Initial Therapy for Advanced Renal Cell Carcinoma - Episode 1

Biology of Clear Cell Renal Cell Carcinoma


Eric A. Jonasch, MD: The discovery of the Von Hippel-Lindau [VHL] gene in clear cell renal cell carcinoma in 1993 has really led to a tremendous increase in our understanding of kidney cancer biology, specifically clear cell renal cell carcinoma biology. The VHL gene, when mutated, results in upregulation of HIF or hypoxia-inducible factor, which results in a very angiogenic tumor. We have a whole series of agents that have been developed that actually target this, either the VEGF itself or the receptors: drugs like sunitinib, pazopanib, axitinib, cabozantinib, and lenvatinib.

The other thing that we know about renal cell carcinoma—and again, particularly about clear cell renal cell carcinoma—is that they’re very immune infiltrated. This actually provides us with real opportunities to use novel checkpoint therapies. A lot of the things that we’re seeing now that are coming out are these combinations of immunotherapy, blocking checkpoints, as well as antiangiogenic agents.

The last thing that’s really happening is that with our understanding of HIF biology, agents that actually target HIF-1alpha or, more importantly HIF-2alpha, have also been developed and there are going to be some exciting new things coming out over the next few years in that arena.

Elizabeth R. Plimack, MD: VEGF has been a target in renal cell carcinoma for the last decade. And I think VEGF therapy is actually still a mainstay of treatment for the disease. We’ve proven that sequential VEGF therapy can have therapeutic impact, and the VEGF pathway is key to renal cell carcinoma angiogenesis and pathogenesis in general. Novel targets for renal cell carcinoma can be looked at more broadly than just the VEGF pathway, but recently what’s really interesting are HIF-2alpha inhibitors that inhibit the VEGF pathway at its base. And we’ll be hearing about some of those at the meeting this week.

We’re fortunate, those of us who treat kidney cancer, to have multiple treatment options, multiple drugs that we can select for our patients. But really, I think of it as 3 categories of drugs currently. We have VEGF inhibition, we have mTOR inhibition, and we have immunotherapy with checkpoint inhibition. It’s really only 3 mechanisms of action. They’re very different. VEGF inhibitors are targeted tyrosine kinase inhibitors, mTOR inhibitors target a different pathway, and then immunotherapy is separate altogether in that it really targets the immune system, the T-cells, to engage with and activate it to fight the cancer.

What’s fascinating is when we combine these, we’ve seen really synergistic activity among certain versions of these drugs. For instance, combining axitinib or lenvatinib with immunotherapy looks to be safe and effective. And then combining lenvatinib with everolimus, similarly, seems to be safe and effective. And so those combinations really have upped our game and our ability to get better treatment responses for patients.

Transcript Edited for Clarity