 fusions, we have some great data to talk about with 

 fusion-driven disease. Maria, do you want to lead off on that discussion?

Sure. I think we could probably start with mentioning the different other fusions that we can see in papillary thyroid cancer. The majority again are going to be mutations and fusions in papillary. We do see some actionable mutations and fusions in follicular and Hurthle cell, but they’re very rare, so we’re talking about mostly in papillary and poorly differentiated cases, 

 fusion reported. Actually, I think Lori you reported it, in a patient with papillary thyroid cancer. So, those are things to think about. But starting out with the RET inhibitors, just because 

 fusions are the most common of the fusions in papillary thyroid cancer, we’re going to see those in about 8% to 10% of papillary thyroid cancers, whereas 

 fusions we see in about 3%. You’ll encounter the 

fusion differentiated thyroid cancer [DTC], also for 

 mutated medullary thyroid cancer and lung cancer. In the trial that was published in the 

, there were 17 patients who had RET fusion DTC, and these were patients taken from the phase 1 and 2 trials, so it was data that were put together from the different studies. Fifteen patients were evaluable for response, and of those 15 patients, there was an overall response rate of 80%, which is really fantastic.

Median progression-free survival wasn’t reached, but at 1 year, 64% were progression free. In terms of adverse events, there were some adverse events of hypertension, increased liver function tests. There was some hyponatremia and diarrhea. And if you look at the whole cohort of the 531 patients with 

-aberrant cancer treated on these trials, it was only a 2% discontinuation rate with selpercatinib for treatment-emergent adverse events.

Pralsetinib is also a selective RET inhibitor and is also approved for 

 fusion thyroid cancers. They enrolled 20 patients with 

 fusion-positive thyroid cancer, but only 9 were evaluable for response, so there are less data with pralsetinib. But the overall response rate was again phenomenal. It was 89% who had partial responses, and the median progression-free survival and overall survival were not reached. But at 1 year, 81% of patients were progression free, and in terms of overall survival, the estimated 1-year overall survival was 91%. The adverse event profile is similar but not really the same. It’s interesting that pralsetinib tends to cause more anemia. They also reported more musculoskeletal pain and constipation. Both drugs cause increased liver function tests, but I have changed from one or the other because of increased liver function tests, and it’s been OK on the opposite drug, so that is worth trying. Also, the RET inhibitors can cause hypertension, so this drug did cause hypertension. The discontinuation rate in these patients was 4%, so it’s pretty good.

In terms of the TRK inhibitors, larotrectinib is the one that we have the most data with, but there is also entrectinib, which is approved in 

 fusion-positive solid tumors. For larotrectinib, according to the update of the American Thyroid Association this year [2021], we had data on 29 patients with 

fusion thyroid cancer. This is compiled from 3 different trials, including a pediatric larotrectinib trial. There were 22 patients with differentiated thyroid cancer enrolled, and 21 were evaluable for response. The overall response rate was 86%, and that included 2 complete responses. There was no best response at progression, so again, really stellar outcomes. The median follow-up time was 22 months, and with that, we had a median progression-free survival of 51 months, and overall survival was not reached. But at 2 years, 92% of patients were alive.

The adverse event profile includes anemia, low lymphocytes. Those were the higher-grade adverse events, and these drugs can cause some dizziness and nausea. Patients tend to adjust to that dizziness and it does resolve. There were no patients discontinued from the trial due to treatment-emergent adverse events. In terms of entrectinib, there is a publication for the 54 patients with advanced cancer who had 

fusions, but it only included 5 patients with thyroid cancer. We don’t really know what their subtypes were, and there was 1 partial response out of 5. But almost nothing is known about that thyroid cancer population, so it’s hard to talk about entrectinib in the context of thyroid cancer. We think it’s probably a similar drug, but it does have other targets and so may lead to some off-target effects.

One of the things that I was surprised about initially with the larotrectinib integrated data sets is that if you take out the children with infantile fibrosarcoma driven by 

 fusions and look at the adult patients with solid tumors who were enrolled across the 3 trials, the most common diagnosis is thyroid cancer. In the most updated data, the adults with soft tissue sarcomas and adults with thyroid cancers were the 2 most common adult diagnoses across the larotrectinib experience. I think that’s an underappreciated fact that I like to highlight every chance I get.

Videos

The rationale for targeting actionable mutations in differentiated thyroid cancer with RET and NTRK inhibitors.

RET and NTRK Inhibitors for Differentiated Thyroid Cancer

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

Maria, thank you for that. Let’s have you continue in terms of the general landscape of drugs that we have available for iodine-refractory advanced DTC [differentiated thyroid cancer]. Then Marcia, you could talk a little bit about some of the seminal studies that we’ve done.

