Maria E. Cabanillas, MD, discusses some of the ongoing thyroid cancer clinical trials at The University of Texas MD Anderson Cancer Center, as well as other promising research on the horizon across all subtypes of the disease.
Maria E. Cabanillas, MD
The field of anaplastic thyroid cancer (ATC) has evolved in an unexpected way over the past 5 years, said Maria E. Cabanillas, MD, with last year’s approval of dabrafenib (Tafinlar) and trametinib (Mekinist) marking the first combination to be approved for the treatment of this patient population.
The BRAF/MEK inhibitor combination was approved for the treatment of patients with unresectable or metastaticBRAFV600Epositive ATC, which is an aggressive form of thyroid cancer.
“It’s just incredible, and I never would have thought 5 to 10 years ago that we would be sitting here talking about an approved drug for ATC,” Cabanillas said.
Cabanillas, of The University of Texas MD Anderson Cancer Center, emphasized the instrumental role that patients have played in thyroid cancer research by participating in clinical trials, as well as the need for continued research to expand the treatments available for all subtypes of thyroid cancer.
One ongoing phase II trial at MD Anderson is investigating the addition of atezolizumab (Tecentriq) to targeted therapies in patients with ATC. Patients are separated into 4 cohorts based on their driver mutations. Patients with ATC who have aBRAFV600E mutation receive the anti-PD-L1 agent in combination with vemurafenib (Zelboraf) and cobimetinib (Cotellic). The second cohort is made up of patients withRASorNF1mutations, and those patients will receive atezolizumab with cobimetinib.
The third cohort of patients is comprised of patients who don’t have any of those mutations but still meet the study criteria. These patients receive atezolizumab in combination with bevacizumab (Avastin). In addition, patients that do not meet the entry criteria for any of those cohorts are put into the fourth cohort and receive atezolizumab plus a cytotoxic chemotherapy of either paclitaxel (Taxol) or nab-paclitaxel (Abraxane).
In an interview withTargeted Oncology,Cabanillas, an oncologic endocrinologist, associate professor, and the faculty director in the department of endocrine neoplasia at MD Anderson, discussed the trials ongoing for patients with thyroid cancer at her center, as well as other research on the horizon in ATC, differentiated thyroid cancer (DTC), medullary thyroid cancer (MTC), and papillary thyroid cancer (PTC).
TARGETED ONCOLOGY:Can you discuss some background on your ongoing trial of immunotherapy plus targeted therapy in ATC?
Cabanillas:The atezolizumab trial is a trial that combines this anti-PD-L1 drug, atezolizumab, with targeted therapies. This basically personalizes it so that the driver mutation in the tumor is matched to the targeted therapy.
We have 4 different cohorts. The first cohort is patients who have aBRAFV600E mutation in their tumor. They are put on the atezolizumab, which everyone gets, but in addition, they are put on vemurafenib and cobimetinib, which are drugs that are approved forBRAF-mutated melanoma. In the second cohort, patients who have either aRASmutation or [an]NF1[mutation], and those patients are treated with atezolizumab and cobimetinib, the MEK inhibitor that is approved for melanoma. If you don’t have any of those mutations, then those patients are put in cohort 3, which [receives] atezolizumab with bevacizumab. If the patient doesn’t qualify for any of those, if they just don’t meet the entry criteria for any of those, then they are put in cohort 4, which is essentially cytotoxic chemotherapy with atezolizumab. We use either paclitaxel or nab-paclitaxel.
What we know about ATC is that genetically, they are very distinct; it’s not all 1 disease. ATC is essentially the end stage, you could say, of differentiated thyroid cancer (DTC). DTC is papillary, follicular, and Hurthle cell. These well-differentiated tumors can become more aggressive, acquiring new mutations, and then dedifferentiate into ATC. In summary, ATCs are usually derived from a papillary, Hurthle cell, or follicular thyroid cancer and sometimes co-exists within the tumor, giving us a clue as to which thyroid cancer it may have evolved from.
