Toni Choueiri, MD: Dr. Braun, what about KEYNOTE-426 in a minute?
David A. Braun, MD, PhD: KEYNOTE-426 really was a landmark study. It really was the leader of the pack in terms of combining IO [immuno-oncology] with TKI therapies, as Dr. Orenstein mentioned. So, it was a phase three randomized trial of the combination of pembrolizumab, the anti-PD-1 antibody, with axitinib, a very specific VEGF/RTKI. So, that combination against sunitinib. And really demonstrated in the initial findings, superiority across the board. So, complete in terms of response rate, progression free survival, overall survival really led the field in terms of bringing IO plus TKI combinations to the forefront in kidney cancer. Now, as time has gone on, I think one of the interesting things, just as many have observed is, whereas for CheckMate-214 there's this really durable response, there definitely is benefit of pembrolizumab plus axitinib. But at least numerically, some of those seeming benefits have gotten a little bit smaller over time. Whereas the initial publication from Dr. Rini in New England Journal, there was really- What was a jaw dropping hazard ratio for overall survival of 0.53. As the follow up has increased, that hazard ratio has gone a little bit higher, and it's gone closer and closer to within the range of benefit but currently 0.73 for overall survival. So, the question in my mind is, is that a bit of a canary in a coalmine for IO [immuno-oncology] plus TKI in general in terms of whether there's that same durability that we see with the IO/IO ipi [ipilimumab] based combination. But nevertheless, still a landmark study. It's a really attractive first line option for many with advanced clear cell kidney cancer.
Toni Choueiri, MD: And I can comment a bit on the new kid on the block, which is a combination of lenvatinib, another TKI, plus pembrolizumab. This was the CLEAR Trial. And actually the CLEAR trial is the only trial now among all these VEGF/IO combination or IO/IO combinations that had a three arm. Control was sunitinib but they went two experimental treatment, the lenvatinib/pembro [pembrolizumab], that's the VEGF/IO, but also lenvatinib/everolimus. A regimen approved in second line post-progression on TKI [tyrosine kinase inhibitor]. And it's only the lenvatinib/pembro arm that showed a progression free survival, a response rate benefit and an overall survival benefit. The combination of lenvatinib/everolimus was thought to be a potential frontline runner in a non-IO setting but unfortunately, despite the response rate and the PFS [progression-free survival] benefit, overall survival was not met and the hazard ratio actually for OS [overall survival] was over one, this combination. Len/everolimus wasn't approved but the len/pembro [lenvatinib/pembrolizumab] was approved. Interesting enough, the response rate was the highest to date, over 70% from a phase three trial. The CR, 16% and the PFS close to two years here was that combination. Of course, we don't want to compare across trials, but one of the things was the len/pembro [lenvatinib/pembrolizumab] as well as the axi/pembro [axitinib/pembrolizumab] is the baseline criteria tend to favor a bit, just a bit more so IMVC favorable risk patients. So, I think these are the most important. Hopefully, you will ask about the things and the trials that are your most interested with including some including triplet as well as some of the intergroup trials.
This transcript has been edited for clarity.
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