So, listen, maybe Marcia, you can help us wrap up by helping us think about future directions in advance DTC [differentiated thyroid cancer].

: I think that there’s a lot of future directions and I think where a lot of them have been mentioned already with upcoming trials where we’re looking at other combinations for RET, RAI [radioactive iodine], redifferentiation. There are definitely multiple studies coming up where either kinase inhibitors are being partnered with each other or with immunotherapy. I think that we definitely have a bad, unmet need in anaplastic thyroid cancer—still haven’t done anything that really has made a big impact with the exception of the BRAF inhibitors—which I do think helps some of those patients with anaplastic. Of course, the third of them that might have BRAF mutations, but two-thirds of them don’t have BRAF mutations and are a huge unmet need. And now although already we’re starting to get unmet need with the patients who have advanced thyroid cancer that have failed the therapies that we have now.

I’m really hopeful that we’ll maybe find more targets that we could hit, that we’ll be able to do these targeted therapies really have been such a joy to work with because the side effect profiles have been lower and the response rates have been so high I think we’re just going to continue to go in these 4 or 5 directions. I think we’re going to get a little bit more data about head-to-head which is the better first-line and what’s a better second-line, which we haven’t really had that much data for. I know that there’s a RET inhibitor study right now that we have going on at our site. Many of you have at your sites randomizing patients to either RET inhibitors upfront versus standard of care or for medullary thyroid cancer, for instance.

We’re going to start to get some of those studies under our belts. They might start to give us more direction where to go in the first-line, because a lot of these phase 2’s you can’t compare really side-to-side to some of the larger studies. It’ll be nice to get some really good, randomized trials to figure out some of the sequencing in the future.

Yes. I agree that the selpercatinib [Retevmo] and pralsetinib [Gavreto] randomized trials are so important, not just for their primary end point but also for that other important question about is there a sequence that’s better. If you develop acquired resistance on selpercatinib or pralsetinib, can you still have activity with lenvatinib [Lenvima] or cabozantinib [Cabometyx] and MTC [medullary thyroid cancer]?

Speaking of cabozantinib, I’d asked Naifa, which cabozantinib are we talking about in DTC? So those of us who do thyroid cancer are used to thinking about cabozantinib as Cometriq—the FDA [Food and Drug Administration] approved formulation for medullary thyroid cancer. Naifa, do you want to unmute, say one word about Cometriq versus Cabometyx?

: Yes. Sorry, I didn’t answer your question, didn’t mean to ignore it. So basically, it can get very confusing because we all use generic names every day and even when we’re writing it out, and the formulations are very different and so they cannot be interchanged. And so, cabozantinib was looked at 60 milligrams a day and that’s under the brand name of Cabometyx. And it’s very different from the cabozantinib under the brand name Cometriq from medullary thyroid cancer where that was 140 milligrams. Now, they’ve completely changed the formulation but they’re not equivalent and we have to be really careful. And that’s even different from kidney cancer for physicians that treat both.

Thank you for that point of clarification. Maria and Giuseppe, any other thoughts that you may have in terms of future directions—things that we don’t want to miss, Maria?

 Yes. I think a Hurthle cell is a real opportunity. We’ve made great strides in anaplastic thyroid cancer and in differentiated thyroid cancer and medullary thyroid cancer. But Hurthle cell is one of those orphan diseases and it’s a rare type of differentiated thyroid cancer. We didn’t talk much about it today. It does respond well to lenvatinib but we know that we need other therapies because, like I said this is a marathon, [and] at some point we’ve got to switch to something else or a patient can’t tolerate it. I think we have a trial coming up with immunotherapy in Hurthle cell and so that to me is the next frontier.

