Initial Therapy for Advanced Renal Cell Carcinoma - Episode 6

Favorable-Risk RCC: Frontline VEGF TKI/IO Combinations


Eric A. Jonasch, MD: The therapies that we currently use as monotherapy are good at prolonging progression-free survival. They haven’t officially or formally demonstrated overall survival advantage in those phase III trials but are reasonable agents. What we are seeing with TKI [tyrosine kinase inhibitor]–I/O [immuno-oncology] combinations is that these agents in combination are resulting in a small cure fraction and a clear prolongation of survival compared with TKI monotherapy.

Elizabeth R. Plimack, MD: Adding immunotherapy in any way, either on its own or in combination, brings this unpredictable risk to the situation. Just 1 dose of immunotherapy can trigger an autoimmune event either shortly after that infusion or months to years down the road. We’ve seen autoimmune adverse events that occur in patients who have been off their immunotherapy, sometimes even for years.

The unpredictable nature is the most uneasy aspect of the immunotherapies, in my opinion. Combining ipilimumab and nivolumab together, 2 immunotherapies, led to about 50% of patients requiring steroids; 35% of those were high-dose steroids. That’s to reverse these autoimmune events. That seems to me to be pretty high. We don’t have those numbers for the axitinib-pembrolizumab combination, but we know whenever we add immunotherapy that the immune system can go haywire and attack the body’s healthy tissue. Those adverse events are sometimes hard to mitigate.

In rare circumstances, they can be fatal, and so bringing this unpredictable possibility of something really bad happening to the patient isn’t something we do lightly. It’s something we spend quite some time explaining to the patient. There is a 70% to 85% chance you’ll do fine and you won’t have 1 of those events, but there is a small but very real chance that you’ll have a severe reaction to this medication that we’ll have to treat. And those are tough to go through. I think the unpredictability of immunotherapy is the hardest aspect of that therapy.

Eric A. Jonasch, MD: One of the big questions is whether we should be sequencing TKIs followed by I/O therapies or whether we should be combining these agents up front. It really comes down to whether you want an individual to get their best shot in the frontline setting for their treatment.

About 50% of individuals do not move on to second-line therapy. It really is incumbent upon us to give them their best regimen at the beginning. For that reason I prefer giving combination therapy up front. The other thing is whether the combination of I/O and a TKI in the frontline setting is synergistic or additive and the definition of what synergism is. In my opinion, the ability to achieve a complete response versus a sustained durable response really would be an indication of some form of synergy because we don’t see that with TKI monotherapy. And we see that very rarely with I/O monotherapy.

There was also a trial that came out at ESMO [the European Society for Medical Oncology Conference], the TITAN study, where patients were started on nivolumab and then had ipilimumab added on if they progressed. The complete response rate in that study was considerably lower than what we saw, for example, with the ipilimumab-nivolumab CheckMate 214 study. There’s something about giving 2 drugs together—whether it’s an I/O-TKI combination or an I/O-I/O combination—in the frontline setting that seems to result in that cure rate that’s higher than what we see in the sequential type of approach to treatment.

Elizabeth R. Plimack, MD: The idea of sequence is really what we used to do. We used to pick a first-line, then a second-line, and then a third-line agent. If you’re going to start with a single-agent VEGF TKI, you’ve decided to sequence because that patient will likely see immunotherapy in their future. You’ve just chosen to add it later. Again, what we tend to say is that we’re making a decision about what to try next, not either-or. If you start with pazopanib as a frontline therapy, it doesn’t mean you’re choosing not to use immunotherapy. It just means that’s what you’re trying first. Every patient is treated in a stepwise fashion. They’re treated with their first agent. When it stops working, we take stock of the field, the clinical trials we have available, and the data that are available, and we advise them on the next step. Subsequent to that, we do the same. Whether we start with combination therapy or we start with 1 agent and then go to another, it’s really the same paradigm of placing your bet on 1 treatment, picking it, trying it, hoping it works, and if it doesn’t, readjusting based on emerging evidence.

Transcript Edited for Clarity