I’ll talk about the different classes of inhibitors we have, and then I’ll hand that over to Marcia. Thyroid cancers are very vascular tumors. They respond very well to VEGF receptor inhibitors. We have a lot of VEGF receptor inhibitors approved for the different types of thyroid cancers. But we also have more targeted therapies, such as BRAF inhibitors, RET inhibitors, NTRK inhibitors. The majority of those molecular aberrations are actually going to be found in papillary thyroid cancer, and sometimes in poorly differentiated thyroid cancers that are derived from papillary thyroid cancers.

So, we do want to know the genetics as we’ve mentioned before. Then the other thing that we can talk a little about is immunotherapy or checkpoint inhibitors in patients with differentiated thyroid cancer. And I can talk a bit about that later. But unfortunately, most differentiated thyroid cancers have a low PD-L1 score. A minority can have more aggressive ones, they can have higher PD-L1 scores. And thyroid cancer in general, even anaplastic thyroid cancer has low tumor mutation burden compared to tumors such as lung cancer and melanoma. And so, we don’t think as much about using checkpoint inhibitors, especially as a single agent, in these patients. But more and more we’re trying to learn about how we can combine them with other therapies, and we have some clinical trials that support some of that.

: I guess I’ll take off from that and just dive in. Mostly, I think the large trials we have that led to FDA approvals are at this point, the first 2 categories that Maria mentioned. We have the seminal trials on the first- and second-line approved therapies, and then there are also ones that have been approved that are more targeted. I’ll let somebody else get into the second group. Among the first group we have, the first approved agent was sorafenib, and it was in the DECISION trial. It took patients who were RAI [radioactive iodine] refractory who were progressing and basically randomized them 1:1 to sorafenib at 400 mg twice a day versus placebo. That came back as a positive trial. The progression-free survival showed an improvement from 5.8 months to 10.8 months, with a hazard ratio of 0.58. And based on that, that was the first FDA-approved drug in this setting.

Right on the heels of that, a lenvatinib trial completed, and that was the SELECT study. That was randomized I believe 2:1, and randomized patients to lenvatinib at a starting dose of 24 mg compared to placebo. Now we actually had an improvement, the placebo arm showed a little more aggressive…progression-free survival of around 3.2 to 3.6 months, I believe…. But the bottom line is it went from that all the way up to 18 months in the treatment-naive patients and 15 months in patients who had previously received a VEGF receptor inhibitor. The hazard ratio in that case was even lower at 0.22. And I think many people have switched to make lenvatinib their first-line therapy based on these really strong results from the SELECT trial.

Most recently, just this last summer, the COSMIC-311 study, which showed the activity of cabozantinib in the second line after sorafenib, after lenvatinib, or after both, also came back as a positive trial and showed an improvement in progression-free survival from 2 months up to 11 months. This led to the FDA approval of cabozantinib in the second-line setting. Again, that was 2:1, and that trial was halted early because it reached one of its primary end points after only 100 patients had been on study for 6 months. So, at its first data analysis point it reached its primary end point, and the data safety monitoring committee actually recommended it to be stopped because it had already shown its efficacy.

The updated data are actually what I said, which is 1.9 months from the placebo arm and 11 months in the treatment arm. And I will just point out that that setting is very different from the first line and the SELECT and DECISION trials because those patients were rapidly progressing. So, it’s really important for people to know that when things start to go badly and people have already been on sorafenib for a long time, or lenvatinib for a long time or both, many times the speed of the disease has really picked up. And that’s an important thing to be able to anticipate because getting these drugs sometimes can take a few weeks.

So really at the first hint that you have multiple sites of disease that are progressing, you want to make sure you’re already lining up your next-line therapy, or your patient may get so sick so quickly that you won’t have the opportunity to treat them. The toxicity profiles among these 3 are, I would say comparable. It’s like a bouquet of flowers with the same flowers. Of course, no 2 bouquets are exactly alike, even if they have the same flowers. There are varying degrees of hand-foot skin reaction, diarrhea, hypertension. With lenvatinib, the most important thing is the hypertension, which seems to be biggest and most worrisome thing that we have right off the bat.

The most important way to manage AEs [adverse events] is No. 1, education, to educate the patient before they even start. Let them know that taking ibuprofen can help them with their hand-foot skin reaction. I call in prescriptions for antihypertensives before they even start the lenvatinib, so if it’s a weekend they can just go and pick it up and start those therapies if their blood pressures go over 150/90 mm Hg. So preemptively I try to get them in as good a spot as possible, and then when they’re on therapy, I try to jump on them as fast as possible. The saying goes that most adverse events don’t become a grade 3 without being a grade 1 or a grade 2 first. And if you can intervene at that point, that can make a huge difference. So that’s sort of my top-line view of those 3 agents. Of course, there’s more to be said, but these right now I think have been the tried-and-true workhorses for all comers. We can use these regardless of what the biomarkers say. And sometimes if I can’t get a biopsy quick enough to tell me that they have a 

 fusion, I can start them on lenvatinib or sorafenib while I’m waiting to get the genetics back.

