ASCO GU Data Updates: KEYNOTE-564 and CheckMate 914

A roundtable discussion, moderated by Brad McGregor, MD, focused on the latest data in RCC treatment and management, including data from the American Society of Clinical Oncology Genitourinary Cancers Symposium 2024. Dr. McGregor was joined by Rana McKay, MD; Elizabeth Wulff-Burchfield, MD; and Alan Tan, MD.

In the first segment of the roundtable series, the panel discussed two studies that assessed adjuvant treatment: KEYNOTE-564 and CheckMate 914.

Watch the next segment in this series.

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Dr. McGregor: We’re really excited to be here, as we conclude the 20th anniversary of the GU Cancer Symposium, with GU Oncology Now, talking about some updates from the last day, always the last day of the symposium, the kidney cancer day. I would argue, maybe because I treat kidney cancer, that I think this is probably the most exciting day of the meeting, and we saw some really impressive data on long-term follow-up as well as some exciting adjuvant data.

I think before we go into the metastatic disease, let’s really focus on the adjuvant setting because that’s going to be where we can hopefully cure patients and put us out of a job. We had 2 nice updates in adjuvant. We had KEYNOTE-564 and we had CheckMate 914. Libby, what are your thoughts about this data now that you put into context?

Dr. Wulff-Burchfield: It’s a great time to be a genitourinary medical oncologist. We have better tools than, frankly, I imagined when I was a trainee that I’d have to offer patients with advanced or with high-risk kidney cancer. It was fantastic to see that KEYNOTE-564 has demonstrated benefit to overall survival for patients receiving pembrolizumab in the adjuvant setting, and it really cements it as the greatest innovation that medical oncology has had to offer to patients with more locally advanced kidney cancer.

Dr. McGregor: Toni [Choueiri] even alluded to this, like since 1973, how many patients have been in trials, and this is the first trial to show any sort of overall sort of benefit. But Alan, do you want to talk about like what patients sort of fit into that trial?

Dr. Tan: When the first data set came out a couple years ago, I think there was still a third of people saying that they would do it. A third would say they would do it for select populations and a third of people would say that they wouldn’t do it at all. But I think now that you actually have overall survival as the benchmark that has been met, I don’t see how you couldn’t at least talk to the patient. I can understand if the patient has a lower risk maybe T2 or maybe T3, you could perhaps argue that that patient might not be at that highest risk population, but in the melanoma world, the patients have been getting adjuvant immunotherapy for several years without overall survival advantage. It always confused me why it was such a tough decision in kidney cancer, where patients really do desire the opportunity to have a cure. Sure, 50% of patients are probably over-treated in this population and they’re probably cured with surgery, but that’s a high percentage of patients that aren’t cured with surgery and they should get some adjuvant therapy.

Dr. McKay: I think of all of the studies that were presented at the meeting, hands down, the data for KEYNOTE-564 were the most impactful. This is a landmark time across all solid tumor malignancies and hematologic malignancies, I guess. We have demonstrated that adjuvant immunotherapy actually improves overall survival.

This is a huge win for our patients and something that I think can be even applied into practice next week when you’re seeing your patients in the clinic. I think it’s really highly relevant. I think the biggest thing that people grapple with around the receipt of therapy is patient selection and are we selecting the right patients that do have the highest risk because the way that we treat people in the frontline is a little bit different. In the adjuvant setting now with monotherapy is different than our combination IO regimens in frontline. There’s this grappling of, I’m over-treating some, I’m under treating some, but there’s a group that’s in the sweet spot and how can we better define that group.

Right now, in the absence of a biomarker, we really have to align with the eligibility criteria for the trial, which is T2 grade 4, T3, T4, N1, M1 NED, and N1 patients. I think these data are really, landmark. I think they’re absolutely practice changing.

Dr. McGregor: For clear cell I think is a key point. We really want this thing to happen in our papillary and chromophobe clear cell. The M1 NED, that’s a very small subset, but really pronounced benefit from looking at TFS. Uniquely, it was like those early progressors within that first year. To your point, patient selection it a key aspect, and we’ve had a lot of other trials that have been presented with adjuvant therapy. We had the PROSPER trial looking at perioperative nivolumab. We had a trial looking at adjuvant atezolizumab. We had 6 months of nivolumab/ipilimumab we saw that from CheckMate 904. Then Dr. [Robert] Motzer presented updates from the second cohort looking at 6 months of nivolumab versus placebo.

Dr. McKay: I think the big question is, are those patients that you’re not curing in first line or in adjuvant, are they the same patients that you can actually cure them when they get to metastatic.

I don’t know that we know the answer to that, because those patients would potentially evolve to become favorable risk and we know the profiles for those individuals. I don’t I don’t know that we know that you can absolutely say the patients that are going to respond adjuvantly when they’re metastatic. I don’t think we can say that they’re the same population, so just save it for later.

Dr. Wulff-Burchfield: It’s tough, though, because we all have those intellectual questions, and in oncology with our patients who have advanced disease, we’re playing a chess game the whole time. From the moment we meet that patient, we’re trying to figure out how to position things perfectly, but it is hard to not know that, but it seems pretty clear that adjuvant pembrolizumab has great value and should be offered. Adjuvant nivolumab, we don’t have the justification to offer that right now.

