So, listen, maybe Marcia, you can help us wrap up by helping us think about future directions in advance DTC [differentiated thyroid cancer].

: I think that there’s a lot of future directions and I think where a lot of them have been mentioned already with upcoming trials where we’re looking at other combinations for RET, RAI [radioactive iodine], redifferentiation. There are definitely multiple studies coming up where either kinase inhibitors are being partnered with each other or with immunotherapy. I think that we definitely have a bad, unmet need in anaplastic thyroid cancer—still haven’t done anything that really has made a big impact with the exception of the BRAF inhibitors—which I do think helps some of those patients with anaplastic. Of course, the third of them that might have BRAF mutations, but two-thirds of them don’t have BRAF mutations and are a huge unmet need. And now although already we’re starting to get unmet need with the patients who have advanced thyroid cancer that have failed the therapies that we have now.

I’m really hopeful that we’ll maybe find more targets that we could hit, that we’ll be able to do these targeted therapies really have been such a joy to work with because the side effect profiles have been lower and the response rates have been so high I think we’re just going to continue to go in these 4 or 5 directions. I think we’re going to get a little bit more data about head-to-head which is the better first-line and what’s a better second-line, which we haven’t really had that much data for. I know that there’s a RET inhibitor study right now that we have going on at our site. Many of you have at your sites randomizing patients to either RET inhibitors upfront versus standard of care or for medullary thyroid cancer, for instance.

We’re going to start to get some of those studies under our belts. They might start to give us more direction where to go in the first-line, because a lot of these phase 2’s you can’t compare really side-to-side to some of the larger studies. It’ll be nice to get some really good, randomized trials to figure out some of the sequencing in the future.

Yes. I agree that the selpercatinib [Retevmo] and pralsetinib [Gavreto] randomized trials are so important, not just for their primary end point but also for that other important question about is there a sequence that’s better. If you develop acquired resistance on selpercatinib or pralsetinib, can you still have activity with lenvatinib [Lenvima] or cabozantinib [Cabometyx] and MTC [medullary thyroid cancer]?

Speaking of cabozantinib, I’d asked Naifa, which cabozantinib are we talking about in DTC? So those of us who do thyroid cancer are used to thinking about cabozantinib as Cometriq—the FDA [Food and Drug Administration] approved formulation for medullary thyroid cancer. Naifa, do you want to unmute, say one word about Cometriq versus Cabometyx?

: Yes. Sorry, I didn’t answer your question, didn’t mean to ignore it. So basically, it can get very confusing because we all use generic names every day and even when we’re writing it out, and the formulations are very different and so they cannot be interchanged. And so, cabozantinib was looked at 60 milligrams a day and that’s under the brand name of Cabometyx. And it’s very different from the cabozantinib under the brand name Cometriq from medullary thyroid cancer where that was 140 milligrams. Now, they’ve completely changed the formulation but they’re not equivalent and we have to be really careful. And that’s even different from kidney cancer for physicians that treat both.

Thank you for that point of clarification. Maria and Giuseppe, any other thoughts that you may have in terms of future directions—things that we don’t want to miss, Maria?

 Yes. I think a Hurthle cell is a real opportunity. We’ve made great strides in anaplastic thyroid cancer and in differentiated thyroid cancer and medullary thyroid cancer. But Hurthle cell is one of those orphan diseases and it’s a rare type of differentiated thyroid cancer. We didn’t talk much about it today. It does respond well to lenvatinib but we know that we need other therapies because, like I said this is a marathon, [and] at some point we’ve got to switch to something else or a patient can’t tolerate it. I think we have a trial coming up with immunotherapy in Hurthle cell and so that to me is the next frontier.

