Eric J. Sherman, MD, provides an update on the different subtypes and therapies for thyroid cancer. Dr. Sherman also identifies the FDA approved agents to treat thyroid cancers with RET fusion and TRK fusion, and compendium approved treatment for BRAF mutation driven thyroid cancers.
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it is now my pleasure to introduce Dr Eric Sherman. He is a medical oncologist at Memorial Sloan Kettering Cancer Center. Dr. Sherman is well known for his work in the field of thyroid cancer, and his topic this afternoon is updates on systemic therapies for thyroid cancer. Please welcome him. Remember, if you have questions, use the chat function and we will address them during the panel discussion. Hello, there. I like to introduce myself is Dr Eric Sherman and like to thank the sponsors for inviting me to give this talk today. My talk. Taste good. Talk about an update on the systemic therapies for thyroid cancer. When we talk about thyroid cancer, we're really talking about thyroid cancer from two different cell types. One is from flicker cell thyroid thyroid cells. Um, and that's the more typical ones that we see papillary, follicular cell and her to sell. As you can see from the slide, it does fall into a spectrum where, while there are the well differentiated thyroid cancers, they can easily turn to more poorly differentiated Often, um, these are ones with more vacations that are attached to it and then eventually can get to the point where it's what we call anaplastic thyroid cancer and a plastic thyroid. Cancer is a very different type of thyroid. Cancer is very rare, but it's also very aggressive and very resistant to therapies. While there is a lot of research being done in a plastic thyroid cancer because of how deadly it is, um, that is not going to be the subject of my talk today. And I'm more focused on the on the on the fuck yourself thyroid cancers and then measuring thyroid cancers, metro thyroid cancers or cancers that come from a C cell. So this is a different cell type than the typical follicular cell thyroid cancers that we see. And I'm gonna first start by talking about measuring thyroid cancer as that is really where we've seen a lot of changes in how we treat the disease happened over the past year, and it's actually a very exciting time in veterinary thyroid cancer treatment. When we take a Metroid thyroid cancer, it actually is a neuro endocrine tumor, and you can see that it's supposed to snap the folks and and chroma grand positive, so it's a little bit different than you typically see with other with flicker cell thyroid cancers. They also staying positive for C A and calcitonin. What they do is they don't stain positive for thorough globulin. So sometimes if the pathologist is not thinking about this ahead of time and they don't do these other four stains, and they just find the tumor negative for the globe and the main mistakenly think that this is an a plastic thyroid cancer and typically at Memorial, we will actually test for anyone with an a plastic thyroid cancer to make sure it's not measurably thyroid cancer and by mistake. Now, when we talk about measuring fire cancer, one of the most interesting things about it is the question. Is this hereditary Met Hillary or sporadic? And the reason why this is interesting is that 20 to 25% of all metro thyroid cancers are actually hereditary. These are germline mutations in the red proto oncogene. It is inherited or assembly dominant. There are three main subtypes meant to a meant to be and familiar measuring thyroid cancer. These meet these. All these hereditary forms are based on mutations in the red proto oncogene and each of the different syndromes or really have a mutation that's in a different part of the red product Uncle Gene all together. And it is this red proto oncogene that is a driver of the cancer, as this will single through multiple pathways that regulate survival, cell growth survive and differentiation. It is very, very important that when a patient presents with measuring thyroid cancer for first time, it should be considered hereditary until proven otherwise. 3 to 6% of patients with a negative family history will end up having a drumline mutation and all patients mystery thyroid cancer should undergo genetic testing. As an example, a patient I saw just last week for the second visit we found this 57 year old woman has no family history of thyroid cancer. And to our surprise, yes, we found out that they did that. She does have men's to a so this needs to be done for all patients. The other reason this is really important is because before an operation, they need to be evaluated for a field chroma, Saitama and hyperglycemia, as this will lead to complications during the R, and this is not done and for our patients before they go to the operating room for the first time. We either check a toy for our urine collection for men in deference or a plasma fractionated man. Deference to make sure I feel chromosome chromosome tomoe does not exist. Even in sporadic measure of thyroid cancers, reputations are very important, and about 45 some people believe it may even be 50% or higher will actually have a reputation in the tumor cell. So we know Red is an extremely important target and driver of measuring fire cancer in a large percentage of them. And so when we look at what we want to target to treatment for thyroid cancers, red is one of the first things we have to think about. And there are many times and conscious inhibitors that will have activity against red, along with many other targets that will hit. And if you protest, have suggested that activity of sometimes County senators are dependent on the site of the reputation, though, so it doesn't work against all reputations, but just some other important targets that make this ar