The New Frontier: Treating Advanced Kidney Cancer - Episode 10

Upfront Immunotherapy for Metastatic Kidney Cancer

Transcript:Robert A. Figlin, MD: So, I think, David, that summary by Toni puts us on alert for what may be a paradigm shift in what’s available in the frontline setting with respect to TKIs. Now, having said that, we’re challenged by almost every trial that’s pivotal in the frontline setting using I-Os, using sunitinib as its control arm. But the I-Os have entered our world in the second-line setting, and they’re soon to enter our world, because the trials have been completed or are close to being completed in the frontline setting. Talk to us about what your thoughts are about the evolution of I-Os to the front line and then we’ll expand that with Eric speaking about some combination therapies.

Eric Jonasch, MD: I think we have a long track record, 20 years, of using immunotherapy in the frontline setting with interleukin-2, and a lack of development with that. We’ve done some trials. We did an entinostat trial with high-dose IL-2 that looks interesting, but needs follow-up. First-line immunotherapy is something that may be worth pursuing. We have several trials that are about to report. Some of them are classic I-Os, some of them are other types of therapies—ipilimumab/nivolumab versus standard dose sunitinib, standard dose sunitinib with addition of the Argos vaccine product, AGS-003, and also a couple of others that are coming. And so, from that perspective, how do we sort this out versus cabozantinib? I think the answer is that we’re going to have to do other trials. I’m fine with sunitinib being a standard the way we’re using it because we now have more than a decade of understanding what that gives us. But, if we’re going to get 2 changes in the benchmark, in other words, particularly if the CABOSUN overall survival data are positive—show an overall survival advantage versus standard dose sunitinib—and one of the immunotherapy trials hits and changes our paradigm, I think we have, in one way, rationalized our choice. But we have a choice between I-O in combination, generally with a VEGF TKI or a vaccine and a TKI, which might be the third-generation VEGF TKI in the form of cabozantinib. That’s going to be a problem for us.

How do I deal with that? Well, I’m involved in a lot of these trials. It’s very interesting that we’ve been able to build the way we have. And I think we’re going to start looking at combinations of cabozantinib, which has some immune effects with some of the immuno-oncology drugs, and I think that’s very interesting. There’s a great trial from Andrea Apolo in both renal cell and urothelial cancer. She’s presenting some more data on it at this meeting, which I think is a very good one. And these are the sorts of trials that we’re going to have to do and build upon if we’re going to address this question.

Robert A. Figlin, MD: Eric, we’re on the precipice of really understanding whether I-Os alone or in combination, whether it’s in combination with another I-O or in combination with a targeted agent, are going to be ready for prime-time in the not too distant future. Any insights into your thoughts, mechanism, approaches about these trials, and how we’re going to have to think about them?

Eric Jonasch, MD: Let’s talk about whether there’s any rationale for, for example, a TKI/I-O combination. We have some data from our sunitinib presurgical study that shows that if you look at sunitinib-treated renal cell carcinomas compared to untreated controls, it seems to increase T cell infiltrate. One of the challenges in terms of how I-Os don’t work is if you don’t get the immune cells into the microenvironment, it’s a problem. If they’re in there, then you have a checkpoint that’s counter regulating. That’s a problem. Possibly, with a combination of anti-VEGF therapy, and we’re not sure how it does it, there’s a couple of putative mechanisms that are being investigated, but there’s a rationale for that combination. Maybe what you’re doing is you’re creating an immunologically hot environment, and then you’re knocking down the key checkpoint that’s preventing those activated T cells from killing the tumor.

Obviously, if you look at studies and review articles, there are tons of checkpoints. How do we actually approach a patient when we have this panoply of agents and choices? I think it really comes down to being able to understand individual tumor biology, and, again, this is a process of evolution. Now what we’re doing is we’re doing early phase clinical trials with lots of biopsies. I call it the “Model T Fords” perhaps of monitoring immune biology, and we really need to move beyond that. Are there some promising combinations? As David was just commenting before, a drug like cabozantinib, which is also modulating both the innate immune system as well as the adaptive immune system potentially, could be very, very exciting. So, I think those combinations I really look forward to seeing how efficacious they are.

And there are a number of clinical trials that are coming down the pipeline. In terms of clinical trials, at this ASCO GU, there is a trial of atezolizumab, which is a PD-L1 inhibitor, plus bevacizumab versus atezolizumab alone versus sunitinib. It is a 305-patient study that is being presented by David McDermott. And the data show that from a progression-free survival perspective, if you don’t select for PD-L1, there isn’t a great big difference. Even when you do select for PD-L1, which up until now hasn’t really been shown to be a good predictive biomarker in other studies, there’s a trend towards improved detection. But the overall response rate in this trial, the progression-free status at 1 year, are modest. I think we really need to probably dig into this trial a little bit more to see whether there’s maybe some gold in there. For example, we don’t yet know what the CR rate is in these arms. These are the sorts of data that we’re probably going to find out at the course of this meeting, and these will help us then decide on whether or not this is a harbinger of great things to come or a cautionary tale.

Transcript Edited for Clarity