Please welcome to the main stage Dr. Mimi Hu. Good morning everyone. I really feel like I'm on some kind of like rock star performance stage when coming out of here. So my name is Dr. Mimi Hu. I'm a professor in the Department of Endocrine Neoplasia at MD Anderson Cancer Center in Houston, Texas. It is my sincere pleasure today to introduce my colleague and very good friend Dr. Maria Cabanillas. Dr. Cabanillas is an oncologic endocrinologist at the University of Texas MD Anderson Cancer Center in Houston, Texas. She's a tenured professor and faculty director of clinical research in the Department of Endocrine Neoplasia. She treats both early and advanced thyroid cancers including medullary differentiated and anaplastic thyroid cancer. Her research is focused on molecular targeted therapies and immunotherapy in this area. She's led the effort to create FAST which stands for Facilitating Anaplastic Thyroid Cancer Specialized Treatment at MD Anderson. This comprises a multidisciplinary group which focuses their efforts on streamlining the process to see these complex patients tailor treatment plans based on the molecular abnormalities in the tumor and designing clinical trials for this patient population. This team sees the highest volume of anaplastic thyroid cancer in the nation. She serves as the principal investigator in several clinical trials for the treatment of advanced thyroid cancer. She recently completed her service on the Anaplastic Thyroid Cancer Guidelines Committee for the American Thyroid Association which was published last year. Besides taking excellent care of her patients, she spends a lot of her free time tending to her garden and her worms and camping. She is this year's recipient of the Ace Hossain Gharib Educational Lectureship Award which will be presented this afternoon. She's speaking to us today on targeted therapies in anaplastic thyroid cancer. Maria, come on the stage. Good morning. Okay, I'm gonna stand a little bit to to my right here so I can actually see. I want to thank the organizing committee first of all and it's really exciting to be back in person. It's nice to actually give a talk where you're not the only person in the room and you're not wearing pajama pants. So, you know, I actually had to go out and buy new clothes because all I had were scrubs. So anyway, it's wonderful to be here this morning and I'm gonna talk to you about advanced thyroid cancer and targeted therapies that we're using these days. These are my disclosures. Okay, so in order to really understand advanced thyroid cancers, you have to understand where they came from, right? So of course you all know that there are two major categories of cells in the thyroid. There are more than two, but there are two that we really think of as where we these cancers are derived from the epithelial follicular cells which are the predominant cells that secrete thyroglobulin and then there are the C cells that are neuroendocrine cells. Those secrete calcitonin and CEA. We have medullary thyroid cancers that come from those cells and from the epithelial follicular cells we have our differentiated thyroid cancers that are your papillary follicular herthal cell. When those start to acquire more and more mutations, so you see some of the mutations up here. I don't know if my pointer works or not. Nope. So you see some of the mutations listed up there. These are the driver fusions or driver mutations that these more well-differentiated thyroid cancers start off having. When they start to de-differentiate, they're becoming poorly differentiated and later anaplastic thyroid cancer, they retain that driver fusion but they acquire these late event mutations and conferring more aggressiveness of that tumor and then the prognosis of course is not as good. From the medullary thyroid cancers, these have very few mutations usually, either RET or RAS, and sometimes we get less differentiated medullary thyroid cancers but they're very rare. This is just showing again kind of what we think of as a spectrum of disease in differentiated thyroid cancer going from benign neoplasms all the way to undifferentiated tumors and you can see that as they start to acquire more and more mutations, they become more aggressive in these higher grade histologies but the point is that they do retain that driver or that fusion that started the tumor. That's important because this is what we're targeting. We're not targeting those late event mutations at this time. We're really targeting those early drivers. Two signaling pathways that are important in differentiated and anaplastic and medullary, sorry I've left medullary off there, but the two major pathways are MAP kinase and PI3 kinase pathways and we have a lot of different mutations that are targetable along those pathways. You see the long list of drugs there that we're going to discuss in this session but really the way I think of targeted therapy in thyroid cancers is having two major classes of therapy. We have our anti-angiogenic therapies and then we have our gene or mutation driven therapies and so if you think about them that way it's a little bit easier to choose the right drug for your patient. So let's talk about systemic therapy. The first thing I want to talk about is when to treat because with other solid tumors, for example lung cancer, those are always treated. If they're metastatic and not resectable, those are always treated with systemic therapy. So patients get very confused, they show up, they don't understand why am I wanting to observe this patient and not putting them on chemo and so we're going to talk a little bit about that, talk about the different therapy options and then some newer modalities, basically as neoadjuvant therapies and re-differentiation therapy. So let's talk about the past. Before 2013, we essentially for DTC had two options, right? You could either take it out and give radioiodine and go back to surgery and give more radioiodine and medullary thyroid cancer you basically, you know, was it resectable or not and that's all we had and we had a lot of patients that failed these and didn't have many options. So this is now the list of options for our patients. These are all the FDA approved drugs for