Expert Discusses What's Next for Opdivo in Kidney Cancer

Opdivo (nivolumab) improved both survival and quality of life for patients with advanced renal cell carcinoma (RCC) and is changing the way the disease is treated.

The potential for the PD-1 inhibitor, which was approved by the FDA in advanced RCC based on findings from the CheckMate-025 trial in November 2015, has only continued to grow since it first hit the market. A recent analysis, which looked at long-term data from phase 1 and phase 2 clinical trials of single-agent Opdivo in RCC, found that one-third of patients were still alive at four and five years. In addition, responses were shown to be consistent across patient subgroups.

These findings are significant, says David F. McDermott, director of the Biologic Therapy Program at Beth Israel Deaconess Medical Center.

“Compared to what we were dealing with five or 10 years ago with kidney cancer, these are encouraging data,” he says. “The interesting thing about Opdivo is that this may have an impact on a broader range of patients. Obviously, we need to look at it in the phase 3 trial and we will need more maturity of that data, but it is very promising.”

What were the goals of your analysis?

In an interview with CURE, McDermott provides further insight on the long-term efficacy and safety of Opdivo and its role in RCC. He also discusses potential combination regimens, as well as challenges with sequencing Opdivo.In the phase 3 CheckMate-025 trial, Opdivo was significantly superior to Afinitor (everolimus) in patients who had failed prior antiangiogenic therapy, with improvements in overall survival (OS), quality of life and safety. However, the follow-up on that trial was relatively short, with a minimum of 14 months.

The question we tried to address looking at the phase 1 and phase 2 trials was, with longer follow-up, what might we see in the phase 3 trial? This was a way of potentially looking into the future. We looked at the outcomes of about 200 patients who were treated on the phase 1 and phase 2 studies, and we found some interesting things. For example, the median OS was 22 months in the phase 1 and 2 trials. Now, with over 48 months of follow-up on both trials, approximately one-third of patients were alive at four years. In the phase 2 trial, where we have five years of follow-up, one-third of patients were alive, as well.

What did you learn in terms of the safety profile of Opdivo?

Do you think Opdivo is here to stay in RCC?

Then, we started comparing what we saw in subsets of patients in those trials with what we saw in the phase 3 trial. We looked at some clinical characteristics as they related to long-term outcome on the phase 1 and 2 trials. What we found was that neither prognostic group, initial response or performance status seemed to predict which patients would be alive at four years. This means that we saw survivals in all subgroups, which is very interesting to us. You would think that survival would be lower in patients who had poor-risk disease, progression as their best response, or reduced performance status.When you give an immunotherapy for two years or more, there is a question as to what the toxicity will look like. Interestingly, similar to how the responses happen early within the first six months, so does most of the toxicity. If you look behind six months in the phase 1 and 2 trials, the toxicity incidence seems to decrease. Out beyond 30 months in the phase 2 trial, we didn’t observe any treatment-related adverse events. That is encouraging for patients who need chronic therapy to remain in benefit. They are not accumulating significant toxicities—at least not on that trial.Absolutely. The phase 3 trial is about the cleanest study that we have ever had in kidney cancer. We saw clear improvements in OS, quality of life, and safety. They were meaningful improvements—not just statistically significant improvements. Patients benefit from a chance not just for long-term survival, but a benefit that lasts when the drug is stopped.

Are there studies investigating Opdivo in combination with other agents in RCC?

Although it doesn’t happen in most patients, it is a very exciting potential benefit for patients. We need to increase those numbers, we need to potentially shorten the duration of treatment for patients who are in response, and we need to look at combinations. We also need to look at better selection, since over one-third of patients didn’t seem to benefit much from Opdivo. We need to improve all of those things. There is a lot of interest in doing that, so hopefully we can expand its benefit. However, it is here to stay for sure.Some of these combinations have already made their way into phase 3 trials. For example, the CTLA-4 and PD-1 combination of Yervoy (ipilimumab) and Opdivo is already in phase 3 trials. We are awaiting those results. There are some VEGF strategies being combined with PD-1/PD-L1 blockades that are either in phase 3 trials or moving there.

Are there challenges with sequencing immunotherapies?

In the next few years, we are hopefully going to see PD-1 as a backbone with a variety of frontline options for patients. The right patient might be able to receive it earlier in the course of their disease.That is the big question. With all these new agents, how do we prioritize them? It is hard because we don’t have a lot of comparative data to compare new agents, such as Cabometyx (cabozantinib). That has also been shown to improve response rate, PFS and OS in a similar population. That is another option for patients, which is exciting.

What I prefer about PD-1 blockade is that, on top of the OS benefit, you also see relatively good tolerability in most patients. However, there can be rare and serious side effects. With PD-1, you also see improvements in quality of life. It is very appealing to patients. I tend to use Opdivo as a second-line option, but Cabometyx is a completely reasonable option in that space. With both agents improving survival, that is great for patients.