An overview of the types of targeted drug classes available to treat differentiated thyroid cancer at various clinical stages.

Targeted Treatments for Differentiated Thyroid Cancer

Maria, do you want to talk a little about other things that might come into play in terms of making this decision about when to start treatment? I also want to reiterate Marcia’s point about there definitely being a role for disease monitoring. But we don’t necessarily want to withhold treatment until patients are symptomatic, because then I think the opportunity to enjoy the clinical benefits from the therapies we have that really do work very well is diminished. But Maria, what other factors are important that you take into account when you’re thinking about when to pull the trigger and start treatment for patients?

It’s a combination of things. I look of course at the usual things, the performance status and comorbidities, that’s the obvious one. And usually by now I know what the genetics are. If I’m even thinking about doing systemic therapy, I’ve already sent their tumor off for molecular testing. And so, I start thinking about what would be the possible treatments for this patient? And what are the toxicities associated with that treatment in relation, how is that going to affect my patient who has all these different comorbidities? I really take that into consideration, what the adverse effects are of each drug and the potential drug that I need to use. I oftentimes will try to also see how I can reset their clock, meaning I’m trying to see if there’s a way that I can push that start date off another year, another 2 years. Because we know that with all of these targeted therapies, eventually these patients are not going to respond to them. If they respond initially, they won’t respond forever.

I try to push that start date off as much as I can. I think about whether there is some type of localized focal therapy that I can do in this patient to keep them off systemics for a little while longer. That might be resecting a metastasis. It might be giving them external beam radiation like SBRT [stereotactic body radiation therapy] to a growing lung metastasis. If everything else is stable and there’s one that’s giving us problems, I may biopsy it first to make sure it’s not anaplastic. But then I will give them some stereotactic radiation.

Is there a metastasis that’s going to cause a really big problem in this patient if I don’t do something about it? Maybe there’s a large hilar node, and even though the patient’s asymptomatic, it’s in a bad place. I probably don’t want to wait too long to treat that patient, or will keep a very close eye on the patient so that I can treat them in time before they develop a problem. Bone metastases are also the usual kind, thinking about whether they’re going to fracture, whether this is too close to the spinal cord and we need to do something before they become symptomatic from it.

Then I’m always thinking about brain metastases because we don’t think very much about brain metastases in differentiated thyroid cancer. We kind of associate that more with anaplastic thyroid cancer. But these patients can get brain metastases, and they’re asymptomatic until it’s no longer asymptomatic. Then you’ve got a big problem on your hands. And so, I do some brain surveillance too with MRI or CT. I don’t do it every time. I’ll sometimes think about doing it once a year in these patients and try to treat things before they become a problem.

 I’m glad you mentioned the incidence of brain metastases. In the studies that have been done that we need to start talking about very soon, there is an incidence of brain metastases in anywhere up to about 10% in our patients with advanced thyroid cancer. So it’s definitely something that I think has been underappreciated until recently.

Maria E. Cabanillas, MD, describes what triggers her to initiate therapy for differentiated thyroid cancer and variables that impact treatment choice.

When to Initiate Therapy for Differentiated Thyroid Cancer

Lori J. Wirth, MD, associate professor of medicine, Harvard Medical School, medical director, Center for Head and Neck Cancers, Massachusetts General Hospital, discusses the utility of tipifarnib in patients with head and neck cancer whose tumors harbor 

The phase 2 KO-TIP-001 trial (NCT02383927) investigated the activity of tipifarnib in 

-mutant head and neck cancer. The AIM-HN cohort included 59 patients with high 

 variant allele frequency (VAF) and 21 patients with low 

Patients with high VAF frequency of 20% or more achieved more frequent responses with the agent, with an overall response rate of 56%, according to Wirth. The responses were durable, and a long median progression-free survival (PFS) was also observed with tipifarnib, Wirth says. Patients who received the agent experienced a median PFS of 6.1 months vs 2.8 months with their last therapy received.

Furthermore, tipifarnib was generally well tolerated. Adverse effects (AEs) included bone marrow toxicity, fatigue, and other grade 1 or 2 AEs, Wirth adds. Tipifarnib is not currently approved by the FDA for patients with head and neck cancer, Wirth adds. Following the November 2011 FDA approval of the EGFR monoclonal antibody cetuximab (Erbitux) for patients with head and neck cancer, tipifarnib may be next in line for this patient population, Wirth concludes.

Lori J. Wirth, MD, discusses the utility of tipifarnib in patients with head and neck cancer whose tumors harbor HRAS mutations.

