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Metastatic RCC: Mechanisms of Resistance

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: I don’t think much is really known about resistance to TKIs [tyrosine kinase inhibitors] in RCC. We’ve been studying this for over 10 years—probably 15, since the drugs are really in use in trials—and I don’t think there are great biologic insights into why some patients respond wonderfully for years and others blow right through it. People have looked at all sorts of factors: other antigenic factors, etcetera. There are tantalizing clues and this and that, but nothing from a clinical standpoint where I know, when I’m putting a patient on a drug, what their response is going to be. It’s still very much empiric.

The biology of progression of kidney cancer is not well known. We recently looked at some samples from the IMmotion151 study, looked at gene expression, and had some interesting results in that favorable-risk patients were a more angiogenic phenotype whereas intermediate/poor-risk patients were a more immune or inflamed phenotype. While those are clinical classifications, there’s a biologic underpinning to those classifications. It may be that we’re going to start to understand these clinical differences and put patients into biologic subgroups instead of clinical subgroups. But we’re really just starting down that road.

David F. McDermott, MD: With VEGF-targeted strategies, when you hit kidney cancer with an anti-VEGF strategy, those tumors become hypoxic. They start amplifying certain genes and certain proteins that probably lead to resistance. Some of those pathways—FGF and c-MET, for example, and others that have been identified in mouse models—are potentially driving that angiogenic escape that probably leads to tumor regrowth.

We now have agents that target some of these angiogenic escape mechanisms. For example, cabozantinib targets VEGF and c-MET, which is an escape mechanism. Lenvatinib targets VEGF and FGF, which is another potential escape mechanism. The hope is that with these multitargeted agents, we can delay resistance. But we’re certainly not eliminating it in our outpatients, and much more work needs to be done on that side.

With immunotherapy, it’s a little more complicated, and we really need to learn from human tissues to understand what human resistance to these therapies is like. Most resistance is probably innate. At the beginning, it’s already established. Tumors have multiple ways in which they can escape an immune response. For example, they can downregulate HLA [human leukocyte antigen] mechanisms, which helps downregulate antigen presentation. They can present immune checkpoints, as we’ve talked about with PD-1 [programmed cell death protein 1] and CTLA-4 [cytotoxic T-lymphocyte–associated protein 4].

But there are also a list of other immune checkpoints that can be activated in that setting. They can make immunosuppressive factors like TGF-β1, which we’re now targeting, we hope, in early clinical trials. There are other suppressive mechanisms. For example, they can call in regulatory T cells from the periphery to try to suppress an immune response. Tumors are pretty nasty when it comes to different ways they can evade an immune response. And now, we need to learn which tumor is evading the immune system and by which mechanism, so we can design combinations for specific patients. But it’s not going to be easy because the mechanisms are broad, and we’re still not perfect at identifying what the key mechanisms are in each individual patient.

Brian Rini, MD: Pseudoprogression, if you look at the data from trials, is probably in 5% or 10% of patients. We talk about it like it occurs in every patient, but it doesn’t. Unfortunately, most patients’ progression is real progression. Practically, if I have a patient at the end of ipilimumab/nivolumab induction or nivolumab monotherapy, I don’t scan until 12 weeks. Because if you scan them early, you can be misled by pseudoprogression. At 12 weeks, even if they have a little bit of progression but they’re clinically well and tolerating it, I’ll generally keep going for another 12 weeks. Not even so much for pseudoprogression but just for delayed response, even though on average the time to response is very quick. There are certainly patients who can respond more slowly over time. If they’re clinically well, there’s probably not a hurry to rush them to their next therapy. I think it happens in a relatively small percentage of patients, but I do take a clinical approach to account for it.

David F. McDermott, MD: The issue of sequencing and overcoming resistance is a great question. Over the last year or so, we’ve seen 3 positive studies that essentially took the prior first-line strategy, which was blocking VEGF, and the prior second-line strategy, which was inhibiting PD-1, and fused them together and compared them to the standard of care, sunitinib. All 3 trials have met their primary endpoints. That’s atezolizumab and bevacizumab; axitinib and avelumab; and most recently axitinib and pembrolizumab: all positive phase III trials. What do we do with this?

We think the results from most of these patients are additive. Essentially, we’re combining a potent VEGF strategy with a potent immune checkpoint strategy, and we’re capturing different groups of patients with a combination. We’re preventing resistance to both mechanisms. There are probably some patients who get a true synergistic benefit with these combinations though. We see that in the deep responses, in the complete responses, that are generated. It’ll be very interesting to see if these patients can actually enter a remission of their disease, which is a true test of any effective immune therapy. If you can actually stop the drug, it is exciting for patients. For a variety of reasons and because the adverse effects get better, they don’t need to come to the doctors as often. But I don’t think we’re there yet. I don’t think we know that VEGF/PD-1 is truly synergistic yet the way we’ve seen with some prior immunotherapy combinations.

