CHECKMATE-914 Phase 3 Kidney Cancer Trial [2022]
CHECKMATE-914 Trial
I’m going to talk to you today about CHECKMATE-914 clinical trial, which was an adjuvant study of Ipilimumab plus Nivolumab (in combination) in high risk resected kidney cancer.
The background of this study (CHECKMATE-914 trial) is that About a year or so ago, we had the first data for adjuvant (treatment) immun0therapy and kidney cancer (localized renal cell carcinoma RCC), which was from the keynote study of adjuvant Pembrolizumab versus placebo and resected, high risk localized kidney cancer. That study (CHECKMATE-914 trial) and its follow up showed a significant disease-free survival advantage, a trend towards overall survival (disease free survival), but not yet significant.
So the data is still pending, but based on that data, the drug was FDA approved and is relatively commonly used in that circumstance of, again, resected high risk kidney cancer (localized renal cell carcinoma). On this background, several other studies were conducted. CHECKMATE-914 (trial) is one of those studies. The study (CHECKMATE-914 trial) gave 6 months of adjuvant (treatment) Ipi/Nivo (Nivolumab and Ipilimumab) compared to placebo in a very similar high risk resected population.
Somewhat surprisingly, this study was negative. It did not show a disease free survival (DFS) advantage in patients who received Ipi/Nivo (Nivolumab and Ipilimumab) in that setting. It’s a little bit hard to explain. We know Ipi/Nivo (Nivolumab and Ipilimumab) is active in the advanced (cancers) setting. It’s an approved regimen based on CHECKMATE-214. So the drugs are clearly active.
Immune therapy is clearly active based on the Pembrolizumab study, so the field is scratching. It’s a little bit about these results. There was difficulty delivering the. So I believe only just over 50% of patients got all doses of Ipi/Nivo (Nivolumab and Ipilimumab). It can be a very toxic regimen, especially in this setting.
And so it may have just been a drug delivery issue. Not enough drugs were given. It was also only six months of therapy compared to 12 months of Pembrolizumab. So maybe, you know, the amount of therapy and duration of therapy really matter in this setting. Having said that, the study (CHECKMATE-914 trial) was pretty flat. So, you know, whereas the Pembrolizumab study was cleanly positive, this was flatly negative.
So it may be, but it seems to me there’d be more than that. There’d be more than just what I mentioned about drug delivery or duration. But otherwise, the populations appeared fairly similar from a (high) risk standpoint. I don’t think there were, you know, other major differences in patient (populations) characteristics. So, importantly, there is a (study comparing) Nivolumab monotherapy arm of that clinical trial that has yet to be reported.
It was added later. That’s probably the most similar to the Pembrolizumab study and so we’ll see what that shows, you know, in the next year or so when it’s reported and, and again, maybe it’s just a toxicity issue. The other thing to mention is that there were two other studies that reported ESMO, along with the Checkmates study (CHECKMATE-914 trial (Ipi/Nivo (Nivolumab and Ipilimumab)), which were also negative.
One was EMOTION-010. What a study that was. Adjuvant Atezolizumab a PDL1 inhibitor versus placebo, and there was a US cooperative group study called prosper, which was a single dose of neoadjuvant (study comparing) nivolumab (incombination) plus adjuvant (treatment) nivolumab versus observation. Both those studies were similarly negative. There is no benefit to being disease-free survival (DFS) or overall survival.
The Atezolizumab study may explain why PDL1 inhibitors are probably less active in kidney cancer (localized renal cell carcinoma) than PD1 inhibitors, at least in combination in the advanced setting, maybe a single agent in the advanced (cancers) setting. So that study was very similar to Keynote, but again, negative. And then the US Cooperative Group study had a lot of problems in getting drugs into patients. Giving neoadjuvant therapy is more difficult.