It was interesting to think through, because of some of the earlier incredible efforts, but disappointments in some of the other trials, like PROSPER, for example, I think there has been a lot of theorizing about why that trial was not positive. Today, seeing that CheckMate 914 was negative also kind of raises questions. Was it really just design? Is it the molecule? Is it the populations? There’s some very hypothesis generating.

Dr. Tan: I think it leaves a lot of unanswered questions too. What do you guys think about PD-L1 versus PD-1? Or do we really think there’s a difference between nivolumab and pembrolizumab? Was it the 6 months versus the 12 months?

Dr. McKay: I absolutely agree with you, Alan. I think it’s multifactorial. I do think PD-L1 and PD-1 aren’t created equal in kidney cancer. I think there’s differences. As we think about CheckMate 914, it’s always easy to play Monday morning quarterback and look in hindsight and say the trial should have been designed like this.

But they included T1 patients. They excluded M1 NED patients, which are going to drive events and be higher risk. It was 6 months of therapy. The nivolumab monotherapy was grossly underpowered. It’s hard to say; I think there were design issues there, eligible patient criteria issues there.

Dr. Wulff-Burchfield: It’s sort of more about yes that trial is negative, but I think there are some of us who are still in the place of saying is that product? Are we convinced that that product really couldn’t ever affect it? I don’t think we’re necessarily convinced, but we have to see; the data speaks for itself. That’s kind of where things stand today.

Dr. McGregor: To that point, I think we should really commend thinking differently. A year of pembrolizumab, the year of immunotherapy is relatively arbitrary. Why do we do a year? I mean, I was actually really excited when we heard about CheckMate 914. I’m like, this is fantastic. Six months is so much better for our patients. Maybe they’ll have lower toxicities. Unfortunately, it didn’t pan out. It’s easy to look back and say, it’s obviously making it 6 months. But at the time I was actually really excited for that approach.

Dr. Tan: I don’t really think it’s the duration either because if you look at the DFS curves for nivolumab, it’s right along with the control arm, whereas with KEYNOTE-564, it actually separates within that first 6 months. What does that really tell us there? Especially the receptor occupancy studies. If you stopped at 6 months, do you think that receptor is actually off at 12 months?

Dr. Wulff-Burchfield: I agree. That target binding occupancy is high for a long time.

Dr. McKay: I think this data is awesome. Clearly, we’re helping some of our patients, but there are still some patients that progress. I think we can still do better in the adjuvant setting. Brad, you’ve been coordinating a study through the Cooperative Groups, which is going to integrate IO/TKI, short-term TKI, in the adjuvant space so I think we need to continue to support these studies to kind of capture that population.

Dr. Tan: This is for sure the backbone that we need to study, if the TKI should be included and I think HIF2 alpha should be also studied, and it actually already is.

Dr. McGregor: We’re greedy, but we see this great study. How do we do better? We want to do better for our patients.

Dr. Wulff-Burchfield: We owe it to our patients. We always need to do our best for them. They’re our purpose.

Dr. McGregor: I’m really excited. I think we have a solid foundation which we can build upon. We have a trial which showed an OS benefit. Let’s take it and run with it and let’s try to do better. Find the right patients, and maybe there’s patients you don’t need. We can do studies, look at what we have. As we do that, let’s try to add more. Let’s improve that. Right now, there’s a 5% improvement in survival at 4 years. Let’s make it 8%, 10%. Let’s shoot higher. Really exciting.

Dr. Tan: In kidney cancer, we’re not very good with the biomarker, unfortunately, and ctDNA is underperforming currently with commercial assays, so I’m really glad that your trial is going to be looking into some really interesting correlatives to try to see what we can do in that space.

Dr. McKay: Push the needle forward.

Dr. McGregor: I agree with Rana. I think that was probably one of the most impactful trials. It’s already approved. I think we’ll change the way we counsel our patients though.

Dr. Wulff-Burchfield: I agree. It will make those conversations much simpler. I just think less burdensome for the patient because we owe it to them to provide them comprehensive counseling and to make sure they have all the information they need to make an as informed decision as possible. When we did not have OS benefit, that was a lot to take in given the risks of these agents, but now it will be a relief, I think, on our part and theirs and their people who love them to know that, that they could be embarking on something with proven value that they can really conceive and embrace.

Dr. McGregor: What do patients think about this? Disease-free survival, we think about it, even though sometimes I don’t get it like, what does that exactly mean? But overall survival is so clear. Even if it’s for a year. Hopefully you have a better chance of being alive at 4 years than not, so I think it settles the debate in my mind with all these negative trials, like what do we do? But I think clearly it’s a positive trial.

Dr. McKay: Totally impactful.

Dr. McGregor: As we talked about, unfortunately that doesn’t always work. We still have patients that are going to relapse, so what do we do next? We’ve had phase 3 after phase 3 trial for a while. Now we’re actually seeing long-term follow-up.