Martin H. Voss, MD: There’s a longstanding tradition of using immunotherapy in the management of metastatic kidney cancer, and much of the biology really lends itself well to these approaches. We know that this tumor type is often highly infiltrated, meaning if we examine kidney cancer tissue under the microscope or using next-generation sequencing, we find a high degree of infiltrating immune cells in the microenvironment of the tumor. So, that by itself suggested immunotherapy may be effective.

There are various types of immunotherapy that have been successfully employed for the treatment of kidney cancer. Most recently, there has been an approval for a PD-1 inhibitor, and checkpoint inhibitors in general are being considered now a new standard class of actions in this disease. Checkpoint inhibitors can target inhibitory checkpoints such as PD-1 or CTLA4. They can also target activating checkpoints such as CD70 or OX40, and many of such treatments are actually being investigated actively for kidney cancer.

Beyond that, there are several other ways to manipulate the immune system and hope to have a good antitumor effect. That includes cytokines, which have a longstanding tradition in kidney cancer and continue to do so, but also manipulators of the immune microenvironment such as adenosine receptor antagonists, macrophage inhibitors such as CSF1 inhibitors, and also drugs that target metabolisms such as glutaminase inhibitors or IDL1 inhibitors. So, really, there’s a multitude of new avenues that have been explored to harness response to the immune system of the patient.

PD-L1 expression, of course, is a logical biomarker to explore in any disease that has been treated with a PD-1 or a PD-L1 inhibitor. And testing of PD-L1 expression in tumor tissues has been incorporated since the very beginning of developing the strategies in RCC. What we’ve learned in the early development of PD-1 and PD-L1 inhibitors is the extent of target expression, meaning PD-L1 expression either on the tumor cells or the immune cells does track with the likelihood of response. But a very important message we learned is that patients with low expression levels can still have an excellent benefit from these therapies. In the phase III setting on the CheckMate-025 study, which was a randomized trial comparing nivolumab to everolimus, we saw that the extent of the benefit that the novel drug, nivolumab, demonstrated over everolimus did not at all depend on PD-L1 expression. What that means is patients, whether they had high or low PD-L1 expression, had better overall survival and higher objective response rates with the checkpoint inhibitor compared with the gold standard at the time, everolimus. So, ultimately, there should be PD-L1 expressions of relevance for biomarker development and academic exploration of this disease, but currently, it has no role in clinical practice the way it may have in lung cancer.

Thomas Hutson, DO, PharmD, FACP: The safety and efficacy of nivolumab as a second-line agent is outstanding. I have found no additional toxicity in my patients when I use it. It has been well tolerated and well received by my patients. They enjoyed the ability to come into clinic and, in 30 to 60 minutes, receive an infusion with minimal to no side effects, especially because, remember, many of these patients have already received frontline VEGF inhibitors and have had toxicities. At most, my patients experience fatigue and flu-like illnesses. When I look at the several hundred patients I’ve treated, I’ve had only 1 or 2 who had such a severe toxicity that required me to discontinue therapy and utilize steroids to resolve the toxicity. That was arthritis, almost like a rheumatoid arthritis—type condition, that resulted in complete discontinuation of the therapy.

James J. Hsieh, MD, PhD: So, the question is when and where, and can we use the immune checkpoint inhibitor as a frontline treatment by itself or in combination? It’s a very, very interesting question, and it’s a very, very important question. I think in the future what we’re going to see is that checkpoint inhibitor will be a frontline but not as monotherapy. That’s my take on it because, again, every time I talk about treatment, it’s based on mechanism. It’s not really just based on A’s or B’s, available or not.

Matchup treatment transformed the way we treat kidney cancer. Because you work on 18% of patients, 30% of patients will have response, and 50% of patients have stable disease. But if you take a look at checkpoint inhibitors, it’s working. Response rate may be 20% to 25%, and maybe 30% of patients will have stable disease. So, you are missing the chance to get maybe 30% of patients to progress on a single-agent PD-1 or PD-L1 antibody. You’re giving them a higher chance to progress instead of giving them a benefit. I am not a big fan of monotherapy of checkpoint inhibitor. I’m a big fan of combination. And I think it’s because you’re combining different mechanisms, and we know that with VEGF inhibitors, some of them will modulate the immune response, too.

When you put them together, this is why we’re going to see it. Because the most recent trial that we’re going to see from now on—actually starting for the past couple of years—it’s already starting from bevacizumab/atezolizumab. It’s actually showing some efficacy there. So, now you’re going to see lenvatinib plus a PD-1 antibody, axitinib plus a PD-1 antibody, and cabozantinib plus a PD-1 antibody. All of these are frontline treatments, and I think they are going to beat sunitinib. That’s what everybody was using; sunitinib is the one, the golden boy. But not everyone wants to beat sunitinib. And that’s telling us what’s in the future. And the response, that’s why it’s a golden age, because it is a combination therapy. We migrate this through the modern age of monotherapy, where the golden age is with combination therapy.

Transcript Edited for Clarity