: I mentioned axitinib or the lenvatinib/everolimus combination because if my second line is nivolumab, I would tend to go with axitinib in the third line. If my second line is cabozantinib, I don’t think axitinib is going to do a great job after a patient is progressing on cabozantinib. I think for those patients, the combination of lenvatinib/everolimus would be my favorite combination.

Robert Alter, MD: You could always think about high-dose IL-2 somewhere down the line.

Neeraj Agarwal, MD: First line.

Robert Alter, MD: There are data on using it second and third line in the right patient population. It’s going to be a small volume of that. Again, there were data on using it second and third line in patients with slow-growing disease—excellent performance status patients—but let’s not forget that high-dose IL-2 does offer a benefit even in first-line therapy. We talked about this.

Neeraj Agarwal, MD: Absolutely. No other therapy has such a long track record of complete durable response as IL-2.

Robert Alter, MD: Right. Back to our philosophy up front.

Neeraj Agarwal, MD: Still, we are one of the few practices in the country that continues to use high-dose IL-2.

Robert Alter, MD: It does offer our patients a therapy that may postpone the inevitability of chronic therapy. If you do have a patient who has even a partial response, it may be quite durable, and it may postpone the need to go on a continuous therapy for years.

Transcript Edited for Clarity 

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Transcript: 

Daniel George, MD: Now we’re getting into the second-line space. Bob, when you’re looking at a patient who has progressed, what are the factors that you’re going through in your mind to judge what their prognosis is and what you’re going to give them for the next treatment?

Robert Alter, MD: Historically, we’ve always used a limited number of classes of drugs. We had TKIs and we had mTORs. I think when you deal with community oncologists where the bulk of their practices is colon cancer, lung cancer, or breast cancer, they’ve always been told to change mechanisms, so we used that: It was a TKI, mTOR, TKI, then mTOR, which is how we lived until 2012. Tom Hutson tells me stories from when he was back in Cleveland Clinic when they only had 2 drugs. You got sunitinib and you got sorafenib, and when you progressed you went back on sunitinib or you went back on sorafenib. They still had patients who responded. I think that was really the foundation of a TKI followed by a TKI.

The first thing I do when I have my patients is look at the response that they had, obviously, tolerability, how they handled the therapy, and the duration of the therapy that they received. I still believe, based upon the AXIS clinical trial and upon the METEOR clinical trial, that you can actually have a TKI followed by a TKI with significant success. If you have a patient who had good tolerability to the therapy, if you had significant success—I would consider that 6 to 9 months of no progression—I may still consider utilizing a TKI. Now we have nivolumab, and I think we have to respect the benefit that it can offer. When it comes to how we sequence next, I always like to look at patients’ functional quality of life. Obviously, you have to make sure that they are not only tolerating the medicines well but also if they have aged in front of us. I still think the duration of response is important. I don’t look as much for the partial response. I think that if you even looked at the temsirolimus data, you can have a partial response and then progression shortly thereafter. To me, that’s not a durable therapy. To me, the duration is much more important than the initial response itself.

I think the tumor burden is going to be important. Whether they’re progressing or what organs that they’re progressing in—I think you feel this panic if they’re progressing in an organ or if they’re getting very symptomatic—may make us react in a certain way. I use the example of Lenvima (lenvatinib)/everolimus, where the data were intriguing initially. I had a patient of mine who had a very good response to a TKI and then rapidly progressed, so I put him on that combination, and he had a remarkable response within a week. All his symptoms resolved and the tumor shrank. At the same time, too, I’ve had that response with nivolumab.

Again, sometimes you don’t know where you’re going, but you really have to recognize that it’s the patient, the tumor burden, and the duration of response. The generation has skipped already, but they still believe that IV therapy is the way to go: Pills don’t work; intravenous does work. They’ve taken a pill. They now have had negative reinforcement because their pill has not worked, and they feel compelled to go to an IV form. Prior to nivolumab, we had temsirolimus, which I don’t think was our best safety net. But now that we do have an IV therapy, patients feel a little bit more of a sense that they’re getting “real” therapy compared with a pill.

Nicholas J. Vogelzang, MD, FASCO, FACP: The television tells them to take that.