Transcript Edited for Clarity
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Transcript: 

Brian Rini, MD: I don’t think much is really known about resistance to TKIs [tyrosine kinase inhibitors] in RCC. We’ve been studying this for over 10 years—probably 15, since the drugs are really in use in trials—and I don’t think there are great biologic insights into why some patients respond wonderfully for years and others blow right through it. People have looked at all sorts of factors: other antigenic factors, etcetera. There are tantalizing clues and this and that, but nothing from a clinical standpoint where I know, when I’m putting a patient on a drug, what their response is going to be. It’s still very much empiric.

The biology of progression of kidney cancer is not well known. We recently looked at some samples from the IMmotion151 study, looked at gene expression, and had some interesting results in that favorable-risk patients were a more angiogenic phenotype whereas intermediate/poor-risk patients were a more immune or inflamed phenotype. While those are clinical classifications, there’s a biologic underpinning to those classifications. It may be that we’re going to start to understand these clinical differences and put patients into biologic subgroups instead of clinical subgroups. But we’re really just starting down that road.

David F. McDermott, MD: With VEGF-targeted strategies, when you hit kidney cancer with an anti-VEGF strategy, those tumors become hypoxic. They start amplifying certain genes and certain proteins that probably lead to resistance. Some of those pathways—FGF and c-MET, for example, and others that have been identified in mouse models—are potentially driving that angiogenic escape that probably leads to tumor regrowth.

We now have agents that target some of these angiogenic escape mechanisms. For example, cabozantinib targets VEGF and c-MET, which is an escape mechanism. Lenvatinib targets VEGF and FGF, which is another potential escape mechanism. The hope is that with these multitargeted agents, we can delay resistance. But we’re certainly not eliminating it in our outpatients, and much more work needs to be done on that side.

With immunotherapy, it’s a little more complicated, and we really need to learn from human tissues to understand what human resistance to these therapies is like. Most resistance is probably innate. At the beginning, it’s already established. Tumors have multiple ways in which they can escape an immune response. For example, they can downregulate HLA [human leukocyte antigen] mechanisms, which helps downregulate antigen presentation. They can present immune checkpoints, as we’ve talked about with PD-1 [programmed cell death protein 1] and CTLA-4 [cytotoxic T-lymphocyte–associated protein 4].

But there are also a list of other immune checkpoints that can be activated in that setting. They can make immunosuppressive factors like TGF-β1, which we’re now targeting, we hope, in early clinical trials. There are other suppressive mechanisms. For example, they can call in regulatory T cells from the periphery to try to suppress an immune response. Tumors are pretty nasty when it comes to different ways they can evade an immune response. And now, we need to learn which tumor is evading the immune system and by which mechanism, so we can design combinations for specific patients. But it’s not going to be easy because the mechanisms are broad, and we’re still not perfect at identifying what the key mechanisms are in each individual patient.

Brian Rini, MD: Pseudoprogression, if you look at the data from trials, is probably in 5% or 10% of patients. We talk about it like it occurs in every patient, but it doesn’t. Unfortunately, most patients’ progression is real progression. Practically, if I have a patient at the end of ipilimumab/nivolumab induction or nivolumab monotherapy, I don’t scan until 12 weeks. Because if you scan them early, you can be misled by pseudoprogression. At 12 weeks, even if they have a little bit of progression but they’re clinically well and tolerating it, I’ll generally keep going for another 12 weeks. Not even so much for pseudoprogression but just for delayed response, even though on average the time to response is very quick. There are certainly patients who can respond more slowly over time. If they’re clinically well, there’s probably not a hurry to rush them to their next therapy. I think it happens in a relatively small percentage of patients, but I do take a clinical approach to account for it.

David F. McDermott, MD: The issue of sequencing and overcoming resistance is a great question. Over the last year or so, we’ve seen 3 positive studies that essentially took the prior first-line strategy, which was blocking VEGF, and the prior second-line strategy, which was inhibiting PD-1, and fused them together and compared them to the standard of care, sunitinib. All 3 trials have met their primary endpoints. That’s atezolizumab and bevacizumab; axitinib and avelumab; and most recently axitinib and pembrolizumab: all positive phase III trials. What do we do with this?

We think the results from most of these patients are additive. Essentially, we’re combining a potent VEGF strategy with a potent immune checkpoint strategy, and we’re capturing different groups of patients with a combination. We’re preventing resistance to both mechanisms. There are probably some patients who get a true synergistic benefit with these combinations though. We see that in the deep responses, in the complete responses, that are generated. It’ll be very interesting to see if these patients can actually enter a remission of their disease, which is a true test of any effective immune therapy. If you can actually stop the drug, it is exciting for patients. For a variety of reasons and because the adverse effects get better, they don’t need to come to the doctors as often. But I don’t think we’re there yet. I don’t think we know that VEGF/PD-1 is truly synergistic yet the way we’ve seen with some prior immunotherapy combinations.

Transcript Edited for Clarity
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