Selecting an Optimal Second-Line Regimen for mRCC


Sumanta Kumar Pal, MD: A good discussion around frontline therapy. Now, there still are going to be a healthy number of patients, despite our goal of complete responses, who need second-line treatments. And Neeraj, I was really impressed during our Twitter chat regarding how you developed this construct around approaching second-line treatment with frontline regimens like nivolumab-ipilimumab, axitinib-avelumab, and so forth.

Neeraj Agarwal, MD: I think patients have different goals. When they are seeing us for the first time, they want to live longer and live better. Complete responses probably take the priority over everything else. But by the time we are seeing patients in the second-line therapy and third-line therapy [settings], I think more reality has set in. I think patients still want to live longer, and we know that complete responses still can happen, but they may not happen and are less likely to happen.

I think we are looking at patients who are starting second-line therapy and considering all the drugs we have and how these drugs are able to induce responses and progression-free survival benefit. In my view, overall survival and complete responses were the most dominant talking points between my patients and me. By second-line and third-line treatment, I’m looking at response rates and progression-free survival. So that’s a shift that is happening in my clinic when I’m talking to these patients.

I’m looking at progression-free survival benefit and primary progressive disease rates, which is just the opposite of complete responses. So what is the likelihood of an agent being associated with high primary progressive disease rates as the best response? Because as we know, these patients are likely not going to see the subsequent line of therapy if they have progressive disease in the second-line setting. So keeping those in mind, I look at agents who are really good from the prospective of progression-free survival benefit and are least likely to result in high primary progressive disease rates.

There are 4 choices right now: nivolumab, cabozantinib, axitinib, and the lenvatinib-everolimus combination. So I tend to put the lenvatinib-everolimus combination on the side for now because that is a 2-agent combination that is more toxic and more expensive. If you just talk about axitinib, nivolumab, and cabozantinib, I think among these 3 drugs, cabozantinib seems to be most attractive to me because the primary progressive disease rates were only 12% as opposed to, say, 35% with nivolumab, a relatively much higher number. Still, its progression-free survival rate is the best as a monotherapy in the salvage therapy setting.

Sumanta Kumar Pal, MD: I think my sentiments echo yours. Progressive disease rates, response rates—those are all so key when you’re looking at second-line therapy. It certainly is a different juxtaposition versus first-line therapy, and I tend to use cabozantinib. Any differing thoughts there?

Bradley McGregor, MD: I agree. We tend to use cabozantinib. And as we move forward and we’re still seeing VEGF I-O [immuno-oncology] combinations or I-O alone, the question is where are the data after that? When you have VEGF and I-O, are you progressing on I-O or are you progressing on VEGF? And so we actually looked at that retrospectively with cabozantinib in the post—I-O setting. So close to 100 patients were looked at, and response rates were well over 25% in patients who had progressed on I-O. So independent of I-O therapy, cabozantinib is certainly an active agent in the second line.

Tian Zhang, MD: Yes, absolutely. I just worry, because we’re adopting more of these VEGF-immunotherapy combinations in that frontline setting, about what they are resistant to—as you say, Brad, when they’re progressing and what we should be sequencing. But we do know that the VEGF inhibitors tend to have activity even after other VEGF inhibitors. So cabozantinib certainly has activity after sunitinib and pazopanib regimens. With axitinib, we have great data for the second-line setting as well. So we’re really thinking about the right patient and the tolerability of the agents. I think it’s a quality of life issue, right? In the second-line setting, we’re talking about patients who have been on multiple lines of treatment. They’re a little bit frailer. We want to get them to live longer but also maintain their quality of life while living longer.

Sumanta Kumar Pal, MD: That makes sense. On a related note, I just wonder if there are any patients nowadays whom you might ever consider rechallenging with the same agent. I remember at 1 of the first ASCO GU Genitourinary Cancers Symposium conferences I ever went to, Brian Rini, MD, presented data related to what I’ll call a sunitinib sandwich. Patients start on sunitinib frontline, they get a handful of therapies thereafter, and—really for lack of available agents—they went back to it. These days, can you foresee that happening?

Tian Zhang, MD: There are so many great lines of treatment now. The beauty of having multiple lines of treatment for our patients is that there are so many ways we can sequence. I don’t foresee rechallenging with an agent, and that’s why I tell my patients that we really need to optimize the time on an agent and manage their toxicities. Or if there’s a tiny bit of progression, watch it a little bit more and try to optimize this length of time that we have on each regimen. Because once we go on to a different regimen, I’m not going to circle back to the original 1 and try to figure out who should be getting what treatments in the next line.

Neeraj Agarwal, MD: One situation I can think of is if you induct somebody with ipilimumab-nivolumab combination, the patient receives complete response or partial response, you stop the therapy, and after 1 year they have rapid disease progression and they require a TKI [tyrosine kinase inhibitor]. Once the TKI fails them, after that I think it is reasonable to go back to the ipilimumab-nivolumab combination or nivolumab monotherapy.

Tian Zhang, MD: Yes, because you’ve seen that disease activity early on, right?

Neeraj Agarwal, MD: And they have not progressed on those immune checkpoint inhibitors early on, so there may be room to use them.

Tian Zhang, MD: That’s right.

Neeraj Agarwal, MD: But beyond that, I don’t think there is a space for rechallenge.

Sumanta Kumar Pal, MD: That makes perfect sense to me. Brad, I’m going to ask you about a situation that comes up, and I’m sure it comes up in your practice as well. You get a referral from the community for a patient, for instance, who failed on nivolumab and then got switched over to atezolizumab, for instance, with the rationale being you go from PD-1 [programmed cell death protein 1] to PD-L1 [programmed death-ligand 1] inhibition. Is there any credibility to that approach?

Bradley McGregor, MD: I think right now, the data show that it’s probably not an effective approach. And we took a look at several patients who had switched from 1 I-O therapy to another, and none of those patients responded. That’s been looked at in ongoing clinical trials in which it’s not just switching from 1 to the other but switching to nivolumab and adding another agent to try to tweak that immune response. So with not just switching but doing something more than switching, I think there’s certainly an appeal in that approach. But regarding just switching from nivolumab to atezolizumab, at this point we don’t have data. It’s just that’s not going to be efficacious for our patients.

Tian Zhang, MD: I think if the patient is really interested in more immunotherapy at that point, I’d much rather do a novel immunotherapy combination or something else where we’re adding to that.

Sumanta Kumar Pal, MD: Yes, I think that’s an important message. Going from PD-1 to PD-L1 at this point in time doesn’t really seem to make a lot of sense.

Transcript Edited for Clarity

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