It was conducted when COVID patients needed a biopsy. For various reasons, about a quarter of patients never got the intended therapy, and we don’t know all the details yet. So I hope this doesn’t close the book on neoadjuvant therapy and kidney cancer (localized renal cell carcinoma). We saw some melanoma data at ESMO that was very promising.
So the scientific rationale makes sense. The delivery and the execution of the study weren’t ideal. And I think the jury’s still out, but nonetheless, it’s a negative study. So in adjuvant immune therapy and kidney cancer (localized renal cell carcinoma), we now have one positive study with Pembrolizumab, three negative studies that I just alluded to, and one study pending with Mab and Tremelimumab.
So, the field is kind of taking a step back a little bit. I think Pembrolizumab is the results are still positive. It’s still a good drug and will be used in that setting, but I think when you have three negative studies, although we can explain each one, it certainly causes you to step back and get some perspective and maybe think about the benefit risk in a little different light than we did before.
And I do discuss this with patients when I’m talking about Pembrolizumab that, hey, just so you know, there are three studies that were negative and, you know, want to have that sort of more thorough benefit-risk discussion with patients. So we’ll wait for that final study. We’ll see how this other data matures.
We’ll see the manuscripts, which give more detail. But the field of adjuvant immune therapy and kidney cancer, I think, is very much an evolution.
What Made You Study Kidney Cancer?
So my journey into kidney cancer began when I was probably a resident at the University of Chicago, which was in the late nineties.
And my mentor there was a doctor named Nick Bogo, who actually just passed away in the last several weeks. And Nick was a very charismatic, enthusiastic oncologist, and I got caught up in his energy when I was a resident. I knew I liked research and clinical research, so I was thinking about oncology and maybe cardiology.
As they sort of naturally lend themselves to that, and then I got on service with Nick and just sort of got caught up in his teaching and his enthusiasm and decided I wanted to be an oncologist. And then when I started my fellowship, which was also at UCSF, this would’ve been in 1998.
I started working with him and Walt Staler and got involved in some projects, and I really like GU oncology (genitourinary cancers) more broadly because there are four very different diseases that have different treatments and different patients. I like working with urologists and kidney cancer patients. At the time, again, this is in the late nineties, had one FDA approved drug high dose center, Interleukin-2 (IL-2) it was well before the TKI (tyrosine kinase inhibitor) era and then now the immune therapy or et cetera.
So it was really at a point. In my estimation, there was a lot of opportunity. It was the people, it was the institution, it was the timing. It was an opportunity. And then pretty soon after that, when I started, my first faculty job at UCSF was when the TKI started to be developed and be tested in kidney cancer. It is pretty clear.
There was activity, and things sort of took off from there over the last two decades.
Dr. Brian Rini – COSMIC-313 Phase 3 Kidney Cancer Trial [2022]
Link
https://oncologytube.com/v/41347
Brian Rini, MD – About The Author, Credentials, and Affiliations
Dr. Rini is the Chief of Clinical Trials, Ingram Professor of Cancer Research and the Professor of Medicine (Medical Hematology/Medical Oncology) at Vanderbilt Ingram Cancer Center.
He was the associate Professor of Medicine at Case Western Reserve University’s Cleveland Clinic Lerner College of Medicine in Cleveland, Ohio is Dr. Brian I. Rini. Rini received his medical degree from Case Western Reserve University. As an Associate Director for Clinical Research at the Cleveland Clinic Taussig Cancer Institute and a member of the Department of Solid Tumor Oncology, Dr. Rini’s research is concentrated on genitourinary cancers.
Dr. Rini received her medical degree from the Ohio State University College of Medicine in Columbus, which is located in the state of Ohio. After finishing his residency in internal medicine at the University of Chicago Hospitals in Illinois, Dr. Rini went on to receive a fellowship in hematology and oncology at the University of Chicago. At the Cleveland Clinic, Dr. Rini’s primary areas of research interest have been centered on renal cell carcinoma (RCC) as well as prostate cancer, with a special emphasis on antiangiogenic therapy and immunotherapy.