: To me, I said that briefly before, but if I had the genie in a bottle coming out my first wish would be to have a tissue-based test that can tell me who is radioactive iodine sensitive and who is not. I still believe that we treat so many patients in whom the iodine is not effective, and we don’t do a good service to them. And we need really to dissect the molecular biology of the cancer cell and understand who can respond and who doesn’t on the tissue. And I do think that the tools are there because we understand this so much better than we did in the past that we should be able to tell. And I’m hopeful that in the next few years I will sit in front of a patient and look at a report and say, “Well, I don’t think radioactive iodine is a good thing for you. Maybe we can try with redifferentiation but not as it is.” And the other person is, “Oh, wow, you’re a great candidate.” I think if there is any cancer set will be wiped off by the radioactive iodine, that would be my real hope for the future.

: Can I just say one thing, Lori? I’m sitting here thinking about where we were 10 years ago, and I think that we all have to really be appreciative of the fact that 10 years ago we had nothing approved. There are not a lot of cancer types where such great research, collaboration and advancements have happened. We’ve had now 3 FDA approvals, multiple phase 2’s that are showing activity, and then 3 more targeted therapies also getting FDA approval. I just want to say kudos to the whole thyroid world. I think that the research has really gone and really shown a big difference. And I think that the people who benefit the most are patients from all of these drugs.

I think that is a great note to end this program on. I completely agree that the last decade has been a world of progress for our patients. I think that many patients’ lives have really been changed dramatically by all of the hard work that the people have been putting into this work to get new drugs for our patients with thyroid cancer. Listen, let me thank you all for this rich and informative discussion. And I really appreciate your joining me in today’s discussion. Thank you again also to our viewing audience. We hope that you found this 

 Peer Exchange discussion to be useful and informative. Good night, everyone.

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An overview of therapies in the pipeline for differentiated thyroid cancer and their potential effect on clinical decision-making.

Novel Treatment Advances in Differentiated Thyroid Cancer

I think it would be great if you briefly discussed the BRAF inhibition and then also pembrolizumab [Keytruda]. We have an embarrassment to riches now really with patients with thyroid cancer. How do we think about sequencing, and does the cabozantinib [Cabometyx] approval in the second-line setting, how do we foresee that changing or impacting on the sequencing of these therapies? So go ahead.

 I’ll just continue on with the pembrolizumab trial, which only enrolled as a small number of differentiated thyroid cancer patients. Twenty-two patients is comparable to these selective inhibitors but these patients had to have at least 1% PD-L1 [programmed death-ligand 1] expression. As I mentioned in differentiated thyroid cancer, we don’t see high PD-L1 expression and so not surprising that there was only a 9% partial response rate. The majority of patients having stable disease. However, the issue that I have with this clinical trial is that it didn’t require progression for trial entry and so I don’t know if a lot of those patients actually had stable disease before going on study and that’s why we’re seeing a 55% stable disease as the best response.

The median progression-free survival was only about 7 months and the median overall survival wasn’t reached. But the 6.8 months for progression-free survival is not terribly impressive and the adverse events are pretty much what you would expect with checkpoint inhibition. They saw the usual interstitial lung disease, pneumonitis, and they saw colitis and hypothyroidism. With the BRAF inhibitors, the BRAF inhibitors are interesting. We’ve been researching BRAF inhibitors and thyroid cancer for a long time.

The first trial that was specifically for thyroid cancer was a phase 2 trial with vemurafenib [Zelboraf] and that was open-label. It was nonrandomized, so everybody received drug and the patients were divided into 2 cohorts. They were the treatment-naïve patients and previously treated patients. As you would expect, the treatment-naïve patients did better. It was about a 39% partial response rate, 58% had stable disease, and 4% had progression as their best response. But I’ll point out that the median progression-free survival in this group was 18 months, which is what I was alluding to before is that the progression-free survival is pretty long in these patients on BRAF inhibitors which is why we like them. The median overall survival had not been reached when we published the trial.

