Treatment Options in RAI-refractory DTC in Second Line and Beyond


Lori Wirth, MD, discusses the role of cabozantinib in the second-line setting for patients with radioiodine-refractory differentiated thyroid cancer and reviews the results from the COSMIC-311 trial.

Matthew Fowler: Dr Wirth, let’s take a look at treatment options in RAI [radioactive iodine]-refractory DTC [differentiated thyroid cancer] in the second line and beyond. What factors do you consider when selecting the appropriate treatment in second-line or beyond setting?

Lori Wirth, MD: Well, that would have been a harder question to answer if you’d asked me a year ago, but now, fortunately, we have some new data from the COSMIC-311 trial. So we’ve now got great guidance on second-line therapy for iodine-refractory DTC. The COSMIC-311 trial randomized patients who had progressed on prior therapy for DTC, primarily VEGFR multikinase therapy, particularly with Lenvatinib [Lenvima], but there were other drugs that were allowed as well. Patients were randomized in a 2:1 fashion to cabozantinib [Cabometyx] versus placebo. The COSMIC-311 trial showed that there was a significant improvement in progression-free survival in the patients that were randomized to cabozantinib compared to placebo. With a hazard ratio that was really, really good. The hazard ratio was 0.2. It was on the basis of the COSMIC-311 trial that the FDA [Food and Drug Administration]-approved cabozantinib in the second-line setting for patients with iodine-refractory DTC. It’s great to have those data. I think, in general, I know the—we now have 3 VEGFR multikinase inhibitors that are approved. Both lenvatinib and sorafenib [Nexavar] have approvals in the first line, and then cabozantinib now has an approval in the second line. We’ve got 2 drugs for 2 lines of therapy. Should we use sorafenib because it’s approved for the first line, and then the cabozantinib in the second line? I think, in general, the answer is no. And the reason I say that is because we also have to look at the sequence of therapies. In the sorafenib trial, we just didn’t have patients that had been previously treated that were enrolled in that trial. We don’t really know how well sorafenib might perform in the second line. It’s an open question. Whereas we do know, with good data from a randomized trial, that cabozantinib performs well in the second-line setting. So my usual sequence is lenvatinib is first line and cabozantinib in the second line. Of course, if there are the genotype-directed therapies that are available, those need to be worked in appropriately as well. If, for example, a patient has had a MKN first line, and they have a RET fusion or NTRK fusion, I would certainly use one of the NTRK or RET-directed therapies in those patients prior to cabozantinib because of the good activity that we’ve seen in the phase 1/2 trials in those patient populations. And then there’s the question, of course, of the BRAF V600E mutation. There is a clinical trial that’s underway right now investigating dabrafenib [Tafinlar] and trametinib [Mekinist] in a second-line setting in the BRAF-mutant iodine-refractory DTC. That’s an international trial, so we’ll have good data at some point in the hopefully not-too-distant future, whether or not there’s a role for BRAF-directed therapy for these patients.

Matthew Fowler: Right. And my next question was around COSMIC-311. so you did a really great job of talking a bit about that and really surveying the treatment landscape, including cabozantinib. I wanted to ask you what your experience has been using cabozantinib for the treatment of DTC.

Lori Wirth, MD: Well, first of all, I would say that when I first found in using cabozantinib for DTC was that I had to make sure that I was distinguishing it from cabozantinib for MTC. There are different formulations of cabozantinib for DTC and MTC, and it’s very important to make sure that you’re ordering the right cabozantinib at the right dose for DTC and not what you’re doing for your MTC patients. And the first prescription that I wrote for cabozantinib for DTC, my specialty pharmacy called me and said, after I had spent an hour making sure I was ordering it the right way, my specialty pharmacy said, “Dr Wirth, didn’t you mean to order…” And so, that is a potential pitfall in terms of a medical error that we want to make sure that we’re not ordering. I have certainly begun to use it as my standard of care for our patients, and what I say, so far so good.

Matthew Fowler: With cabozantinib treatment, what are some of the common toxicities you see with it and how are they managed?

Lori Wirth, MD: With cabozantinib in DTC, we see a similar adverse event profile that we do with the other VEG inhibitors. So we do see our old friends diarrhea, hypertension, fatigue. You can see transaminitis in these patients. Occasionally, we can see QTC prolongation, so we have to monitor patients’ blood pressure, their labs. We have to check their baseline labs, EKGs [electrocardiogram] in patients, and monitor those things on treatment. There is a unique toxicity, where cabozantinib can affect the pigmentation of peoples’ skin, also their hair. So many patients will develop a bit of a pallor and lose that pigmentation in their hair. And I definitely mention that to patients to expect when I am consenting patients for treatment with cabozantinib. It is most patients do experience those pigmentation changes, which is really interesting. But overall, I would say that cabozantinib at this FDA-approved dose is well-tolerated in patients. And these are patients that in general have been on prior VEGFR MKIs [multikinase inhibitors] and many of them have been on prior VEGFR MKIs for many months. And so far, in my anecdotal experience, I have found that treatment with cabozantinib is very doable. And similarly, to the COSMIC-311 study, we do see patients responding to therapy or having minor responses and at least not progressing.

Matthew Fowler: Perfect. Thank you so much for that.

Transcript edited for clarity.

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