Risk Stratification in Metastatic Renal Cell Carcinoma - Episode 2

Favorable-Risk mRCC: Choosing Appropriate Frontline Therapy


Sumanta Kumar Pal, MD: Maybe I’ll ask you to take that 1 step further, Neeraj. Which TKI [tyrosine kinase inhibitor] are you using—sunitinib, pazopanib, cabozantinib—for good-risk patients?

Neeraj Agarwal, MD: So even though cabozantinib has not been specifically looked at in the good-risk patients, what I glean from the CheckMate 214 trial is that VEGF-TKIs are more active than immune checkpoint inhibitors in good-risk patients. So that was the first message I got from the trial. And then my next step is, which is the best VEGF-TKI? And there’s no doubt in my mind that cabozantinib was very clearly superior to sunitinib in the cabozantinib trial in the first-line setting, although the patient population was intermediate- to poor-risk patients. It was a patient population with a more aggressive disease biology. So extrapolating from that, I have no doubt that cabozantinib is my drug of choice for our good-risk patients.

Sumanta Kumar Pal, MD: That tends to be my practice too. I think it was maybe a pragmatic decision that those patients weren’t included in cabosun [cabozantinib-sunitinib]. So I agree with you completely there.

Tian Zhang, MD: I’ll counter that and put in just from a purist’s standpoint that the cabosun [cabozantinib-sunitinib] trial really only enrolled intermediate- and poor-risk patients and really didn’t enroll the favorable-risk patients. And as you said it, Neeraj, there are very biologically different patient populations. And so even though the label does include all metastatic advanced renal cell carcinomas for cabozantinib, I tend to favor using sunitinib and pazopanib in that first-line setting and then holding on to cabozantinib in the second-line setting, and this gives our patients an extra line of treatment.

Neeraj Agarwal, MD: I think I partly agree with you. At the same time, we know the data from IMDC [International Metastatic Renal Cell Carcinoma Database Consortium] are small, around 7,500 patients. And just to give a little background to the audience, IMDC is a consortium of 23 cancer centers, mostly academic cancer centers across the world, and the data were published last year on kidney cancer. Of 7500 patients who received first-line therapy, only 51% of those original patients were able to receive second-line therapy. And then if you look at patients who were receiving third-line therapy, we’re talking more around 23% of the original patient population. And by the time you’re talking about fourth-line therapy, less than 8% of patients received fourth-line therapy. So in my view, we should choose the best option at a given time point for a given patient, with complete disregard to mechanism of action or our personal passions for a given drug or mechanism, any way we want to describe it. I personally think we need to pick the best treatment option for a given patient. And if I’m choosing a VEGF-TKI, I’m going to choose the best VEGF-TKI for a given patient. And based on that rationale, I tend to pick up cabozantinib, even in favorable-risk patients.

Sumanta Kumar Pal, MD: And I understand, Brad, you’re trying to actually gather some data related to cabozantinib in good risk patients, correct?

Bradley McGregor, MD: Yes. We’re trying to establish that. Obviously looking at academic centers, a lot of these patients with good-risk disease are often put on trials. So trying to find these data in a retrospective fashion has been challenging to truly see what the activity with cabozantinib is in these good-risk patients. It’s something we’re actively trying to look at.

I think I would like to comment, though. We are always trying to look to the best options for these patients. And so if I had a patient with good-risk disease who comes in my office says, “Listen, I really want immunotherapy,” I don’t think it’s wrong to pursue nivolumab and ipilimumab in these patients. And as we’re looking at CheckMate 214 data, yes, the PFS [progression-free survival] and all response rates are improved with sunitinib, but there’s still an impressive complete response [CR] rate in these patients with good-risk disease, much more so than with sunitinib, a mere 10%.

