Contemporary Management of Metastatic Renal Cell Carcinoma - Episode 5

NCCN Guideline Changes for First- & Beyond-First-Line RCC Therapy

Transcript: Daniel J. George, MD: Let’s switch gears a little and talk now about guidelines, because the reality is that we are more and more dependent on these guidelines—for the insurance approval, the compendium approval—of our management. They are affecting all of us in some way, in how we practice. They’re also helpful in terms of being able to look at the spectrum of studies and how they’re weighted by our peers. Bob, do you want to walk us through maybe the NCCN [National Comprehensive Cancer Network Guidelines]? We all probably use them more than any, and they’ve been recently updated in terms of its format. Can you tell us what’s going on there?

Robert S. Alter, MD: Sure. After the ASCO GUCS [American Society of Clinical Oncology Genitourinary Cancers Symposium] meeting in 2019, the information we received was similar to what it was in ASCO 2018—the changes now using IO/TKI [immuno-oncology/tyrosine kinase inhibitor] therapy have really become more robust. The approach about how we look at our NCCN Guidelines in practice definitely gives us a guide. It gives us the ability of feeling reassured with the data that we have for it to have that implemented into our guidelines and treatment managements for our patients.

The recent changes that they have had, they’ve actually moved the IO/TKI to a preferred regimen. They’ve moved away from first-line, second-line, or primary therapy to subsequent therapy and now to a preferred regimen. They’ve actually given the pembrolizumab-axitinib a preferred category 2a, and they’ve changed sunitinib as well as pazopanib into a category 2a when they both were category 1. This is now giving us more insight that our usage of first-line TKI therapy may be moving away from how we’ve been practicing based on the newer regimens that we’re going to be seeing, what has already been presented as well as future FDA approval.

They’ve also now approved these agents as subsequent therapy. Axitinib-pembrolizumab is now approved as a subsequent therapy, and so is nivolumab-ipilimumab. Again, utilizing the immunotherapy approaches to our patient care as compared with just using single-agent nivolumab as we have used in the past.

Daniel J. George, MD: I think this is progress. I look at this and say, now we’re getting past sort of the level 1, level 2 story. And just really what does this experienced panel think in terms of appropriate uses and stuff? One other thing—they split this into the sort of good risk and intermediate kind of poor risk. Joe, do you want to talk just a little bit about how you look at risk stratification in renal cell carcinoma [RCC]?

Chung-Han Lee, MD, PhD: Yes, there are multiple risk stratification schemes. One commonly used within the trials is IMDC [International Metastatic RCC Database Consortium], and another that’s commonly used in clinical trials is MSKCC [Memorial Sloan Kettering Cancer Center] risk. Both I think are very valid ways to stratify patients in terms of their risk categories.

Where risk stratification hadn’t really come into play was with CheckMate 214, in which there was that divergence—initial divergence—between how the intermediate—poor-risk people did as compared with the favorable-risk people when they were on a dual checkpoint inhibitor as compared with sunitinib.

That being said, in the TKI/IO era it becomes a little bit less clear whether we still need this type of risk stratification—because of the incorporation of a TKI within—to the regimen. So certainly there’s going to be further stratification and further ways we can think about risk. But right now, when we are thinking about what our preferred first-line choice will be, part of that will still depend slightly on risk and whether or not you’re going to be taking the TKI/IO approach versus the IO/IO approach.

Nizar M. Tannir, MD, FACP: Dan, I’d like to challenge the NCCN recommendations for favorable risk. And I would like to hear your thoughts, each you, about this.

The NCCN Guidelines now recommend pembrolizumab-axitinib combination as preferred for favorable risk. Obviously this is on the KEYNOTE-426, and we understand that pembrolizumab-axitinib beat sunitinib for all risk groups, but really, as you brought it up, Joe, the reason it did that for OS [overall survival] is that the patients on the sunitinib arm didn’t have a chance to get a second-line immune checkpoint inhibitor.

In the US, or in a country where you have the option of getting an immune checkpoint inhibitor in the second line, I am not convinced that pembrolizumab-axitinib should be offered to all patients with favorable risk. In my opinion there is that patient who you could treat with a TKI monotherapy and at progression add the checkpoint inhibitor or vice versa.

There are some impressive data with pembrolizumab as monotherapy also in clear cell RCC in first line, and then you can add the TKI at progression. I am not convinced that, in an environment or a scenario where you have access to the second-line immune checkpoint, you necessarily need to do the combination. Until I see a trial showing that the combination is better than the sequential treatment, there is still a scenario where you can treat the patient with favorable risk with monotherapy followed by monotherapy.

Robert S. Alter, MD: I have patients whom I’ve seen, too, in this past month, where there are contraindications that treat them with a tyrosine kinase inhibitor as a first-line therapy. To cite the data we have now, utilizing an IO/TKI when you’re restricted not to give them a TKI as a first-line therapy, I’ve been able to give these patients combination IO/IO—or give them ipilimumab and nivolumab as a first-line favorable risk. And that is sometimes where we have some restrictions with some insurances, but you can cross the line and recognize that some patients may not be candidates of TKIs. Now the question is in favorable risk, how do we take care of those patients?

Daniel J. George, MD: Well, there’s the other option, too, right, which is to say, well, these are favorable risk patients. We think they’re going to live a long time. We’re concerned about their comorbidities and ability to tolerate a TKI. What about just starting with a drug like pembrolizumab alone?

Transcript Edited for Clarity