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Selecting Second-Line Therapy for Metastatic RCC

Insights From: Brian Rini,MD, Cleveland Clinic Main Campus; David F. McDermott, MD, Harvard Cancer Center
Published: Wednesday, Dec 05, 2018



Transcript: 

Brian Rini, MD: The usual trigger to switch therapy is disease progression. Sometimes it’s obvious, and other times it’s subtler. I don’t know if immune therapy is necessarily different than targeted therapy. With targeted therapy, sometimes patients—especially patients who respond—are at their nadir of tumor burden for a while. Then they start to slowly increase, and it’s a new little lung nodule here or it’s 2 mm there. From scan to scan, it’s not much different; but over time, they’re clearly progressing. That’s a pretty common pattern we see. Sometimes, those are the toughest decisions: when to pull them off a therapy that is probably still helping them and switch them to a therapy that we don’t know is going to work or not. I think it’s an equation of perceived benefit, how much benefit is left, and also risk. If they’re not tolerating a drug very well, a TKI [tyrosine kinase inhibitor] will tend to beat people up over months and years. That makes it easier to switch to something else.

The treatment options for relapsed or refractory RCC obviously depend on what patients are refractory to. If people are getting an immune combination upfront, ipilimumab/nivolumab, then we would generally turn to a VEGF TKI, in part because that’s what’s left. But they’re very active in that setting. We published some data at ASCO [American Society of Clinical Oncology] with axitinib, which we have a lot of experience in with a prospective trial and is really quite active after immune-based therapy. If patients have a VEGF therapy upfront, either monotherapy or in combination, they’re also going to go on to a VEGF therapy.

Right now, even though we’re adding agents and shuffling how we approach patients a little bit, there’s still work to do in the refractory setting. We’re going to burn a lot of bridges upfront and we’re going to cure some patients, but there’s still going to be plenty of patients who get through that initial combination therapy and need more therapy. That is an area of investigation moving forward.

David F. McDermott, MD: It has gotten a little bit confusing because a lot of our second-line strategies have been moved up to the front line. In the very near future, we’ll have patients receiving combinations in the front line: for example, with PD-1 [programmed cell death protein 1] and CTLA-4 [cytotoxic T-lymphocyte–associated protein 4] therapy. In those patients who receive I-O/I-O [immuno-oncology] combinations, the answer of what to do second is pretty clear. Those patients have not seen a VEGF strategy. It’s probably more likely to work in those patients, and so we’re going to be applying single agents that we’ve traditionally used in the second-line like cabozantinib and axitinib. I think we’ll see positive effects of that sequence.

The other sequence is a little more difficult. When we move to VEGF/PD-1 strategies, which will be more in 2019, the answer to the question of what to do when patients fail both is that we don’t know. We’re going to need to do trials in that setting. I have some worry though that it may be harder to treat those patients with second-line therapy, in part because if the data hold up in actual clinical practice, which we expect it to do, the patients will be on VEGF for say 12 months, 18 months, or 24 months, much longer than they were in the prior sequence strategy. I’m not so sure that anti-VEGF strategies will work as well in a patient who has been exposed in the first-line setting to twice as much anti-VEGF therapy than we have been traditionally using. We’re going to need to do trials in that space. We’re going to need to answer that question. Right now, we don’t have a firm answer to that question.

Brian Rini, MD: I don’t really think so much about staying within or switching classes. I think that’s more marketing than it is science, to be honest. I make a decision at the time I’m seeing a patient. What do I think is best for this patient? What gives him the highest chance of cure, the best benefit/risk ratio, etcetera? When that benefit runs out, or the risk becomes more than the benefit, I switch and look at what’s available then. I don’t necessarily plot out how I’m going to use this mechanism and then that one and then another one. I’m not aware of data showing that’s useful, and it’s hard to do. It’s hard to do because I tend to make decisions one treatment at a time.

Transcsript Edited for Clarity 
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Transcript: 

Brian Rini, MD: The usual trigger to switch therapy is disease progression. Sometimes it’s obvious, and other times it’s subtler. I don’t know if immune therapy is necessarily different than targeted therapy. With targeted therapy, sometimes patients—especially patients who respond—are at their nadir of tumor burden for a while. Then they start to slowly increase, and it’s a new little lung nodule here or it’s 2 mm there. From scan to scan, it’s not much different; but over time, they’re clearly progressing. That’s a pretty common pattern we see. Sometimes, those are the toughest decisions: when to pull them off a therapy that is probably still helping them and switch them to a therapy that we don’t know is going to work or not. I think it’s an equation of perceived benefit, how much benefit is left, and also risk. If they’re not tolerating a drug very well, a TKI [tyrosine kinase inhibitor] will tend to beat people up over months and years. That makes it easier to switch to something else.

The treatment options for relapsed or refractory RCC obviously depend on what patients are refractory to. If people are getting an immune combination upfront, ipilimumab/nivolumab, then we would generally turn to a VEGF TKI, in part because that’s what’s left. But they’re very active in that setting. We published some data at ASCO [American Society of Clinical Oncology] with axitinib, which we have a lot of experience in with a prospective trial and is really quite active after immune-based therapy. If patients have a VEGF therapy upfront, either monotherapy or in combination, they’re also going to go on to a VEGF therapy.

Right now, even though we’re adding agents and shuffling how we approach patients a little bit, there’s still work to do in the refractory setting. We’re going to burn a lot of bridges upfront and we’re going to cure some patients, but there’s still going to be plenty of patients who get through that initial combination therapy and need more therapy. That is an area of investigation moving forward.

David F. McDermott, MD: It has gotten a little bit confusing because a lot of our second-line strategies have been moved up to the front line. In the very near future, we’ll have patients receiving combinations in the front line: for example, with PD-1 [programmed cell death protein 1] and CTLA-4 [cytotoxic T-lymphocyte–associated protein 4] therapy. In those patients who receive I-O/I-O [immuno-oncology] combinations, the answer of what to do second is pretty clear. Those patients have not seen a VEGF strategy. It’s probably more likely to work in those patients, and so we’re going to be applying single agents that we’ve traditionally used in the second-line like cabozantinib and axitinib. I think we’ll see positive effects of that sequence.

The other sequence is a little more difficult. When we move to VEGF/PD-1 strategies, which will be more in 2019, the answer to the question of what to do when patients fail both is that we don’t know. We’re going to need to do trials in that setting. I have some worry though that it may be harder to treat those patients with second-line therapy, in part because if the data hold up in actual clinical practice, which we expect it to do, the patients will be on VEGF for say 12 months, 18 months, or 24 months, much longer than they were in the prior sequence strategy. I’m not so sure that anti-VEGF strategies will work as well in a patient who has been exposed in the first-line setting to twice as much anti-VEGF therapy than we have been traditionally using. We’re going to need to do trials in that space. We’re going to need to answer that question. Right now, we don’t have a firm answer to that question.

Brian Rini, MD: I don’t really think so much about staying within or switching classes. I think that’s more marketing than it is science, to be honest. I make a decision at the time I’m seeing a patient. What do I think is best for this patient? What gives him the highest chance of cure, the best benefit/risk ratio, etcetera? When that benefit runs out, or the risk becomes more than the benefit, I switch and look at what’s available then. I don’t necessarily plot out how I’m going to use this mechanism and then that one and then another one. I’m not aware of data showing that’s useful, and it’s hard to do. It’s hard to do because I tend to make decisions one treatment at a time.

Transcsript Edited for Clarity 
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