R. Michael Tuttle, MD: Let me ask you my last real practical question. When I send somebody to any of you guys, you’re looking at individual patients. We’ve got two FDA approved drugs. How do you decipher for that individual patient? Do I choose one versus the other? Are there certain patterns? From a real practical standpoint, how do you decide with the patient sitting in front of you, which one? You’ve got to decide which one to start. It eventually comes down to your decision, Marcia. How do you think through that decision?

Marcia S. Brose, MD, PhD: The answer is yes.

R. Michael Tuttle, MD: I thought so. And I would only assume that Eric and Frank would agree to yes. How do you think about this?

Marcia S. Brose, MD, PhD: The first thing you have to understand is 100% of my patients will get both drugs. So, that’s the first thing. Then, for the most part, it will depend on comorbidities. If they’re over 60, because of the data, I might consider doing lenvatinib first in the over-60 population. But then on the other side of that, we have this story that lenvatinib works very well in second-line. Remember, we want to make this cancer into a chronic disease, and so I am lining up not usually just two, because I’ll have three or four other clinical trials after that. I’m going to try to take as many active agents as I can and extend them as long as possible. I don’t really know what the activity of sorafenib is after lenvatinib. It’s data we badly need because you can’t really… Since the lenvatinib patients were clearly sicker, people’s experience right now giving sorafenib after lenvatinib may not work because the patient population was so different.

So, when people say, ‘Oh, I’ve given sorafenib after lenvatinib,’ it’s not objective. It’s not apples-to-apples, so we can’t say that. But we do know that if we give sorafenib first, then follow it with lenvatinib, they can get two long periods. All of these things again will go into it, and there’s not really a right answer right now. But we will have to do it to the patient, and response will play into it. I need response, I might take lenvatinib.

R. Michael Tuttle, MD: Eric, what do you think about it?

Eric Sherman, MD: Pretty much similar to what Marcia just said. To me, actually, for the majority of patients, I’m going to start with sorafenib first. The data are that lenvatinib works pretty close in second-line as it does in the first-line setting. We know that it works in the second-line setting after a VEGF TKI. With sorafenib, it was a first-line study. We know it works in the first-line. We do not know that it really works in the second-line after lenvatinib. So, in the majority of my patients, the way I look at it is, it’s not a sprint. It’s going to be a marathon, and I want to be able to go from one drug to another to another. And it’s a very rare thyroid cancer that I’m only going to be able to get one drug and that’s it. In the majority of my patients, I’ll start with sorafenib, then I’ll go with lenvatinib. The big exception is going to be the patient with very aggressive disease. If I have someone who’s becoming symptomatic very quickly, if they’re very aggressive, almost near anaplastic-type disease, then I’m going to go with, I think, the drug that’s the best. And I think even though they have not been compared head-to-head, when we look at the phase III data of both studies, lenvatinib looks like a better drug.

R. Michael Tuttle, MD: In terms of response shrinking.

Eric Sherman, MD: In terms of response rate, in terms of progression-free survival. It is not a head-to-head comparison, and you have to take that as a caveat. But when you look at comparing one to another, like the two phase III studies, that response rate is much, much higher with lenvatinib; the progression-free survival looks larger. So, if I have a really, really aggressive disease, I want to use lenvatinib first. But the majority of my patients I usually see before that happens, and I’m going to start with sorafenib first, followed by lenvatinib.

R. Michael Tuttle, MD: Frank, where are you on this?

Frank Worden, MD: Yes. I could echo the same thing. I’ve had patients where I’ve given them lenvatinib and then give them sorafenib and they crash. They just don’t do as well. Is this just my experience? It’s hard to tell based on the biology of the tumor, perhaps. I don’t know. Or clinically are they just not as fit as they would have been? But I do the same thing: I start with sorafenib, and even with data from Marcia and from Eric about adding mTOR inhibitors, I start with sorafenib. And then with progression, if I can petition to get everolimus, for example, based on their data—I’ll add everolimus before I actually go to lenvatinib. But, if a patient, again, needs a response right away because the disease burden is big but there are a lot of symptoms, then I’ll start with lenvatinib.

Naifa Busaidy, MD, FACP, FACE: I think there’s a couple other things that I want to add. I don’t have a rule of always sorafenib first. I agree with everybody that you look at the burden of disease, the timing that you need the shrinkage, as well as the comorbidities of that patient and their lifestyle. Are they a person that’s at high risk for hand-foot, laborers? Or are they somebody who fatigue really will crunch their day or hypertension is going to be really bad? And I think you have to take the whole picture, quality of life, symptoms, comorbidities, burden of disease, everything that’s been said to help you choose that drug and what’s right for that patient. I don’t think we have a rule until we have that data, because like what’s been pointed out, we don’t have that head-to-head. We don’t know the right answer. You can get nice shrinkage with both drugs, depending on if you choose the right patient population. I think the jury is still out.

Marcia S. Brose, MD, PhD: Even with sorafenib, the phase III trial had a response rate of 12.2%. I will point out that 90% of the people who give this regularly are probably getting a higher response rate than that, and I mean in the phase III, we were getting like a 20% to 30% response rate. So, it really is unclear that if we did a head-to-head where it would fall. They’re probably closer together than they look, if you were to just look at the phase IIIs.

R. Michael Tuttle, MD: This is a good problem to have. We’ve got two drugs.

Marcia S. Brose, MD, PhD: Yes, two active drugs.

R. Michael Tuttle, MD: That we know are active drugs—they both improve progression-free survival—and then we’re going right where we started at the beginning of this talk, how do we figure out the right drug for the right patient at the right time?

Eric Sherman, MD: One thing I do want to point out is while we do have two FDA-approved drugs, and they’re good drugs, neither of them are great drugs. Clinical trials are still, to me, a way that you have to really think about going—even if it means in the first-line setting, if you have the right clinical trial, that it’s something you hadn’t happened to consider. So, I think we still have a long way to go in thyroid cancer. The fact that there are two FDA-approved drugs doesn’t mean those are the only two ways we should be going about it. If there’s a clinical trial available, a lot of times we have to think about that even in the first-line setting.

Naifa Busaidy, MD, FACP, FACE: The way that we explain it to patients if they’re saying, ‘You have these FDA approved trials, why should I do this research?’ Because you never know when that drug or that combination of drugs will be that cure or will do better than this. So, FDA-approved drugs are always available, as long as it’s the right setting.

Transcript Edited for Clarity