Evaluating I-O Monotherapy's Value in Treating mRCC

Transcript:

Sumanta Kumar Pal, MD: On that same topic, Neeraj—nivolumab-ipilimumab versus nivolumab monotherapy—you talked a little bit earlier about using either 1 in the second-line setting. What has been your experience in terms of the difference in toxicity profile between monotherapy and doublet I-O [immuno-oncology] therapy.

Neeraj Agarwal, MD: Well, if you compare the first-line data with the second-line data, there is a big caveat that by the time patients are in the second-line setting, they may have higher-volume disease. It may be indicative of better disease biology, which is allowing them to go up to second-line therapy. There are a lot of caveats and different patient populations. But we are not seeing the complete responses [CRs] with single-agent nivolumab to the extent we see with ipilimumab-nivolumab. So I think that’s my first take on this: For complete responses, the whole point that we use immunotherapy, ipilimumab is necessary from the efficacy perspective. But from the toxicity perspective, we see a really exponential increase in toxicities with the combination of ipilimumab and nivolumab. So I think it’s a balancing act for each of these patients. In the second-line setting, I tend to go with nivolumab alone because those are the data, even though the NCCN [National Comprehensive Cancer Network] Guidelines allow us to use ipilimumab-nivolumab in the second line. But based on the data, I tend to use nivolumab alone in the second line.

Sumanta Kumar Pal, MD: Brad, it looks like you had a thought on that.

Bradley McGregor, MD: Yes, I think with the idea of nivolumab and ipilimumab, 1 of the critiques of CheckMate 214 to report is that there’s no single-agent nivolumab arm and less than 30% crossover to immunotherapy following sunitinib. And so I think that’s an important question to ask, because we actually have a phase II clinical trial called OMNIVORE, which is trying to look at this very question. So we start patients with nivolumab monotherapy, and then based on response, we will add in ipilimumab. So if those patients don’t have a PR [partial response] after 8 weeks of therapy, then we’ll try to rescue them with ipilimumab, if you will. There are those patients in whom nivolumab, PD-1 [programmed cell death protein 1] blockade alone, may be sufficient, and we can limit the toxicities of ipilimumab in those patients and offer it only to those patients who need it. And so that’s ongoing. I think it’ll ask a very important question.

Tian Zhang, MD: I really like that. So sometimes we’re able to add in ipilimumab to nivolumab for patients progressing on nivolumab and salvage patients who may not be responding as well. This way, you’re collecting these prospectively studied patients, and I think that’s a great trial.

Neeraj Agarwal, MD: You are leading a trial, Tian, with a very similar adaptive design. And I think that’s the future. That’s going to happen. We know that not every regimen is right for every patient, right?

Tian Zhang, MD: Sure.

Neeraj Agarwal, MD: So tell me about your trial.

Tian Zhang, MD: Absolutely. You’re absolutely right, it’s an adaptive phase III trial that we’re leading out of the Alliance cooperative group, and it will likely open this May, but it’s a very large trial that is enrolling patients with intermediate- to poor-risk metastatic clear-cell kidney cancer.

We’re starting with that induction that’s really based off the CheckMate 214 regimen. So up to 4 cycles of ipilimumab-nivolumab. If people run into toxicity issues in the first 2 or 3 cycles, they can skip the last 1 or 2 cycles. And then, based on the response seen in that first 3-month imaging, we’re adapting the trial to the arm of the treatment that they’re going to subsequently receive.

So the complete response patients, they really don’t need any added toxicities. Those patients should get nivolumab alone per CheckMate 214. The patients who have progressive disease, those patients really shouldn’t be on nivolumab monotherapy, and so those patients are going on to receive cabozantinib alone. So we’ll have some sequencing data there as well.

And then everyone in between: the non—complete response, non–progressive disease patients; anyone with a stable disease; or even some of the partial responses. Those patients will be randomized to either receiving nivolumab alone or the combination of nivolumab and cabozantinib. And so we’re really excited about this trial, and we’re really glad to have support throughout all the cooperative groups, including [ECOG-ACRIN Cancer Research Group] and SWOG [Cancer Research Network]. And we hope that we’ll be able to think about when the right time is to add in that VEGF combination while still capitalizing on the complete responses that ipilimumab-nivolumab can give us.

So overall, the primary endpoint of our study is overall survival, and then there are some key secondary endpoints that I really like. So there’s progression-free survival, but there’s also 1-year complete response rate. So we’re really hoping to improve the complete responses that we see from CheckMate 214. And when patients get to that 1-year mark, we’re actually putting in as part of the trial a discontinuation of treatment for those patients. And so when that happens, we can follow these patients and see, do they have durable responses off treatment? Who recurs. Why? Or with other patient characteristics, we can figure out who will have early recurrences off treatment. Now I think all of those are pretty clinically useful and meaningful questions for us to think about as a community.

Sumanta Kumar Pal, MD: That’s great, Tian. And this portion of the discussion is on a high note, talking about the CR population. If you get a CR with nivolumab and ipilimumab, what was the rationale behind stopping at that 1-year mark?

Tian Zhang, MD: We really have very limited data in this setting. And so it’s really about limiting the toxicities that we’ve been discussing quite a bit, and those toxicities that are immune-mediated can happen at any point during a patient’s treatment. And so from our clinical experiences, we have been stopping patients at 1 year of complete response. Most of my patients have not recurred yet, but again, we have very short follow-up of these patients, because we’ve only adapted using these regimens in the last 2 years. So as time goes on, we’ll learn more about that, and I think this is a way that we can prospectively study that endpoint of 1 year of complete response.

Sumanta Kumar Pal, MD: I think it has to be some sort of landmark, so 1 year sounds reasonable to me.

Transcript Edited for Clarity