 Differentiated thyroid cancer historically has been treated by mostly surgery and radioactive iodine. It was usually cured, and in most cases it still is cured, by those 2 modalities. However, there’s about 10% to 15% of patients in whom even after surgery and radioactive iodine the tumor may recur. In those cases, if radioactive iodine is no longer taken up by the tumor or the tumor has grown anyway, other options were needed.

Starting in about 2012 we had the first access to the kinase inhibitor sorafenib. Shortly after that, in 2014, the kinase inhibitor lenvatinib was approved. Both of these are multikinase inhibitors and provided patients with significant progression-free survival for the first time, giving patients a systemic option for treating their cancer.

The phase 3 SELECT trial was a randomized placebo-controlled trial comparing lenvatinib with placebo in patients with differentiated thyroid cancer that was no longer responsive to radioactive iodine who also were not candidates for curative surgery.

This trial was a watershed trial for getting the approval of lenvatinib, both in the United States and in the European Union, as well as other places globally. The patient selection was any patient who was radioactive iodine refractory, but they also have to have progressing disease within the prior 13 months or so.

When we looked at the comparator between placebo or the patients who got lenvatinib, randomization was 2:1, the patients who received lenvatinib were significantly more likely to have a longer progression-free survival than the patients on the placebo arm. The placebo arm patients had a progression-free survival of about 3.8 months, whereas the patients who were on lenvatinib had a progression-free survival of 18 months. This is quite significant as far as patients and patient care goes, and it was the basis for the approval of lenvatinib at that time.

In addition, we also saw very significant overall response rates of 62% and an overall survival that was not actually reached in the original trial. However, subsequent data that we found looking at analysis later on, showed that in the subgroup of patients who were over 65 and had received lenvatinib were statistically living significantly longer than patients who had been assigned the placebo group.

This is 1 of the first times that overall survival seemed to be extended in patients with different differentiated thyroid cancer on any kind of inhibitor therapy.

Phase 3 SELECT Trial Overview

 Of the patients who achieved the partial response in the SELECT trial on lenvatinib, most of these responses were significantly durable. They lasted for many months, and even longer than the 18-month progression-free survival obviously.

In practice, outside the clinical trial, sometimes patients can get a clinical benefit for even longer if the single sites at the time of progression are able to seek out with just radiation or surgery. This is a drug that we now use for an extended period of time in patients.

Unlike other cancers, where the duration of exposure to a drug might be on the order of weeks and months, for patients with thyroid cancer on lenvatinib for anywhere from months to years, it became very important to be able to manage toxicity. The major toxicity associated with lenvatinib and differentiated thyroid cancer was high blood pressure. For that reason, over 60% of patients had to reduce their dose from the starting dose of 24 mg down to either 20 mg or 14 mg within the first 2 months.

These patients actually had to have a dose reduction, but in spite of that did very well. Additional studies are ongoing to see whether we could actually start at a lower dose instead of a higher dose and still get the same efficacy, but the data are not available at this time. Other toxicities that are seen in patients with lenvatinib include loss of weight, particularly loss of muscle mass with sarcopenia, as well as diarrhea. Of course, all these can be interconnected. Fatigue is also another significant adverse effect.

I find that the diarrhea also explains for all these because when patients are not controlling the number of bowel movements they are having a day, they tend to get dehydrated, get more fatigued, and sometimes have more depression, and all these things actually can lead to decrease of efficacy.

It’s really important that patients know how to not only control their blood pressure—which is the thing you have to worry the most in the first month or 2—but also long term, manage the diarrhea, either using Imodium or diet control measures.

In addition, what we do to help patients maintain their weight is to actually have them do strength training. The strength training helps counteract the sarcopenia effect of the lenvatinib and can be very helpful. We prefer not to use dose reduction to help manage adverse effects, but occasionally that can’t be avoided, in which case we often start at 24 mg and then go down to 20 mg. The most common cause for dose reduction in my clinic was patients who have high blood pressure who could not be controlled with 2 or 3 agents.

Occasionally patients also need even more often dose reduction; I tend to use dose interruption. That is a very useful tool to be used a little more commonly, and it’s not uncommon. Especially given what I just said about the GI [gastrointestinal] toxicity, that a 2-week holiday, sometimes for patients who have been on the drug for a couple of years, can really help reset the GI tract, help the diarrhea calm down. Then many times the patients can restart at the same dose and still get the same benefit, but now their GI symptoms are much more controlled.

Rather than using dose reductions, we prefer to use dose holidays. The exception to that is that dose holidays doesn’t help me figure out what blood pressure medicines you need. Because as soon as you restart it, you’re going to need to start the blood pressure medicines again.

But it is important because many of our patients are on multiple blood pressure medicines. If for some reason they go on a dose holiday for GI toxicity, it’s important to remember that they need to stop the antihypertensives that they were on because of the lenvatinib, or they might end up hypotensive.

