Advances in Systemic Therapy of Differentiated Thyroid Cancer in Second Line and Beyond - Episode 2

Frontline Treatment Options for RAI-refractory DTC

Lori Wirth, MD, defines radioiodine-refractory differentiated thyroid cancer and discusses frontline treatment options for patients with the disease.

Matthew Fowler: Dr Wirth, let’s get into some of the frontline treatment options for radioiodine-refractory DTC [differentiated thyroid cancer]. How exactly do you define radioiodine-refractory DTC?

Lori Wirth, MD: I think from a medical oncology point of view, it is important to know that there is a definition for radioiodine-refractory differentiated thyroid cancer. This isn’t something that we learn in our oncology fellowships necessarily, but we want to make sure that patients who need treatment for their DTC aren’t going to be best treated with radioactive iodine if we’re going to be giving them cancer drugs. There is a definition of radioactive-iodine refractory thyroid cancer that’s been laid out by the American Thyroid Association [ATA], and the ATA guidelines do go into detail. There are 4 criteria for iodine refractory differentiated thyroid cancer, which is basically to be simple about it, if patients have known deposits of thyroid cancer and they’ve had radioactive iodine treatment or scan with radioactive iodine, then they have a nuclear medicine scan, and those deposits of thyroid cancer don’t take up radioactive iodine, they have iodine-refractory disease. Or if patients have some spots of disease that take up radioactive iodine but others that don’t that also counts as iodine-refractory disease. Another criterion is if a patient has been treated with radioactive iodine but in a short period of time, such as 12 or 14 months, their cancer progresses, then the reactive iodine didn’t do them any good, so that counts as well. And then lastly, it’s about that at some point if a patient has received more and more radioactive iodine and they still have persistent thyroid cancer, that there’s really little benefit to further radioactive iodine. There’s not a great cut off of that total dose from a research point of view but it’s generally accepted that at around 600 millicuries or 800 millicuries of radioactive iodine is about the maximum that in general most people should be getting.

Matthew Fowler: Are there clinical and molecular features more or less likely to be associated with refractoriness to radioiodine?

Lori Wirth, MD: Indeed, there are both clinical and molecular features. In general, there are some histologies that are more likely to be sensitive to radioactive iodine. A classic variant of papillary thyroid cancer is more likely to be sensitive. There are subtypes of papillary thyroid cancer that are more aggressive. The most common of which is the tall-cell variant. That goes along very frequently with BRAF V600E mutation. Those cancers tend to be less likely to take up radioactive iodine. And then other diagnoses as well, particularly hurthle cell thyroid carcinomas and poorly differentiated thyroid carcinomas are less likely to take up radioactive iodine. And then from a molecular point of view, the mutation BRAF V600E is the most common mutation, driver mutation that we see in differentiated thyroid cancers. That’s the most common mutation that we see in papillary thyroid cancers that are the most common DTC. And when a BRAF V600E mutation is present, it upregulates the MAP [mitogen-activated protein] kinase pathway, that goes along with downregulation of things like the sodium iodine symporter that gets radioactive iodine into cells. So thyroid cancers that harbor BRAF V600E is 1 of the most common molecular features, especially if that’s coexistent with another mutation in the TERT [telomerase reverse transcriptase] promoter.

Matthew Fowler: I wanted to ask you what factors you take into consideration when deciding between starting treatment immediately and active surveillance for patients with RR-DTC [radioiodine-refractory differentiated thyroid cancer]?

Lori Wirth, MD: Matthew, I like that question very much because this [is] one that I struggle with on a daily basis in clinic. So the decision to start treatment with MPIs for patients with iodine-refractory DTC can be easy, can be an no brainer, and in other cases can be difficult. So the no brainer cases are patients who have iodine-refractory disease who have enough disease so that they’re symptomatic. They can’t wait around to get better, and patients who are symptomatic generally don’t respond as well to our therapies as well. So patients who are symptomatic from walking through the clinic door should be started on therapy in general, or patients with so much disease that you know that they’re going to be symptomatic very soon, those patients need to start therapy now as well. On the other end of the spectrum are patients with very low volume disease, where they’re clearly asymptomatic and they’re not going to be symptomatic any time soon. Most of us in general take the approach that we should at least follow those patients by active surveillance or disease monitoring for some time to get a handle on the case of disease. Some patients will have very slowly progressive disease, and they probably don’t need to start any therapy other than levothyroxine to keep their TSH [thyroid stimulating hormone] suppressed. And I followed a number of patients for a number of years in that category who are perfectly fine, and I don’t want to mess with that. It’s really the middle category where it can be difficult, when patients have moderate volume disease that’s slow growing or low volume disease but more rapidly growing. There aren’t numbers necessarily that we can pin on this but that’s where I think it’s challenging. There are some data from subset analyses from the SELECT trial. However, that I think provides some guidance. For example, we’ve recently seen that when patients with iodine-refractory DTC have lung mets [metastases], and then were randomized to lend that and it were placebo, those patients that had lung mets that were as small as 1 cm in size actually had an overall survival benefit compared to the patients that were randomized to placebo, even though almost 90% of the patients that were randomized to placebo crossed over and received lenvatinib [Lenvima] at the time of progression at a median of only 4 months. So that suggests that for patients who have lung metastases, an overall survival benefit is one of the most important things that we don’t want to wait too long to initiate therapy. There have been some other subset analyses as well that suggests that in general when patients have progressive disease, there’s more clinical benefit with advocacy response rates, progression-free survival, when treatment is initiated a little bit earlier rather than a little bit later.