thyroid cancer and in green, the first four in green, because they're the anti-angiogenic category that I was talking about. The ones in blue, the last four, are the ones that are more directed towards a fusion or a mutation. So the first four, like I said, are the anti-angiogenic. Seraphinib, Linvatinib approved for radioiodine refractory differentiated thyroid cancer. Vandetinib, Cabozantinib for medullary thyroid cancer and then Cabozantinib received an additional indication last year for second-line therapy and differentiated thyroid cancer. I'm not going to talk much about second-line therapy because really we're, you know, kind of discussing more of the upfront therapies and that's a talk that's longer than an hour. So these have very good responses. You see their, you know, responses in the double digits with Linvatinib up to 65%. So really good responses. The ones that are in blue, Dibrafin, Intrametinib, Larotrectinib, Selprocatinib and Pralsetinib are more directed therapies. We're going to talk about all of these and look at those response rates. So RR's response rate, you see the response rates are, you know, in anywhere from 56 to 89%. I mean these are really good responses in differentiated thyroid cancer and in medullary thyroid cancer for the RET inhibitors. Okay, so let's talk about when to treat because this is really kind of the most confusing thing, I think, is how do you explain to your patient that they don't need a TKI, a kinase inhibitor? Well, most differentiated thyroid cancers and medullary thyroid cancer patients have very indolent disease even when it's metastatic and they don't require systemic therapy sometimes for many years and actually Mimi Hu presented at the tumor board a patient with medullary thyroid cancer that actually didn't need treatment for like a decade. So this is not uncommon even with metastatic disease. With differentiated thyroid cancer we start off always suppressing the TSH, as you know. We give them radioiodine. If that doesn't work anymore, you know, then we still observe them and if it does work we observe them. We can always go back and give them more radioiodine. Localized therapies or focal therapies, I think, are, you know, I don't have, I don't talk much about it in this session because it is a long discussion, but these are critical. We can keep patients off kinase inhibitors for a very long time by doing this, you know, resecting a metastasis if it's like a single metastasis, giving external beam radiation, for example, to a bone metastasis that might be painful or progressing, especially when they have oligometastatic disease. This is a really great modality. Cryoablation, embolization, and so we really should think about how to keep patients off systemic therapies when they really have a small amount of disease. Bone metastases can, you know, we can target those with zoledronic acid and denosumab and we do that sometimes, but, you know, we have limitations with these drugs. If all of this fails, though, and the patient is progressing and has clinically significant disease, it's one of those things that when I see it I can tell you that they have it, but it's very hard to explain, but basically, you know, if the patient has progression, if anything is symptomatic or threatening an organ, and or if it is on the larger side, meaning about to me it's like one and a half to two centimeters lesions, I'm thinking of treating that patient systemically if I can't give them focal therapies. So that is basically the algorithm that we use for when to start systemic therapy. Okay, so the next question is what is advanced thyroid cancer, right? Because it's another one of those that I can, if you show me the case, I can tell you if that's an advanced thyroid cancer, but it's very hard to define, right? So for years we've been trying to, you know, write protocols that say, you know, aggressive thyroid cancers, but then, you know, you had to then define that, and it's very hard. So this year we put out this nice consensus statement, the American Head and Neck Society Endocrine Surgery Section and ITOG, and essentially defined advanced thyroid cancer. So under statement seven, that's the easy one, so I'm going to start with the bottom one there. Statement seven basically says that if the patient has anaplastic thyroid cancer, they should be considered advanced. Even if the patient has had that tumor fully resected and doesn't have any apparent disease, or even if the patient had a micro ATC, sometimes you have this big papillary with a tiny focus of ATC, those are considered advanced thyroid cancers and therefore you should be getting molecular testing on those patients. The other one, the other statement, statement six is a long one there, but it defines what could be an advanced thyroid cancer, right, in the right clinical setting. So not set in stone, but bulky invasive disease that's inoperable, that's the primary disease or local regional disease, anatomically detectable clinically recurrent disease, again in the right clinical setting, distant metastatic disease with mediastine, including venustinal disease, biochemical or structural doubling time of less than six months, gross residual neck disease when further resection is not feasible or has to be delayed, poorly differentiated or other aggressive pathology, radioiodine non-avid unresponsive disease, unresponsive to TSH suppression, and then imminent threat of the tumor, you know, to an organ, and then other features that portend aggressive behavior, whatever that means. But, you know, this is kind of the first time that we've really put written down on paper what it means to have advanced disease and therefore you should have molecular testing done. So how do we do molecular testing? That's the next question that I get a lot of, and there are really two ways of doing this. In the United States what we do is the preferred, which is on your left, the preferred is essentially sending the tumor off for broad panel that has, you know, it's comprehensive DNA mutations, also RNA fusions are tested. The slow way and the economical way, which, you know, we don't think a whole lot about these things in the United States, but in other countries it's very