Transcript:R. Michael Tuttle, MD: Eric, help me overlay the lenvatinib story now. We know the sorafenib story. It’s been around for a long time. We’ve used it. Tell me about the lenvatinib trial because it’s now FDA-approved, too. Give me the same sort of high-level view that Marcia did for the sorafenib trial.

Eric Sherman, MD: Lenvatinib was a little bit different in the sense that sorafenib was already FDA-approved when we were looking at this in thyroid cancer. It was an FDA-approved drug for kidney cancer. Lenvatinib did not get its approval until thyroid cancer. A lot of it was based on phase II data. This was a drug that, while it was another VEGF TKI, it hit other targets, especially FGF, which most other drugs did not do as well. And, it was extremely good at inhibiting VEGF, probably better than most other ones out there, as well. When they did the phase II study, they had amazingly high response rates. And not only did we have amazingly high response rates in patients who were never treated before, they actually had extremely high response rates, about 45%, in the group of patients who had prior VEGF TKIs in the past. So, this was a group that looked extremely good just from the phase II.

Now, when you went to the phase III study, they also allowed a crossover. And, it was not the story of sorafenib, where a lot of people won’t be able to get sorafenib off study. In some ways, that does dilute the overall survival benefit that you might like to see overall. In this group of patients, the placebo group did worse than you saw with the DECISION study. There are various explanations about why that might be the case. My feeling has always been that people got a lot more used to using sorafenib and using other drugs, and I think people were a little bit more selective in the patients that they put in. So, I would be surprised if they had as many of those 1-cm nodules in that study, as you might have. Now, I don’t know that for sure.

Marcia S. Brose, MD, PhD: It was RECIST 1.1, so 1.0 lesions weren’t. They required 1.1.

R. Michael Tuttle, MD: So, they had to be the minimum. Marcia, the survival benefit from the lenvatinib, what’s the story with that now?

Marcia S. Brose, MD, PhD: Did you want to say a little bit about more about the study design, and then I’d be happy to add in overall survival analysis.

Eric Sherman, MD: It was a randomized study, but it allowed just enough first-line patients and, also, patients who had already progressed on prior VEGF TKI. So, they had two groups of patients that they were looking at. And, while they did combine everything together, they also showed that in both groups there was going to be a benefit. The primary outcome, because of the crossover, was progression-free survival. So, although, overall survival was looked at as a secondary outcome—and I think it was interesting with this drug what they ended up seeing—at the same time, progression-free survival was the benefit. And, they showed that progression-free survival was significantly longer in the group that got the drug compared to placebo, both in the first-line setting as well as in the second-line setting. This was the first time, right now; the only study out there that has looked at this second-line group of patients in a randomized placebo-controlled phase III study. We end up seeing the benefit in both groups in response rates—extremely high—including for patients who had a complete response, which is not something that, as far as I know, has really been reported in any other VEGF TKI study. So, definitely a lot of interest and really amazing results from this study.

Marcia S. Brose, MD, PhD: When we look at overall survival, in both studies, overall survival was not statistically significant as expected. In the lenvatinib trial, it stratified in a prospective way by age, less than or greater than 60. And, we were looking at these data because we wanted to know that the toxicity was actually okay in the older patients. As it turns out, it is. It’s actually very, very good. But it didn’t make any sense to do that analysis if it didn’t work. So, we looked at efficacy, and there’s a bit of a surprise there. Using these criteria—which did select for pretty aggressive patients—it turns out that for the patients who were under 60, that there still was no overall survival detected. But, for patients over 60, there was a statistically significant improvement in survival with a hazard ratio of around 0.6. So, that actually is the first time in a prospective study, in a prospective analysis, that overall survival has been shown to be improved.

I do believe that we’re improving overall survival in the other study. There are probably statistical reasons why we can’t see it, not enough events in those other groups. But this was the first time that was shown, and it is also significant because I think it really is saying that we’re having an impact. And, then, you add together the response rates at 63%, and the fact that progression-free survival went from 3.6 months to 18 months or 15 months in the second-line setting, you have a very active drug. But now, for the first time, you can add another drug on top of that for half the patients basically. And we tried to look at all the reasons why that could be. Were they less likely to get second lines of therapy? Were they sicker? And no matter what analysis it was, if anything, it said that the older patients should have done worse. So, all the data, it’s the first time that we’ve seen that.

R. Michael Tuttle, MD: It’s a very promising structure. Naifa, the side-effect profile of lenvatinib, anything special about it? We have all these ‘ibs’ out there.

Naifa Busaidy, MD, FACP, FACE: The side effects that we’re seeing with lenvatinib are similar to many anti-VEGF therapies, but there’s a couple of things I want to point out. About 40% to 60% of patients are having hypertension, and so, actually, when the drug is sent to the patient, they get a sphygmomanometer with instructions to check their blood pressures because they can be quite severe. But, you can also see heart failure with or without the hypertension, as well, and, then, diarrhea. We don’t see as much hand-foot as we do with some of the other drugs, but weight loss and muscle loss was quite significant. And, so, some of the things that Marcia had pointed out earlier is getting your patient ready for exercise, the muscle strength, improving the performance status before you start these drugs because we can really make them go downhill otherwise.

Muscle and weight loss is actually of particular interest to me. We’re doing a study looking at these patients before they start the therapy, and, then, on the therapy; and what sort of physical performance things can we do to improve that on therapy. People say, ‘Oh, it’s just because they have diarrhea and decreased appetite, that that’s why they’re losing weight.’ We actually think there’s an independent mechanism that these drugs are causing weight loss through either the MAP-kinase or some of the PI3-kinase pathways in some other drugs.

But, then, there’s also life-threatening things. So, patients—especially those patients who have had external beam radiotherapy before and now you’re giving them a drug like lenvatinib or any of these anti-VEGF therapies—are at increased risk of fistulas, and we’re seeing them more and more commonly, unfortunately, especially if there’s not a flap there between and thinner skin. And GI fistulas can be problematic. They’re rare thankfully, but they are a possibility, and we need to warn patients about this and be thinking about it in each particular patient. Do they have a history of diverticulosis? Are these things possibilities? And then myocardial infarctions and pulmonary emboli and is this patient at risk for that? They’re not typically things we think about in the patient with thyroid cancer like we do in pancreatic cancer, but they are there. And now we’ve added another drug that can do that to them. So, these are things that we just need to be thinking about all the time and putting that patient at the center.

Frank Worden, MD: But, in addition to that, along with the deconditioning comes the fatigue.

Naifa Busaidy, MD, FACP, FACE: Or, fatigue, yes.

Frank Worden, MD: I think these drugs have profound fatigue, and so if you look at the lenvatinib study, there was a large percentage of patients who had dose interruptions, or decrease in their dosages based on the side-effect profile. And, I find in my own practice, fatigue is really right up there in addition to these other things we worry about. So, it’s not uncommon that we’ll give people breaks, and then we start the drug with not really any effect on the outcome. I think that’s important for people to understand, that that fatigue should not be diminished.

Transcript Edited for Clarity