Lori Wirth, MD: 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.

Maria E. Cabanillas, MD: 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.

Marcia Brose, MD, PhD, FASCO: 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 TRK or a RET fusion, I can start them on lenvatinib or sorafenib while I’m waiting to get the genetics back.

Transcript edited for clarity.