Second-Line Treatment Approaches for DTC

Lori Wirth, MD: Naifa, can we get back to this question of lines of therapy and how is the recent approval for cabozantinib [Cabometyx] going to impact on that? And then, maybe any words of wisdom on which cabozantinib are we talking about again?

Naifa L. Busaidy, MD, FACP, FACE: Yes. All great questions as usual Lori. I want to take a step back when we talk about second-line of therapy. Just very often we talk about reassessing the patient at any point of their thyroid cancer. Once these patients have been on first-line therapy and have failed first-line therapy, whether it’s due to AEs [adverse events] or progression, we need to remember to reassess, right? Again, first, do no harm. And so, looking at their performance status and where the tumor is and the tumor burden and the way they’ve progressed, I think is very important. And we have to remember that multimodal therapy does exist.

And I think Maria had talked about this earlier, so if they were doing really well on—let’s just throw out there—they were on first-line lenvatinib [Lenvima] therapy and everything else had stabilized or shrunk but they have that 1 hilar node or that 1 lung met (metastasis) that just keeps growing, we could continue that therapy and do stereotactic radiation. So remembering that multimodal therapy exists and that your multidisciplinary colleagues are around to ask these questions before you say, “Hey, we’re going to go to second-line therapy.” By definition, they failed first-line therapy, but it doesn’t mean that you can’t continue it because we’re on this marathon.

That’s the first thing in the reassessment—how’s the patient feeling, what the patient wants, where the tumor is. But in addition to that we need to reassess the brain met situation. Coming back to what Maria and Lori had talked about, every time we change therapy, we reassess with a new brain MRI and we’ll do those periodically depending on how aggressive the disease is. But I think it’s important to emphasize that we don’t know the true incidence and that we want to take care of those brain metastases in general, first with the exception of potentially small brain metastases in the BRAF mutated tumors. And so, reassessing with brain MRIs, potentially PETs [positron emission tomography], and then going forward.

Now, when we talk about second-line therapies it depends on what their first-line therapy was and what their AEs were from it. If they’ve had lenvatinib, potentially they’ve lost a lot of weight, they’re thinner, they lost a lot of muscle and reassessing and rehabbing them, hopefully throughout we’ve been doing that. But the drug that is FDA [Food and Drug Administration] approved for second-line therapy, as Marcia had mentioned, is cabozantinib, and she beautifully outlined that data where the median progression that was a randomization 2:1. And those patients had immediate progression for survival of 11 months versus 1.9 months. And the reason I’m repeating those numbers is that I think people are like, “Oh, well, those numbers aren’t really impressive,” and I think that they should be. Three-quarters of those patients failed at least 1 line had been exposed to one-line therapy and a quarter of those patients two-line therapies, anti-VEGF [vascular endothelial growth factor] to get on the trial they had to have failed those. And so, if your placebo is progressing in 1.9 months that’s already less, as Marcia had pointed out, than your 2 first-line therapies, previously. I realize these are not head-to-head, but we got to think about it in those terms. And so, this long marathon now you’ve prolonged their progression.

I do think that it’s great that there is an official indication of second-line therapy because a lot of times while there are many people who are treating off-label all the time second-line and fighting insurances and appealing, now we actually will have an indication. It makes it that much easier to actually get the cabozantinib after having failed first-line therapy.

I think there is controversy, as you heard on this panel, like there is to any cancer as to what you go [with] first. At our institution, when we get their biomarker testing, we always go with a selective therapy. First, it doesn’t mean it’s necessarily the right thing to do but especially depending if you’re worried about the anti-VEGF, but then in the second-line therapy now we have an official indication. But if the patient was exposed to anti-VEGF and the biomarkers weren’t checked and then they came to us we will check the biomarkers and switch them to second-line. While we have data about the official indication for that, we do have data about using those selective inhibitors in second-line therapy as these patients were spattered on all those trials of those selective inhibitors. I think I’m happy that we have lots of options for second-line therapy but remember to keep the patient in mind and think about multimodal therapy.

Now, I do want to throw in here about quality of life. We did mention talking to the patients about their performance status, etc., but I will say that as physicians we underestimate patients’ quality of life. And there is some unpublished data, and this was in medullary thyroid cancer, but just to point out we tend to say that these patients are asymptomatic. Marcia and Lori had both talked about maybe we don’t want to wait till they’re symptomatic, but we also may be missing the boat. A lot of the patients with medullary thyroid cancer had looked like stage 4 lung cancer patients and doctors were saying, “Hey, they’re asymptomatic,” and so thinking about that and better tools of looking at quality of life is important as we think about this long marathon.

Marcia Brose, MD, PhD, FASCO: I’d like to just add one thing about that which is that the data that came out from the SELECT study is really interesting. The dose-finding study, the 211 Study that followed the SELECT study, because we always assume that quality of life would be better if we gave lower doses. And what’s really interesting about that study is that it randomized patients to the 24 milligrams starting dose and the 18 milligrams a lower dose. And everybody, including myself, expected that the lower dose would be 1. just as efficacious; 2. safer; and 3. have a better quality of life. And it turned out that it wasn’t as good on efficacy, and it turned out that safety it was virtually identical; and [with regard to] quality of life there was a little bit of a bump, but it was the same in both groups.

I think what that says to me is that it brings us back to the importance of the physician and managing these side effects. When a side effect comes up there’s definitely a hit on the quality of life. But the importance of the intervention and the person who’s giving this therapy, it is so important that the therapist, the physicians stay engaged and aggressively treat those side effects to maintain that quality of life. Because that’s maybe where some people feel a little bit more comfortable with some drugs versus others, because it really has to do with being really involved with managing those side effects. And I think that all of the drugs we’ve talked about today can always be improved by a really good, attentive physician, close interaction communication, and close follow-up after starting those. So I just want to put that plug in because I think that’s really what the data shows is important.

Lori Wirth, MD: And Marcia, you’re talking about the lenvatinib Study 211.

Marcia Brose, MD, PhD, FASCO: Correct. They randomized patients between 18 milligrams as a starting dose versus 24 milligrams. Out of concern of the VEGF receptor side effects a lot of physicians have been either avoiding lenvatinib or starting at a lower dose. And really what that showed was that you could still get a good response and manage the side effects, and it didn’t really matter. I think that was not necessarily what we would have predicted but I do think at the end of the day it says, no matter what drugs we’re talking about, the importance of the physician in proactively managing the side effects.

Lori Wirth, MD: Yes. I agree.

Transcript edited for clarity.