Matthew Fowler: And so, for those patients that are showing symptoms that you decided you wanted to start with treatment, what are some of the frontline options for this group of patients that you’re considering?

Lori Wirth, MD: In this day and age, I think that we do want to make sure that we’ve done molecular testing in all of the patients that we’re starting on systemic therapies for iodine-refractory DTC because there are some actionable alterations that we don’t want to miss. And the treatment, the molecular diagnosis—the molecular diagnostics can take some time to get. And so, I generally order that testing earlier while I’m beginning to think about systemic therapy for patients. We can identify patients that harbor RET fusions or NTRK fusions, and in the U.S., RET- and NTRK-directed therapy is FDA [Food and Drug Administration]-approved for patients with iodine-refractory progressive DTC, and those approvals are line agnostic, so molecular diagnostics are important. If patients don’t have an actionable alteration, or they have a BRAF V600E mutation, which is a not uncommon finding, and those patients need therapy in general, I prefer and I think most of my colleagues prefer, starting with an MKI [multikinase inhibitor] therapy. Particularly, because for the BRAF V600E mutation patients, so far in phase 2 studies, we haven’t seen that BRAF-directed therapy outperforms lenvatinib data from the SELECT trial. So, in general, we don’t us BRAF-directed therapy off label for those patients, and in general for patients who don’t have a RET fusion or NTRK fusion driving their thyroid cancer, I will start patients on lenvatinib as the first-line MKI.

Matthew Fowler: Right, and so you kind of got into this next question a little bit regarding lenvatinib. So I’ll focus on sorafenib [Nexavar]. Which patient is most suitable for sorafenib treatment?

Lori Wirth, MD: The patients that were enrolled in the SELECT trial with lenvatinib were a little bit different than the patients that were enrolled in the DECISION [trial] with sorafenib. The patients in the lenvatinib trial had a little bit more aggressive disease, for example. So that might be 1 thing for providers to take into account. There’s a slightly different side effect profile with lenvatinib and sorafenib as well. So with lenvatinib, we do see more frequent grade 3 or 4 hypertension than is seen with sorafenib, though we can see hypertension. Hypertension is a class effect with all of these drugs, so you can definitely see it with sorafenib as well. If I’m taking care of a patient who has hypertension that’s already kind of difficult to manage, they might already be on 3 antihypertensive drugs, they could have difficulty with blood pressure control with lenvatinib, so that would be a good patient to consider sorafenib with the first-line therapy rather than lenvatinib. Those nuances with the side effect profile I think are important to consider.

Matthew Fowler: I’m glad you brought up the toxicities because that’s where I want to close this section of our conversation on. What toxicities have been observed following treatment with frontline TKIs [tyrosine kinase inhibitors] and how are they typically managed?

Lori Wirth, MD: The side effect profile with the VEGFR multikinase inhibitors really is fairly consistent from drug to drug, though there are some finer nuances. But in general, we see hypertension, diarrhea, fatigue, hand-foot syndrome, some mild transaminitis as common adverse events across these VEGFR multikinase inhibitors. I think it’s important, particularly with thyroid cancer and particularly because we’re often following patients with active surveillance for some time before starting an MKI, that we think about pre-habilitation in these patients, focusing on blood pressure control, making sure that patients have well-controlled blood pressure before we start them on therapies. And also, we do see over time, along with the diarrhea and fatigue, we see weight loss. We see some loss of muscle mass. People just kind of poop out, and we think that if you can help patients get involved in things that can really help with a healthy—leading a healthy lifestyle, that that can kind of help prepare them for the road ahead as well. I like to encourage people to get good exercise, to get into healthy diet habits if they don’t already do so, and then do some general weightbearing exercise to help maintain their body mass. And then on treatment, of course, it’s important to really take care of these patients. These are not patients who you can start on an oral drug and have them come back for restaging scans 2 weeks later. The hypertension onset can be very quick, so I have patients monitor their blood pressure at home, and I give them instructions on when to call when their blood pressure goes up. And we don’t wait and see what’s going to happen with their blood pressure. If we see hypertension emerging, in general, we start antihypertensive therapy earlier rather than waiting to see how bad it’s going to get. The other tricky thing, of course, is diarrhea, and diet modifications can help a lot. Over-the-counter treatments, such as Imodium, help a lot. And I always like to get our dietician colleagues involved with patients earlier rather than later because the things that we normally kind of think to tell patients to take to fatten up also can often precipitate diarrhea in patients. Just having them take milkshakes and ice cream often makes the diarrhea worse. And so, it can be tricky, actually, to manage the combination of diarrhea and weight loss for patients. And the other thing that I do a lot is I circle back with patients on these diet approaches because no one wants to stick with a boring, dull diarrhea diet for day after day, week after week, month after month. People get tired and they want to enjoy themselves. But it’s good to let people do that and then circle back and try to bring things in again at some point in the future.

Matthew Fowler: I think that’s really great information. Thank you so much for that.

Transcript edited for clarity.