Long-Term Ipi/Nivo RCC Data Show Durability Across Risk Groups

Ulka Vaishampayan, MBBS

Professor of Internal Medicine

Director of the Phase I program

Rogel Cancer Center, University of Michigan

Ann Arbor MI

Targeted Oncology: What are the most updated data supporting dual immune checkpoint inhibitor therapy in patients with advanced clear cell renal cell carcinoma (RCC)?

Vaishampayan: This was the CheckMate 214 study [NCT02231749] with nivolumab [Opdivo] and ipilimumab [Yervoy]. The ipilimumab dose was 1 mg/kg every 3 weeks, and nivolumab was 3 mg/kg, with a maximum of 4 doses of ipilimumab. Arm B was sunitinib [Sutent]. Treatment [continued] until progression or unacceptable toxicity; all different risk groups were involved but the study was powered to look at PFS [progression-free survival] and OS [overall survival] in the patient population with intermediate or poor risk. The primary end points were objective response rate, OS, and PFS.

The data on OS now with over 8 years follow-up showed at a median follow-up of 99 months, one-third of the [intermediate/poor risk] patients were alive [32.9% OS rate with ipilimumab/nivolumab vs 22.0% with sunitinib at 90 months].¹ That is the track record so to speak, because they’ve had longer time than the other studies. But the bottom line is, that tail end of the OS curve that was sustained with ipilimumab/nivolumab is remarkable. The median changed [since previous follow-up]. There was a 20.7-month difference [in OS between ipilimumab/nivolumab and sunitinib in the intermediate/poor risk population].

Is the median OS in the comparator arm of sunitinib of 26.0 months notable on its own?

I don’t know [because] some of them were potentially salvaged with immune checkpoint inhibitor [ICI] therapy. Doing single-agent treatment sequentially definitely [was done], because single-agent nivolumab was approved right around the time when the study had started or was happening through accrual.

What was the duration of therapy with nivolumab in this study?

This is the only study where the ICI therapy was continued [indefinitely]. For this study, we had no guarantees that we could get it [off trial] if we stopped the patient. For the patients who were benefiting, I was too scared to stop them.

Do you now stop at 2 years based on the data from other studies where ICI was discontinued?

I at least start having the discussion to [stop nivolumab], and a few of them I have stopped and put on something else. So I’m doing that. After single-agent nivolumab…I’ve had some relapses 2 to 3 years later, where I’ve had to restart that way, but it’s been slow. Nobody’s relapsed with major symptomatic disease, as far as I can tell. The moment [nivolumab] was approved and I was assured that I would be able to get it, all of us started having that discussion on stopping the therapy. But all the other VEGF TKI [tyrosine kinase inhibitor] and ICI combinations have used that limit for ICI, 2 years maximum. [The longest I treated a patient for] was 4 and a half years, then I stopped him.

What do we know about the outcomes across the risk groups with ipilimumab/nivolumab?

Looking at the intermediate-poor risk [population] vs favorable risk, favorable risk has always been the dilemma in ipilimumab/nivolumab. Is [favorable-risk disease] where we should go with a single-agent TKI? [Ipilimumab/nivolumab] is showing an [OS] benefit now in the longer term, approximately 8% improvement [42.8% OS rate at 90 months with ipilimumab/nivolumab vs 34.4% with sunitinib], but these are the patients who have the possibility of being able to sequence and do all the different possibilities.

It makes you think about in the favorable-risk [group]—should you offer that long-term vision, especially for the young, otherwise healthy patients even if they are asymptomatic? Looking at the long game, it is important to consider. Right now, the FDA approval is in intermediate and poor risk. In those patients, you’re seeing that difference in OS with the tail end of the curve. [When] both these groups are combined, it came to about a 11% difference at the tail end. What’s interesting is that the curves separated very early on, in the first 4 to 6 months, and it continues all these years.

There is a difference in PFS now at 24 months. At 12 months, we didn’t have a big difference. But at 2 years, the curves started to separate and [the PFS rate is 25.5% for sunitinib] vs 36.8% [for ipilimumab/nivolumab]. The patients who are showing PFS also continue to stay alive in the longer term. We know long-term OS is 33% in this patient population.

For the responders, the magnitude of difference is much bigger. We’ve always known that when you pick responders [there is a greater difference]. But it is important to see that if somebody is responding to ipilimumab/nivolumab, you can say that your chances of going longer term are 50/50, which is a pretty good statistic to give patients. It is the same thing for favorable-risk patients; if they’re responding, it takes them a while to respond. But when they do, 37% [continue to respond at 90 months with ipilimumab/nivolumab] vs 14% [with sunitinib]. With a TKI, they don’t last that long progression-free, but duration of response does tend to make a difference. With the complete responders, there was an 80% chance that they would stay in long-term OS [53 of 66 complete responses ongoing]. So if they have a response, it’s about 50/50 long-term remission, and if they have a complete response it’s even higher.

_Reference:

_{1. Tannir NM, Escudier B, McDermott DF, et al. Nivolumab plus ipilimumab (NIVO+IPI) vs sunitinib (SUN) for first-line treatment of advanced renal cell carcinoma (aRCC): Long-term follow-up data from the phase 3 CheckMate 214 trial. J Clin Oncol. 2024;42(suppl_4):363. doi:10.1200/JCO.2024.42.4_suppl.363}