Robert Alter, MD: Yes, but not for that indication—for a different indication. I think it’s not just the tumor burden. It’s the symptoms, where the disease is, and how rapidly the disease is progressing. As we said before, it’s a multitude of everything that you have to piece together, and this is really the art of how we take care of our patients. It’s not as simple as you progress, and therefore your next therapy is a given sequence.

Nicholas J. Vogelzang, MD, FASCO, FACP: The issue is if you progressed on a TKI at first line, I still think that cabozantinib and nivolumab are equally appropriate but for separate subsets of patients. Monty Pal and I had a meeting for ASCO review, and I said that cabozantinib is like my Ghostbuster drug. Who do you go to? If you’ve got a really bad problem, I’m going to use cabozantinib right away. If I got a little bit more of a slow tempo, I’m going to use nivolumab. And then if they progress right through nivolumab—which, believe it or not, does happen—then I’ll have cabozantinib as a backup or I’ll use lenvatinib/everolimus. Those are more or less the issues. Now, from my perspective, I am eager to ask you guys this. If you’ve used cabozantinib up front, what do you do after an immune therapy? What do you do after Opdivo (nivolumab)?

Neeraj Agarwal, MD: After cabozantinib?

Nicholas J. Vogelzang, MD, FASCO, FACP: Yes. You used cabozantinib up front, and now you’ve used nivolumab second, I would imagine. What are you going to do?

Neeraj Agarwal, MD: I think a third-line option is still not very clear, even with ipilimumab/nivolumab coming on board. Let’s say the combination gets approved and you give it first line followed by cabozantinib second line, what do you do in the third line? I think the question about the best third-line option is completely unanswered right now. Nobody knows, in my view. If I give cabozantinib first, I will use nivolumab second, but I don’t really know what a third-line option is, because there has not been a serious, pure third-line trial that we have seen. In absence of high-level data, I think I will use axitinib or lenvatinib with everolimus.

Robert Alter, MD: I do like that lenvatinib/everolimus does offer a new mechanism because you’re now giving an mTOR in there, plus you already have the security of giving a TKI with that. Again, I’ve used it in a handful of patients—I could literally count them on 1 hand—but I’ve seen some patients have dramatic responses. But it is toxic, and that’s the problem. I’ve used lenvatinib when it came to thyroid cancer, as well. The toxicity to that initial dose requires reduction as we’ve had with Cometriq (cabozantinib), which was for thyroid cancer. But I think we’re learning that these TKIs are toxic, especially if you’re getting them third and fourth line. They are going to have a dose adjustment—there has to be one—yet they still give significant benefit to our patients. I think we should definitely believe that, as you say, moving forward is going to be interesting with axitinib working so well with I-O combination. We’re going to eventually use that down the line, too. But I think we can’t forget where we came from. I’m forgetting Nexavar (sorafenib). I’ve got that.

Nicholas J. Vogelzang, MD, FASCO, FACP: Interferon.

Robert Alter, MD: I totally forgot about that.

Neeraj Agarwal, MD: I mentioned axitinib or the lenvatinib/everolimus combination because if my second line is nivolumab, I would tend to go with axitinib in the third line. If my second line is cabozantinib, I don’t think axitinib is going to do a great job after a patient is progressing on cabozantinib. I think for those patients, the combination of lenvatinib/everolimus would be my favorite combination.

Robert Alter, MD: You could always think about high-dose IL-2 somewhere down the line.

Neeraj Agarwal, MD: First line.

Robert Alter, MD: There are data on using it second and third line in the right patient population. It’s going to be a small volume of that. Again, there were data on using it second and third line in patients with slow-growing disease—excellent performance status patients—but let’s not forget that high-dose IL-2 does offer a benefit even in first-line therapy. We talked about this.

Neeraj Agarwal, MD: Absolutely. No other therapy has such a long track record of complete durable response as IL-2.

Robert Alter, MD: Right. Back to our philosophy up front.

Neeraj Agarwal, MD: Still, we are one of the few practices in the country that continues to use high-dose IL-2.

Robert Alter, MD: It does offer our patients a therapy that may postpone the inevitability of chronic therapy. If you do have a patient who has even a partial response, it may be quite durable, and it may postpone the need to go on a continuous therapy for years.

Transcript Edited for Clarity 
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