important to think about that, is that we do multi-step testing. What does that mean? Well, the most common mutation in differentiated thyroid cancer is BRAF, right? So you can send, this is just an example, you can send for BRAF by immunohistochemistry, this is just a stain in the slide, or a PCR test, really bringing down that cost, and if the patient has a BRAF mutation, you basically don't need to proceed to do fusions, to try and find fusions, right? So that's a cheaper way of doing it, but it's very slow and it wastes a lot of tumor, and so we don't really do that anymore in the U.S. So let's talk about treatment, starting with the anti-angiogenics. I'm going to talk about the frontline therapies, so for differentiated thyroid cancer we have two approved therapies, serafinib and lenvatinib, and you see that these were phase 3 trials compared against placebo, and you know, very, very good, very good progression-free survival, and this was approved, you know, now many years ago. Well, the one thing that you should understand, the difference between the two drugs is the potency. So lenvatinib is a much more potent drug than serafinib, and with more potency, yes, you get better responses, but with more potency, you also get more toxicity, and so sometimes, you know, that's something that we really need to think about. I'm going to kind of run through that in another slide, but it's important to understand these differences. For medullary thyroid cancer, we have two approved drugs, vandetinib and cabozantinib. Again, compared against placebo, very good progression, medium progression-free survival compared to placebo, and again, cabozantinib has now another indication in thyroid, which is second line for patients who've already progressed on their first-line therapy. Antiandrogenics, relative contraindications. So, you know, we really think about these a lot when we're going to start an antiandrogenic drug, and so should you, because these drugs can be very toxic to patients, especially if they already have poor cardiac function or they have a recent myocardial infarction. This is a problem because these drugs cause a lot of hypertension, and when you have a lot of hypertension, you can have cardiac dysfunction, you can have heart attacks, and that is something that really needs to be thought about. So, if they've had a recent MI, we don't put them on these drugs. Uncontrolled hypertension, because the drugs cause a lot of hypertension, you've got to get control of their blood pressures before you start these drugs. Large unhealed wounds will not heal. If they're small, sometimes they'll close, sometimes they won't, but if they're large, they're not going to heal on antiandrogenic, and so you need to either let the patient heal or put them on a different drug. If they've had a history of colitis, diverticulitis, intestinal perforation, recent bowel surgery, I've even seen this in patients who had remote bowel surgery, so had bowel surgery 10 years ago, that these drugs can cause perforation, and that gets very, very ugly. Tumor invading the trachea or esophagus or the great vessels, because we have seen carotid blowouts with these patients on these drugs. We've seen tracheoesophageal fistulas, we've seen fistulas with other organs like the skin, and so we need to be very cognizant of this. If the patient has had like a recent surgery to resect part of the trachea, that can cause a TE fistula if you put them on these drugs. If they have already hemoptysis or they're using anticoagulants, these drugs can can cause more hemoptysis, and so we need to be careful with those patients, at least warn them that if they're bleeding, if they're coughing up blood, they need to go to the emergency room immediately. Very low body weight is kind of a relative, very soft indication, contraindication, because these kinase inhibitors cause such severe weight loss, we're very careful with patients who already have a very low BMI because this is one of the major reasons that I have to take patients off these anti-angiogenic drugs is because they lose so much weight, I can't continue treating them. So the bottom line here is the anti-angiogenics are not safe for everyone. And so thank goodness we have more targeted therapies now. I want to point this out to you is that your pathologist may be the one that kind of tells you, hey, this patient might have a fusion. So fusions are very, very rare in differentiated thyroid cancer. They're also extremely rare in medullary thyroid cancer. These are patients with poorly differentiated thyroid cancers, and what they show in this very nice paper is that there are some clues that the pathologist can hone in on, such as multinodular growth, prominent fibrosis, extensive lymphovascular invasion, mixed papillary follicular solid architecture. So I'm not a pathologist. I couldn't begin to tell you what those beautiful pictures show, but I'm sure the pathologists out there can help us with that. But basically, I think we're going to start seeing a lot more publications on this topic. I do think that this is going to be kind of the hot topic because you're trying to find a needle in the haystack, essentially, when you're looking for fusions. And so this may be your first clue. Okay, so let's talk about RET. So lots of talk of RET recently, right, because we have now two approved drugs. In medullary thyroid cancer, we see quite a bit of RET mutations. In papillary, poorly differentiated, and anaplastic thyroid cancer, we see RET fusions, okay. Mutations in medullary, fusions in DTC, ATC. And of course, in non-small lung cancer, we see RET fusions. So we have these two selective RET inhibitors. We now call them prosetinib and cell percatenib, but you might still hear the old term, which is BLU667 and LOXO292. Okay, let's start with cell percatenib in medullary thyroid cancer. These beautiful waterfall plots are the kind that we love to see in oncology, where the majority of patients, whether they had previously treated disease or they had treatment-naive disease, had really high response rates and really deep responses, right. I mean, each bar is one patient, and that's the change from baseline. And so, you know, 69% in previously treated