rass mutations, which we'll see about 15% while Metro thyroid cancers and what sort of surprises us all is that actually, HRS is probably one of the more common of those mutations. And this is important because there is some studies using furnace or transfer ace inhibitors for the treatment of tumors that are driven by hrs. Anti estrogen, says Asians, because these are very vascular tumors are important. So math a satin so metastatic receptors so important and see a may also be important target. However, there's no question that the most important of all this is red. The first one, the really first drugs that was looked at in the treatment of respiratory cancer has been different. And that is an opponent inhibitor of wild type, amputated, activated red. And it was really noted by Sam Wells that this existed. And it was important that this may actually be studied and with measured thyroid cancer, as rare as it was that people really are formed, still coming from really not that interested in it and a lot because of what? How, how Sam was really kept pushing this issue, that this was finally studying. But in addition to read vindictive also targets fetch Far and e Jafar, and both of these can also be extremely important in the treatment of Metro with our cancer as well. The early phase two studies were all very positive and it went into a Phase three study. The Phase three study did not require that eternity right, mutant, and you can see indignant versus placebo of indigenous showed an improvement and progression free survival. What is also noted is that the group that got placebo did extremely well, and the reason for this was that this study did not require the US had progressed recently in order to get onto the study. This was one of the first large studies in metro thyroid cancer, and no one really knew whether it could accrue well to or not. So it was really allowed all commerce with anyone with the Metro Thyroid cancer can get on it. When you look at response rates, vindictive look fantastic, with a response rate of 45%. And while placebo group had a 13% response rate, 12 of those 13 patients, actually we're already receiving different in an open label phase they had already crossed over. So it was it was a little bit of a false read altogether, um, objective responses were also very durable. And this and based on this study, vindication was FDA proof. The treatment measuring thyroid cancer, the next drug that was looked at with cables at nip and cables. And it is a potent oral target therapy inhibits Met venture far too, as well as red and really, the group at M. D. Anderson noted early on that with this hitting red that you really want to focus on patients Metro with thyroid cancer. To get onto the Phase One study and from the Phase one study, he actually saw a 29% confirmed response rate by resist with the disease control rate of around 68%. So this looks very promising on the early study and really from the Phase one study, it went directly to a Phase three study. In this Phase three study, you see an improvement in progression free survival of cables and nip over placebo. The one thing to note is that the placebo arm is doing much worse in this study compared to the medium study and even the composite farm looks like it does worse. The difference is, though this study required progression was within 13 or 14 months, but they require progression to get onto the study, so it is a different population. So while we know that this is also an active agent in the treatment of Venturi thyroid cancer as it's been definite, there's no way to compare the two from both studies. The one thing this like did allow us prior been distant abuse. And there were a few people had personal vendetta that did respond on Capitol Latin. The thing about these drugs, though, is that they're dirty molecules and other drugs that also show activity in Medford thyroid cancer. Back then, Sarafin, IP and certain IP both uh no hit red. But he hit many, many other targets that Jafar be Ralf IVF R C met seek it. And while these drugs all show activity, the one thing that's important to figure out is Is red really the important target? Could it be Vetra far? Could it be e jafar? Could it be semen? The other thing that that we know is that if these other targets that definitely drive toxicity and no one from these studies even knew what toxicities would be based on red by itself. But these other toxicities limit the dozing and then limit the ability to inhibit red as well. So based on this type of data, several companies then decided to say, Hey, maybe we should look at red and this goes a little bit further because we do know from the exam state, which is the capital Sana study that red is very still very important, even though these other targets may be important. If you look at only the tumors that have a red M 9 18 a mutation, what you see is an improvement in overall survival, and those that got randomized cameras that nip to those that that were randomized to placebo and progression free survival a gigantic difference if you're around my scalpel. Shannon. However, if the tumor did not have a red 9 18 t mutation, there is almost no difference in overall survival and very little difference in progression free survival. So it does suggest that while these drugs hit many targets and these other targets could be important, it is to rent that drives the activity of these, uh, agents. So several agents for several companies decided to really take a look at Let's try to hit Red specifically and try our best to avoid these other off target effects. And the two that really have been looked at most is processing it and supper cabinet. And just to sort of give, like an advanced look at what we're about to look at more closely. The FDA approved these for thyroid cancer for both those with