[In regard to] the adverse event [AE] profile, it’s interesting because vemurafenib has a slightly different AE profile than dabrafenib [Tafinlar] does. Vemurafenib causes more issues with arthralgias, more skin toxicities. I would say that I would see a little bit more hand-foot with vemurafenib and then all the BRAF inhibitors, of course, can cause squamous cell carcinomas of the skin. That’s a class effect. There is a dabrafenib plus-or-minus trametinib [Mekinist] trial that is not been published yet in a peer-reviewed journal, but we do know results from abstract and poster presentations. So this was a nice trial. It was designed so that [it] had 1 arm of patients that were just on dabrafenib and then another arm of patients that were on the combination of dabrafenib plus trametinib. And then the dabrafenib patients were able to crossover to dabrafenib/trametinib if they progressed on that single agent.

This was randomized between arm A and B. Patients who received single-agent dabrafenib had a response rate of 38%, and in the combination arm it was 33%. The median progression-free survival was 11 months in arm A [the single agent], and 15 in arm B [the combination], but that was not a statistically significant difference. And then the adverse event profile with dabrafenib—the number 1 problem that we have with dabrafenib is the fever that it causes in some patients. That fever in most patients tends to go away after about 2 or 3 months but it is difficult to manage in some patients. We really have a hard time managing fever. It can also cause anemia and the usual fatigue, nausea, skin disorders. All BRAF inhibitors can cause some alopecia also but it’s usually just hair thinning.

Those are the 2 major trials with BRAF inhibitors in thyroid cancer and as you said, we will have a larger trial with dabrafenib/trametinib. But I want to just mention here that redifferentiation therapy is essentially restoring the ability of the tumor to take up radioiodine again by giving them some type of agent. And the only success we’ve had with this ever—because we’ve been trying this for a very long time in thyroid cancer—is with the BRAF inhibitors. And so, that’s really kind of exciting data but we don’t have very large trials in patients with distant metastatic disease. We have these very small studies but that is a nice strategy, especially patients who are already on a BRAF inhibitor and they haven’t really reached their lifetime cumulative dose for radioiodine, is that we’ll sometimes see if they’re taking up radioiodine, do a diagnostic whole-body scan to see, and then give them radioiodine if they take up radioiodine. And then we can stop the therapy which is nice for patients to have that drug holiday and then we watch for progression to see what the radioiodine is doing.

Now, this has also been a strategy that’s been reported with case reports for the other selective inhibitors. So with the NTRK and RET inhibitors there is a trial that will be started with selpercatinib [Retevmo] to do this very thing. The really exciting stuff that’s on the horizon with these selective inhibitors because radioiodine when it works it works really well, and patients don't have to take a pill all the time and you can avoid having them be on these inhibitors for a long term. But we really do need to know what the long-term effects are for these patients. We have seen some patients transform to anaplastic thyroid cancer and that’s concerning to us. The verdict is still out on that strategy of redifferentiation.

Yes. So, another off-label conversation but a really interesting one that we’ve also treated, and I’m taking that approach with a number of patients here. I’ve treated a number of patients with Giuseppe. I’m wondering Giuseppe, what your take is on…is there with redifferentiation? Apart from the fact that we definitely need more data.

 Well, see it’s all wishful thinking of course but it is very encouraging because the principle is there. Basically, my dream as an endocrinologist who mostly manages radioactive iodine in this patient is first to have a good test that tells me which patient is going to be resistant and who doesn’t before I treat them with radioactive iodine. That’s my goal. And then, in those who are resistant, then being able to abolish that resistance with the agents that on the adjuvant setting are able to allow me to treat these patients off the surgery and having them on the potentially toxic medication but only for a short period of time. And then, hit the tomb of a radioactive iodine hoping that it will work, and then stop there and monitor the patient. That would be my ideal outcome of all these studies. As you all said this is off-label, the data is limited but it’s really what we’re looking at as endocrinologists right now.

The role of BRAF inhibitors and checkpoint inhibitors in differentiated thyroid cancer, and potential considerations for using BRAF inhibition as redifferentiation therapy.

Giuseppe Barbesino, MD

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