Clinical Trials Defining the NCCN Guidelines for Frontline Treatment of mRCC

Daniel J. George, MD: Monty, you can summarize for us some of the trials that define the National Comprehensive Cancer Network [NCCN] guidelines and some of the other guidelines we have for frontline therapy that have changed in the last 2 to 3 years to define both the TKI [tyrosine-kinase inhibitor] space in frontline therapy as monotherapy, as well as now the combinations IO [immune-oncology]/IO and IO/TKI. Walk us through the top-level studies and data that led to those approvals in the frontline space.

Sumanta K. Pal, MD: I'm going to try to do this in 2 minutes or less. It all started with CheckMate 214, didn’t it, which was the study of nivolumab/ipilimumab versus sunitinib in the frontline setting. We were all amazed with the initial data suggesting a profound benefit in progression-free survival, response rate, and overall survival, particularly in those individuals with intermediate- or poor-risk disease. Still, there is something to be said for how to manage good-risk patients based on that study. We can certainly dive into the details of that later.

The next study to report out is one that we don't talk that much about these days, but it has increasing relevance in other diseases; this is the trial with bevacizumab with atezolizumab versus sunitinib.This study demonstrated an improvement in progression-free survival with bevacizumab/atezolizumab versus sunitinib, but it fell short of demonstrating a benefit in overall survival. It's a little different from the data that we're seeing emerge with bevacizumab/atezolizumab in the context of lung cancer, recently with Impower150 in hepatocellular carcinoma, for instance. The topic of discussion today is going to be how to juxtapose the nivolumab/ipilimumab regimen against 2 other regimens, one being axitinib and pembrolizumab, looked at in the KEYNOTE-426 study against sunitinib. There you see a benefit in overall survival in the overarching cohort and certainly a benefit in response rate and progression-free survival across a stratum. The axitinib/avelumab study, or JAVELIN Renal 101, was a trial that looked at that regimen against sunitinib once again. That study showed a benefit in progression-free survival across a stratum, but it failed to show an improvement, at least to date, in overall survival.

How was that, Dan? Does that give you the gist of the studies?

Daniel J. George, MD: That’s great. The only study you missed was CABOSUN, and I'm not going to take offense. It was our Alliance study; we were one of the first studies to look at the intermediate- and poor-risk populations and show a difference in TKIs, that maybe not all TKIs are the same and that cabozantinib showed some progression-free survival superiority over sunitinib in that frontline setting.I'll give you an A- overall; it was a great segment.

Sumanta K. Pal, MD: That was one of my favorite trials, I can't believe I forgot it. Please don't kick me off the program.

Daniel J. George, MD: I won't. You’re forgiven, you’re absolutely forgiven. It's difficult because these trials are all done fairly contemporaneously with each other, so we don't have comparisons head-to-head, right? We have everything compared to sunitinib or VEGF-targeted therapy. We're seeing now superiority with these combinations over monotherapy, but the question comes up: are they all showing the same benefit, or are there subpopulations for which one approach may be a bit more preferable to another approach?

Transcript Edited for Clarity