is a home run, 73% in naive is absolutely wonderful. And the great thing is that the toxicity compared to anti-angiogenic drugs is much lower. We still have issues, right. We still do see toxicity, but patients feel a lot better on these drugs if they've ever been on cabozantinib, vandatinib, or the other anti-angiogenic drugs that really can tell you the difference. RET fusions, like I said, it's like finding a needle in the haystack, so you see far fewer patients on this slide. These were 19 patients with a response rate even higher, 71%. These patients included a patient with anaplastic thyroid cancer that responded. Those are in purple. One ATC responded, and two patients with poorly differentiated thyroid cancer had a response. So even in more advanced disease, we're still seeing responses. This is important because we, you know, we used to think, well, if you're just targeting one thing and the one, you know, fusion or mutation and the patient has all these late event mutations, are you going to get a response? And the answer is yes, you actually get very good responses. Pralsetinib is the second drug that was approved for RET fusion or RET mutated thyroid cancer. And again, really good responses, you know, 60% in the previously treated medullary patients and 71% in patients that were treatment naive. And then they had the RET fusion cohort. These were all patients with well-differentiated thyroid cancer. They're all papillary thyroid cancer patients and really a fantastic response rate of 89%. Okay, so moving on to the Ntrek inhibitors, and I'm only going to talk about larotrectinib because this is the drug that we have the most data for thyroid cancer in. But there is another drug called Ntrek inhibitors also approved for Ntrek fusion solid tumors. This was recently published in EJE this year, but I'm going to show you the slides that we presented at ATA last year, which is basically very similar to what was just published. So you see here the responses in differentiated, anaplastic, and then all thyroid. There were 22 differentiated thyroid cancer patients, 86% response rate. That's truly amazing. Anaplastic, there were seven patients and there was a response rate of 29%, so a lot less than in your differentiated thyroid cancers. But still we did see responses. These are the survival curves, and what I want to point out is in blue are the differentiated thyroid cancer patients, and in green is the anaplastic thyroid cancer patients. And you see there's a huge difference between the survival curves between DTC and ATC. And so the point here is really just to show you that in DTC these responses are durable. They're not short-lived, they're very long-lived. The problem in ATC is that these patients progress very quickly. And so, you know, I treat a lot of ATC and I always say that we should be treating ATC like we treat acute leukemias. You'd never treat an acute leukemia with one drug because they quickly develop resistance. Same thing with anaplastic thyroid cancer. I think we need multiple drugs in these patients, and that's why you're seeing that these are not very durable. Okay, let's go to BRAF-mutated thyroid cancers because this is kind of where we have the most exciting data in my opinion, of course, because I treat a lot of anaplastic thyroid cancer. So, Dibrafnitrametanib is FDA-approved for ATC with a BRAF V600E mutation. It only works for V600E. You can see some responses with other BRAF mutations, but the BRAF fusions do not respond to this drug, to this drug combination. But this was approved in, gosh, I forgot, 2018, I think, based on 16 patients that we published at the time. Now, we have more patients than that, but it was based on just 16 patients. It's incredible. The FDA approved a drug for 16 patients. The key entry criteria were, the biggest problem with this study is that the patients had to swallow. Now, about 40% of my patients with ATC can't swallow. That excluded about half of the patients that we could have enrolled on this study. There's global enrollment, and global enrollment, we were able to get about 26 patients or so eventually on this study because the criteria were very strict. But anyway, in this publication, 69% response rate, overall survival at one year was 80%. We just published the update on this at the beginning of this year, and the median overall survival is 14 and a half months, 14 and a half months for anaplastic thyroid cancer. I don't, you know, incredible, but can we do better, I guess, is the question. These are your, this is the waterfall plot showing really deep responses in that first graph there. So these were, these patients, not only did they respond really well, but they respond really quickly, and I'm going to show you an example of that. And then these are durable responses, median overall survival is over a year. But this is an example of one of our patients that was transferred into MD Anderson. She came in with that tracheostomy, and this tumor was coming through her skin. And we quickly determined that she had a BRAF mutation, put her on dibrafinib, trametinib, and we can talk about how we did that in a patient that couldn't swallow. If you want to discuss that, I'm happy to talk to you about it. After four weeks, she comes back to the clinic, still with her tracheostomy, but her skin is completely clear. So these, and these responses happen very quickly. I'll sometimes call my patients that I just started on, you know, like on a Thursday, and I'll call them over the weekend and say, how are you feeling? Are you breathing any better? And usually by the third day, they can tell a significant difference and they're starting to swallow. Okay, what about BRAF inhibitors in differentiated thyroid cancer? So we have two kind of larger studies, the Vemurafinib study, which was published a long time ago now, it seems like an eternity. And then dibrafinib, trametinib, which has just been accepted for publication in thyroid, so that you should be able to see that soon. But essentially the answer is yes, BRAF inhibitors work in differentiated thyroid cancer. This is just a table I put together comparing across the different treatments because we had the Vemurafinib treatment naive