Those are distinct thyroid cancers, so thinking of ATC as one cancer is really not correct; you have to think about which line it derived from because that end stage tumor, that ATC tumor, retains the driver mutations from which it was derived from. For example, if it was a PTC with aBRAFmutation and it became undifferentiated, ATC, that tumor still has thatBRAFmutation. Genetically, these are very different tumors. We’re trying to match them to the best targeted therapy, and then by adding the immunotherapy, we think these will work better together.
In ATC, the real driving force behind pairing all these different chemotherapies together with immunotherapies was because these tumors grow so fast that immunotherapy often times was too slow to stop the growth in time before the patient would die. We are trying to slow down the cancer with the targeted therapies that work very quickly. Targeted therapies, such as BRAF inhibitors, work within days in ATC patients, relieving symptoms from the tumor compression on the esophagus and trachea. By then giving them the immunotherapy, we are hoping we will get an even better response and a more sustained response, even though it may not be a response very early to the immunotherapy. The targeted therapy is bridging them to allow enough time for the immunotherapy to start to work.
TARGETED ONCOLOGY:What other trials are enrolling for patients with ATC and other thyroid cancers?
Cabanillas:There are a number of clinical trials. Starting with ATC, we have many colleagues that we work with at other academic institutions who have clinical trials for ATC. One of them that is of interest is going on at Dana-Farber. This is a trial with ipilimumab plus nivolumab (Opdivo) for ATC, and that is an interesting trial. We think these drugs work a little differently in the immune system, so they would complement each other.
In ATC, the immunotherapy trials are very interesting. Memorial Sloan Kettering also has some immunotherapy trials, such as paclitaxel plus an immunotherapy drug. That is another trial that will be interesting to see.There is a trial that closed last year that had been open for ATC with a drug called lenvatinib (Lenvima). The trial closed early, so we can build on the knowledge that we obtained from that study, but those results have not been made public yet.
For DTC, there are a lot of interesting trials going on. The most interesting one is with a drug called selumetinib. Selumetinib is a MEK inhibitor. There’s a small pilot study that was published a few years ago now with selumetinib to help restore the ability of these tumors to take up radioactive iodine. Radioactive iodine is a great treatment when it works. Often times the tumors will not be able to take up the radioactive iodine anymore (we call this radioactive iodine refractory), in which case it may cause more harm than good to the patient. With selumetinib, what we think is that it redifferentiates the tumor so that it has the capacity to take up the radioactive iodine. The trial is open at many centers in the United States.
The trial is double blinded and placebo-controlled. Half of the patients get selumetinib and half of them get placebo. After several weeks, all patients receive radioactive iodine. We’re trying to look and see if there is any difference between these patients who have been treated with selumetinib and radioactive iodine versus placebo and radioactive iodine. We will see if the selumetinib really does help restore that radioactive iodine uptake.
The BRAF inhibitors have also been shown to restore radioactive iodine uptake. Small studies with dabrafenib and vemurafenib have been published which show that these drugs hold promise for redifferentiation therapy.
I think that’s the hottest research right now in DTC. Unfortunately, though, there are patients that have had the [maximum amount] of radioactive iodine that they can get safely, so they’ve reached their limit of radioactive iodine that we don’t usually want to go over. That kind of treatment is not something that they can have, so we have to think about what else we can treat these patients with.
The other interesting things are kind of along the lines of what we are doing with ATC by combining immunotherapy with targeted therapy. There’s this clinical trial with lenvatinib plus pembrolizumab (Keytruda) in DTC. That’s a 2-arm trial for patients who are naïve to lenvatinib and can go on lenvatinib/pembrolizumab. In patients who have been on lenvatinib but it’s no longer working, pembrolizumab is added to the lenvatinib regimen. That’s a really interesting study. The first arm is almost fulling enrolled but the second arm of patients who have already been on lenvatinib where we are adding in the pembrolizumab still has plenty of spots.
There is also a cabozantinib (Cometriq) plus nivolumab trial in DTC, which I think will also be interesting. This is very similar to the lenvatinib/pembrolizumab trial. There is also a second-line cabozantinib trial for DTC ongoing. Those are probably the most interesting trials in DTC.
