Managing Thyroid Adverse Events From Checkpoint Inhibitors

This transcript has been edited for clarity.

Kaniksha Desai, MD: Welcome to the Thyroid Stimulating Podcast. This podcast was created in partnership with the American Thyroid Association to discuss up-to-date diagnosis and management of a wide array of thyroid diseases.

For today's episode, we are focusing on a very specific, yet increasingly relevant topic: the thyroid immune-related adverse effects of immune checkpoint inhibitors, a groundbreaking class of drugs that have revolutionized cancer treatment but come with their own set of challenges.

We'll explore the mechanisms of action of immune checkpoint inhibitors, then delve into the common thyroid-related adverse effects these treatments can induce, and then discuss how these are diagnosed, managed, and monitored in clinical practice.

Joining us today is Dr Afreen Shariff, an associate professor of medicine at Duke University School of Medicine, with expertise in endocrine diseases in cancer patients.

Dr Shariff completed her internal medicine training at East Carolina University's Brody School of Medicine and fellowship in endocrinology from Duke University School of Medicine.

She is currently the director of the Duke Endo-Oncology Program and an associate director for the Cancer Therapy Toxicity Program at the Duke Center for Cancer Immunotherapy.

Her clinical work and research are focused on high-value care for managing endocrine diseases in cancer patients, for which she has received the 2023 Innovator Award from the Association of Community Cancer Centers and now serves on their board of trustees.

Additionally, she is the host of a medical podcast series, Checkpoint NOW, where she highlights shared decision-making between oncologists and subspecialists for management of checkpoint inhibitor toxicities. Thank you for joining us today.

Afreen Shariff, MD: Thank you for having me on the podcast today. It's such a delight to meet you and record this podcast.

Desai: I wanted to start by quickly reviewing checkpoint inhibitors, a brief background about them, and how they've changed the landscape of oncology.

Shariff: Absolutely. Now, 2011 really marked a pivotal moment in oncology with the approval of ipilimumab, the first US Food and Drug Administration (FDA)-approved immune checkpoint inhibitor for nondetectable metastatic melanoma.

Following suit, in 2014, pembrolizumab and nivolumab gained FDA approval for melanoma treatment. Since then, there has been a remarkable surge in FDA approvals exceeding 50-plus indications, with several more in the pipeline. Undoubtedly, this has revolutionized the approach of oncologists toward patient care.

Presently, checkpoint inhibitors are being integrated into combination chemotherapy regimens for adjuvant, neoadjuvant, and early-stage cancers, really reflecting a significant shift in treatment paradigms. In short, immune checkpoint inhibitors have really taken the market by storm and are here to stay.

Desai: Since they're here to stay, we've also noticed some significant side effects from these medications. This podcast focuses on thyroid, so I wanted to go over some of the common thyroid-related adverse effects associated with the use of these immune checkpoint inhibitors.

Shariff: The most common one that we encounter, seen in about 15% patients, is immune-related thyroiditis, which presents very similarly to traditional thyroiditis, except I call it the cousin of the same family because the presentation and the phenotypic description of patients is a little different from what we see in traditional practice.

What we end up seeing more commonly, in about 15% of patients, is thyroiditis, and less commonly, Graves disease, which is seen in less than 1% of patients.

Desai: Do you ever see hypothyroidism?

Shariff: We do. It's quite common, actually, to see patients with hypothyroidism. In fact, when we talk about thyroiditis, we're talking about a movement in the patient's thyroid from being thyrotoxic to what we call a hypothyroid state.

The way I explain this in very simple terms: The thyroid gland is a water balloon full of thyroid hormone. When these immune checkpoint inhibitors really hit the thyroid gland, that balloon breaks up into pieces.

What happens initially and very abruptly after this immune-mediated adverse event or adverse reaction occurs in the thyroid is that you have a big surge or a big release of preformed thyroid hormone, which results in thyrotoxicosis or a hyperthyroid phase in patients.

Most often, this phase converts into what we call a hypothyroid state. I say that very clearly as a phase and a state because, most often, this is the trajectory of how patients proceed from being hyperthyroid to hypothyroid.

Some patients can also present directly with hypothyroidism because we haven't had enough time or chance to review or look at their labs, and they transitioned very quickly from being hyperthyroid to hypothyroid.

Desai: Speaking of labs, is this the best way to monitor patients? Should they get labs frequently before they get started at the time of treatment, or how often should we get labs for these patients?