patients, Vemurafinib previously treated patients, dibrafinib alone, dibrafinib plus trametinib. But the bottom line is that we see pretty good responses in a lot of stable disease. Now, how can we integrate what we have learned about kinase inhibitors and what we already know about surgery and radioiodine, which is what we've been doing for years and years in differentiated thyroid cancer. And, you know, I call this part kind of returning to our roots because I'm an endocrinologist, I'm not an oncologist, but I do treat with these kinase inhibitors, but, you know, my roots are in endocrinology. And so it's really kind of exciting to put these modalities together now. So this was our first publication. We're working on a follow-up publication here, but this is patients with anaplastic thyroid cancer who we treated with dibrafinib trametinib plus or minus pembrolizumab. Because remember I told you that I, you know, we strongly believe patients need to be treated with multiple drugs. And what I'm showing you here is six patients, the PET scan before dibrafinib trametinib and the PET scan after dibrafinib trametinib for those six patients. So you see really nice responses. Some of them look like complete metabolic responses. And then after that, those patients went to surgery. So they had started out as inoperable patients, inoperable meaning we don't want to, you know, have to do a laryngectomy or do some, you know, really horrific surgery on them. Sometimes their carotid was involved and we couldn't really operate. So essentially after they went on dibrafinib trametinib, they had surgeries done. And the only thing I want to point out here is that these patients had R0, R1 surgeries. So those were, you know, either complete pathologic, complete surgeries. The margins were completely free. Or they had just, you know, a little bit of disease, residual disease. So the median follow-up time after 15 months, sorry, the median follow-up was 15.5 months when we published this and the 12-month survival was 83%. We have more updated data that shows that these patients are living past two years now. So why do we operate on ATC? Because this is the question I get a lot. There's always a surgeon that stands up at ATA and says, why are you doing this to these patients? And my answer is because the response to kinase inhibitors is not eternal, okay? They start to develop resistance. And when they develop resistance in the neck, it's a nightmare, right? So this is just an example of one of our patients that we published in thyroid. The lady had, she had her primary tumor, but I'm showing you her scalp metastasis here. And after dibrafinib trametinib, she has this really beautiful response where you see, you know, no more FDG uptake in the area, couldn't even see the tumor there. And then after many months, it starts to show up again and then it starts to really grow. And she starts to feel that growth. So we took her to surgery and just the point of this is to show you, so we removed this tumor and removed her thyroid at the same time. And it's just to show you that this lady, she started off with a BRAF mutation, that's the baseline thyroid biopsy, with a couple other mutations. After dibrafinib trametinib, she shows up with that BRAF mutation again, some of her other mutations that she had, some new ones, but KRAS shows up. And RAS is really our, the biggest headache for us because we have nothing to target RAS. And these patients, when they start to progress, they do very, very poorly. They go downhill very quickly. So I want to take out that tumor before this happens. And that's the rationale for removing them. Okay, so this is just some of our retrospective data that we had put together in a publication in JAMA Oncology. There were 20 patients with BRAF mutations that, you know, that we operated on. And then we had our patients that were not operated on. And the bottom line here is that these patients do much better. Of course, it's biased because it's retrospective. We're now doing a prospective study. So if you want to send your patients to us with BRAF mutated ATC, we're happy to enroll them on the study so that we can show in a prospective manner that this benefits patients. Okay, so I promise this is one of my last slides on anaplastic. I get very excited about the topic, but I just want to kind of want to show you how this has changed, right? So before 2021, we all used what I call the cookbook method. Your patient with stage 4B anaplastic walked in, you know, you look up the recipe, which said if they had 4B, ask the surgeon if they can have surgery. If the answer is yes, you go to surgery. If the, after that, you then give them chemoradiation. And if the surgeon said no, then you just go straight to chemoradiation. That was the cookbook. Really easy. Didn't have to think much about it. But the problem with this method is that after a year or within a year, about 70% of patients are progressing and then your headache is back. So we put together this team called FAST that Mimi talked about in the introduction. And now what we do is that we start with the targeted therapy. We treat them for about three months. We ask ourselves whether this tumor is now meaningfully operable. And if it is, we go to surgery. We then give them chemorads. If they're not operable, we continue them on dibrafinib, trimetinib, or whatever B-Ref MEK inhibitor you're using, or the patient can go for radiation. Now we also treat 4C patients in this manner. But in the guidelines, it specifically only talks about 4B patients because we didn't really have the data to back up the 4C patients at this time. Okay, so now we'll talk about redifferentiation, which is probably the topic that most of you want to hear about. So redifferentiation simply means restoring the ability to concentrate radioiodine in that tumor. And the way we do this is by inhibiting along the MAP kinase pathway. So we can use B-Ref inhibitors for patients who have B-Ref mutations. We can use MEK inhibitors for patients who don't have B-Ref mutations. Oftentimes they'll have a RAS mutation. And then for Ntrek and RETFusion patients, we're now starting to see some data in that. So why do this, right? I mean, why complicate things? Just