refuge ins, which is what we see on Flickr thyroid cancer as well as those with Red Mutant, which is what we see mystery thyroid cancer. And these are very specific and highly potent red inhibitors. Do you work on all types of reputations, not just one as well as red fusions. And they include that they actually work against gatekeeper mutations, which generally vindictively capitals at number, not thought to work against. They are significantly more selective for ready to venture far, so you don't see as much of the VHF effects. However, there are some veggie of toxicity toxicities, toxicity scene, so it's not like these are totally clean, but they are fairly clean. So first looking at supper catnip dormitory, thyroid cancer. You see response rates that are extremely high 73% 69% you're seeing complete responses which we've never seen before. And you see that progression free survival looks really quite amazing with this. So this looks like an extremely effective drug. Are they better than the dictum cabals at it? Well, they have not been randomized against. It is a separate study. But really, when you look at this, it this does look like that these might really look like better drug altogether. Similarly, with prostate nip is that you see basically similar activity. It can. I don't think we can compare percent into capital catnip because of their different studies. Response rates are not that far apart, but you definitely see that that they both really worked extremely well. One interesting thing is that when you look at the night group that are truly naive to those have prior capital, that they invent different. You're not seeing that much difference between response rates, and you're not seeing that much difference and progression free survival. So it still brings up the question. But sequencing these drugs because while we know prostate nip and let's go back, we know supper catnip work extremely well, and those that are already progressed on either of entity or capital that we right now we do not yet know if the opposite is true. In terms of safety profile, these ropes are great. Only less than 2% of the patients on supercontinent study actually progressed. I'm sorry that progress had the drug discontinued the treatment related toxicities. You see very few great four events going on. Even the great three events are not that much. Hypertension is one that we do have to watch out for. The other thing that we do see is elevations in the hepatic enzymes, not to the point that I think these are. I find this to be extremely worrisome. But usually holding the drug and trying a little bit of a lower dose will often help take care of that. And patients seem to do extremely well from my experience. So this is a fairly safe drug, much better safety stuff that we actually see with either vented or compose an IP Um, although like cities, have not been compared directly against each other. So in conclusion, multi targeting Chinese receptor inhibitors can hit many targets. The advantages that more than one target may be important disease treatment, the disadvantage is that at least two additional toxicity and the inability initially really determine what is important. Target and off target toxicities can limit the ability to inhibit primary target New rest. Specific numbers have not undergone randomized studies yet, although they are starting to undergo these randomized studies, and these are going on in both the United States as well as overseas. Initial data seem to suggest that he may be having better efficacy and less toxicity. In addition, second generation red inhibitors are being studied already. But sequencing is still a very valid question, and very important is that much work still needs to be done in the red wild type population. Because we still don't know there's even vindictive Cabazon that really have any benefit in this population. And this is something that you know. It still has enough patients, military, thyroid cancer or red wild type, and we still have to figure out what is the best way to treat them now, for the rest of my talking won't talk about firing cancer or full of her cell origin. So when we talk about this, we're really talking about papillary follicular harmful cells as well as anti plastic. The vast majority of the patients are papillary thyroid cancers. And when we look at thyroid cancer back in 2000, so that's when I really started As an attending were about 18 to 19,000 cases per year. About 1200 people died. This has gone up in 2017 to all right around 113,000 cases. And that's about what it is also, uh, nowadays and the death rates going up slightly. So there's definitely this big increase in the rate of thyroid cancer. In fact, is one of in terms of business is one of the fastest growing of all cancers out there. Some of this is a detection error, so it's not. There's a bias in there that we do more scans. We find more early thyroid cancers, but there is part of it is that there really is an increase, and we don't right now, I think category, understanding what that is. So let's talk about our I or refractory thyroid cancer, because that's really what I'm gonna be focused on. Not how to treat early thyroid cancer, not how to treat with radioactive iodine and the main beginning ways that we treated this disease is with VFR tyrosine kinase inhibitors. There's two main drugs that will look at and both of them got FDA approved. In fact, they're the only FDA approved, um, that Jeff Taricani signatures fourth, thyroid cancer. Right now one is wrapping up and other ones like catnip. Both were randomized studies against placebo. You can see that both them had improvement in both response rate as well as progression. Free. Survival is a similar situation where we see that one looks a lot better than the other responsibly of 65% with