Nephrectomy Versus Systemic Therapy and Risk Stratification in Papillary, Non-Papillary 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 third segment of this roundtable series, the panelists review the use of systemic therapy and how it compares to nephrectomy for papillary and non-papillary disease.

Watch the fourth part of this series: IO/IO, IO/TKI Therapy for nccRCC and Its Effect on Next-Line Treatment

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Dr. Joyce:
You can’t invite a urologist to a party talking about metastatic renal cell carcinoma and not talk about surgery and cytoreductive nephrectomy, metastasectomy. Does this then change how you guys refer patients to a urologist to do surgery? Are you of the camp that believes, yeah, we should be definitely starting these patients on systemic therapy, seeing how they respond, and then maybe there’s a window of when we can intervene operatively and get the cancer out and then give them a trial off of systemic therapy? Or are there certain patients who you see and it’s oligometastatic that, you know, maybe just lymph node disease that we can resect very easily surgically? Are those patients you would consider sending to your urology colleagues to operate on?

Dr. Albiges:
Well, this is a question where I certainly don’t lump all together all the histologies. And so, if we’re referring to papillary RCC, I really feel that we need the surgeon, because in some case, there is a need of lymph node dissection up front in a patient that has secondary metastatic disease and where we don’t start systemic therapy, notably because in the past our systemic therapy were not that effective.

So to me, we really need to have a multidisciplinary approach and discuss this kind of case in tumor board. That being said, if we decide to start with systemic therapy up front in a patient that has not only great downsizing of metastatic sites but major response, I’m keen on bringing back the case to the tumor board to discuss the delayed cytoreductive nephrectomy.

In the past, that did not happen because the situation was not that frequent. I think it’s only starting now, but for this kind of case, I like to really be cautious around that and wait to see if the response is sustained over time. So I would not jump to surgery until at least one year of major response.

Dr. Joyce:
Yeah, I think that has generally been our practice as well. It’s an interesting point, though, that maybe there is some advantage in using the body’s immune system before surgery and giving them systemic therapy, seeing how they respond, and then acting, as opposed to pulling the trigger up front and being a little bit hasty with surgery. So I agree. It’s intriguing to think about, and ultimately we don’t know, right? We don’t have enough data. Everything’s retrospective in this space, so it’s really hard to make these decisions.

You talked a little bit about PD-L1 status. How are you approaching these patients as far as risk stratification? In clear cell, we historically use the IMDC risk stratification to make some decisions based on treatment. Are you using the same kind of methodology and thought process in a non-clear cell patient, or is there a different way of looking at these patients when they walk in your clinic?

Dr. Albiges:
Sure. So back in 2013 or ’15, the IMDC generated their prognostic tool also in papillary RCC. And I think it is good to use it, because it gives you a sense of the prognosis of your patient. But that was built at the time where we didn’t have IO strategy in those patients. So it’s still a work in progress to assess the prognosis.

Getting back to PD-L1, I’m not routinely using it for non-clear cell. I agree with you that the data we saw in SUNNIFORECAST were quite interesting, and to me it questioned the interest of PD-1 staining for CTLA-4, because we see consistency in the clear cell study, in the adjuvant study, as well now in SUNNIFORECAST. So we are using it for randomized phase III in clear cell RCC, but we haven’t yet moved forward for non-clear cell.

Dr. Joyce:
And then this MET-driven status, evaluating that, just to give you some numbers from the CALYPSO trial, which looked at durvalumab and savolitinib, complete response rate 33% versus the 29% overall that’s in the PD-L1 status, but MET-driven status, that complete response rate was up to 53%. So are there other biomarkers here we could be looking at, other genetic testing we could be looking at that might help us decide on treatments? Or no, are we not there yet?

Dr. Albiges:
I mean, maybe you want to mention around what we’ve been generating around gene expression profiling. But with regard to MET-driven definition and use, the good news, as we stressed earlier, is that we now have biomarker-guided trials. SAVOIR paved the way. SAMETA is on its way as well. So here we’ll see if the rationale of having a P-1 or PL-1 inhibition on top of a VGF TKI will play a role in the biomarker-selected patient population. I think we have to be careful around… one thing is that this biomarker is highly prognostic and not necessarily predictive of response. We do know that patient with MET-driven tumors tend to have less aggressive disease, and they used to fall into the type I group. So when you compare type I to type II, the type I had more indolent tumor growth.

Dr. Joyce:
Right. So we’ve talked about papillary a lot, but there are other subtypes here that we could talk about, medullary, collecting duct. Are you using a similar approach in those patients, or what is your approach when you see somebody who’s a non-papillary, non-clear cell renal cell carcinoma?

Dr. Beckermann:
Yeah, I’ll say that the biology is just such different capacity. For example, renal medullary carcinoma, so it is a very different approach. They’re leaning on smaller studies but looking at more traditional cytotoxic chemotherapy, trying to get genetic testing, looking for genetic drivers of the disease there to see what I can offer in the sequential treatment landscape. So…

Dr. Joyce:
Anything else you want to add?

Dr. Albiges:
Yeah, so I definitely don’t cluster altogether the non-clear cell, non-papillary. We are very fortunate in France to have a national network with second pathological review for all non-clear cell, and then we have a national virtual tumor board to see if we can refer the patient for dedicated clinical trial. And so to me, a chromophobe RCC, and I would love to hear from you guys, is a different entity than of course medullary as you stressed, but also translocation RCC and so on. So I think it’s important that we’re getting better at defining what we’re looking at and then generating at least retrospective data.