: To me, I said that briefly before, but if I had the genie in a bottle coming out my first wish would be to have a tissue-based test that can tell me who is radioactive iodine sensitive and who is not. I still believe that we treat so many patients in whom the iodine is not effective, and we don’t do a good service to them. And we need really to dissect the molecular biology of the cancer cell and understand who can respond and who doesn’t on the tissue. And I do think that the tools are there because we understand this so much better than we did in the past that we should be able to tell. And I’m hopeful that in the next few years I will sit in front of a patient and look at a report and say, “Well, I don’t think radioactive iodine is a good thing for you. Maybe we can try with redifferentiation but not as it is.” And the other person is, “Oh, wow, you’re a great candidate.” I think if there is any cancer set will be wiped off by the radioactive iodine, that would be my real hope for the future.

: Can I just say one thing, Lori? I’m sitting here thinking about where we were 10 years ago, and I think that we all have to really be appreciative of the fact that 10 years ago we had nothing approved. There are not a lot of cancer types where such great research, collaboration and advancements have happened. We’ve had now 3 FDA approvals, multiple phase 2’s that are showing activity, and then 3 more targeted therapies also getting FDA approval. I just want to say kudos to the whole thyroid world. I think that the research has really gone and really shown a big difference. And I think that the people who benefit the most are patients from all of these drugs.

I think that is a great note to end this program on. I completely agree that the last decade has been a world of progress for our patients. I think that many patients’ lives have really been changed dramatically by all of the hard work that the people have been putting into this work to get new drugs for our patients with thyroid cancer. Listen, let me thank you all for this rich and informative discussion. And I really appreciate your joining me in today’s discussion. Thank you again also to our viewing audience. We hope that you found this 

 Peer Exchange discussion to be useful and informative. Good night, everyone.

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An overview of therapies in the pipeline for differentiated thyroid cancer and their potential effect on clinical decision-making.

Novel Treatment Advances in Differentiated Thyroid Cancer

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?

: 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.

: 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.

And Marcia, you’re talking about the lenvatinib Study 211.

: 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.

Naifa L. Busaidy, MD, FACP, FACE, recognizes the importance of reassessing patients prior to considering a second-line therapy for differentiated thyroid cancer.

Second-Line Treatment Approaches for DTC

I want to ask you 2 questions, and then I’ll make 1 point. My point is with lenvatinib, the hypertension can kick in really quickly. So, do you have your patients monitor their blood pressure at home?

: Yes. Sorry, go ahead. What’s the second question?

Well, actually, I have 2 more questions. What do you do with a patient with a 

 V600E mutation who’s progressing and needs systemic therapy? And do you think lenvatinib, sorafenib, whatever, do you think these drugs offer an overall survival benefit? Because with the studies, the SELECT and DECISION trials, both had crossover for the patients who were on placebo, when they had disease progression, they were allowed to cross over and receive the active drug, and the majority of patients received the active drug. So that could negate an overall survival benefit.

: The crossover definitely makes it harder. There were some initial data in the SELECT trial in the patients over 65 years old that there was an overall survival benefit. What that basically has told me is that the older patients don’t tolerate any progression, and they often can succumb to their disease at the time of their next progression. Whereas the younger patients might be able to manage a little bit of progression and cross over and not have any ill effects toward overall survival. That starts to suggest that there’s an overall survival benefit, and there might be more of an overall survival benefit, but it’s hard to discern because of the crossover. I think we have enough of a suggestion that yes, that is something. I don’t necessarily use that though as a reason to treat everybody once they have a 2-mm nodule because of the toxicity. But I think that the smaller and smaller the disease is when we start it, the difference between the placebo arm and the treatment arm is probably going to come closer together.

mutations, the BRAF inhibitors do provide additional activity, which again, I’m sure we’ll go over in the next section. I don’t find that their response rates are as high as what we see with lenvatinib with a 63% response rate, and so I don’t necessarily use a BRAF inhibitor before. But if patients are having a lot of trouble with say the hypertension or toxicities related to the 3 drugs I mentioned, that is certainly a good drug to go to as another option, and regardless, that will be an option at some point in their treatment. So, if they’re having a rough time with the VEGF receptor inhibitors, giving them a break and going to a BRAF inhibitor is absolutely where I probably would use the BRAF inhibitors. I think I forgot what your third question is.