SELECT Trial: Toxicity, Duration of Response, and Dose Reduction

 One of the most important things in giving patients lenvatinib or any of the agents for systemic therapy of differentiated thyroid cancer is being able to define the population that would most benefit. These agents are approved only if they’re radioactive iodine-refractory patients. That means that iodine has been used in the past and either was not absorbed by the cancer, so they’re iodine nonhabit, or was taken up by their cancer but they proceeded to progress anyway. In which case that patient would be considered radioactive iodine refractory.

In the actual trial there was another criterion that if patient had exceeded 600 millicuries, they’re also basically considered radioactive iodine refractory. That tends to be a little more of a controversial criterion but certainly was important in the study. In most patients, the basis is that most patients, if they’re going to get a benefit and be cured by radioactive iodine, usually are cured by the time they’ve had 400 millicuries and certainly by 600 millicuries. That’s the justification for that, although it was rarely used in the study.

Patients who now are being treated occasionally with lenvatinib. Some of them are not even eligible for radioactive iodine, and this includes patients who have large masses in the neck that are not amenable to surgery. When patients have a full impact thyroid gland, radioactive iodine is not indicated.

There are some approaches to make them radioactive iodine amenable by trying to ablate the thyroid using radioactive iodine first and then doing a treatment dose. However, in our experience, if we do that, we still end up with a tumor that obviously was more aggressive, possibly more poorly differentiated. In most cases those patients won’t pick up iodine anyway. In general we tend to say that patients who still have an intact thyroid due to a basic cancer are in general a patient profile that I would not find amenable to radioactive iodine therapy.

For patients who do have radioactive iodine–refractory differentiated thyroid cancer, sorafenib and lenvatinib are now approved by the FDA, the European Union, and many countries globally for the treatment of this cancer. Sorafenib was approved initially, and lenvatinib was approved 2 years later.

How I decide which to use is an interesting question, because there can be some times when I’ll prefer 1 over the other. In most cases I tend to pick lenvatinib first. The answer to why that is: We already know we have good data that show, from the 

 paper, that patients who are over 65 years old, if they get lenvatinib, are more likely to have an increase in overall survival. That has not been shown for sorafenib, and for that reason for patients over age 65, as a general rule I will choose lenvatinib first.

A reason not to take lenvatinib goes back to the AE [adverse-event] profile. For a patient who has a lot of trouble controlling their blood pressure, and I do have 1, who’s already on 3 blood pressure medicines without being on lenvatinib, it’s going to be very difficult to control if they’re started on lenvatinib. Those are the patients that I might start first on ceritinib.

I have to pick and choose a little which patients I use. But in most cases lenvatinib—given its really good response rate of over 60% and its fairly well-tolerated adverse-effect profile—in general is my first choice of treatment.

There are some patients who might have more indolent disease. With some countries, because of approvals, sometimes lenvatinib is not available, in which case obviously sorafenib would be used first. But in cases where both are available, it is important to know that if you did have to choose sorafenib first, or if the patients have been on sorafenib for a while, maybe before lenvatinib was approved in your country, there were interesting data from the SELECT trial that said that if they received lenvatinib in the first line, they got 18-month progression-free survival. But if they received it in the second line, and in most cases it was second-line sorafenib, the progression-free survival was 15 months, which is still rather good.

Virtually all my patients will be exposed to lenvatinib unless there’s a very strong contraindication. For the most part, I find this helps most of my patients have a very good progression-free survival.

One caveat is that because of the toxicity profiles, they are not insignificant, they can be dangerous. It’s important that the person—not the investigator but the practitioner who’s prescribing it—has a close relationship with a patient. Because of the blood pressure issues, we recommend patients come in every 2 weeks for the first 2 cycles to make sure their blood pressure is well controlled. Sometimes what we’ll do is actually give them the prescription for an antihypertensive, so if it starts to go up while they’re at home, between visits, they’re able to go to a pharmacy and actually get a prescription filled in time to be able to bring that blood pressure back down.

Managing adverse effects is not trivial with lenvatinib or sorafenib. It’s very important to have a close relationship with a patient, especially good communication during those first 2 to 6 months to manage any adverse effects that might be coming up.

What is Radioiodine-Refractory DTC?

 Currently the NCCN [National Comprehensive Cancer Center] Guidelines recommend either sorafenib or lenvatinib for the treatment patients who have RAI [radioactive iodine]–refractory differentiated thyroid cancer. There’s actually a preference for using lenvatinib to follow if all other comorbidities and everything else is equal. The basis for that, on the opinion of the experts who wrote the NCCN Guidelines, is that there is a higher response rate with lenvatinib over sorafenib. That, together with the fact that there’s an overall survival advantage, is why lenvatinib is currently preferred in the first-line setting.

