What APs Need to Know: RET-Mutated Thyroid Cancers

Megan May

Hi, Carolyn. Thanks for joining me today to discuss RET-mutated thyroid cancers. This is really an exciting time for this subset of thyroid cancers since we now have two RET inhibitors that we can use in this setting, selpercatinib and pralsetinib. Selpercatinib is approved in metastatic or advanced medullary thyroid cancer with a RET mutation,¹ and both of these RET inhibitors are approved for metastatic or advanced thyroid cancer with RET gene fusion if the patient is refractory to radioactive iodine.^1,2 More recently, selpercatinib also received a second accelerated approval for adult patients with locally advanced or metastatic solid tumors with a RET gene fusion who have progressed on or following prior systemic therapy.³ Now that we have these great options available, can you start by telling us specifically more about RET mutations that are within thyroid cancer?

Carolyn Grande

Sure, Megan. In 2023, there are estimated to be nearly 44,000 cases of thyroid cancer diagnosed,⁴ and of those patients diagnosed with thyroid cancer, we have data from 2011 to 2015 that breaks that down into its subgroups. You can think about subgroups in terms of differentiated thyroid cancer, undifferentiated thyroid cancer, and medullary thyroid cancer. The data shows us that 89.8% of thyroid cancer diagnoses that are differentiated are of the papillary thyroid cancer type, while 4.5% are follicular thyroid cancer, 1.8% are oncocytic, 0.8% are the undifferentiated aggressive type of thyroid cancer known as anaplastic thyroid cancer, and 1.6% are medullary thyroid cancer.⁵

Medullary thyroid cancer is a little bit different than the differentiated thyroid cancer in that it arises from neuroendocrine parafollicular C cells of the thyroid. There are two subtypes of medullary thyroid cancer: sporadic, which accounts for about 80% of medullary thyroid cancer, and inherited tumor syndrome, which accounts for about 20% of medullary thyroid cancer.³ In papillary thyroid cancer, less than 10% have a RET fusion. In medullary thyroid cancer, RET-point mutations are found in greater than 60% of those with sporadic medullary thyroid cancer and 98% in those with germline medullary thyroid cancer.^6,7

Megan May

Thanks for going over all of that. I know it can get really confusing with all of the different types of thyroid cancers, especially since we treat each of them a little bit differently. What I'm going to talk about next is selpercatinib. It got its first FDA approval from the LIBRETTO-001 trial,⁸ and then more recently the confirmatory phase III study, the LIBRETTO-531 trial. This trial evaluated selpercatinib in the first-line setting for patients with metastatic RET-mutated medullary thyroid cancer. It compared selpercatinib to cabozantinib or vandetanib. So far we have the interim analysis, which showed that the study did meet the criteria for positive progression-free survival. At the 12-month follow-up, the median progression-free survival in the selpercatinib arm was not reached, and the median progression-free survival in the control arm was 16.8 months.⁹

Another thing we need to think about with these cancers are brain metastasis, and if these agents play a role in managing that. The study showed that patients with measurable baseline brain metastasis who got selpercatinib had an intracranial response rate of 82.4% compared to 58.3% for the patients who received cabozantinib or vandetanib.⁸ Since there is central nervous system activity with selpercatinib, patients might be spared now from having to get whole-brain radiation.

The other trial I wanted to mention is the ARROW study, a phase I/II trial that evaluated pralsetinib for the treatment of advanced or metastatic RET-mutated thyroid cancer. These results were divided based on whether the patient had received previous treatment or not, and also if patients had thyroid cancer of any type versus medullary thyroid cancer. For the patients who were previously treated for medullary thyroid cancer, the overall response rate was 52%. In the treatment-naive patients with medullary thyroid cancer, the overall response rate was 72%. And then in general, for patients with thyroid cancer who had previously received treatment, the overall response rate was 86%.¹⁰

One thing everyone should be aware of is, initially, in December of 2020 pralsetinib had an accelerated approval in RET-mutated medullary thyroid cancer. However, the manufacturer voluntarily withdrew that in June of this year, and they did that because the confirmatory phase III ACCELERATE MCT trial was not pursued due to the feasibility of the trial.¹¹

Looking at safety between these two, the trials showed that they had similar side effects. There was more dry mouth, fatigue, nausea, QT prolongation, and edema with selpercatinib,¹² whereas pralsetinib had more hematologic toxicities associated with it.¹³ Carolyn, using all of this information that we know about these two agents, how do you decide which treatment to use and when?

