Transcript: Matthew T. Campbell, MD, MS: I would like to comment on a couple of things. The NORDIC-SUN trial is very smart, in terms of design, because they’re using the IMDC [International Metastatic Renal Cell Carcinoma Database Consortium] score after the initial rounds of nivolumab-ipilimumab. It does evolve. Patients who are responding well who are initially poor-risk patients can often really improve in both their performance status as well as their laboratory markers that help guide the IMDC score. I think that’s a really good decision. I like the way this is being designed. The surgery team sits down with the medical oncology team, and there’s a consensus about the potential benefit for the cytoreductive nephrectomy. A multidisciplinary approach can really help frame decisions for whether a cytoreductive nephrectomy makes sense for patients.

Tian Zhang, MD: I agree. Matt, what you highlight is really great—in thinking about the multidisciplinary care, especially when we’re making this decision for cytoreductive nephrectomy. Thinking about patients who have a bulky primary tumor or a very symptomatic primary tumor that’s bleeding or is maybe causing a lot of pain—those are the patients who we’re really thinking about for up-front nephrectomy in this time when we have very active systemic therapies. But only the trials will show us randomized data in terms of who actually benefits from the nephrectomy.

Ulka Vaishampayan, MD: Clearly, our systemic therapy has gotten better. Now we can rely on it, as Matt and Tian mentioned, for getting a response and improving patients’ performance status and overall condition, especially if it is deteriorated from the cancer itself. The other point that I would bring up is this is a patient population that has been underrepresented in most clinical trials. The initial sunitinib trials did not include these patients. They were required to have nephrectomy prior to going on the studies. Even now, in the recent immunotherapy-based studies, the proportion of patients with this kind of presentation is only about 20% to 30%.

Rana R. McKay, MD: Ulka, you bring up a wonderful point. As we think about what a response means, and depth of response, and complete responses, we have to keep in mind that, yeah, you’re absolutely right. Eighty percent of patients who enrolled on the I/O [immuno-oncology]—I/O or I/O-VEGF frontline trials had a cytoreductive nephrectomy or had a nephrectomy previously. So it’s important in the context of response interpretation.

Mehmet Asim Bilen, MD: There was subgroup data from a trial presented at ESMO [European Society for Medical Oncology Congress] in 2019. They looked at patients who had a kidney in place. This is a small percentage, as Rana mentioned. But when we look at those patients, they still have a good reduction in size of their primary tumor. I think this tells us that these I/O-VEGF agents are working for distant metastases and, at the same time, the primary site. Now we have good agents. We just have to try to select the right patient for the right sequence. I think that is key.

Ulka Vaishampayan, MD: It does appear that there is a slightly lower survival outcome in this patient population. Because we haven’t done focused trials on this patient population, I think the PROBE trial, with the overall survival primary end point, and these other 2 trials will help us establish a baseline in this patient population.

Matthew T. Campbell, MD, MS: At MD Anderson Cancer Center, we had a study that included 120 patients who received up-front immunotherapy. Just under half of those patients received a cytoreductive nephrectomy on that study. There is some thought that the cytoreductive nephrectomies are becoming more challenging after immunotherapy exposure, and that’s being highlighted at some of the meetings. The other thing we’ve noticed that’s quite interesting is that it’s not always just a shrink in the tumor. Sometimes, there are characteristic changes. A lot of these tumors can become quite cystic compared with when they start off. So I really think we need to continue to learn how we’re going to judge response as opposed to change in size.

Ulka Vaishampayan, MD: Correct. Yeah, absolutely. Toxicity monitoring is going to be paramount, especially because of the inflammation and the immune-related reactions that these patients may have and because that might impact cytoreductive nephrectomy. Thank you very much for this discussion. Now we will move on to the next question.

Transcript Edited for Clarity