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Understanding the Biology of Kidney Cancer

Insights From: Martin H. Voss, MD, Memorial Sloan Kettering Cancer Center; Thomas Hutson, DO, PharmD, FACP, Baylor University Medical Center; Texas Oncology; James J. Hsieh, MD, PhD, Washington University School of Medicine
Published: Monday, Jul 17, 2017



Transcript:
 

Martin H. Voss, MD: Renal cell carcinoma is a model disease for using a better understanding of the underlying biology to treat patients with targeted therapies. This dates back to our early understanding of the fact that functional loss of the Von Hippel–Lindau protein, VHL, leads to upregulation of various downstream effectors—most importantly the vascular endothelial growth factor, which drives tumor angiogenesis.

Over the last 10 years, we’ve seen a revolution in this disease through the development of serial agents that make use of this knowledge and effectively target tumor neovasculature in our patients. As the next step, we have now learned that a quiet resistance to these medications can also be understood by investigating the underlying biology. For instance, we know that certain kinases on tumor cells can be upregulated in patients after some time of treatment with angiogenesis drugs.

Some of the newer agents we have on the market already take that into account and were developed specifically with that knowledge in mind—targeting these other kinase proteins that can be active in cells with a TKI.

James J. Hsieh, MD, PhD: The treatment of kidney cancer has evolved over the past 15 years. I call it, when we were in the cytokine era, a dark age, and that was before 2005. The reason we were in a dark age was not because cytokines were bad drugs; it’s just because kidney cancer is refractory to conventional chemotherapy and radiation therapy. So, the cytokine era give us 2 drugs—interferon and IL-2 (interleukin-2). They gave patients 100% toxicity, but the response rate was low: 5% to 10%. That’s why I call it a dark age. We treated everybody with exactly the same toxicity and some benefit.

Then, we went into an era that I call the modern age. That was from 2005 to 2014. Within that era—within that timeframe of 10 years—we had 7 new drugs approved for metastatic kidney cancer patients. They include 2 different mechanisms: one is a VEGF inhibitor and one is an mTOR inhibitor. VEGF inhibition includes 5 drugs: Avastin [bevacizumab], pazopanib, sunitinib, sorafenib, and axitinib.

There are 2 mTOR inhibitors: everolimus and temsirolimus. These 2 drugs actually transformed the landscape of how we treat kidney cancer. We start with the cytokine era—I call it a dark age, because the median survival for a patient with metastatic kidney cancer was 15 months. In the modern era, we were actually able to double the median survival to 30 months. So, I think that is very, very interesting. I feel more human, really treating my patient—I can give them hope.

Now, we’re actually getting into an era of which I call the golden age, because from 2015—the latter half of 2015 and the early half of 2016—we had 3 drugs approved. These 3 drugs represent 3 additional mechanisms. One is cabozantinib, one is lenvatinib, and one is nivolumab. With these drugs available—and I think there will be additional drugs coming up on the market, like ipilimumab and things like that—I call it a golden age. Our goal should be aiming to double the median survival, again, to 60 months. And that’s why I think the landscape has changed so much.

Martin H. Voss, MD: Over the years, our understanding of the biology of kidney cancer variance has greatly improved. We now know that kidney cancer, as an entity, is really made up of many different variants. Our understanding of that used to be very rudimentary. One of the most commonly cited classifications used—the Heidelberg classification—that was published in the 1990s, really just grouped patients together based on microscopic morphology and immunohistochemistry. At the time, it defined the variants that we all know well, now—clear cell kidney cancer, papillary kidney cancers, chromophobe kidney cancers, and so forth.

But since the development of newer technologies, our understanding of the underlying biology for all of these variants has greatly improved. The best example for that is The Cancer Genome Atlas project, the TCGA, which has now done separate explorations of the biologies for the main kidney cancer entities. The original TCGA characterization for clear cell kidney cancer was published several years ago in Nature. Subsequent to that, we had the papillary kidney cancer TCGA characterization in The New England Journal of Medicine. We’ve had the chromophobe kidney cancer TCGA characterization. Those efforts, which were multicenter efforts throughout the United States, really helped us to understand the molecular underpinnings of all these variants and help us now to learn that within these common variants, there are subgroups that behave differently and should be treated differently in the future.

