Treating Advanced Renal Cell Carcinoma - Episode 7
Transcript:Robert A. Figlin, MD: So, Martin, that leads us nicely to a very complicated area. So here we’re talking about radiographic progression or clinical progression on a targeted agent and along comes our newest agent improved in the clinic, nivolumab, a checkpoint inhibitor. To set the stage, help us understand the population that was studied, the results from the pivotal trial that was published in the New England Journal. And really, from your point of view, when do you think it’s appropriate to think about using checkpoint inhibitors in kidney cancer? And lastly, and I’ll ask Nizar and Sandy to weigh in, we’re different than melanoma and different than lung cancer. We may not have a biomarker to help us choose the winner, so to speak, so it’s a very complicated area and, as Nizar pointed out, there is this area of so-called pseudoprogression. So help us synthesize that body of information so that someone who’s thinking about a checkpoint inhibitor for their patient can decide when and if to use it and then how to evaluate its benefit.
Martin H. Voss, MD: So checkpoint inhibitors, particularly PD-1 and PD-L1 inhibitors, have now been in clinical trials for RCC for a few years. But nivolumab, the first approved agent, has really only been on the market with an FDA label for advanced kidney cancer since the fall of last year, 2015. And the agent was approved based on the pivotal CheckMate 025 study, as you say was published in the New England Journal of Medicine in 2015. And it was a phase III trial that enrolled patients who had been treated with one or two prior TKI VEGF-directed agents. It randomized patients to receive either nivolumab at a dose of 3 mgs/kg every two weeks intravenously or everolimus, which based on the RECORD-1 trial and is FDA-approved in patients pretreated with one or two prior TKIs—so really the best standard of care for comparison in a randomized trial.
The primary endpoint for this study—and that was very interesting and highly anticipated by the field—was overall survival. So the trial set out to show a median overall survival benefit of nivolumab over everolimus, and that is something we haven’t seen in a while. Many of the agents—in fact, all agents, with the exception of temsirolimus—are FDA-labeled for advanced kidney cancer and were approved based on pivotal trials that showed progression-free survival benefit. And it’s been difficult in the past to show overall survival due to the fact that patients go on to receive other agents.
The reason that overall survival was chosen for nivolumab on the CheckMate 025 study was due to a signal that was seen on the phase II randomized dose-finding study, a large trial of about 100 patients that received nivolumab at different doses. And looking at the progression-free and overall survival data on that phase II study, median progression-free survival didn’t seem to be so striking compared to historical controls. But the median OS signal was quite strong on the phase II trial and ultimately motivated the primary endpoint of OS. Certainly, the mechanism of action, immune induction with hope for a more lasting effect against cancer biology than a tyrosine kinase inhibitor, also motivated that choice of a primary endpoint.
The trial was positive. It did prove superior in terms of median overall survival, which was, I believe, around 20, 25 months for the nivolumab compared to around 19 months for the everolimus. There are various secondary endpoints that were investigated on the study. Progression-free survival, interestingly, was not different between the two agents. But what’s most relevant to me was that tolerance was also compared, as was quality of life, patients’ reported outcomes. And all of those favored investigational agents. So nivolumab did have a more favorable toxicity profile, and that’s certainly been my experience also in practice compared to the mTOR inhibitor. And quality of life measures were significantly better for nivolumab compared to everolimus.
Back to your other question. How do we integrate this data now in how oncologists should choose the agent for the treatment of advanced kidney cancer? So I think it’s important to keep in mind that the phase III data that led to the approval of this agent was in VEGF inhibitor—pretreated patients. Patients that have failed treatment with a VEGF TKI can be considered for this drug. That’s where we have safety data and where we have efficacy data; certainly reasonable to consider it as a second or third-line agent in patients that reflect the study population of CheckMate 025.
My own experience—and I think that’s important to investigators, I should say to oncologists who are not used to using these agents on clinical trials—is that nivolumab is a very tolerable agent to give. The largest downside to it are frequent trips to a clinic; patients have to come every two weeks to receive the agent. But any patient who’s been pretreated with a TKI or two will tell you that they’ll gladly do that for a little bit and feel better on a day-to-day basis in terms of their toxicity profile. It’s important to know about toxicities, and I think it’s something that the field has to learn about. These are different toxicities from what we’re used to from molecularly targeted agents, and they can be misinterpreted and mismanaged.
So all the toxicities we see with these checkpoint inhibitors, we think they are mediated by the immune system, and they can be vague and low-grade like fever or just fatigue. And they can be very organ-specific, and it’s unusual to see that for nivolumab alone, but they can also be high-grade and can put a patient into the hospital requiring steroids. On the phase III trial, grade 3 and 4 toxicities were not infrequent. About 20% of patients treated with nivolumab on the study had treatment emergent events that were grade 3 or 4. In my experience, if recognized early and treated well, these are very manageable toxicities.
Transcript Edited for Clarity