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Emerging Therapies in Differentiated Thyroid Cancer

Insights From: Marcia S. Brose, MD, PhD Abramson Cancer Center; Johannes Smit, MD, PhD Radboud University Nijmegen Medical Center
Published: Friday, Dec 14, 2018



Transcript: 

Marcia S. Brose, MD, PhD:
We do know that the BRAF inhibitors are there for patients who have a BRAF mutation. That’s actually been documented over the last few years. So I wouldn’t necessarily say that the BRAF inhibitors are emerging, but they are agents that we would consider using after sorafenib and lenvatinib. Because sorafenib and lenvatinib have more data and are both FDA approved, those tend to be used first. Then we would go to a BRAF inhibitor if they have a BRAF mutation.

Similarly, there are emerging therapies for people with TRK translocations or RET point mutations or translocations. As those clinical trials come to their fruition, we might choose some of those activities, specifically for the small number of patients who have those mutations.
For all-comers, with recent data that we’ve shown through a phase II study with cabozantinib, we know that this drug is very active in this tumor type as well. There is also data on this from Ohio State. So we have 2 phase II trials that are completed and show that cabozantinib also works in differentiated thyroid cancer.

Many oncologists are aware that cabozantinib is FDA approved in medullary thyroid cancer. Now we actually have data that say that it’s active in the phase II setting. Going forward, there is a phase III study that will test the drug in the second- and third-line setting. So after either of the other drugs, you can go to cabozantinib as a second or third drug or beyond. And so that’s another emerging therapy. I’ve seen great activity in my patients who’ve gotten to it in the second-line, third-line, or fourth-line setting. Some have even used it later, and it’s also a very active agent. So that’s another exciting agent coming down the pike.

Eric J. Sherman, MD: The use of immunotherapy is an extremely good question for thyroid cancer. There has been only 1 published study with immunotherapy in differentiated thyroid cancer. That was a study with pembrolizumab. It was in PD-1 [programmed cell death protein 1]–positive patients. The response rate was not very impressive—only around 9%—but there wasn’t that bad of a median progression-free survival—around 6 months. This was not as good as you see with the TKIs [tyrosine kinase inhibitors] but is still something that is doable.
It was something that seemed to be used only in follicular and papillary thyroid cancers. The reason why I mentioned that is that there have been more and more data in Hürthle cell thyroid cancer. The mutation burden in these tumors is higher than you see in papillary thyroid cancer. These may have better targets altogether. We have seen a few patients who actually seem to be good candidates for immunotherapy, and I do have to say that I do treat a few patients off-study with immunotherapy and see some activity.

There are patients for whom you just cannot give a VEGF TKI to, either because they had a bad side effect that never goes away or have high blood pressure that cannot be controlled. For patients whom we’ve used every other drug for and who are using immunotherapy, I’ve had many patients who are able get their disease in check after awhile.

Johannes (Jan) Smit, MD, PhD: The problem in thyroid cancer, as in all cancers, is that patients can become resistant to treatment. In many cancers, many molecular pathways are being activated. If we treat patients with a drug that targets only a few of those pathways, we can expect that the cancer, in the end, escapes from the inhibiting effects of the drugs by activating other pathways. Also, novel mutations can occur that bypass the effects of the treatments.

So I really believe that combination treatments that target multiple pathways are important. Examples of those combinations of treatments would be those that target both the PI3-kinase pathway and the RET/ROS/RAF pathway, but there are other combinations that you can think of, especially combinations of immunotherapy and kinase inhibitor treatment.

Eric J. Sherman, MD: I think the more exciting thing that is going to happen with immunotherapy is going to be using it in combination with other therapies. So using immunotherapy, PD-1 drugs, with something else.

There is a national study that the University of Colorado is running, looking at a combination of pembrolizumab and lenvatinib. There has already been a lot of exciting data in other cancers using lenvatinib and pembrolizumab together. And so using it in thyroid cancer makes a lot of sense. This is something that we should be excited about. In addition, we have a study looking at using radioactive iodine, a small dose, with durvalumab, a PD-L1 [programmed death-ligand 1] antibody. There is a lot of rationale for using a little bit of radiation. It is like having a bit of an abscopal effect. Also, by using Thyrogen, there is an increased antigen presentation to try to improve responses to immunotherapy.

There are going to be many other combinations coming around. Within the next 6 to 12 months, we’ll probably have 4 different immunotherapy studies going on in differentiated thyroid cancer using different combinations.

While I think PD-1 as a single agent does not seem to have a lot of activity, it does work with some patients and is something that can be done when other drugs cannot be used. It should at least be considered. But I think the combinations are where most of the excitement exists. We’re going to see a lot of studies occur over the next few years. They will look to see if these combinations end up working better.


