CheckMate 8Y8 Trial in Progress: What Are the Implications for This Doublet?

A roundtable discussion, moderated by Brian Rini, MD, of the Vanderbilt University Medical Center, focused on the spectrum of therapy for frontline renal cell carcinoma (RCC), including a comparison of monotherapy and doublet and triplet treatment options. Dr. Rini was joined by a panel that included Monty Pal, MD; Moshe Ornstein, MD; and Shuchi Gulati, MD, MSc.

In the next segment of the roundtable series, the panel discusses the CheckMate 8Y8 clinical trial, which compared nivolumab versus ipilimumab/nivolumab to determine the role of ipilimumab in patients with RCC.

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Dr. Rini: I’m going to jump ahead here to a trial we haven’t heard about yet, which is CheckMate-8Y8, which is nivolumab versus ipilimumab/nivolumab because the question is really around the role of ipilimumab. I think it has waxed and waned a little bit in RCC where it’s super important, there’s definitely a tail, to I’m not really sure.

We see this nivolumab monotherapy data and it look pretty good. It looks pretty darn good. Smaller study, not big randomized. Monty, maybe start with you. 8Y8 is ipilimumab/nivolumab versus nivolumab. We haven’t seen data yet, but probably should in the next year, maybe in the next 6 months. Predict what that trial is going to show and if you think the results, whatever that may be, are really going to shift the field, or is it going to be, if I’m an ipilimumab/nivolumab user, I don’t care. It’s a small study, I’m still going to use it. Is it going to make people shift their treatment patterns?

Dr. Pal: I think there’s going to be an advantage with ipilimumab/nivolumab over nivolumab monotherapy. The reason I’m suggesting that is that if you look across all of these single-arm experiences with monotherapy with immuno-oncology (IO), I think the high water mark might be Dave’s [McDermott, MD] data with pembrolizumab, with the response rates in the 30% range. I don’t see us getting to that mark of 40% to 45% with ipilimumab/nivolumab. That’s in the context of an international, phase 3 clinical trial. My prediction is there’s going to be a benefit. The degree to which we see benefit is going to questionable. Is it a non-inferiority study?

Dr. Rini: I don’t think it’s non-inferiority. It’s not big enough. I don’t remember if it’s progression-free survival (PFS) or overall response rate. It’s fairly small, which is a problem—smallish by phase 3 standards. I think it’s in the 450 range, so the power is limited.

Dr. Pal: That’s an issue, because I predict what we’re going to see is perhaps an advantage with ipilimumab/nivolumab, but even if it’s non-significant, I’m still probably going to favor that over monotherapy frontline.

Dr. Ornstein: You’re still going to end up with the same question. If there’s a marginal benefit to ipilimumab/nivolumab then the ipilimumab/nivolumab believers will say, the marginal benefit may hold out to the very end, and that’s why we’re giving this combination. We are not going to have that with nivolumab monotherapy. We’ll see.

Dr. Gulati: The question about what’s the specific population that did derive benefits? I don’t think this argument will go away because maybe we’ll see a bigger benefit for patients who have sarcomatoid histology, so I think this discussion will probably still happen, although we’ll have more data.

Dr. Rini: I think it’s a fine trial. I agree with basically the consensus that there will be some small differences, maybe a 5% response rate difference, and I don’t know, PFS will be 3 months more. There won’t be a survival difference. That tail of the curve, we’re certainly not going to see with initial data. To your point, Moshe, we’ll have to wait. If you’re in the ipilimumab/nivolumab camp, this will not take you out of it. If you’re in the IO/tyrosine kinase inhibitor (TKI) camp, this will not put you in it.

Dr. Ornstein: I think the question is, does it change the minds of the regulatory authorities overseas?

Dr. Rini: Right. That’s why it was done, so stay tuned for that.

Dr. Pal: This whole dialogue around contribution of components with immunotherapy is so interesting. Because I think we’re starting to enter into this era where you have components like LAG-3, which as monotherapy probably don’t do a whole lot. But they’re intended to really augment the IO backbone that they’re put upon. I think there’s going to be a lot of this down the line.

Dr. Rini: …as we get more immune drugs.

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Continue on to watch the next roundtable segment.