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RCC: Establishing Particular Agents' Roles in Sequencing

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



Transcript:

David F. McDermott, MD: I think it can be said that for nivolumab, one of the exciting things about the dataset of the CheckMate 025 study is that the benefit accrues across many different subgroups. Regardless of patient age, regardless of sites of disease, and regardless of number of prior therapies, we see benefit.

One group that had a very good benefit in the CheckMate 025 study was the poor-risk group, where the hazard ratio is less than 0.5 for the benefit of nivolumab compared to everolimus. One of the very interesting things about immune checkpoint blockade in general is that we see some of our best responses in some of our worse behaving tumors, which is so contrary to everything we’ve seen before with chemotherapy or hormonal therapy. Some of the less aggressive tumors tend to respond most to those approaches.

There’s something about a poor-risk tumor where, at least in some cases, it probably generates an immune response at the time it’s diagnosed. It’s in those patients where the tumor has already been recognized by the immune system—the immune cells have gotten into the tumor and the tumor’s defending itself with PD-L1 [programmed cell death protein 1]—that these checkpoints can make a difference. That’s great for patients because in the past, our old therapies like VEGF TKIs [tyrosine kinase inhibitors] really underperformed in that group of patients, but less so with nivolumab.

The NIVOREN trial was a large French study. They pooled over 700 patients from their experience in France. What it essentially does is give us a real-world sense of what nivolumab would do outside the clinical trial setting. One of the things we get criticized a lot for is heavily selecting our patients for trials, and the question becomes in a less selected group, how would the drug perform? Would it be less efficacious, more toxic? Well, in this group of over 700 patients, that was not the case.

We saw the same list of adverse effects and the same frequency of severe adverse effects. It was no more toxic. They saw a very similar clinical activity as far as antitumor activity in that group as well. It gives us a sense that when we’re thinking of immune checkpoint blockade in the community, it’s pretty applicable in that space. I think that’s what has driven the uptake of immune checkpoint blockade across multiple tumors: it’s relatively easy to give. Most people feel better on it than our older treatments. That’s not to say it’s not tricky at times. The adverse effects can be a major challenge to manage, but single-agent PD-1 goes over well with both patient and clinician.

Brian Rini, MD: There are different TKIs in kidney cancer, different VEGF TKIs. I think our use of them probably depends a little more on how they were developed. I think when they were first developed, we thought they were all the same. That’s clearly not the case. There are toxicity differences and there are efficacy differences as well. Sunitinib and pazopanib were developed as frontline drugs. They tend to be used frontline or not at all. Sunitinib is I think a little more toxic, a little tougher to take. The COMPARZ trial showed them to be noninferior, although my bias is still that sunitinib is a little better drug. I tend to use pazopanib in older, frailer patients. Sunitinib is in the opposite group. We’re probably giving 60% or 70% sunitinib frontline and the rest pazopanib, when we give TKI monotherapy.

Sorafenib is not used much anymore, as it’s efficacy low, toxicity high. We use a lot of axitinib in the second-line setting after immune therapy now. It’s a nice drug in that it has a short half-life. It’s very titratable. With oral drugs, not everybody is going to respond to the dose or tolerate the same dose, so a lot of our TKIs are very clunky. You can’t really adjust dose terribly well. With axitinib, because it comes in 1-mg tablets and has a very short half-life, you can do that. It makes it a little more cumbersome to give, but I think at the end of the day patients get to the right exposure, the right dose, which leads to optimal outcomes.

Pazopanib is one of the newer TKIs. Its efficacy is largely demonstrated in the refractory setting, and that’s where I tend to use it. It can be a tougher drug toxicity-wise, especially at 60 mg, which I usually start people at. Lenvatinib is the latest comer, although it was approved in combination with everolimus. I think it’s a clearly active TKI. They’ve all taken these unique and totally different development paths, which have a lot to do with who owned the drug and what the setting was, etcetera. There are differences.

I think moving into the immunotherapy era, what’s different is that they’re not all combinable with immune therapy. Sunitinib and pazopanib are really not combinable for various reasons. They won’t be part of combination regimens, whereas axitinib is very combinable and has primarily been the combination partner. The way we look at them has shifted now that they’re combination partners and not standalone agents.

