Adjuvant Treatments and Systemic Therapy for nccRCC

In a roundtable focused on non-clear cell renal cell carcinoma, moderator Daniel Joyce, MD, of Vanderbilt University Medical Center, led panelists David McDermott, MD, of Beth Israel Deaconess Medical Center; Katy Beckermann, MD, PhD, of Vanderbilt University Medical Center; and Laurence Albiges, MD, PhD, of Institut Gustave Roussy in a discussion on the management of differing disease states, new approaches such as IO/TKI and PD-L1, novel trials, and adjuvant treatments.

In the final segment of this roundtable, the panelists discuss the potential of adjuvant treatments and systemic therapy for patients with nccRCC and high-risk features.

Watch the beginning of this roundtable series here: Management of Papillary Metastatic nccRCC

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Dr. Joyce:
I’m going to shift gears a little bit. We’ve talked a lot about metastatic disease, but obviously there’s a lot of enthusiasm with adjuvant treatments after surgery for clear cell renal cell carcinoma. What about non-clear cell? Are these patients with high-risk features after nephrectomy? Are you thinking about starting a systemic therapy? You mentioned the KEYNOTE-427 trial, pembro showing some response, pembro and clear cell now we’re in papillary. Do we want to use it there? Are you using it there, or is it too early? What are your thoughts?

Dr. McDermott:
Well, that was a lot of questions at once. I think my impulse, maybe others, is to want to use it there, but we don’t, based on KEYNOTE-427, which suggests that it’s almost as active in a metastatic setting as it is in clear cell, PD-1 that is, pembrolizumab, but we don’t have data, because we didn’t include those patients in the trials. Going forward, we need to include them. To me that’s lesson number one. And I think there are some Merck trials, and Dr. Albiges can talk about that, are trying to include papillary patients going forward. So to me, we need to be doing that. Whether you are doing that in clinic, it’s hard because if you recommend it with a patient, and then insurance and the U.S. says, we’re not going to pay for this because it’s not indicated, then it’s problematic.

So in my practice we’re generally following the rules of KEYNOTE-564. Were they eligible for that study? Yes or no. Were they at higher risk? Which is something Dr. Beckermann can talk about, versus intermediate risk. We’re using it. But we’re not going off that indication yet, even though we might want to with patients. And there’s also the risk associated with it. So that’s part of the reason why I generally offer that therapy to patients who are at higher risk, and we don’t really understand the risk in the adjuvant setting for non-clear cell the same way. I don’t know what others think about that.

Dr. Beckermann:
I think we don’t have the data, the indication. I tend to stick to the trial, and I think maybe the one place where I would consider it potentially is if it was a patient who had high risk, and sarcomatoid features, because this is kind of the one pathologic finding where we know these patients do respond better. So as far as a non-clear cell, that would be maybe my trigger. I don’t know about you Dr. Albiges.

Dr. Albiges:
So we’re really limited to the approval for the use of this agent in Europe, and so as long it is not established through a prospective study, we cannot prescribe this. I’m not saying the rationale is not here, but we don’t have data yet to support that. And there were some patients enrolled including in REMPART study, but that will be a very little number of patients. So not able, I feel, to answer the full question. And as you stress, some trials are now being built to allow some of those subtypes like, the papillary in the adjuvant prospective study. That’s the case with the mRNA vaccine trial that has been developed on top of pembrolizumab versus pembrolizumab. So that’s a work in progress.

Dr. McDermott:
Dan, one other thing I would add to that is, in patients who may have a localized papillary cancer, and this is an old school thought, some of those patients will have a recurrence but in nodes. So that brings up the question, do you do that surgery? Yes or no? But to me it means, you at least follow those patients a little more closely, because if they have a local recurrence, you might be able to render them NED with surgery. So I’m not offering adjuvant treatment, but I’m insisting on patients coming in for scans if you think they might be at risk.

Dr. Joyce:
It’s interesting too from a surgical standpoint, there is, I think, a need to, if there’s any sign of clinical node-positive disease in a non-clear cell histology, going after those nodes probably does make a lot of sense. Whereas in the clear cell, the data really there’s no support of doing it as far as the survival outcome. But in the non-clear cell, I think it really does make a difference to go after them and really clean things out at the time of surgery.

Dr. McDermott:
Agreed.

Dr. Joyce:
This has been really great. I feel like we have a really good discussion around where we’re at, the new exciting data coming, but where do you see things going in the future? What would you like to see in this space that would really help direct your treatment? Are there new biomarkers on the horizon that you’re aware of that might help here? What are the next steps?

Dr. McDermott:
So as I mentioned earlier, I think we’re learning a lot more about these tumors than we used to know and subdividing them in a more granular way, which is good. We’ve proven we can do these trials. The question is, what are the next sort of targets, is what you’re essentially asking for. And I think that is different, in different places. So for example, in translocation, kidney cancer, there’s recent publications looking at full sequencing of these tumors, RNA, DNA, that’s actually potentially come up with a couple of potential targets for future trials. But we’re going to have to work together to execute those trials. So for example, is it looking at CDK4/6 inhibitors, is it looking at theroptosis targeting agents, or is it looking at bites that might target specific antigens on these tumors? I think there are clues coming from people’s labs like, that Hensky lab for chromophobe kidney cancer. Srinivas Viswanathan had an interesting paper in translocation. There are other interesting papers. The group at MD Anderson is doing a lot of work with renal medullary cancer. So those are going to lead to interesting targets to tests.

But we need to work together as a field to execute those trials, because those patients are a subset of a subset. Unless we all band together, we won’t be able to test those agents. But the targets are coming, I think, from the translational research that’s being done in that space.

Dr. Beckermann:
And I think maybe what I’m excited to see next in the field is that there’s a couple randomized phase threes that are going on. And I think just as we’ve come through the years from a single TKI, now thinking about combination, a lot of this has resulted from groups coming together, multi-site trials, and now our pharma partners I think are also investing their effort, and recognizing that there’s a need here as well. So I think that’s what I’m excited to see.

Dr. Albiges:
And having randomized study will allow us to have the contribution of the component. We discussed the IO-IO, IO-TKI, and you want to know what is related to which drug in terms of activity. So I think having randomized data is needed. I think patient advocacy groups are very important to make sure that patients diagnosed with a rare variant histologies get referred to tertiary centers if they can access to trials. And I agree that we need more and more biology for those rare entities, this is where we’ll make a difference. And also the patient can access to innovation like, phase one trials and so on.

Dr. Joyce:
Excellent. Well listen, I can’t thank you all enough for being here, and speaking with me. It was an absolute pleasure. So appreciate it and thank you.