Identifying and Managing Adverse Effects and Drug-Drug Interactions in Patients With RET-mutated Thyroid Cancers

Juna Jovani

Hi Alex. I’d like to talk about RET-mutated thyroid cancers and some of the modalities that have enabled more selective inhibition of RET mutations in this space.

Alex Robinweiler

As a PA, I see all the amazing work that our pharmacists do here. I know part of the picture, which is a patient presents with symptoms, gets biopsied and next-generation sequencing, a mutation is found, there’s a discussion with an oncologist, and then a prescription is written. We hand off that prescription to our pharmacy team to work it up. Can you share what you do at that point, what you think, what your process is? If there's something I can do to help my pharmacist here, that would be great.

Juna Jovani

Great questions! As a pharmacist, we look at all of the clinical data that the providers have completed through the patient history. We also make sure that the patient has a medication reconciliation completed, because a lot of these drugs, especially the RET-mutated drugs, consist of oral medications. It’s up to the pharmacist to provide essential education for the patient regarding side effects, and to deal with adherence and cost issues as well. When we work up a patient, we look at everything that you look at and more. We make sure there are no direct interactions that can be conflicting with some of these oral medications. We also look at the patient's performance status to determine if they're capable, agile, or coordinated enough to take these medications and be able to perform their activities of daily living, because adherence in some of these drugs is essential.

We make sure that we are also looking at corresponding labs to determine if any dose modifications or dose reductions need to be made. We perform a comprehensive clinical review for all of these drugs prior to them being dispensed to the patient. And we also do a consultation with the patient to go over things like if the drug needs to be taken with food or on an empty stomach, and why it's important to keep taking the medication until the provider tells you to stop or an unacceptable toxicity level has been reached. That's a high-level perspective on these medications, especially with certain oral medications.

Alex Robinweiler

Thank you, that's helpful. Of course, non-pharmacists have less understanding of the drug-drug potentials than pharmacists do. Are there any common medications that I should be more careful with, or make sure to remind myself, "Hey, this person's on warfarin, or a certain type of blood thinner, statin medication, or other medication and supplement that might need to be accounted for with respect to liver or kidney toxicity?” Is there anything in particular that I should be mindful of when we prescribe pralsetinib and selpercatinib, the two most common RET inhibitors available?

Juna Jovani

Yes. For example, selpercatinib is approved to treat RET+ medullary thyroid cancers as well as RET+ fusion non-small cell lung cancer, and in some cases any cancer that's driven by RET fusion. This medication needs to be taken at a separate time from any locally given antacids, such as a proton pump inhibitor or any H2 receptor antagonists (or H2RA), as it affects the mechanics of absorption. For instance, selpercatinib needs to be taken 2 hours before or 10 hours after an H2RA, or 2 hours before a locally acting antacid. Some patients also suffer from other comorbidities such as GERD when taking selpercatinib with a proton pump inhibitor, so you want to make sure that a patient administers it with food.

Alex Robinweiler

That’s very helpful. What else should non-pharmacist APPs know?

Juna Jovani

There are also some cytochrome P450 system interactions. Both pralsetinib and selpercatinib are predominantly metabolized via CYP3A4, with pralsetinib also showing metabolism activity via CYP1A2 and CYP2D6. A CYP interaction can lead to toxicities, as it can increase or decrease the efficacy of the drugs depending on if it's an inducer or an inhibitor. So, you want to stay away from any strong CYP inhibitors with these medications. And some of these medications can also cause QTc prolongation. Since we’re in the cancer space, we want to make sure that they're not co-administered, especially with the antiemetics, which can cause potential further potentiation of QTc prolongation.

Alex Robinweiler

Good points. Do you want to talk about some of the more common adverse effects related to these medications that you and I would likely need to counsel patients on? And depending on the grade of these side effects, what would be recommended regarding dose reduction and/or discontinuation?