Transcript Edited for Clarity
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Transcript: 

Marcia S. Brose, MD, PhD:
We do know that the BRAF inhibitors are there for patients who have a BRAF mutation. That’s actually been documented over the last few years. So I wouldn’t necessarily say that the BRAF inhibitors are emerging, but they are agents that we would consider using after sorafenib and lenvatinib. Because sorafenib and lenvatinib have more data and are both FDA approved, those tend to be used first. Then we would go to a BRAF inhibitor if they have a BRAF mutation.

Similarly, there are emerging therapies for people with TRK translocations or RET point mutations or translocations. As those clinical trials come to their fruition, we might choose some of those activities, specifically for the small number of patients who have those mutations.
For all-comers, with recent data that we’ve shown through a phase II study with cabozantinib, we know that this drug is very active in this tumor type as well. There is also data on this from Ohio State. So we have 2 phase II trials that are completed and show that cabozantinib also works in differentiated thyroid cancer.

Many oncologists are aware that cabozantinib is FDA approved in medullary thyroid cancer. Now we actually have data that say that it’s active in the phase II setting. Going forward, there is a phase III study that will test the drug in the second- and third-line setting. So after either of the other drugs, you can go to cabozantinib as a second or third drug or beyond. And so that’s another emerging therapy. I’ve seen great activity in my patients who’ve gotten to it in the second-line, third-line, or fourth-line setting. Some have even used it later, and it’s also a very active agent. So that’s another exciting agent coming down the pike.

Eric J. Sherman, MD: The use of immunotherapy is an extremely good question for thyroid cancer. There has been only 1 published study with immunotherapy in differentiated thyroid cancer. That was a study with pembrolizumab. It was in PD-1 [programmed cell death protein 1]–positive patients. The response rate was not very impressive—only around 9%—but there wasn’t that bad of a median progression-free survival—around 6 months. This was not as good as you see with the TKIs [tyrosine kinase inhibitors] but is still something that is doable.
It was something that seemed to be used only in follicular and papillary thyroid cancers. The reason why I mentioned that is that there have been more and more data in Hürthle cell thyroid cancer. The mutation burden in these tumors is higher than you see in papillary thyroid cancer. These may have better targets altogether. We have seen a few patients who actually seem to be good candidates for immunotherapy, and I do have to say that I do treat a few patients off-study with immunotherapy and see some activity.

There are patients for whom you just cannot give a VEGF TKI to, either because they had a bad side effect that never goes away or have high blood pressure that cannot be controlled. For patients whom we’ve used every other drug for and who are using immunotherapy, I’ve had many patients who are able get their disease in check after awhile.

Johannes (Jan) Smit, MD, PhD: The problem in thyroid cancer, as in all cancers, is that patients can become resistant to treatment. In many cancers, many molecular pathways are being activated. If we treat patients with a drug that targets only a few of those pathways, we can expect that the cancer, in the end, escapes from the inhibiting effects of the drugs by activating other pathways. Also, novel mutations can occur that bypass the effects of the treatments.

So I really believe that combination treatments that target multiple pathways are important. Examples of those combinations of treatments would be those that target both the PI3-kinase pathway and the RET/ROS/RAF pathway, but there are other combinations that you can think of, especially combinations of immunotherapy and kinase inhibitor treatment.

Eric J. Sherman, MD: I think the more exciting thing that is going to happen with immunotherapy is going to be using it in combination with other therapies. So using immunotherapy, PD-1 drugs, with something else.

There is a national study that the University of Colorado is running, looking at a combination of pembrolizumab and lenvatinib. There has already been a lot of exciting data in other cancers using lenvatinib and pembrolizumab together. And so using it in thyroid cancer makes a lot of sense. This is something that we should be excited about. In addition, we have a study looking at using radioactive iodine, a small dose, with durvalumab, a PD-L1 [programmed death-ligand 1] antibody. There is a lot of rationale for using a little bit of radiation. It is like having a bit of an abscopal effect. Also, by using Thyrogen, there is an increased antigen presentation to try to improve responses to immunotherapy.

There are going to be many other combinations coming around. Within the next 6 to 12 months, we’ll probably have 4 different immunotherapy studies going on in differentiated thyroid cancer using different combinations.

While I think PD-1 as a single agent does not seem to have a lot of activity, it does work with some patients and is something that can be done when other drugs cannot be used. It should at least be considered. But I think the combinations are where most of the excitement exists. We’re going to see a lot of studies occur over the next few years. They will look to see if these combinations end up working better.


Transcript Edited for Clarity
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