Shariff: Great question. The good news is that when patients are on active therapy, oncology guidelines actually recommend that patients get TFTs, or thyroid function tests, including a thyroid-stimulating hormone (TSH) and a free thyroxine (T4), and also a total T4 done every time they receive an infusion.

When patients are on immune checkpoint inhibitors, they can receive infusions every 3 weeks or 6 weeks, depending on the regimen, the dose, and the type of treatment or monotherapy vs combination.

The good news is they get labs done very frequently, and it's easier to detect these patients and catch them in which phase the patient is presenting.

Now, whether there is importance of getting TFTs pre-treatment, before the first treatment is done, I would — as an endocrinologist and anecdotally, based on the number of patients that I see with thyroid-related abnormalities — say there is certainly a place and a space for getting TFTs well before the patient's treatment is being planned.

Oftentimes, they get the labs done on the day of the first treatment. Patients who have preexisting autoimmune conditions of the thyroid gland or exposure to iodine previously can have abnormal TFTs prior to them being initiated.

Desai: Speaking of TFTs, do you also recommend getting antibodies at any time for these patients, prior to or during treatment or after diagnosis of thyroiditis? When would you recommend that?

Shariff: It would be great to have that information before patients start treatment. What we've learned with observational studies is that antibodies, especially antimicrosomal antibodies, are present in about 30%-40% of patients and are really not helpful in directing what kind of treatment or monitoring you would recommend for the patient.

For example, if a patient had abnormal TFTs or normal TFTs with a positive antimicrosomal antibody prior to starting treatment, you still wouldn't start the patient on any treatment. You would still monitor them.

These patients are getting their TFTs checked every 3-6 weeks anyway, so it really does not seem to change the way we would practice or make us do things differently.

As an educational opportunity, yes, it would be great to check antibodies prior to patients getting immune checkpoint inhibitors because it perhaps adds more value to who is at higher risk. Clinically, it really doesn't add up, as far as what it would do to change intervention.

Desai: I'm also assuming that family history doesn't make a huge difference if autoimmune conditions run in the family. Do you monitor more frequently or the same?

Shariff: You still monitor the same way. You would expect that these patients would develop immune-mediated thyroid disease or immune-related thyroiditis a bit sooner than, say, another patient who didn't have a family history.

For example, the median time to develop the thyrotoxic phase in patients is about 5 weeks, and to develop hypothyroidism in these patients is about 10 weeks.

If someone had a predisposing condition, other autoimmune conditions, or a family history of thyroid disease, those patients tend to develop thyroiditis sooner than the typical expected median time for development.

Desai: They develop symptoms sooner, but are they more likely to get these complications?

Shariff: The general sense is that we have observational studies to support that the patients who have preexisting conditions and autoimmune conditions have a higher risk of developing immune-related adverse events and even worsening immune-related adverse events.

For example, if someone already has thyroiditis and is on replacement thyroid hormone, the dose may require to be adjusted after they get exposed, telling us that, yes, there are some additional changes happening in progression of diseases despite them having preexisting conditions.

Desai: I know we've been talking about diagnosing and monitoring. As far as treatment goes, what would you recommend? I know it's slightly different from the thyroiditis vs the Graves hyperthyroidism. Can you talk about those?

Shariff: When we're talking about thyroiditis, let's first pick up the thyrotoxic phase. In the thyrotoxic phase, we generally recommend, based on National Comprehensive Cancer Network (NCCN) and American Society of Clinical Oncology (ASCO) Guidelines, to monitor these patients for clinical findings or clinical symptoms.

About one third of these patients are symptomatic. Two thirds of these patients are barely symptomatic despite having abnormal TFTs. When you see that one third or 30% of patients who also have abnormal labs and have symptoms, the most common symptom that you see is palpitations.

What you want to do when you encounter a patient during the thyrotoxic phase or when the patient is hyperthyroid is to monitor them for these symptoms and only treat them symptomatically.

For example, if the patient has a high heart rate, has palpitations, you want to treat them with a beta-blocker. If they have painful thyroiditis, you want to give them an NSAID.

Oftentimes, patients present with painless thyroiditis. I can count on my fingers the number of patients who've actually developed painful thyroiditis. Majority of cases always develop this as painless thyroiditis.

Once you've bridged that phase, which is a thyrotoxic phase, and the patients move into the hypothyroid phase, considering their age and cardiac status, you would want to move to thyroid hormone replacement. The dose can range anywhere between 1 and 1.6 µg/kg.