the botnet only 12% less wrapping it and improvement of progression free survival 5.8 to 10.8 months with wrapping it 3.6 to 18.3 months in Lebanon. So we can't compare these two directly. It really does. Look, most of us that Lebanon is a better drug. Toxicity is an issue. At least somewhere between 68 80% of patients will need, uh, those modifications do the A s. And for most of our clinical experience, the number of probably closest more than 80% than this, 68% seen in select study and somewhere between 14 and 19% people who actually have to discontinue treatment because of adverse events. So if it really does look like the volume is a better drug than strapping it, so we're just not used to that in first. Well, it is the best, it seems, the best route. So let's just do it Well, The problem is, when we looked at the study with love a turnip, the allowed actually patients one priority Ki ay to go into the study. And let's look at the progression free survival in these two wraps ones 15.1 months if they have priority. I, the other one's 18.7 months is a little bit of a difference, but very, very small difference between the two. So we know that the Vatican works pretty well after another T g I. What we do not know is whether other TKs work after Lebanon. And so if drafted, maybe does not work which love us sees that we don't see much activity with traffic after the vat nip. Then maybe it makes more sense to start with a drug like Sarafina get your 10 11, 11 months and then add Lovat, nip where you get 15 months. And now here, you got 25 months between the two drugs. Well, if you start with Lovat nip at 18.7 months and then you don't get any activity from Sarafin Ip. Then you're already you're having less than 20 months. If you start with the botnet. Is that true or not? We don't know because that has not been looked at and right in my study. But it is something to think about because often when I can treat patients with thyroid cancer, If I'm doing this in an efficient manner, I'm watching people carefully. Their disease is not so aggressive that I'm worried that they're going to die in the next 6 to 12 months without us doing anything. Then it kind of makes sense and maybe start with a drug like Saraf nip or another Tiki I, and then go to Lebanon Nip. There also is that we don't have just those two drugs available. United States. Based on many phase two studies, the FCC and guidelines include a number of other following Wiki Tiki s that are approved for the treatment fire, cancer exhibited capitals attentive, postoperative, sitting it and vindictive. And these all have activity. I would question how active indigenous, because there was a Phase three study that really didn't look like there's any difference between that drug placebo. But these other drugs all have shown to have activity and capitals, and the battery just recently completed a randomized Phase three study in the second line setting, which, while the results have been report as being positive, we have not yet seen that presentation yet. So there are a lot of other choices, and a lot of these drugs do look very active, possibly definitely more active than Straffan, although they have not gone through randomized studies. One of the things that we need to think about when we're trying to treat thyroid cancer, though, is that there are a lot of molecular targets that are available, and these are things that we may want to think about when we treat thyroid cancer. When we look at the TCG a data and papillary thyroid cancer, and so this is still early papillary, so it's a little bit different than something we see in more advanced. What we can see is that there are targets available. Be reputations are extremely common. In fact, the most common mutation seen in papillary thyroid cancer. But you also see other fusion genes just like Red and Amtrak. So we're looking at trying to treat thyroid cancer. We don't have to just say, Let's just use the VHF tiki I. It's extremely important to look at the sequencing of the tumor, and you can see be reputations being very common. And we have drugs that hit B rap and track fusion. Genes and refuge in jeans are also somewhat common, not super common, but still about 15% for the total. And these are have potential target. And while we might not have great drugs or any drugs for rats, although maybe something new with actress people are working on that and that is a reasonable target. Um, still, uh, we see that positive about 13%. So these are targets that are available when the tumor has, uh, when we see a thyroid cancer patient and we might be able to use these drugs in addition to the venture, T g. I s. So let's talk about these targets. The first one is be Ralph This is the most common target there, and you may know there's drugs that are approved for the treatment of Barack. Meeting cancers elsewhere, the more often it is a B RAF inhibitor and another big one is definite. Vin Roffman was the first drug that was looked at in this disease, and this was a Phase two study looking at two different chords, one that was naive of of any VHF agent, another one of people who are pre treated with a vet Geoff and then went to them. Or after that, later on, you saw in the naive group a very good response rate of 38 a half percent and the median progression free survival, which is pretty similar to what was always noted with lava. And although this is just a Phase two study in the pre treated group, you see activity, but it doesn't look as good as the naive group 27% response rate and an 8.9 months progression free survival. So this really does look like an activation. So the next thing really look at is what happens to add a mechanism electro magnet to be rap inhibitor in this case definite up in almost every other cancer, with the reputation we have seen that adding