Juna Jovani

I’d love to talk about that. With some of these drugs, several side effects are specific to the drug. Then we also have a class effect of the drug that could potentially cause adverse events or toxicities to the patient. For example, for pralsetinib, some of the most common adverse reactions are hypertension, constipation, and/or diarrhea. Selpercatinib can induce similar gastrointestinal toxicities, such as constipation and/or diarrhea, along with dry mouth, edema, and fatigue. And we want to make sure that these patients, especially the elderly, are well hydrated and that we're monitoring their electrolytes and treating them accordingly. For some of these patients, especially those who have a prior history of bowel issues, we want to make sure that we're prescribing the proper bowel regimen and have antidiarrheals on board as an effective measurement.

For more of a class effect, while selpercatinib and pralsetinib are highly selective toward RET alterations, they can also inhibit the VEGF 1-3 signaling pathway. Therefore, as a class effect, they can cause impaired wound healing. This means we need to let these patients know that if they are having a surgical procedure, their medication may need to be stopped 5-7 days prior due to that risk. We want to also monitor the patient’s thyroid function. These drugs may cause high LFTs, so we want to make sure that we're baseline testing. The care team will obtain a CBC w/diff and CMP for these patients prior to the start and during continuation of treatment.

Alex Robinweiler

If you were to discontinue one of the drugs and it still has the same indication, could you conceivably trial a patient on the other available RET inhibitor?

Juna Jovani

Yes, they may be interchangeable. If the patient experiences excessive side effects with one of the drugs, they may be able to take the other one and not be subjected to the same side effects.

Alex Robinweiler

I understand that hypertension is a fairly common side effect and it’s certainly something that I've seen in my patients. Typically, our practice treats through it while also treating the hypertension. Is there any guidance on this and does the guidance depend on what grade the hypertension is? Should we consider changing or stopping the drug, and as a pharmacist would you prefer to help make that decision or would you defer to provider discretion?

Juna Jovani

As long as the hypertension at baseline is well controlled, there is no reason to not give these medications. However, if a patient develops hypertension and it's not manageable while on treatment, then discontinuation of treatment may be warranted. From a pharmacist perspective, we leave those decisions mostly to the discretion of the provider and patient. We may look for alternatives that could potentially work for the patient. And sometimes you may need an additional referral to cardiology for further workup. Perhaps the hypertension was caused by the medication or maybe there were underlying issues that we weren't aware of to begin with. A proper patient workup is essential. For a lot of medications or a lot of comorbidities, if they're well controlled, we continue on the regimen with appropriate supportive care.

Alex Robinweiler

Thank you for reinforcing my current beliefs and practice.

Juna Jovani

As a provider, what are some of the baseline tests that are needed prior to starting these medications?

Alex Robinweiler

I often end up deferring to the package inserts, but I also look to recommendations from ASCO and other various oncologic organizations. We always do a hepatitis B screen, as well as baseline metabolic labs and blood counts. Given the potential of effects on blood pressure, we want to make sure that the patient’s blood pressure is generally well controlled. With the potential of these drugs causing thyroid dysfunction that would need to be monitored and potentially treated, guidance suggests baseline thyroid studies for selpercatinib.¹ Interestingly, guidance doesn’t call for the same with pralsetinib, but it's likely that if the patient is being treated for thyroid cancer, that would be monitored regardless.  Noting the potential for QTc changes, we may defer to the pharmacy team for guidance. However, if we’re dealing with a patient who's young, doesn't have any cardiac history, and is otherwise healthy, we may not do QTc monitoring or even baseline testing.

If a patient is already on medications that are likely to cause side effects, we’ll often look at appropriate testing and monitor them more closely. A lot of it depends on their risk factors, their other medications, and of course, pharmacy input.

Juna Jovani

That makes sense. Thanks so much for talking with me today. I really appreciated being able to give the pharmacist’s perspective.

Alex Robinweiler

And thanks back to you, Juna. I’m excited to take this information back to my practice.