put them on a B-Ref inhibitor and send them home. The reason that we do this is because after we give them radioiodine, we're able to stop the kinase inhibitor in a lot of patients. And then we can observe them off kinase inhibitors. So all of these kinase inhibitors, they have side effects. Patients feel much better when you've stopped them. So unless they've been on like an Ntrek inhibitor for a long time, like Mimi's case. So the other rationale is that hopefully, because we know that patients that take up radioiodine do much better, would this apply to our patients with redifferentiation? And that's something that we do not know at this time, but hopefully with time we'll have data on that. So this is a very complicated slide. It's simply to show you the strategy, okay? So what we know is that the sodium iodide symporter is expressed on the basolateral membrane in patients who take up, on tumors that take up radioiodine. When they're less differentiated, right, this is the, that is, this is not, it's not really in the right place. It's not being integrated into the membrane and therefore that tumor can't take up radioiodine. And so at the bottom, you see this whole body scan, right? And the patient that's on your right is before dibrafitum, not taking up radioiodine, and then putting the patient on a BRAF inhibitor, this is BRAF mutated, then restores that ability to take up radioiodine, which is the little picture on the left of the whole body scan. So essentially we're targeting that MAP kinase pathway to try and get these tumors to take up radioiodine again. And there are two, you know, there are many studies, okay, but the two, the first two studies was a study with selumetinib where, this was from Memorial Sloan Kettering, where they treated eight of the 12 patients that reached the dosimetry threshold for radioiodine, were treated on a MEK inhibitor, and they saw these really nice responses. Dabrafinib was the next study that was published, it was for BRAF mutated, obviously. Six had uptake on the radioiodine, six of ten, on the whole body scan, and received radioiodine, and you see some nice responses there. The problem with these trials is that they didn't have long-term follow-ups, so we don't know what happens to these patients way down the road. Another study that we did at MD Anderson, which was retrospective, and just to show you these really pretty scans, because these are patients who don't take up radioiodine well, or, you know, they took up radioiodine but not in all of their lesions, and then this is after treating them with either a BRAF or MEK inhibitor, and you see some of them really start to take up a lot of radioiodine. But again, the question is, this is fantastic, it's beautiful to see this, and we were able to keep a lot of these patients off of targeted therapy once we gave them the radioiodine, but we need long-term safety data. So this is the response before we gave them radioiodine, so you see some responses to the BRAF, and the BRAF mutated in the patients who had like RAS mutations or didn't have BRAF or RAS, and then this is the response after radioiodine, so you get, you do get a response from that radioiodine. This is just showing that patients off targeted therapy, okay, so the middle line is where we gave them radioiodine, and then we stopped their targeted therapy, and that's how long they went without having to go back on a targeted therapy. So that's really good for patients. It's also probably good financially, because these are very, very expensive drugs. And this has now been demonstrated with larotrectinib, so that's the Ntrek inhibitor, and selprocatinib, which is one of the two RET inhibitors. These are Ntrek fusion, RET fusion patients who, these are case reports, right, so very little data, but it does appear that these do the same thing that the BRAF and MEK inhibitors can do in terms of restoring radioiodine uptake. Okay, so in summary, we really do have a lot of options now for patients who have thyroid cancer, particularly for medullary and papillary thyroid cancer. We've made major advances in anaplastic thyroid cancer, so it's really not appropriate anymore to just send your patient to hospice without doing any further workup. We need to know if they have a BRAF mutation, because there is an on-label indication for those patients. And we have clinical trials that we would love to enroll patients on, because that's the only way we can get approvals for these drugs. There are new strategies that are kind of making their way. The neoadjuvant use of kinase inhibitors. We're doing this in anaplastic, but I didn't mention that we're also doing this in medullary thyroid cancer for patients who have a RET mutation. Also for differentiated thyroid cancer patients that have a RET fusion, we have a neoadjuvant study. And so it's not just limited to anaplastic thyroid cancer. We're starting to now open these trials and start enrolling them for your DTC and MTC patients. And then redifferentiation therapy to restore the uptake of radioiodine. Again, there are clinical trials for this. These are trials that are very difficult to do. In the U.S., I don't think we have any that are open at the moment. But when we do have more trials open, I recommend that we really try to do this on a clinical trial, because again, we need long-term safety data for that. We don't have it, and that's kind of the only way that we're ever going to know whether it's safe or if it really even benefits the patient. So with that, I want to thank everybody for coming early and listening. This is our endocrine department. This was our endocrine department in 2018. Unfortunately, we didn't get a picture in 2019, and then we haven't really seen each other since. So we've grown in between, but this is all I can show you. All right. Thank you very much. I appreciate it. Thank you. All right. Thank you so much, Maria, for that amazing whirlwind talk on targeted therapy in thyroid cancer. I already see people lining up at the microphone to ask you questions. So we'll start with this microphone right here, sir. Thank you very much, Dr. LaCava, Seattle. First I want to congratulate you. This is one of the most terrifying aspects for a