the combination of the B rapid Met inhibitors together seems to be better than to be wrapping Hibbert alone. So Manisha Shah of Ohio State did a randomized faced A to study. It was a small study, and patient will be wrapped making thyroid cancer. She allowed up to three Prior Tiki. I use is, and people are even randomized to receive that from the bologna or definitely, tremendous. If you got to Africa alone, you then got tremendous at time of progression. The response, the results, actually, So we're sort of surprising response rates were actually less in adaptive tremendous group. And while maybe progression free survival looked a little bit better, we're really seeing not much difference between either of these two arms. So this is the one that few diseases that we really have to question whether the addition of a mechanism for to be wrapping paper has any benefit over B rap and hip alone. Although these were to say these were a small study and you see both arms really very few patients on it when we look at this all together, you can see that the Grafton definite response rates were about the same progression. Free survival. While it looks better with the Moroccan treatment naive, this group with Daphne Malone did have multiple other a lot of time, multiple other lines of treatment. So it's hard to actually make any type of, uh, anything to say about it. The additional payment. It doesn't seem to be that great. What you see is that all this looks a lot worse than what you see with the rap inhibitors in melanoma were responsible for 51% with paraffin Hibbert alone and going up to 64% when you use the combination. It could be, though, the mechanism of resistance in the Remington thyroid cancer is different. And there has been a study that was done Memorial, adding the pattern. It is a small phase one with the idea that adding, um, her three inhibitor, two of the rock inhibitor would lead to better outcomes, and this is based on pre clinical data by Jim Fagan And here in this small study, you see about 69% response rate in 29 months, progression free survival in a group that got had differentiated thyroid cancer and never was previously treated with the ref inhibitor. So here you really can see that maybe there are other mechanisms or other combinations that might really work well in this. In this cancer, the next thing we'll do is go back to read. So in measuring thyroid cancer Sorry indifferently thyroid cancer there are. They have refuge in jeans, not read mutations like you see in measuring thyroid cancer. The other thing. I would always notice that while you see a group of tumors having read fusion genes, a lot of them are very curable in the early stage. And it's we don't see as many refugees genes in the metastatic ari I refractory stage. But we do see some. And here you can see in the process of, um, study a 91% response rate with a very good progression free survival. Uh, in those who are receiving processing it much better than you see. With almost any other treatment you can expect out there, Separate cabinet is about the exact same. Yes, it looks a little bit worse. It's a different study, so you really can't compare the two plus two of the patients on Supper Canada study had an A plastic, although one interesting actually had a good response. The other one did not median progression free survival of 20 months. So this really looks like a very good target. Are very good drug to use when a refuge in gene exists and one of the reasons why it's important to know the sequencing of the tumor. The last thing that's important is and transfusion jeans. So there are examples of a drug called Larry Track Nip, which is high selective against various contract um, jeans. They are highly active in all cancers and track 15, and their FDA approved for treatment of an transfusions independent of what tissue it is. So thyroid cancer is included. There has not been any really great studies in thyroid cancer, but marshal growth at 88 2018. They present this small series of patients seven patients who had an interest fusion gene on the large Technip study, and what you see is very good response rates. The only two that were not reported to have a response or those who, um, they didn't have measurable disease and even a patient with an a plastic had a partial response with a median progression free survival of 7.7 months. And I can tell you that we actually treated We have two patients with anaplastic thyroid cancer within transfusion jeans, and they're both doing extremely well, um, using Amtrak inhibitors. So this is definitely something that is a very, uh, reasonable. And it looks like a very active agent. Um, if an interact fusion gene does exist, So in conclusion, there has been significant advancement in treatment of our A refractory thyroid cancer over the past 15 years. Exactly amazing. What's been going on? Sequencing of any thyroid cancer near the time that systemic therapy may be acquired really should be done. There are at least two drugs right now. They're FDA approved and others that are competitive improved, that can be used if the right target exists. FDA approved agents three thyroid cancer with refuge in and try fusion genes and its companion proof of the treatment of the rock music driven thyroid cancers as well. So we are able to at least the United States get drugs. They hit these targets and be able to use these drugs in addition to the more traditional standard, the HFR targeted therapies. So I'd like to thank everyone for Allow me to talk today. You know, there's a lot knowing about thyroid cancer is an extremely interesting disease because these targets exist. And it's amazing the advances that have been done both in our understanding of thyroid cancer as well as our treatment of thyroid cancer over the past 15 years. Thank you very much.