Can I jump in here though really quickly? I think Naifa and I do it a little differently. We actually oftentimes will start with BRAF inhibitors instead of starting with lenvatinib or sorafenib, and that’s because of the different toxicity profile, and sometimes it’s difficult to treat these older patients, especially when they have a lot of comorbidities with the VEGF receptor inhibitors. I can talk later about the BRAF inhibitors and what has been shown in terms of efficacy. But when I think about treating systemically, I’m thinking about that marathon that we’re starting. Yes, I’ll get more partial responses with lenvatinib, but in terms of how long we’re going to have a response or stability, that’s really what’s going on in my mind, how can we get the most out of every single drug. And so, if my patient has lost now 30 lb on a VEGF receptor inhibitor and is debilitated, I may not be able to get them on another therapy. Whereas if I start the other way around, they might be in better shape to start on a VEGF receptor inhibitor later. I’m not saying that’s the right way, that’s just the way that we do it and the way we think about systemic therapy. We’re thinking about the marathon.

: Do you find that Lori, that you’re less likely to be able to go on to BRAF inhibitor after one of the VEGF receptor inhibitors? How do you do it?

I would say, first of all, this is an off-label discussion in terms of using BRAF-directed therapy in the first line. In general, that’s not something that I would definitely advocate, and I usually use a VEGF or a multikinase inhibitor as a first-line therapy, and I generally use lenvatinib as a first-line therapy. I think Maria’s point is well taken, that patients can be on these drugs for 3 or 4 years. The median duration of response is almost 3 years with lenvatinib, and so you have to be able to make sure that a patient stays well throughout that time. It can be challenging. Fortunately, there will be a trial investigating dabrafenib and trametinib in the second- or third-line setting for 

 mutated iodine-factory DTC [differentiated thyroid cancer]. So, we will have data that I think will be very useful in guiding us in the future.

: I have one other thing about that. All of you alluded to this, but I just want to point it out. Potentially, one other use for patients who may need BRAF inhibitors depends on the organ involved. So, if you have tumor invading the trachea, or blood vessels wrapped around even the adventitia or the intima, you may want to think about using a drug that has less anti-VEGF activity, just for the potential for fistulas, or carotid bleeds, or what have you. For those patients who have that more advanced disease, you may want to think about using one of those, if it’s a known alteration in the tumor, whether it’s 

. I know you’re talking about different lines of therapy, but it’s just something to keep in mind, the tumor involved, tumor factors and patient factors. It was already mentioned about hypertension, etc.

Considerations regarding approaches to sequencing therapies for differentiated thyroid cancer.

Systemic Therapy Algorithms in DTC

Naifa L. Busaidy, MD, associate professor, MD Anderson Cancer Center, discusses the results of a cooperative study that investigated the association between long-term thyroid hormone suppression therapy (THST) and improved outcomes in patients with differentiated thyroid cancer (DTC).

Busaidy says the study, which followed 5000 patients, examined if excess thyroid hormone can improve disease-free survival. It is known that in thyroid cancer, giving a patient excess thyroid hormone will decrease recurrence risk but physicians do not know how much hormone thyroid suppression is most effective.

The study found that thyroid hormone suppression is important for the first 3 years but suppressing the patient beyond 3 years might not be necessary. Busaidy says the study also showed that physicians do not need to aggressively use THST. Suppressing the thyroid hormone can cause adverse events, such as irregular heartbeat and osteoporosis.

Busaidy says it is important to weigh the risks and benefits of each patient.

View more from the 2014 ATA Annual Meeting

Naifa L. Busaidy, MD, associate professor, MD Anderson Cancer Center, discusses the results of a cooperative study that investigated the association between long-term thyroid hormone suppression therapy and improved outcomes in patients.

Naifa L. Busaidy, MD, FACP, FACE

Articles

Novel Treatment Advances in Differentiated Thyroid Cancer

Second-Line Treatment Approaches for DTC

Systemic Therapy Algorithms in DTC

Dr. Busaidy on the Association Between THST and Improved Outcomes