Frontline Therapy for mRCC: Sequencing and Goals



Sumanta Kumar Pal, MD: I’m going to shift gears now. We talked a lot during our Twitter conversation about these recent FDA submissions for axitinib-pembrolizumab, for axitinib-avelumab, and so forth. I wanted to get a sense—before we really jump into the nitty-gritty of the day—of how the goals of treatment really evolve as we’re going through therapy. So when you’re looking at a patient in the frontline setting, Brad, what are you looking at in terms of goals of treatment?

Bradley McGregor, MD: Regarding goals of treatment, fortunately, what we used to think was a completely incurable disease may not be the case anymore. So with the advent of CheckMate 214, there’s a thought that we can offer these patients what was once unattainable, which is a cure, a complete response [CR] rate. So that’s really what we want to think about. Is that something that we can offer these patients? Are we able to offer them a complete response rate and, hopefully, a prolonged treatment-free interval if not a cure? So I think that’s something that has really changed in the past couple of years.

You used to say, “Well, we cannot cure you,” but maybe that’s not the case anymore. And so I think that’s going to be something you have to entertain, and that comes into play when you start thinking about what decisions you make. Because although the data for the TKI [tyrosine kinase inhibitor] combinations are certainly very intriguing with impressive response rates and improvement in overall survival with some of them, the CR rates that we’ve seen are still going to be the highest, at least right now, with nivolumab-ipilimumab. So that needs to be something that you take into consideration with a patient when you’re talking about their options and what their goals are.

Sumanta Kumar Pal, MD: Can you talk more about that, Tian? What’s the goal of CR in this setting?

Tian Zhang, MD: It’s been, as you say, unattainable for a lot of our patients, and if we can actually get their disease to completely melt away on their scans—say their lung nodules disappear and their liver metastases go away—it’s an amazing feeling to say that to a patient. And if we can enact that 10%, 10.8% complete response rate in the nivolumab-ipilimumab patients, we’re all in.

I think sometimes when we’re selecting strategies in that first-line setting, though, we talk a little bit about earlier control of disease, and so some of these VEGF and I-O [immuno-oncology] combinations may give us that faster time to response. And so there are patients who are very frail and [whom] we really need to get to a faster response in. Those are the patients we’re pointing toward TKIs first or TKI plus I-O strategies in that first-line setting.

Sumanta Kumar Pal, MD: That makes sense. Now I guess this isn’t 1 of the longitudinal goals, Neeraj, but there certainly are a healthy cohort of patients with de novo metastatic disease for whom we’re still thinking about cytoreductive nephrectomy. Does that weigh at all into your decision making frontline?

Neeraj Agarwal, MD: Absolutely, especially when we know that we cannot use VEGF TKIs for these patients who are going for cytoreductive nephrectomy. I don’t think it is not going to be pursued, this strategy, even with the negative CARMENA trial. In our practice, cytoreductive nephrectomy is very much pursued for patients who are at favorable risk or on the better side of intermediate risk. There’s a very substantial number of patients who are undergoing cytoreductive nephrectomy. And for these patients, the best regimen I can think of is the ipilimumab-nivolumab regimen. Because surgeons can actually operate while they’re getting treatment with ipilimumab-nivolumab, unlike VEGF [TKIs], for which wound healing is always a concern for those patients.

Sumanta Kumar Pal, MD: I tend to agree with you there. It becomes such an issue when to discontinue a drug, that delay in starting therapy. There are no surgeons here at the table, so tell us what’s happening at Duke Cancer Institute, Tian.

Tian Zhang, MD: I think it’s really a pattern of patient selection, and I think you’re right. The CARMENA trial enrolled patients with a lot of extra renal disease burden. So it was a high burden of metastatic disease. And so we saw from the CARMENA trial that sunitinib actually gets a portion of those patients to consolidate those nephrectomies, right? And there were about 38 patients who actually had a nephrectomy after they started this early on sunitinib.

In our practice, it’s patient selection and a matter of disease burden outside the kidney. And if there’s minimal disease outside the kidney and it makes sense—the primary is bleeding, causing hematuria and symptoms—absolutely that is the first step. It’s a multidisciplinary discussion, but that first step with nephrectomy makes sense.

I think if the patient has larger disease outside the kidney, this is a patient who we should be talking about a little bit more. If I use a systemic agent early on, will that give a little bit more systemic control so that I can actually get this person to a consolidative nephrectomy? I actually just referred my first patient who had a great response in his lungs, retroperitoneal lymph nodes, from ipilimumab-nivolumab. I referred him last week for a nephrectomy. So in those cases it also makes sense to really affect some systemic disease control and then get the kidney removed.

Neeraj Agarwal, MD: And for not only consolidative patterns of the nephrectomy but those patients who just got nephrectomy done. We still had to wait for wound healing to happen before we could even start any treatment in the recent past, right? Now with immunotherapy, with checkpoint inhibitors, we can start them on therapy the day after nephrectomy.

Tian Zhang, MD: Right, if they’re out of the hospital.

Neeraj Agarwal, MD: Yes. I’m just making a point that it’s so attractive from that perspective.

Tian Zhang, MD: Absolutely.

Bradley McGregor, MD: I can say our rates of cytoreductive nephrectomy have dropped significantly since the CARMENA trial. I think the CARMENA trial, despite its limitations, really shows that systemic therapy up front is the most important thing, and you don’t want to have a delay in systemic therapy. So our policy has really been to put these patients on systemic therapy up front, unless they’re symptomatic or have oligometastatic disease. We’re looking at control of all disease. We’re really pursuing systemic therapy up front. And then, as everyone said, we’re thinking about nephrectomy in the future. And I do agree that immunotherapy is great and that you don’t have to make that decision about, “When do I stop therapy? When is it safe to stop therapy to take them to surgery?” You’re able to continue systemic therapy as they move on to surgical procedure.

Tian Zhang, MD: There’s a great trial coming out of SWOG Cancer Research Network of cytoreductive nephrectomy in this setting and when to do that. So do you want to speak a little bit about that?

Sumanta Kumar Pal, MD: It’s an interesting study. Hyung Kim from Cedars-Sinai and Ulka Vaishampayan from Karmanos Cancer Institute are going to be leading a study in which patients uniformly get nivolumab and ipilimumab, and there’s a randomization between either no nephrectomy or deferred nephrectomy. I think it’s a very pragmatic design. It allows us as medical oncologists to get that patient going on therapy right away and then segue into surgery—if they’re randomized to such—at a later time point.

Transcript Edited for Clarity

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