Examining TKI Combinations in Advanced RCC - Episode 1

Frontline Treatment of Advanced Renal Cell Carcinoma

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The panelists discuss frontline treatment for renal cell carcinoma, highlighting TKIs targeting VEGFR and the mechanisms of action for currently approved therapeutics.

Robert J. Motzer, MD: Hello, and thank you for joining this Targeted Oncology™ presentation titled, “Examining TKI Combinations in Advanced RCC.” Over the past 2 years, there has been rapid expansion of first-line options for advanced kidney cancer. With the approval of the I/O–I/O [immuno-oncology] combination of nivolumab plus ipilimumab, to the more recent approvals of TKI [tyrosine kinase inhibitor]–I/O combinations, such as axitinib plus pembrolizumab and cabozantinib plus nivolumab, we have many options for our patients across risk groups. But we are faced with the tough questions of what combination to use, and for whom. I am Dr Robert Motzer, an attending physician at Memorial Sloan Kettering Cancer Center. Joining me today are my colleagues Dr Toni Choueiri, the director of Lank Center of Genitourinary Oncology at Dana-Farber Cancer Institute and a professor of medicine at Harvard Medical School in Boston, Massachusetts; and Dr Thomas Hutson, co-chair of Urologic Cancer Research and Treatment Center at Texas Oncology–Baylor Sammons Cancer Center and a professor of medicine at Texas A&M College of Madison in Dallas, Texas. Thank you so much for joining us. 

Let’s begin. First, let’s provide a bit of a historical perspective on the treatment of RCC [renal cell carcinoma], which has historically been a difficult cancer to treat based on its high level of resistance to chemotherapy drugs. The response rate to chemotherapy drugs is very low, and for many years, the treatment for renal cell carcinoma was cytokine therapy with interferon and interleukin 2. The prognosis was poor, and the overall survival on average was less than a year with these treatments. But there was really a breakthrough in the treatment of advanced clear-cell carcinoma of the kidney with tyrosine kinase inhibitors that target VEGF receptor. Tom, what is the rationale for TKIs targeting VEGF? Can you discuss some of the TKIs you commonly use for treatment of advanced RCC?

Thomas E. Hutson, DO, PharmD: Absolutely, Bob, and thank you for asking. The advance really came back in 1993 with the original Science publication, linking a von Hippel–Lindau gene mutation as the germline mutation associated with that syndrome, which as you know is associated with a high predilection for clear-cell renal cell cancer. Later was the discovery that the von Hippel–Lindau mutation had been acquired as a somatic mutation loss of function or hypermethylation of that gene, resulting in increased HIF [hypoxia-inducible factor] activity within the cancer cell. HIF translates ultimately into VEGF, and we all know that VEGF is what we believe to be the most potent angiogenic factor and a factor that cancer uses to grow its blood supply. To me, that was the sunitinib discovery of linking a genetic abnormality, with that downstream target being VEGF. 

Obviously, there was a lot of interest by the pharma companies and scientists to define ways that one can inhibit VEGF. Naturally, bevacizumab being an antibody to VEGF is been explored, but we actually found that inhibiting receptor, the receptor kinase using a kinase inhibitor was more practical and more potent. And so, that led to the design of our early generation drugs sorafenib and sunitinib, which their landmark approvals really heralded the new era and treatment of kidney cancer, where we saw in some cases, what we believe to be almost double or tripling of the survival with response rates and clinical benefit rates at very high levels ,such that we could start a therapy on a patient with clear-cell and expect that this patient would have a benefit in at least a stable disease.

But really, your question was about what were they aimed at. They were aimed at this inhibition of VEGF, which was tied with the driver mutation and the von Hippel–Lindau. We’ve subsequently developed what I’d consider newer-generation therapies. Pazopanib came on the scene, plus drugs like axitinib, cabozantinib, and lenvatinib. We just saw tivozanib’s FDA regulatory approval. So we really have a handful of VEGF inhibitors, which have salient differences and differences, not only in the potency at which they inhibit VEGF receptor but also in their ability to inhibit some off-target receptors. Some of these receptors we believe to be important in the pathogenesis and resistance mechanisms. The VEGF receptor tyrosine kinase inhibitor class, Bob, has been the mainstay, at least the backbone of the treatment strategy to kidney cancer. At some level it remains that way today.

This transcript was edited for clarity.