clinical endocrinologist to be confronted with. I am curious not to kind of compliment what you all do, but it's very, very difficult once we recognize these tumors to know who to send them to. Obviously Sloan Kettering, you, the Seattle Cancer Care Alliance, but I really think ACE should step forward, talk with you, and we should have like a website where we can click into and know how to facilitate immediate evaluation. Following up on that, you know, your team, how do you treat patients? Do you have a place for them to stay? Do you have coordinators? I mean, people are seeing, okay, we get out to two years, but not much beyond that. So how do we, this is impactful because my next door neighbor's brother died literally two weeks ago from anaplastic thyroid cancer, and I've spoken briefly with it. And his onset to demise was six months. And so I was wondering if you could speak to some of the challenges for the patient and how your coordinators or your team deals with that. And then I would really like to see kind of a national clearinghouse where we know where to send these patients so they can get the most current therapies that are available because it's very, very challenging, even in cities where we have this to say who to send them to and so on and so forth. So thank you. Right. Yes. Thank you. So I believe you're specifically talking about the anaplastic program. So we have this program where, you know, once a patient identifies themselves or a referral is for anaplastic thyroid cancer, or even suspected anaplastic thyroid cancer, we try and get the appointment for the patient very, very quickly. And so we have these dedicated, what I call hidden slots, right, for anaplastic patients so that they're able to be seen very quickly. The support that we, and essentially what we do is that we streamline everything so that we get everything done in a week. We try and get all of the testing done in a week. And we try and give them an answer on what we're going to do for them within a week. Sometimes that's not possible, but oftentimes it is. In terms of support, of course, we have our social workers that help patients find places to stay and whatnot. But we also do support patients with a travel fund for anaplastic thyroid cancer. And you know, thank goodness through philanthropy, we've been able to continue funding that. And so we do try and help them so that they can get a little bit of support for that week or sometimes longer that they're having to come and stay at MD Anderson. Just to supplement that, I just want to emphasize, you know, for rare diseases, anaplastic thyroid cancer, medullary thyroid cancer, I think you just do have to know the centers of excellence where they have a lot of experience with this. So we are open and welcome to your patients that you have these kind of rare diseases. It's not a common practice around any academic institution, right? You really do need the specialists who have seen this and know how to get the testing quickly. Okay. Yes, sir. Giuseppe Barbesino from Boston. Thank you, Maria, for your wonderful lecture and especially the advances that you have driven in this area. I was wondering, when you do the re-differentiation, especially with BRAF inhibitors, especially with diffused lung metastases, sometimes you'll see really impressive uptake in the lungs, like 30%. And so my question is whether you give them empiric doses of radioactive iodine without even knowing what the uptake is going to be or whether you do dosimetry, because with that kind of uptake, you actually can have lung damage and interstitial lung disease as an outcome, even if you treat the patient and you erase the cancer. So I was wondering, do you recommend dosimetry? How do you handle that? Yeah, so that's a great question. And it's actually the reason why we need some long-term safety data. We do sometimes give empiric doses. Let me give you two answers, right? We usually do just a diagnostic whole body scan. And based on that, the majority of my patients, I still treat them even if they don't take up radioiodine. Okay. I give empiric doses because what we've seen is that if you delay the post-treatment scan for a week, you'll still, even if they had a negative whole body scan in the beginning, they do take up radioiodine. Not all of them, but a good portion of them. In terms of dosimetry, we do dosimetry at MD Anderson. You know, the problem is there's a lot of issues with how long it takes to get all of that done and how many doses of thyrogen you need and all that. So it's a bit prolonged and more complicated. And so I know some people do a lot of dosimetry. I don't do a lot of dosimetry, but I do stick to doses that are either 100 or 150. I don't go over that because that one that I showed that had a lot of uptake, that gentleman had a bone metastasis. And so I gave him 200 millicuries and he had a tremendous amount of uptake, you know, in his lungs. Thankfully, he didn't have any issues with his lungs, but he could have. So I stick to either 100 or 150 for safety, until we know. Yes, sir. Raif, Riyadh, Saudi Arabia. Thank you. Elegant and very useful talk. My question is in the same line of re-differentiation. When you use those targeted therapy, when do you decide to stop after the dosing? And do you repeat those dosing later on if there is an uptake? Yeah, that's a very good question. So we have a little protocol that we've put together and our guide is to stop 72 hours after the radioiodine has been administered. The patient has to be on the drug during, you know, leading up to radioiodine and when they get radioiodine. And then three days later, we tell them that they can stop. In terms of re-treatment, you know, we take them off the kinase inhibitor and follow them closely, right? Because sometimes even when you have uptake, those patients are not responding, they progress. And so we follow them closely. Usually if they have a response, the response lasts about a year to a year and a half. And then we can consider re-treating them. But a lot of these patients have already received so much radioiodine that we can't give them more. And so then they sometimes end up on kinase inhibitors. I think also the question is how long do you