So if you have a patient and if they’re in that 10%, they get CR rate, that’s the best option for that patient. And of course we don’t have the biomarkers yet to say, “Who are those patients?” But I don’t think it’s unreasonable to consider immunotherapy in some of these good-risk patients. Long-term, especially with toxicities in nivolumab and ipilimumab, understand that there are risks associated with that regimen and immunotherapy versus TKIs. I don’t think immunotherapy is necessarily contraindicated in these good-risk patients, albeit the data that show, statistically speaking, their response rates and PFS are better with sunitinib.

Sumanta Kumar Pal, MD: I’ll take the moderator’s prerogative and just suggest that the challenge here—and Tian, you had a great slide about this on our tweet chat—is that nivolumab-ipilimumab really isn’t for the faint of heart. It comes with pretty substantial toxicity. You run into about 25% of patients who can’t complete the full cycle of therapy and 60% steroid usage. So it’s a pretty tough regimen. Thinking about it from the context of being a more tolerable regimen, to me, is sometimes a little paradoxical.

And I’m going to stay on this theme of some of the other immunotherapy regimens we might use for kidney cancer. And Brad, I’m going to keep the conversation going with you. What’s your thought on bevacizumab-interferon and high-dose interleukin-2 [IL-2]? These are 2 regimens we had in years past. Maybe focus on high-dose IL-2. Is there a right patient for that regimen now?

Bradley McGregor, MD: Yes, but I think that interferon has been gone for a while. I think high-dose IL-2 is still being utilized just because of that CR rate, although there’s short-term toxicity that requires ICU [intensive care unit] admission. There are still those patients who had a very durable CR with potential for a long-term remission. Now with the advent of nivolumab-ipilimumab, I think the role of IL-2 is certainly diminishing. In that 30-month follow-up that they presented at GI ASCO [Gastrointestinal Cancers Symposium], we see that the CR rates tend to be very much durable. The CR rates were 11%, and over 90% of them are durable. Patients had stopped therapy and maintained that CR rate. So clearly as you get more and more follow-up, nivolumab-ipilimumab looks to be playing a role and providing a durable remission for these patients, comparable with or even better than that seen with IL-2. So I think the role of IL-2 certainly is diminishing in these patients.

Tian Zhang, MD: I completely agree. So since ESMO [European Society for Medical Oncology] 2017 Congress, where we were first presented the CheckMate 214 data, I think we’ve stopped giving any high-dose IL-2 to patients at Duke Cancer Institute. I want to pick up there and from our discussions around ipilimumab-nivolumab, that 10.8% complete response rate, we’re really shooting for complete responses in these patients and really trying to maintain those complete responses.

So there was an interesting segment in the 30-month survival data that of the patients who discontinued for complete responses, actually about half of them didn’t have to go back on treatment at the 2-year mark. So this is a really great thing for our patients, that they can have some good treatment-free intervals, and we’re seeing some data out of CheckMate 214 about treatment-free survival periods. And that’s a really meaningful time, in which patients are off treatment. They’re not experiencing these toxicities, and I think it’s clinically meaningful.

Sumanta Kumar Pal, MD: Interesting. And staying with the theme of IL-2, when I think of IL-2, I often think of Huntsman Cancer Institute at the University of Utah. It’s a very high-volume IL-2 center. Has your practice changed at all now with new immunotherapy regimens?

Neeraj Agarwal, MD: Yes. Similar to Duke and what Tian said, we switched after we saw the data of complete response is happening in almost 10% of patients. That was the whole reason we pursued high-dose IL-2. It was for those complete responses. And also, IL-2 services in most of the university hospital’s cancer center are also driven by local referrals from practicing community oncologists. It was much easier to get those referrals 10 years ago when we did not have anything to treat our patients with. The only option was high-dose IL-2. Now, moving forward 10 years, we have more than 13 different treatment options for these patients. And there is lot less enthusiasm for community doctors to refer patients for high-dose IL-2. So I think given both the really astounding efficacy of ipilimumab-nivolumab combination from the perspective of complete responses and decreasing referrals, we have also stopped giving high-dose IL-2.

Transcript Edited for Clarity