Expert Discusses 2-Year Update of Pivotal Nivolumab RCC Trial

Elizabeth Plimack, MD

The benefit with nivolumab (Opdivo) versus everolimus (Afinitor) among patients with metastatic renal cell carcinoma (RCC) enrolled in the pivotal CheckMate-025 trial was sustained at ≥26 months of follow-up.

“At 2 years, we have 52% of patients on the nivolumab arm still alive. Again, the curves continue to remain separated and it looks like there is a bit of a plateau as well. There’s no new safety signal as patients get further out so that is also encouraging,” Elizabeth Plimack, MD, lead author of the 2-year efficacy update, said in an interview with OncLive at the 2016 Kidney Cancer Symposium.

Based on the primary analysis of CheckMate-025, the FDA approved nivolumab in November 2015 as a treatment for patients with metastatic RCC following prior antiangiogenic therapy. In the initial trial findings, nivolumab improved median overall survival (OS) by 5.4 months versus everolimus.

CheckMate-025 randomized 821 pretreated patients with advanced or metastatic clear-cell RCC in a 1:1 ratio to nivolumab or everolimus. Of the randomized patients, 803 received treatment. Nivolumab was administered intravenously at 3 mg/kg every 2 weeks (n = 406) and everolimus was given orally at 10 mg daily (n = 397).

The long-term data showed that at a minimum follow-up of 26 months, the median OS was 26 months with nivolumab versus 19.7 months with everolimus (HR, 0.73; P = .0006). The 1-year OS rates were 76% with nivolumab versus 67% with everolimus. The 2-year OS rates were 52% versus 42%, respectively. The overall response rate was 26% with nivolumab compared with 5% with everolimus.

There were no new safety signals and treatment-related adverse events (AEs) remained lower with nivolumab. All-grade AEs occurred in 79% of patients receiving nivolumab and 88% of patients treated with everolimus. Grade 3/4 AEs occurred in 20% and 37% of the 2 arms, respectively.

OncLive: Please provide an overview of your CheckMate-025 trial update.

In her interview, Plimack, chief of the Division of Genitourinary Medical Oncology and Director of Genitourinary Clinical Research, associate professor, Department of Hematology/Oncology, Fox Chase Cancer Center, discussed the 2-year data, as well as the remaining questions with nivolumab in this setting.Plimack: We have a poster here presenting data for nivolumab for the CheckMate-025 trial. That was the randomized trial comparing nivolumab to everolimus. We have data now with the minimum follow-up of 26 months for all patients. What's interesting is we're seeing preserved overall survival benefits.

What are the key remaining questions with nivolumab in this setting?

How do you decide if a patient should receive nivolumab over another therapy in this setting?

At 2 years, we have 52% of patients on the nivolumab arm still alive. Again, the curves continue to remain separated and it looks like there is a bit of a plateau as well. There’s no new safety signal as patients get further out so that is also encouraging. Of the patients who responded to nivolumab in the trial, almost a third of their responses—29%—have been maintained now at over 2 years. For this second-line trial, the median overall survival was 26 months, which was coincidentally the same as the minimum follow-up. That’s the longest survival we've seen in this setting overall.We don't know exactly when to give it, how to give it in combination, or where it works best. I think the one thing we do know is that our goal is durable response and cancer control, whether or not achieving this requires chronic treatment is not yet known. It's not clear yet that we're seeing that, although time will tell, when we're 10 years out from the first nivolumab studies, then we'll really know how durable these responses are. But right now, for this randomized trial of nivolumab in the second-line setting, we are 2 years out, so we have the benefit of data for that length of time and it's encouraging to see that patients are still doing well and there does appear to be a tail emerging on the curve.I think it's tricky. There are a lot of different options. There are more TKI options—there’s the TKI combination with lenvatinib (Lenvima)/everolimus (Afinitor), and the TKIs cabozantinib (Cabometyx) and axitinib (Inlyta) are still players—and then of course nivolumab.

The key in my practice is whether they had a nice response to their frontline TKI. If they did, I try to squeeze more out of that TKI pathway with another TKI approach. I think if they blew right through it, moving to nivolumab makes sense.

What immune-related adverse events do you normally see with nivolumab?

I think the key is you're selecting what to do next. Our renal cell patients, fortunately, are surviving long enough to see multiple lines of treatment and it's not uncommon in my practice, to have people in third-, fourth-, and fifth-line treatments for renal cell because they don't emerge as beat up from the newer therapies and also the treatments work better, so the patients are around longer. I think we're just trying to decide how best to sequence and not do “either/or.”There is no normal that we see with the immunotherapies. Unfortunately, they can be autoimmune events, but that category has very disparate features in how they manifest themselves in terms of symptoms. In general, there can be bad things that happen with these drugs and there was a recent article in The New England Journal of Medicine about the rare occurrence of cardiomyopathy as a result of nivolumab, and looking through all of the literature and finding the select few cases. I think it's different than with the TKIs where we can better predict the spectrum of side effects a patient might have, although, we can't predict it for a certain patient.