Carolyn Grande

That's a great question, Megan, and it's something that we face every day in our clinics. I would break down the clinical considerations for selecting optimal therapy into three buckets. One bucket contains patient-specific considerations like what prior therapies they had, what their comorbidities are, and what their current performance status is. The second bucket contains treatment-specific considerations. Clearly biomarker assessment needs to be done and toxicity profile needs to be considered, especially as it relates to the comorbidities and the performance status of the patient. The third bucket contains quality of life considerations, including insurance coverage and the complexity of a regimen. The complexity of the regimen can influence the adherence of patients to their regimens. Patients need access to these drugs in settings that are aware of the drugs and have done biomarker testing. Patients need caregiver support, which is critical. We educate our patients about so much from the time of their diagnosis, and oftentimes it's overload, so having that extra set of ears of another person who's consistently involved in their care can help mitigate any problems moving through treatment. We also consider the patient's lifestyle and how that may influence treatment selection based on potential side effects.

Megan May

That's great. One other thing I wanted to point out is the major role that I play with these patients is evaluating financial toxicity with the medications. Since they're both oral agents, part of my job is to make sure we get insurance approval and that it's affordable for patients. In my practice I've seen that information help the patient make a decision as to which agent we're going to use.

There are just a few other side effects I wanted to mention and how we manage them. Both of these drugs also block anti–vascular endothelial growth factor, so we see impaired wound healing. One thing that's important is to make sure patients know up front that they need to let us know if they have any elective surgeries coming up, because we have to hold these agents before and after any major surgery to allow for wound healing.

The RET inhibitors are also known to cause hypertension, which is related to the ERK activation and CD47 upregulation. When a patient presents with high blood pressure at a clinic, we make sure to rule out any other issues the patient might be having to help determine if it is from the RET inhibitors. At my clinic, we start antihypertensive treatment if the patient's blood pressure is over 140/90. If the patient has cardiovascular disease risk, then we'll start treatment at 130/80. We usually start with amlodipine at a low dose and titrate up. I remind all my providers to be really careful when prescribing these antihypertensive agents because there are several drug-drug interactions with the RET inhibitors. Carolyn, do you have any tips for how you educate patients on monitoring for hypertension?

Carolyn Grande

Yes, Megan, I do. First and foremost, if a patient has a baseline history of hypertension, we need to ascertain that they are well-controlled before initiating therapy with one of these drugs. Then I educate patients on how to monitor their blood pressure: once daily, at the same time of the day and in the same arm. I ask them to get a notebook to journal the readings. I also provide them with the blood pressure parameters that would require a call to call the office.

Additionally, it's important that these patients come into the office. My practice has been that when a patient is initiated on an oral TKI or SMI, they come in two weeks after initiating treatment for an evaluation, lab work, and an exam. I always ask them to bring in their journal as well, for not only the blood pressure recordings, but also any other symptoms that they may have experienced during that time. It's a good way for them to keep track of things. We have patients come in at least every 2 weeks for the first month. When we go back and think about those patient-specific considerations that helped influence our treatment choice, we determine whether they can then come in monthly. Other things that may factor into that are lab abnormalities, which may require them to come in more frequently or to get additional lab work and have it sent into us before their next appointment.

Megan May

We practice similarly as well with bringing the patient in at those time periods. One other thing we do at my clinic is the oncology pharmacist calls 7 days after the patient starts the medication to confirm adherence and ask about any toxicities that are occurring. I mentioned earlier that pralsetinib has higher hematologic issues compared to selpercatinib, and I have seen in our patients that they can get very anemic while getting treatment with pralsetinib.

Carolyn Grande

I think that's important, Megan, especially in terms of getting baseline labs, including baseline CBC with differential, liver function tests, comprehensive metabolic panel including magnesium and phosphate, TSH, and thyroid function studies.

The prescribing information, for both pralsetinib and selpercatinib, is a great reference that provides recommendations on frequency for specific labs that should be checked with these patients once they initiate therapy. Clearly, labs can be done more frequently depending on the grading of abnormalities and their impact on treatment decisions. 

Megan May

Thanks for laying out more of the monitoring parameters when you're using these RET inhibitors. It's always important to remember what labs to do and when they need to be done. At my institution, we build the labs into our treatment plans in the electronic medical record to serve as a reminder to everyone of what labs to order and when to order them.

Carolyn Grande

Wow, that's helpful.

Megan May

Yes, it's been very beneficial for everyone. Thanks for joining me today. This was a great conversation and a great reminder of the new RET inhibitors we have to help manage thyroid cancer.

Carolyn Grande

It's been great talking with you, Megan.