Marcia Brose, MD: Lori, do you want to tell us a little maybe in your case, if this patient does well on lenvatinib for a while and then starts to progress again, would you go to the cabozantinib? Or what would you do next, or do you have other things that you would try?

Lori Wirth, MD: The recent COSMIC-311 trial looked at cabozantinib in the second-line setting for radioiodine [RAI]-refractory DTC [differentiated thyroid cancer] in patients who had progressed on a first-line TKI [tyrosine kinase inhibitors]. I thought it was a definitive study, showing PFS [progression-free survival] benefit, and it’s FDA approved now for the second line. In general, that is my go-to second-line therapy. I now have several patients being treated on label with second-line cabozantinib. The clinical trials are always of interest. You mentioned dabrafenib or BRAF-directed therapy in the second line or beyond. I sometimes think about off-label BRAF-directed therapy in patients who have BRAF-driven disease. This patient doesn’t, so that wouldn’t apply here.

There is the ITOG trial that looked at the combination of lenvatinib and pembrolizumab in iodine-refractory DTC. There were 2 arms to that trial. One was treatment-naive patients who got the combination therapy. Then there was a second arm that had patients with iodine-refractory DTC who progressed on lenvatinib, and then continued on lenvatinib at whatever dose they were on, and pembrolizumab was added. The data haven’t been published yet but were presented last year, and there were patients who were salvaged with the addition of pembrolizumab, in terms of a subset of patients having bonafide partial responses. I’m going to be very curious to see how long the progression-free survival is in that arm of the trial. It’s an attractive idea, particularly given how well lenvatinib as a single agent works in the first-line setting, and then figuring out a way to keep that benefit going when patients do progress. I was fortunate to participate in that clinical trial, so until we completed enrollment, I was favoring putting patients on that clinical trial.

Marcia Brose, MD: Great. Bruce, do you have any advice for some community endocrinologists who might be seeing RAI-refractory thyroid cancer out there?

Bruce Robinson, MD: My main advice would be to try to partner or team with someone who’s got experience looking after patients with this and to learn how to do it because otherwise what tends to happen is the big centers become overwhelmed by the large numbers of these patients. It’s not difficult to know how to look after these patients. The adverse effect profiles are well described, and after a person has looked after half a dozen patients with these drugs, they start to become much more comfortable doing so. My main advice to those people is to form a partnership with a big center, with someone with whom they can discuss issues that arise from time to time.

About cabozantinib as a follow-on for patients who have failed lenvatinib, I participated in the COSMIC-311 trial. I’ve got to say I was a little surprised with the quality of the outcome, but the outcome was the outcome. Patients tend not to tolerate cabozantinib quite as well as they tolerate lenvatinib, and one needs to be prepared for that. But of course, what this has now done is thrown up an additional question for us. We’ve pondered in this session today the timing of the commencement of lenvatinib. Now, of course, the next big question is, when do you stop lenvatinib and start cabozantinib? That’s a big question too because patients do often progress on lenvatinib, but only slowly progress. We of course maintain those patients for as long as we possibly can because we know that if we stop lenvatinib under such circumstances, the disease will generally take off quickly. We’ve got another question that we need to be, frankly, using physician judgment to answer because I doubt it’s going to be possible to construct a trial that will answer that question.

Marcia Brose, MD: And of course, many times when they’re progressing, they’re only progressing in 1 site. We can also go back and do surgery or SBRT [stereotactic body radiation therapy] or something to manage them, and do what we call whack a mole again, to try to keep them on lenvatinib as long as possible. I totally agree, what was interesting about that study for me was how quickly, when they did start to take off on lenvatinib, they took off quickly. While we’re maintaining people on lenvatinib, we need to make sure that we have it figured out how we’re going to be able to switch them over. Because it turned out that initially just being off the lenvatinib for 4 weeks, [there was] wild progression, and a couple of patients almost weren’t able to be treated. The changeover was reduced to 2 weeks for that reason. That’s something everybody has to be very aware of when they do make the switch.

Transcript edited for clarity.