Dr. Wirth on the Utility of Tipifarnib in Head and Neck Cancer 

Lori J. Wirth, MD, associate professor of medicine, Harvard Medical School, medical director, Center for Head and Neck Cancers, Massachusetts General Hospital, discusses the phase 3 LIBRETTO-531 trial (NCT04211337) of selpercatinib (Retevmo) in patients with 

The multicenter, randomized, open-label phase 3 trial is currently underway, Wirth says, and it is comparing the use of selpercatinib with physician’s choice of vandetanib (Caprelsa) or cabozantinib (Cabometyx) in those with progressive, advanced disease that is naïve to kinase inhibitors. In the trial, if patients who receive treatment with either vandetanib or cabozantinib experience disease progression, they have the opportunity to crossover to receive selpercatinib, Wirth explains. 

The primary end point of LIBRETTO-531 is treatment failure-free survival, With adds. This trial might shed light on how to better sequence gene-specific therapy with a multikinase inhibitor in this patient population, Wirth concludes. 

Lori J. Wirth, MD, discusses the phase 3 LIBRETTO-531 trial of selpercatinib in patients with RET-mutant medullary thyroid cancer. 

Dr. Wirth on the LIBRETTO-531 Trial With Selpercatinib in RET+ Medullary Thyroid Cancer 

Lori J. Wirth, MD, associate professor of medicine, Harvard Medical School, medical director, Center for Head and Neck Cancers, Massachusetts General Hospital, discusses takeaways from the SELECT trial in patients with thyroid cancer.

The SELECT trial investigated the use of lenvatinib (Lenvima) compared with placebo in patients with iodine-refractory, differentiated thyroid cancer who had progressed on therapy prior to study entry. Results presented at the 2018 ASCO Annual Meeting showed a significant improvement in progression-free survival with lenvatinib as well as an overall response rate of 65%. Additionally, data indicated that treatment-emergent hypertension was linked to greater benefit in the patients who received lenvatinib compared with those who did not develop hypertension.

Based on these data, Wirth recommends keeping a patient on lenvatinib even if they develop hypertension. Hypertension is a common adverse event of lenvatinib and was seen in more than 70% of patients who received the multikinase inhibitor, said Wirth. She added that it can be managed with anti-hypertensive agents and dose holds.

Dr. Wirth on Takeaways From the SELECT Trial in Thyroid Cancer

Lori J. Wirth, MD, associate professor, Medicine, Harvard Medical School, medical director, Center for Head and Neck Cancers, Massachusetts General Hospital, discusses the use of lenvatinib (Lenvima) in hypertensive patients with thyroid cancer.

The SELECT trial examined the use of lenvatinib compared with placebo in patients with iodine-refractory, differentiated thyroid cancer that had progressed prior to study entry. The topline results that were presented at a prior ASCO Meeting showed that there was a significant improvement in progression-free survival with lenvatinib as well as an overall response rate of 65%, states Wirth.

Therefore, researchers looked at hypertension as a potential pharmacodynamic marker to predict who might show the most benefit from the drug. Hypertension has been shown to be a pharmacodynamic marker in other VEGFR multikinase inhibitors in other tumor types, says Wirth.

Data from the SELECT trial showed that treatment-emergent hypertension correlated with greater benefit in the patients on lenvatinib compared with those who did not develop hypertension, says Wirth. There was also an overall survival benefit in patients who received lenvatinib and subsequently developed treatment-emergent hypertension compared with those who did not.

Lori J. Wirth, MD, associate professor, Medicine, Harvard Medical School, medical director, Center for Head and Neck Cancers, Massachusetts General Hospital, discusses the use of lenvatinib in hypertensive patients with thyroid cancer.

Dr. Wirth on the Use of Lenvatinib in Hypertensive Patients With Thyroid Cancer

Lori J. Wirth, MD, medical director, Center for Head and Neck Cancers, Massachusetts General Hospital, assistant professor, Harvard Medical School, discusses the safety profile of lenvatinib as seen in the phase III SELECT trial, which analyzed lenvatinib (E7080) in patients with 131I-refractory differentiated thyroid cancer.

Wirth says some oncology drugs come at the cost of side effects. The side effects seen with lenvatinib are very similar to the side effects seen with other VEGFR inhibitors and include hypertension, diarrhea, decrease appetite, weight loss, and rash.

Most of the toxicities seen in patients taking lenvatinib on the SELECT trial were grade 1 or 2 and were manageable with dose holds and dose reductions as well as active symptom management and supportive care, Wirth says.

Wirth also notes that 6 patients died during the SELECT trial. Two of the deaths were due to known toxicities of this class of drugs: hematic stroke and pulmonary embolism. The other 4 patients were deemed to have died from general deterioration in their health.

Lori J. Wirth, MD

Articles