treat with the kinase inhibitor prior to the radioiodine? So if it's a URAF mutated or if it's a RAS mutated, how long are you going to treat them? I think anywhere from a month to three months is okay. I usually go longer, three months. But I think even one month, if they're on the drug, like a solid month. The reason that I take them out to three months oftentimes is because they can have side effects that cause the, you know, having to stop the drug and then restart it. And so the month comes up and they're here for radioiodine and they, you know, aren't on their chemo at all or they've been off of it more than they've been on it. So I try and do a little bit longer, but it's probably not necessary if they're on a solid month of drug. Thank you. Yes, ma'am. Hi. Angela Langley. Hello. I can't even recognize you with the mask. Thank you, Dr. Hu and Dr. Cabanillas for a wonderful run through of these advanced thyroid cancers. I just want to make the comment and have Dr. Cabanillas have the opportunity to address the crowd. This meeting, very wonderfully, is made up of a lot of primary care non-endocrine folks. Close to about 30% are non-endocrinologists. So just a step back for those who don't see all of these advanced thyroid cancers. When do you make the leap to order the mutation molecular profile? You know, just to clarify, we don't normally order mutations. This panel that you have just run through for every regular thyroid cancer, every thyroid nodule, please. Yes. Thank you. So I think, it's a great question. And I think there are two important things to address here. One is when do you send it, right? You also don't want to send it on a patient who doesn't need it. And then when they find out they have a BRAF mutation, they start asking Dr. Google what to do. And then they find out that they're going to die. That's not, I mean, it's much more complicated than that, right? And so you really want to be ordering the molecular testing when it's going to become useful to you. If it's going to be 10 years before you have to treat your patient, that, you know, may not even be relevant anymore, right? Because in 10 years, we may not, we may want to know what the mutation is, but we might also want to know these other pathologic findings that you don't, you may not have gotten. So testing too early is probably a mistake. And then testing too late is a mistake because you have to get it, you know, you have to get the information in time to do something with it. It's also important to know what tests, right? It's very important that you send a test that's appropriate for thyroid cancer. There are lots of platforms out there that don't give you all the information that I think you really need for thyroid cancer. And so it's important to understand the different molecular tests and what you're going to get. Yeah. Yes, sir. For patients with anaplastic thyroid cancer who are on therapy and responding, what is your threshold for additional therapy such as Pembrolizumab, progression of course, but what kind of progression? Well we, so we initially published our paper was on patients that had progressed through targeted therapy and then we added Pembrolizumab as early as we could during progression. The problem with that strategy is it's very, very difficult to catch them in time. So what we do now is that we actually add it up front. We have a clinical trial that I hope to publish this year showing that, you know, by doing this up front, by giving them the triplet instead of just two drugs, these patients do live a very long time. So I think it's important to attack the tumor with different strategies and so the answer is that we do it now up front. We don't wait. Okay. I think we have time for just one more question. Sir, go ahead. Okay. Dr. Hanna from Wayne State University, Detroit, Michigan. My question is very exciting to hear about the re-differentiation therapy as I was wondering if there is any place of radioactive treatment after the re-differentiation therapy. Would there be any possibility of giving radioactive iodine treatment for those patients who have re-differentiated? For anaplastic thyroid cancer? Is that the question? Yes. Oh yes. So that's a very complicated answer. I would say in the majority of patients, we wouldn't do it. But we do have patients who, for example, I have a patient where we removed the primary and then he had, you know, small lung metastases that had actually been pretty stable even before he went on therapy and he still had thyroglobulin, he was still making thyroglobulin. And so we couldn't biopsy because they were very small, but we kind of assumed that maybe those are actually papillary thyroid cancer. And I gave him radioiodine and he did take up radioiodine in the lungs, but these are very rare patients and I think the majority, it's probably not applicable. I'm going to take the opportunity to ask one kind of final question to kind of wrap up this. So given the amazing strides that's happened over the last 15 years or so and targeted therapies and everything, what do you consider to be the next unmet need that really needs to be addressed by the field? Where do you see our next area to investigate? Yeah. So I think there are other mutations that we could hopefully in the future could target. Things that are being used in other solid tumors I think makes a lot of sense in some of our thyroid cancer patients. The other thing is, you know, the patients without a BRAF mutation, those patients are very, very difficult. RAS mutations and anaplastic, those patients do very, very poorly. And so we're starting to have some targeted agents for RAS, but unfortunately they're RAS mutations that we don't, we often don't see in thyroid cancer. But I hope that that's coming down the pike and that we'll have something for RAS mutated disease, which I think is our, I think our biggest headache, even in follicular and papillary and medullary. Yes. All right. Well, thank you all so much for your attention today, and I hope you have a wonderful day at ACE today. Thanks.

Dr. Maria Cabanillas

targeted therapies

thyroid cancer

BRAF inhibitors

MEK inhibitors

RET inhibitors

re-differentiation therapy

molecular testing

RAS mutations