Transcript Edited for Clarity 
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Transcript:

David F. McDermott, MD: I think it can be said that for nivolumab, one of the exciting things about the dataset of the CheckMate 025 study is that the benefit accrues across many different subgroups. Regardless of patient age, regardless of sites of disease, and regardless of number of prior therapies, we see benefit.

One group that had a very good benefit in the CheckMate 025 study was the poor-risk group, where the hazard ratio is less than 0.5 for the benefit of nivolumab compared to everolimus. One of the very interesting things about immune checkpoint blockade in general is that we see some of our best responses in some of our worse behaving tumors, which is so contrary to everything we’ve seen before with chemotherapy or hormonal therapy. Some of the less aggressive tumors tend to respond most to those approaches.

There’s something about a poor-risk tumor where, at least in some cases, it probably generates an immune response at the time it’s diagnosed. It’s in those patients where the tumor has already been recognized by the immune system—the immune cells have gotten into the tumor and the tumor’s defending itself with PD-L1 [programmed cell death protein 1]—that these checkpoints can make a difference. That’s great for patients because in the past, our old therapies like VEGF TKIs [tyrosine kinase inhibitors] really underperformed in that group of patients, but less so with nivolumab.

The NIVOREN trial was a large French study. They pooled over 700 patients from their experience in France. What it essentially does is give us a real-world sense of what nivolumab would do outside the clinical trial setting. One of the things we get criticized a lot for is heavily selecting our patients for trials, and the question becomes in a less selected group, how would the drug perform? Would it be less efficacious, more toxic? Well, in this group of over 700 patients, that was not the case.

We saw the same list of adverse effects and the same frequency of severe adverse effects. It was no more toxic. They saw a very similar clinical activity as far as antitumor activity in that group as well. It gives us a sense that when we’re thinking of immune checkpoint blockade in the community, it’s pretty applicable in that space. I think that’s what has driven the uptake of immune checkpoint blockade across multiple tumors: it’s relatively easy to give. Most people feel better on it than our older treatments. That’s not to say it’s not tricky at times. The adverse effects can be a major challenge to manage, but single-agent PD-1 goes over well with both patient and clinician.

Brian Rini, MD: There are different TKIs in kidney cancer, different VEGF TKIs. I think our use of them probably depends a little more on how they were developed. I think when they were first developed, we thought they were all the same. That’s clearly not the case. There are toxicity differences and there are efficacy differences as well. Sunitinib and pazopanib were developed as frontline drugs. They tend to be used frontline or not at all. Sunitinib is I think a little more toxic, a little tougher to take. The COMPARZ trial showed them to be noninferior, although my bias is still that sunitinib is a little better drug. I tend to use pazopanib in older, frailer patients. Sunitinib is in the opposite group. We’re probably giving 60% or 70% sunitinib frontline and the rest pazopanib, when we give TKI monotherapy.

Sorafenib is not used much anymore, as it’s efficacy low, toxicity high. We use a lot of axitinib in the second-line setting after immune therapy now. It’s a nice drug in that it has a short half-life. It’s very titratable. With oral drugs, not everybody is going to respond to the dose or tolerate the same dose, so a lot of our TKIs are very clunky. You can’t really adjust dose terribly well. With axitinib, because it comes in 1-mg tablets and has a very short half-life, you can do that. It makes it a little more cumbersome to give, but I think at the end of the day patients get to the right exposure, the right dose, which leads to optimal outcomes.

Pazopanib is one of the newer TKIs. Its efficacy is largely demonstrated in the refractory setting, and that’s where I tend to use it. It can be a tougher drug toxicity-wise, especially at 60 mg, which I usually start people at. Lenvatinib is the latest comer, although it was approved in combination with everolimus. I think it’s a clearly active TKI. They’ve all taken these unique and totally different development paths, which have a lot to do with who owned the drug and what the setting was, etcetera. There are differences.

I think moving into the immunotherapy era, what’s different is that they’re not all combinable with immune therapy. Sunitinib and pazopanib are really not combinable for various reasons. They won’t be part of combination regimens, whereas axitinib is very combinable and has primarily been the combination partner. The way we look at them has shifted now that they’re combination partners and not standalone agents.

Transcript Edited for Clarity 
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