Tian Zhang, M.D., M.H.S.: Systemic treatments for kidney cancer have evolved over the past 20 years or so. First with cytokines in the 1990s to early 2000s. These were things like interferon alpha and high-dose IL-2 [interleukin 2] that really made a difference for a very small proportion of patients who responded to systemic inflammatory responses. We then understood more about the hypoxia signaling pathways and how clear cell kidney cancer develops, and therefore there was a whole era of small molecules. So oral drugs targeted to blocking blood vessel formation, what we call antiangiogenic agents, or you’ll hear sometimes anti-VEGF [anti-vascular endothelial growth factor] agents. And these are mostly pills that patients take to help block blood vessel formation. And then in the most recent era, the past six years or so, we've seen an advent of immune therapy modulators. So treatments that are really targeted to activate T cells in the patients to attack the cancer cells. These have made it into combination strategies for systemic therapies, both as pure immunotherapy combinations as well as in combination with blood vessel blockade or anti-VEGF strategies.

Chandler H. Park, M.D.: Kidney cancer has evolved in many ways for the benefit of our patients in the past 15 to 20 years. When I was in fellowship training to be an oncologist, we used an immune therapy approach known as IL-2. The rationale behind IL-2 was [that we gave] this medication to stimulate an immune response, but the side effects of the treatment are that the patient’s blood pressure can go low or cause a fast heart rate. So we had to admit them to the ICU [intensive care unit]. And if the blood pressure got too low, we had to give medications called pressers to increase their blood pressure. We don’t really use that as much as we used to because we have much better medications. But after the IL-2 generation, we went to a different class of medication called tyrosine kinase inhibitors [TKIs].

What are TKIs? TKIs are like a key to a lock. So we had these targeted therapy medications that come in pill form. The patient would swallow the pill, and the medication would get absorbed and get into the blood vessel. It would then go to the different areas where the cancer is, where the blood vessels are called vascular endothelial growth factor. So it goes to the area and decreases the blood flow called VEGF. So that’s one class of medication. The evolution of kidney cancer treatment went from IL-2 to TKIs. There are different medications such as sunitinib, which was a TKI. Then we had something called cabozantinib, and then we had lenvatinib and now we had tivozanib. That’s the class of TKIs that decrease the blood flow at the level where the cancer is.

Now, about six years ago, the clinical trial for immunotherapy matured in kidney cancer. The landmark study was called Checkmate 214 [NCT02231749]. And what Checkmate 214 said is that patients with kidney cancer respond well to medications called immunotherapy. Now, what’s immunotherapy? Immunotherapy is an infusion. It looks like an intravenous bag of normal saline fluid that goes into your arm. And inside that fluid is a protein specifically called a checkpoint inhibitor.

What does a checkpoint inhibitor do? I like to use analogies to make things easier. The way I think about it is that some of us watch Star Wars, and they have a force field to protect an area. So kidney cancers and all cancers develop a way to protect themselves, and that is called resistance. We have stuff in our bodies called T cells. There are a type of white blood cell, and their job is to kill cancer. So when cancers develop and become resistant, they develop a force field around themselves. So you have all these T cells trying to get in there, and they don’t even know it exists. So a new class of medications called checkpoint inhibitors was developed. And the checkpoint inhibitor … removes the force field. It removes the checkpoint. So now your own white blood cells, and the T cells realize that there’s cancer in your body, and it starts attacking the cancer.

Immunotherapy is not chemotherapy. Immunotherapy is harvesting your own immune system to kill the cancer. One of the things that happens when patients develop cancer is the cancer cells try to survive. It forces a force field around it to protect itself. And this immunotherapy removes the force field to use your own T cells to kill the cancer. So that’s one of the landmark studies. The first was the IL-2, the second was the TKI and then the third was immunotherapy. So now we’re in that era of [combining] the TKI and the immunotherapy as two different medications to combat the cancer cells of the kidney. That’s where we are right now. We’re in the era of what’s called dual treatments; one medication is TKI, which could be cabozantinib, lenvatinib or axitinib. And then it’s got a dance partner of pembrolizumab or nivolumab based on the studies that we’re going to talk about.

Transcript is AI-generated and edited for clarity and readability.