Panelists: Robert A. Figlin, MD, Cedars-Sinai Medical Center; Thai H. Ho, MD, PhD, Mayo Clinic Arizona; Martin H. Voss, MD, Memorial Sloan Kettering Cancer Center; Michael B. Atkins, MD, Georgetown Lombardi Comprehensive Cancer Center; Sandy Srinivas, MD, Stanford University Medical Center
Robert A. Figlin, MD: Thai, in your practice, we know that there’s also the ipilimumab/nivolumab trial, the CheckMate-214 trial, that’s completing accrual. We’re waiting for the readout. We know that in other diseases, PD-L1 testing can select, in some patients, identification of people that are likely to benefit. How do you approach that for kidney cancer patients?
What Michael just suggested is hypothesis-generating observations that, hopefully, large phase III trials will be able to address. But on a practicing level, it’s important for our listeners to understand where we are today in terms of PD-L1 testing, whether it happens to be in a local laboratory or a central lab. How do you approach that?
Thai H. Ho, MD, PhD: With regard to PD-L1 testing, there are a lot of antibodies out there. There are some from Dako, some from Ventana, and there are different cutoffs. The cutoffs can vary by tumor type. It can be very confusing, to the practicing clinician, when you order one of these tests, as to what to do with the test.
At least in the CheckMate-214 trial for nivolumab, the PD-L1 status, whether you use 1% or 5%, didn’t seem to predict response. And I think the big take-home message, at least in kidney cancer, is that there are patients who are stratified as PD-L1–negative, yet they still respond to immunotherapy. So, I think it can make it a little challenging when using this test as a predictive marker.
With the Jimmy Carter effect, as I like to explain it, patients are coming more to me asking, specifically, for immunotherapy. Having a combination of nivolumab plus something that potentially could boost its activity, maybe at the molecular level, you’re causing some more of this neoantigen spreading where, essentially, as a tumor is lysed, some of these antigens are released and the local dendritic cells pick up these antigens and it causes neoantigen spreading. So, by using these combinations, you may be able to boost efficacy, but there could be a price to pay—as Martin alluded to with tolerability.
Robert A. Figlin, MD: This has been an excellent discussion. Before we end, I’d like to ask each of the panelists for any additional insight regarding the treatment landscape. I’ll go through each of you, individually. Martin, it’s 2017. Where are we today and where are we going to be in 5 years?
Martin H. Voss, MD: We’ve made tremendous progress over the last decade, and I think there has been a real jump in pushing the boundary further over the last 2 years. There’s a whole new avenue of therapy, and also of technologies, that are available to better understand the molecular underpinnings of all this that is now available to us. It provides us with an opportunity, over the next few years, to do more of this, to rationally combine medications, not just because they’re both available, and to use the biology to understand them.
The IMmotion150 trial that Michael described so eloquently really sets the stage for what is to happen in the future. Here we have the first randomized trial to now look at different strategies. It shows us that it’s not always one approach that is the right one, but that we can find ways to understand who might be benefitting from one approach more than the others.
Robert A. Figlin, MD: Michael, your thoughts?
Michael B. Atkins, MD: One thing I want to emphasize is, we’ve studied nivolumab in the second-line setting in patients who’ve progressed after VEGF receptor TKIs, and there are a lot of data to suggest that, in that setting, there’s an increased infiltration of myeloid-derived suppressor cells that come in to help promote angiogenesis after you’ve essentially infarcted the tumor with VEGF inhibitors. That may not be the best time to be using an immunotherapy.
In that setting, it’s still remarkable that we see a 25% response rate, 30% to 40% of patients have tumor shrinkage, and in 4 or 5 years, 30% plus of patients are alive. We have precious little data about how these checkpoint inhibitors work in the frontline setting, as either single agents or as combinations that should be used.
It’s possible, in melanoma, in the frontline setting as first therapy, that immunotherapy works better than if you wait until after tumors have become resistant. It’s possible that the same thing may be the case in kidney cancer. Therefore, I’m very anxious to see the results of the CheckMate-214 trial. I think we need to see some data on what nivolumab, pembrolizumab, or atezolizumab does by itself in the frontline setting. We have a little data in the IMmotion150 trial, and if your goal is to produce a CR, then atezolizumab is your best option of those 3 options in the IMmotion150 study.
There are a tremendous number of other potential immunotherapies that can target specific immunosuppressive cells in the tumor microenvironment. We’re going to see, in a lot of different cancers, whether it’s inhibitors of IDO, inhibitors of myeloid-derived suppressor function, or inhibitors of other checkpoints. And I can envision, in 5 years, immunotherapy as the standard frontline therapy. The combination that someone gets will depend on some assay of their tumor microenvironment.
Robert A. Figlin, MD: Sandy, your thoughts?
Sandy Srinivas, MD: In the last decade, for kidney cancer, we have had a lot of drugs, but it has mostly been palliative. It has been disease prolonging. I’m hoping that the next decade, with bringing immunotherapy up front, will really result in more complete responses, where we can have finite therapy for patients and not have them on therapy for the rest of their lives.
Robert A. Figlin, MD: Thai?
Thai H. Ho, MD, PhD: We mentioned, on the panel several times, that loss of VHL is a common event. It’s very frustrating because, when you look at VHL loss, there’s no relationship as to whether patients respond to VEGF therapy. I think one of the things that is emerging is the concept of these HIF-2 antagonists. Basically, this is downstream of VHL, and when I was going through school, it was considered to be undruggable. Now, they have HIF-2 antagonists that have activity in preclinical models. It’s already started in some of the clinical trials, and it’s a different mechanism from what we have available now. Something like that, that’s outside the current mechanisms that we have, is something worth watching.
Robert A. Figlin, MD: On behalf of our panel, we thank you for joining us, and we hope you found this discussion helpful and informative.