Thomas Powles, MD: Ben, I apologize for focusing on you entirely during the first part, but I’m going to keep going. One thing on which I disagree with just about everyone I know about is around this role, because no one seems to discuss the nephrectomy issue. We have a patient—let’s say they’re 72 years old. They’ve got half-dozen lung metastases. They’ve got an 8-cm primary kidney mass. There obviously is intermediate-risk disease with other parameters. They come in and say, “I’ve been told I have lots of options on what I want to do. There seems to be uncertainty about whether I should have my kidney cut out before I have systemic therapy.” What are you telling that individual?

Benjamin Maughan, MD: Those usually end up being long conversations. What I end up recommending to the patient is very individual and nuanced. In the setting right now, we have unclear data about what to do. There’s a lot of clinical judgment that factors into it. Things like whether surgery will remove the bulk of the disease is 1 of those important features. What’s the pace of their disease? Because there’s a delay that’s inherently introduced when you’re doing surgery. Some of those things are certainly important that I take into consideration.

Thomas Powles, MD: Rana, how would you take this?

Rana McKay, MD: I agree. It’s a personalized decision where you’re having that shared decision-making. It’s not 1 size fits all, no up-front cytoreductive nephrectomy for patients with newly diagnosed metastatic disease. It’s having that discussion. If somebody’s disease burden is low and they feel good, if they have a couple of lung nodules but the bulk of the disease is in their primary, then I don’t think it’s unreasonable to take out their primary. Maybe you’ve delayed them 3 months for their systemic therapy. You can get a sense of their intermediate risk. They don’t have sarcomatoid. They’re not going to blow up in that 3-month period. It’s shared decision-making. I don’t think it’s 1 size fits all. We have the data from CARMENA, but those data are incredibly biased based off the patients who are enrolled in the trial. Ulka, you’re on the PROBE study, which is going to be important in answering the role of cytoreductive nephrectomy and the era of I/O [immuno-oncology] therapy.

Thomas Powles, MD: You talked to us about the PROBE study quickly, which is a bit of a plug as well. It’s likely good.

Ulka Nitin Vaishampayan, MD: Of course, it always helps.

Benjamin Maughan, MD: Indeed. That’s what I think.

Ulka Nitin Vaishampayan, MD: I address these patients presenting with synchronous primary and metastases by first trying to decide if I’m going to offer this patient combination immunotherapy. If it’s oligometastatic, with 1 adrenal metastasis, chances are you’re going to remove it, get the patient in complete remission, and just do surveillance. Barring that, the majority of your synchronous metastatic patients are going to be with a number of multiple metastases, for which you’re going to offer a combination immunotherapy-based regimen.

Then we should do the immune-based regimen first for a set time period. Three months is about where that lies—somewhere between 10 and 14 weeks—and then we assess the disease. If they have a response or stable disease, then they’re eligible for randomization on the SWOG 1931 trial, or PROBE, which randomizes them to get immediate cytoreductive nephrectomy or continue immunotherapy-based regimen.

The big problem is that we don’t have evidence of cytoreductive nephrectomy helping them at this point. Whether the systemic therapy is overpowering enough and has improved in efficacy that the chance that cytoreductive nephrectomy will add something, it could be small. But there are enough preclinical data and some clinical data from melanoma. We just heard that neoadjuvant immune-based regimen followed by local therapy makes a big difference compared with doing up-front cytoreductive nephrectomy and follow-up. The neoadjuvant seems to be superior.

Thomas Powles, MD: A friend of mine named Brian tells me that we shouldn’t be doing delayed cytoreductive nephrectomy as a standard of care as it stands. However, I see a lot of patients who, 6 months into therapy, complete response in different areas. There are 2 cm of remaining kidney mass, and they just want the kidney gone. Eric, you’ve done a huge amount of this or neoadjuvant work. You did some work with sunitinib back in the day in the perioperative neoadjuvant setting. What’s your take on this delayed cytoreductive nephrectomy? Do you agree or disagree with Brian?

Eric Jonasch, MD: It’s hard to know whether the primary that remains in place is having a negative biological effect. At this point, it’s a data-free zone. It’s important that we’re doing studies like PROBE to get some more information. But it’s not necessarily plausible that you’re having a great response everywhere, including that primary tumor. Leaving that primary tumor in place could become a [INAUDIBLE] for further molecular evolution and new metastases development. If you’re seeing shrinkage everywhere, that doesn’t seem plausible. It ends up becoming more of a psychological benefit for the patient. There they say, “We’ve managed to get this piece of disease out; therefore, I’m feeling better.” I’m a little conflicted. We could argue either way whether this will prolong life for the patient to perform that delayed cytoreductive nephrectomy. But if you’re seeing good response everywhere, the likelihood that area is a threat in of itself is probably not high.

Thomas Powles, MD: From an educational perspective, is it fair to say, as a take-home message, that individuals with poor risk disease should not be receiving a cytoreductive nephrectomy? Can we all agree on that?

Eric Jonasch, MD: Absolutely.

Rana McKay, MD: Definitely.

Thomas Powles, MD: Great. Can we agree that in patients with intermediate-risk disease, a multidisciplinary discussion with the surgeons, the oncologist, and the patient is wise? The proof around this is very gray, but we all feel that some patients may benefit from that approach. Do we agree on that?

Benjamin Maughan, MD: Yeah.

Eric Jonasch, MD: I fully agree.

Rana McKay, MD: Yes. I fully agree.

Thomas Powles, MD: The role of cytoreductive nephrectomy delays cytoreductive nephrectomy remained an important question within the PROBE trial. We’re excited about the results of that study.

Ulka Nitin Vaishampayan, MD: Thank you.

Thomas Powles, MD: Is that fair too?

Ulka Nitin Vaishampayan, MD: Yeah.

Benjamin Maughan, MD: Absolutely.

Transcript edited for clarity.