Comorbidities will play into whether you will give sorafenib first versus lenvatinib. If patients have extremely high blood pressure, many times lenvatinib is not the preferred choice, and sorafenib, which can cause higher blood pressure but not to the same extent, would be preferred in that case.

There are also some patients who might have invasive disease in the neck that I might want to control a little more gradually instead of having these very rapid responses, and I have done that in the past. Interestingly, in both cases when I’ve had to use sorafenib first or lenvatinib because of the toxicity or a high-risk setting, many times I eventually have to give the other agent anyway. In the case of lenvatinib, I can start with a lower dose if I’m concerned about either blood pressure or invasive disease.

Age is another interesting marker because we know patients who are over 65 years old will have improved overall survival. I think this is why, in general, lenvatinib is chosen, and half the patients will be over age 65, so that’s a common reason for lenvatinib to be a preferred agent.

The data showing that overall survival was improved are important because this is practice changing, and it was the first time overall survival was shown to be improved in patients who are being treated with a kinase inhibitor in the setting.

Radioiodine-Refractory DTC: NCCN Guidelines

 We know from the SELECT data that patients who get lenvatinib in the first setting have a progression-free survival of 18 months. However, patients who get it in the second have a progression-free survival of 15 months. So there is a slight advantage to giving lenvatinib in the first-line setting. That said, lenvatinib can very much be used in the second-line setting. It’s very helpful in that regard.

An interesting thing that also happens with lenvatinib—and can happen with other kinase inhibitors as well, but we use it especially with lenvatinib—is that many times, patients at the time of progression have only 1 type, 1 location that’s actually progressing. If that’s the case, let’s say they have 100 other nodules that are responding well to lenvatinib, it could be deemed that the clinical benefit of lenvatinib still exists if we could just control the progressing site. Sometimes that’s possible. Either using a surgery, ablation, or external beam radiation to a particular site. I’ve had many patients for whom the progression-free survival can be doubled or tripled by managing solitary sites down the line that share progression.

At this point it is very useful to use lenvatinib in the first-line setting, but even in the second-line setting it’s very active. Most important, we can really expand the duration of the clinical value of lenvatinib by salvaging it with external beam radiation to solitary nodules that may not respond when the rest of the disease is doing quite well.

It’s well known that there are not many community oncologists out there who are actually trained in the treatment of thyroid cancer. Certainly it wasn’t around when I was in training. It’s also quite rare for patients with thyroid cancer to need an oncologist. For that reason, the first advice I have for a community oncologists, if possible, is to refer the patient to a specialist who actually has experience with both the thyroid cancer and the use of these agents.

Treating patients with thyroid cancer with these agents, even if they’re used to using these agents in other settings, can be quite different, particularly in regard to the duration of treatment. Because the patients are on these drugs for so long, many times for years, it is very important that the practitioner understands how to mitigate the problems that come from the adverse event, how to mitigate the issues with high blood pressure control, how to mitigate the problems that come with diarrhea, how to not only administer Imodium but make sure the patient is tracking it and doing the education required to be successful. Because it doesn’t really help anybody, including the practitioner and the patient, if the patient is miserable for the entire time they are on therapy.

The goal for the patient really needs to be not only control of their disease but a good quality of life. Those people who are giving it in the community maybe haven’t used lenvatinib very long, but they’re in a place where referral is not possible and the patient can’t travel to a site of expertise. Most important, a tip I can give to a community oncologists is to stay in close contact with your patients. Make sure they know their blood pressure and are taking it reliably for several days before they start. And make sure they take it every day, twice a day, maybe even in the first week, so high blood pressure can be addressed quickly and effectively. If you have a good partnership with your patient, you can expect to have a good outcome with these agents and especially with lenvatinib in this setting.

As far as unmet needs in the future, in spite of the good success and sometimes the 1-year to several-years responses with patients with lenvatinib, eventually patients will actually progress. In the case of sorafenib, there were some data that adding everolimus might actually help. We still have an unmet need of knowing what to do after sorafenib and lenvatinib. An ongoing phase 3 trial is addressing whether cabozantinib, another kinase inhibitor that’s approved for medullary thyroid cancer, might be active in the phase 3 that’s coming and going.

Additional studies are looking at whether adding immunotherapy might be helpful. Again, the data and the verdict for that are out, so we’re looking forward to just hearing from that hopefully in the coming year.

Radioiodine Refractory Differentiated Thyroid Carcinoma

Phase 3 SELECT Trial Overview

SELECT Trial: Toxicity, Duration of Response, and Dose Reduction

What is Radioiodine-Refractory DTC?

Radioiodine-Refractory DTC: NCCN Guidelines

Multikinase Inhibitor Overall Survival Advantage