COSMIC-313 Phase 3 Kidney Cancer Trial [2022]
COSMIC-313 Kidney Cancer Trial
I’m going to talk today about COSMIC-313 ( Ipi/Nivo (Nivolumab and Ipilimumab)), which is a clinical trial just reported as more of the latest phase 3 data in advanced kidney cancer (advanced renal cell carcinoma).
The background of the COSMIC-313 ( Ipi/Nivo (Nivolumab and Ipilimumab)) study: this was a study looking at Ipi/Nivo (Nivolumab and Ipilimumab) as a comparison arm, which, as you probably know, are two immune therapy drugs that are a common frontline treatment (components) in advanced RCC (advanced renal cell carcinoma). And it was compared to a triple combination that used Ipi/Nivo (Nivolumab and Ipilimumab), adding Cabozantinib, which is a small-molecule VEGF receptor inhibitor.
And so the background of this study (COSMIC-313), as mentioned, is that the Ipi/Nivo (Nivolumab and Ipilimumab)
standard of care, Cabozantinib, and other similar drugs clearly have activity and were what we used before immunotherapy existed. And so to a question that emerged in the field as these immune-based doubles became standard. Would a triplet sort of combining both immune drugs and a VEGF receptor inhibitor provide additional benefit?
So, as we already said, the patients treated in the COSMIC-313 ( Ipi/Nivo (Nivolumab and Ipilimumab)) study were given either the trip, which is what we usually call Ipi/Nivo (in combination with Nivolumab and Ipilimumab) Cabo, or Ipi/Nivo (Nivolumab and Ipilimumab) plus a placebo. So in essence, the ipi is the standard Ipi/Nivo (Nivolumab and Ipilimumab) double. This was frontline clear cell (component) kidney cancer (renal cell carcinoma). It was about, I believe, 800 to 1000 patients treated. What was reported as Ipi/Nivo (in combination with Nivolumab and Ipilimumab) was given to the first 550 patients treated randomized, and it looked at (median) progression-free survival as an (primary) endpoint but also, importantly, overall significant survival benefit and other measures of toxicity.
What was seen as an advantage in (median) progression-free survival? The hazard ratio was about 0.73. Some of the medians haven’t been reached. The follow-up was only about 18 to 20 months. So pretty early data, but a significant advantage in progression-free survival (significant survival benefit). This wasn’t terribly surprising. There’s an approved double of Cabo plus Nivo, so leaving out the Ipilimumab, which showed a pretty robust response rate and progression-free survival (PFS).
So I think when there’s a TKI as part of the regimen, you get enhanced tumor shrinkage, you get higher response rates, and you get longer progression-free survival (PFS). Overall survival was not significant. The data was not shown. It was only mentioned in a press release, which said that the overall survival was not important and was still young.
So there will be other follow-ups for this study (COSMIC-313) and that may or may not reach significance, but not at the present time. And I think most people would take the results as I just relayed them. important, but must be postponed for the sake of overall survival And the reason is that there was a fair amount of toxicity with this triplet. As you might imagine, both Ipi/Nivo (Nivolumab and Ipilimumab) and Cabo separately can be toxic, and certainly combining them can have toxicity.
So almost 60% of patients treated required high-dose steroids. There was a high rate of reduction of Cabozantinib from 40 milligrams to about 20 milligrams on average in the 2 (control) arms. And a lot of dose reductions, discontinuations, grade 3, toxicity, everything that comes as we give patients more drugs.
And so you know, because of the toxicity, some of the drug delivery was compromised. The percentage of patients who got the full four doses of Ipilimumab was reduced by about 15% in the triplet (control) arm and other measures of produced drug delivery that I alluded to. So, while PFS had an advantage.
I believe the majority of folks like myself, who interpreted the data, said we really need to wait for overall survival to adopt this regimen into practice. It’s very difficult to give and results in a high level of toxicity, which may have compromised drug delivery and therefore may have compromised outcomes. Again, we still need to wait to see.
There was a slight response rate advantage, I believe, about 43 versus 37%. Both of those numbers are about what you’d expect with hippy nivo alone. The complete response rate was only 3% in both arms (control arm), which was actually quite. Again, it’s early data that’ll probably go up over time, but I don’t think we saw any non-overall survival signals that would compel us to use the regimen.
For instance, if the CRA was 20%, the response rate was 80%. The PFS was 2.5 to 3 years, some very, you know, gaudy, non-overall survival results could have supported use of that triplet (triple therapy). We didn’t see that, at least in this early report. We didn’t see that. I don’t think we’ll see it. And so, therefore, we’re sort of the use of this regimen will hinge on overall survival.
This study (COSMIC-313) is really important because it’s the first triplet (triple therapy) study for kidney cancer (renal cell carcinoma ARCC). Again, doublets are the standard of care. So this was the first foray into the triplet arena. There are other large triplet studies going on, at least one that Merck is doing, using Belzutifan HIF inhibitor and also a CTLA-4 inhibitor.
So, variations on the theme of COSMIC-313 ( Ipi/Nivo (in combination with Nivolumab and Ipilimumab)), I think, are important in different and different ways. We’ll see how that study turns out. And it may be that, as a field, we’re going to need to take a step back and say, “Gee, we can’t just give all patients three drugs.” Let’s work harder at developing biomarkers. Let’s work harder at strategies, maybe to sequence drugs as opposed to giving everything up front.
I have a feeling that’s kind of where we’re headed as a field. But again, the COSMIC-313 were important data because they were the first triplet (triple therapy) data that we’ve seen in kidney cancer, as mentioned, with more to come. And so we’ll see where the field takes us from here. It is an exciting time in RCC; a lot of is activity in the frontline setting, and this is just the latest wave of therapy.
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 (medical oncology), 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 (trial) research, so I was thinking about clinical oncology and maybe cardiology.
Because they naturally lend themselves to that, and then I got on service with Nick and got caught up in his teaching and 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 geo oncology 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. Again, this was in the late 1990s, and there was only one FDA-approved high-dose center drug at the time, lukin two; this was well before the TKI era, immune therapy, and so on.
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 – CHECKMATE-914 Phase 3 Kidney Cancer Trial [2022]
Link
https://oncologytube.com/v/41348
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 medical hematology and medical 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.