Transcript:R. Michael Tuttle, MD: Tell me, as a group—it’s a perfect segue—where are we going next? What are the trials that we’re doing now that we think are going to kind of be the emerging therapies? We’re not there yet, but we’re over the next…. Marcia, there’s some combination of mTOR and kinase inhibitors. What’s the story?

Marcia S. Brose, MD, PhD: Right. So, we did some data from the sorafenib trial where we actually took tissue at the time of progression, and we saw that the progressing tissue actually was upregulated, had higher activity of AKT pathway activation. In fact, we just had a paper accepted where we actually showed the histology, did quantitative immunohistochemistry. And what that data basically showed, at least in that setting, is if you’re higher than the median, as far as nuclear AKT expression, you’re less likely to get a response. So, that coupled together with the fact that we had some patients who, after sorafenib, went on a combination of a VEGF and an mTOR inhibitor, anecdotally had done really well. We shared a patient that had that.

R. Michael Tuttle, MD: Yes.

Marcia S. Brose, MD, PhD: We started a trial. We actually named it after her. It’s called Lindsey’s trial. And I chose that intentionally because there was no point, in my opinion, when you already are going to get a year to sometimes 2 years on sorafenib alone, I didn’t need to add toxicity up front. But, at the time of progression, we added in everolimus. And we showed that after progression, you could get another 13.9 months. And so that’s 14 months, and that actually wasn’t even the final data cut. So, that’s a significant amount of benefit by adding in an extra agent. And, interestingly, because usually you stop the agent that doesn’t work. But what’s really clear—and we haven’t really mentioned today—is heterogeneity; there’s tumor heterogeneity. Some cells were responding still to sorafenib, and some of them really responded to the mTOR inhibitor. And it turns out if you do one or the other, you have progression if you do either alone. But now you put them together, and now you get this whole additional year-and-a-half, great for my patients. And, interestingly, adding everolimus in at that point added almost no new toxicities. I don’t think we had any grade 3s—or very, very few grade 3s, like a handful of them—ridiculously low numbers for a combination that should have been much more toxic.

R. Michael Tuttle, MD: Exciting new therapy.

Marcia S. Brose, MD, PhD: Yes. I think a combination with mTOR inhibitors is one way to go, and we’re going to do that now, actually, with lenvatinib. We have a lenvatinib/everolimus study going forward, too.

R. Michael Tuttle, MD: Cool. Eric, let me ask you about the BRAF story. The BRAF story and BRAF inhibitors in melanoma is a huge winner. We had some dramatic responses. We’ve got BRAF with thyroid cancer. What’s the story of BRAF inhibitors there?

Eric Sherman, MD: So, there has been a phase II study just completed, and the response rate is pretty acceptable. You see response rates between 30%, 35%, depending on whether it’s first-line or in second-line. It’s not as good as melanoma, but at the same time, it’s pretty good. There’s definitely different things about different cells that have BRAF mutations, that not everything is exactly the same. You see, melanoma is different than thyroid cancer; it’s different than colon cancer and different than lung cancer. There may be ways to try to improve what we may see in a thyroid cancer line. They’re looking to see, what are the things that are being upregulated and what are the pathways of resistance that you may see from BRAF inhibitors?

From Jim Fagin’s lab, we saw that there’s upregulation of the HER-3 pathway and that, at least in the lab when you combine the two together, you end up seeing a much better response. Other mechanisms that people are looking at is try and just do a better job inhibiting the BRAF pathway, such as adding the MEK inhibitor. And there is a randomized study going on right now that’s looking at a BRAF inhibitor versus a combination of BRAF and MEK. There might be other things to that story, as well, better BRAF inhibitors, which are trying to be developed. There are studies trying to look at what are the mechanisms of resistance, inherent resistance for these tumors, and trying to maybe do a better job with the combination and actually allowing better responses and longer responses to treatment.

R. Michael Tuttle, MD: Yes. Naifa, if I get out of the BRAF pathway and the MEK, Dr. Google says immunotherapy is great for every cancer. I looked it up on the way over.

Naifa Busaidy, MD, FACP, FACE: Really?

R. Michael Tuttle, MD: Yes, it says it’s great. I have no idea. But where are we with immunotherapy? Should we be thinking about that?

Naifa Busaidy, MD, FACP, FACE: Yes. So, not a day passes by without a patient coming into our clinic and saying, “Give me that cure. Give me immunotherapy. That is the cure. I’ve heard about it, read about it; it’s in all these magazines I read.” Okay. So, obviously, with the immunotherapy, the goal is to use the patient’s own immune system, upregulate it, fight the tumor. And there are beautiful responses in many cancers. I would say if you look across the board at immunotherapy in all cancers, you get anywhere between 20% and 40% of patients where they’ll get phenomenal responses, like complete responses, and these patients do very well. But, obviously, that leaves 70% to 80% of patients who just don’t respond.

And as far as trying to figure out who are those patients that are going to respond, there’s lots of ongoing studies in other cancers. And they’re trying to figure out who can benefit from the immunotherapy. The way I explain it is, in a thyroid cancer, we need to learn from those other cancers and what’s already been done before—we just put patients on these drugs. Because there is a subset of patients that it’s not going to work in, or what’s the right way to do it. They’ve looked at the immune cells in differentiated thyroid cancer, medullary thyroid cancer, and anaplastic thyroid cancer. There’s a group at MD Anderson, Ramona Dadu and Maria Cabanillas, that are looking at it with the immunotherapy-platform folks. In differentiated thyroid cancer, we don’t see that many immune cells, and so we worry that those patients are not going to be able to respond very well to immunotherapy. We’ve put a few patients on phase I trials, and we haven’t had that many great responses. So, the question is, how do we upregulate that immune system so that immunotherapy can work, and we can have those phenomenal responses?

Some of the things that I think are going to be looked at is, do we give that TKI first—whether it’s lenvatinib, sorafenib, any of the tyrosine kinase inhibitors, or even a BRAF inhibitor—boost up the immune system and then give the immunotherapy? Maybe that will work better. But we have to biopsy those patients to see if the immune infiltrate went up because PD-1 expression hasn’t been very promising in a lot of tumors to say that is a predictor. So, we’ve just got to figure out first the biology, in who it’s working, before we just put immunotherapy into the limelight. That’s personally why I don’t put patients right away into immunotherapy. What they’re doing—similar in other tumors—is looking at whether we give the patient a little bit of radiation, boost the immune system, and then give immunotherapy, the abscopal effect? And so those are things that need to be figured out. What’s the right role in thyroid cancer?

So, I think there will be a role of immunotherapy in differentiated thyroid cancer. I just think we’ve got to figure it out first before we just give it. We owe that to our patients before just putting them on the trials, unless they don’t have any other options, they’ve exhausted everything else. Bryan Haugen is going to be leading a study looking at a PD-1 inhibitor with lenvatinib in combination. It’s not going to be sequential, but that will be one thing to be looking out for that may give us some sort of a signal as to whether that would be working or not. And should it be patients who have small volume tumors that go on this, or the rapidly growing ones? And the more poorly differentiated/anaplastics—should we start with those? So, I think there’s a lot that we don’t know. I think there’s definitely a role. We’ve just got to figure out where and when.

Transcript Edited for Clarity