BRAF Inhibitors and Immunotherapy for Differentiated Thyroid Cancer

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

Lori Wirth, MD: 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.

Maria E. Cabanillas, MD: 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.

Lori Wirth, MD: 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.

Giuseppe Barbesino, MD: 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.

Transcript edited for clarity.

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