In MTC, there’s a lot of exciting stuff going on. The majority of these tumors are driven byRETmutations. I should also mention that a very small portion of PTC is also RET-driven, but that’s because they have a RET fusion not aRETmutation like in MTC. We have these 2 drugs that are selective RET inhibitors, and they are being tested in RET-driven tumors, so we have a lot of MTC patients on those trials. The drugs are from LOXO Oncology and Blueprint Medicines. These are basket trials because you can have lung cancer, prostate cancer, or any cancer that has either a RET fusion orRETmutation. These are looking very interesting for thyroid cancers that are RET-driven. There’s already been some data out there that has been presented on results of these trials. These trials are enrolling in several places throughout the United States. I think those are the ongoing trials that would be of interest to oncologists who are wanting to get their thyroid cancer patients treated on a study.
TARGETED ONCOLOGY:What are the biggest unmet needs in thyroid cancer?
Cabanillas:In terms of the redifferentiation therapy, that’s a real unmet need. I think we need to do more of these trials and look at long-term safety from RAI given in the setting of these selective inhibitors. These trials are note easy to do. They are quite complicated because radioactive iodine is usually given by the endocrinologist and chemotherapies are usually given by the oncologists, with the exception of MD Anderson and a few other institutions where there are oncologic endocrinologists who straddle both worlds.
For ATC, we just need more centers that can do ATC trials because not all the patients can go to these 3 or 4 major centers in the United States; they don’t have access to clinical trials. For a rare disease, we really want to get all of these patients on a clinical trial because if not, you lose the data. If you have a patient that is responding but they are not on trial, it’s just one patient you can report, but that doesn’t get drugs approved for cancer.
The other thing that is a real unmet need is the MTC patients who don’t have aRETmutation because those often times have aRASmutation, andRASis very difficult to target, so that’s an unmet need. Then, of course, the Hurthle cell thyroid cancer, which is a very puzzling disease, doesn’t have any actionable mutations, and there has been some recent genetic work in that area that has been published. It gives us a little more insight as to what drives these tumors, but we are still not anywhere near figuring out how to treat those patients effectively other than what we currently have which is the approved drugs of lenvatinib and sorafenib (Nexavar).
TARGETED ONCOLOGY:What do we still need to understand in the field?
Cabanillas:A lot more work needs to be done. There’s been some work in Hurthle cell thyroid cancer and in early stage PTC to try to understand these tumors on the molecular level, but we really need more data in follicular thyroid cancers and these very aggressive PTCs. While PTC is usually a very indolent disease, there are a subset of patients that have very aggressive cancers. We need to try to understand those tumors a little bit better.
One area of research that I think is really important isBRAF-mutant PTC, as this is the most common mutation in that disease. There’s already been a lot of research in PTC, but we need to be doing trials that will lead to an indication for BRAF inhibitors in PTC withBRAFmutations. That should be the goal of thyroid cancer researchers: how do we get an approved drug for BRAF mutant PTC? This is probably the right way to treat these patients. We can also redifferentiate those tumors with BRAF inhibitors, allowing us to give radioactive iodine and then even possibly stop the drug, allowing patients a drug holiday. I think that should be one of our collective goals as thyroid cancer researchers--to get an indication for a BRAF inhibitor in PTC withBRAFmutation.
TARGETED ONCOLOGY:Where do you see the field evolving in the next 5 to 10 years?
Cabanillas:It’s a funny question only because if you had asked me 5 years ago where the field was going to go in ATC, I never would have thought we would get this far. We have an approved drug combination in ATC, and that’s thanks to doing those clinical trials as I said. Those patients had to travel to MD Anderson and all these other sites they enrolled in to get on a trial. They are the reason that we have an approved drug combination forBRAF-mutated ATC. It’s just incredible, and I never would have thought 5 to 10 years ago that we would be sitting here talking about an approved drug for ATC. It is great that we have a drug combination for BRAF mutated ATC but this is not curative. We need to find a cure for this disease. One way of doing that is in the patients whose cancer has not metastasized to other organs. In those patients, surgery after neoadjuvant BRAF/MEK inhibitor may be possible and may cure the patient. We need to be doing research in this field.