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.

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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

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