Transcript Edited for Clarity

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Transcript:
 

Martin H. Voss, MD: Renal cell carcinoma is a model disease for using a better understanding of the underlying biology to treat patients with targeted therapies. This dates back to our early understanding of the fact that functional loss of the Von Hippel–Lindau protein, VHL, leads to upregulation of various downstream effectors—most importantly the vascular endothelial growth factor, which drives tumor angiogenesis.

Over the last 10 years, we’ve seen a revolution in this disease through the development of serial agents that make use of this knowledge and effectively target tumor neovasculature in our patients. As the next step, we have now learned that a quiet resistance to these medications can also be understood by investigating the underlying biology. For instance, we know that certain kinases on tumor cells can be upregulated in patients after some time of treatment with angiogenesis drugs.

Some of the newer agents we have on the market already take that into account and were developed specifically with that knowledge in mind—targeting these other kinase proteins that can be active in cells with a TKI.

James J. Hsieh, MD, PhD: The treatment of kidney cancer has evolved over the past 15 years. I call it, when we were in the cytokine era, a dark age, and that was before 2005. The reason we were in a dark age was not because cytokines were bad drugs; it’s just because kidney cancer is refractory to conventional chemotherapy and radiation therapy. So, the cytokine era give us 2 drugs—interferon and IL-2 (interleukin-2). They gave patients 100% toxicity, but the response rate was low: 5% to 10%. That’s why I call it a dark age. We treated everybody with exactly the same toxicity and some benefit.

Then, we went into an era that I call the modern age. That was from 2005 to 2014. Within that era—within that timeframe of 10 years—we had 7 new drugs approved for metastatic kidney cancer patients. They include 2 different mechanisms: one is a VEGF inhibitor and one is an mTOR inhibitor. VEGF inhibition includes 5 drugs: Avastin [bevacizumab], pazopanib, sunitinib, sorafenib, and axitinib.

There are 2 mTOR inhibitors: everolimus and temsirolimus. These 2 drugs actually transformed the landscape of how we treat kidney cancer. We start with the cytokine era—I call it a dark age, because the median survival for a patient with metastatic kidney cancer was 15 months. In the modern era, we were actually able to double the median survival to 30 months. So, I think that is very, very interesting. I feel more human, really treating my patient—I can give them hope.

Now, we’re actually getting into an era of which I call the golden age, because from 2015—the latter half of 2015 and the early half of 2016—we had 3 drugs approved. These 3 drugs represent 3 additional mechanisms. One is cabozantinib, one is lenvatinib, and one is nivolumab. With these drugs available—and I think there will be additional drugs coming up on the market, like ipilimumab and things like that—I call it a golden age. Our goal should be aiming to double the median survival, again, to 60 months. And that’s why I think the landscape has changed so much.

Martin H. Voss, MD: Over the years, our understanding of the biology of kidney cancer variance has greatly improved. We now know that kidney cancer, as an entity, is really made up of many different variants. Our understanding of that used to be very rudimentary. One of the most commonly cited classifications used—the Heidelberg classification—that was published in the 1990s, really just grouped patients together based on microscopic morphology and immunohistochemistry. At the time, it defined the variants that we all know well, now—clear cell kidney cancer, papillary kidney cancers, chromophobe kidney cancers, and so forth.

But since the development of newer technologies, our understanding of the underlying biology for all of these variants has greatly improved. The best example for that is The Cancer Genome Atlas project, the TCGA, which has now done separate explorations of the biologies for the main kidney cancer entities. The original TCGA characterization for clear cell kidney cancer was published several years ago in Nature. Subsequent to that, we had the papillary kidney cancer TCGA characterization in The New England Journal of Medicine. We’ve had the chromophobe kidney cancer TCGA characterization. Those efforts, which were multicenter efforts throughout the United States, really helped us to understand the molecular underpinnings of all these variants and help us now to learn that within these common variants, there are subgroups that behave differently and should be treated differently in the future.

Transcript Edited for Clarity

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