A study showed that patients who develop immune checkpoint related hypothyroidism require a slightly lower dose, up to 1.4 µg/kg, compared with patients who had surgically removed thyroid glands. That gives a range of what you would want to do with these patients.

Desai: For many other toxicities, you do gradations of severity, right? For thyroid, do we grade them as mild, moderate, or severe on a grading scale? Do you stop the immunotherapy or do we just treat through the thyroid side effects?

Shariff: Great question. There is a CTCAE [Common Terminology Criteria for Adverse Events] grading that oncologists follow. There is none within the thyroidology world or within the endocrinology world. This is a pretty standard thing that most oncologists follow and collect information on patients who develop adverse events.

They range from 1 to 5, where 1 is basic abnormalities in TFTs, 2 is mild symptoms with abnormal testing, 3 is clinical symptoms that require treatment, 4 is life-threatening, and 5 is death from an adverse event. This is standard across all toxicities that patients develop. They have a grading system that they monitor patients with.

The second question that you asked, regarding what we would do in terms of cancer treatment, we never recommend that patients stop their treatment. The way we envision this is that the thyroid gland is obliterated.

Even if you continue to give them immune checkpoint inhibitors, that thyroid gland is not salvageable. There's no reason to hold off on continued treatment with immune checkpoint inhibitors.

Is there a risk for patients to develop type 1 diabetes or other immune-related adverse events? Absolutely. That should not stop the oncologist from continuing to treat someone with a life-saving medication.

Desai: I wanted to transition a bit to patients. If patients get these side effects, how do they impact quality of life and well-being for these patients? Are there any studies on that?

Shariff: I think this is really important, especially from a patient perspective. I think it's an important aspect that really merits more attention.

Over the past decade, I've cared for numerous patients facing this issue. From my experience, managing checkpoint-related thyroiditis is relatively more straightforward than, say, type 1 diabetes or immune hypophysitis. That's, again, a clinician's perspective. Patients experience and sense things very differently.

During the visits and before patients come to see me, they often express a large amount of anxiety about their diagnosis, its implication for their cancer treatment, and overall well-being.

What I've found is that sitting down with them and addressing these specific concerns can greatly alleviate their worries. I often reassure them that this condition is quite common, easily treatable with thyroid replacement, and does not interfere with their ongoing cancer treatment.

I emphasize that our care will extend far beyond their cancer treatment period, providing ongoing support and management throughout this course. I think by outlining a clear management plan and addressing their questions and concerns, patients generally feel reassured about their current and future plans. This approach really helps them understand what the path forward is.

The only place that I really see or observe that patients have difficulty with quality of life is anecdotally; I've seen patients who receive ongoing treatment with checkpoint inhibitors require multiple dose adjustments for their thyroid replacement.

I often joke with my patients that, when I have to change their thyroid replacement dosing or levothyroxine multiple times, it doesn't mean I don't know what I'm doing; it's just the nature of what you have going on.

This need for adjustments really may stem from the ongoing impact of the checkpoint inhibition or the immune-mediated activation of the immune system on the thyroid gland, and it really takes some time for optimal dosage to be determined. These fluctuating thyroid labs can really impact the quality of life in these patients, amplifying symptoms typically seen in the general population.

Remember, you have to see these patients from a context of cancer treatment. They can have additive effects to their cancer treatment itself and other complications they may be going through.

They may have neuropathy in addition, they may have colitis in addition, they may be losing weight generally from their chemotherapy with immunotherapy treatments. You really have to take a whole-person approach when you're trying to understand the impact of the thyroid on their quality of life.

Desai: Speaking of that, are the thyroid-related side effects more common than some of the other side effects that you discussed, compared with type 1 diabetes, colitis, weight loss, or neuropathy? How do you compare thyroid vs nonthyroid side effects?

Shariff: When we look at the thyroid vs nonthyroid side effects, thyroiditis or thyroid-related toxicities really take one of the top three positions, depending on which trial you pick up.

It's followed closely by colitis with pneumonitis, and in some studies, hepatitis as well. Skin toxicities seem to be quite common. I would put thyroid toxicities among the top three contenders for the most common toxicities that are noted in these patients.

When a pharma company or the guidelines say you have to test someone's thyroid labs every 3 weeks, it tells you that thyroiditis is (1) very common and (2) something that you can treat easily and move on, and they want you to monitor it very closely.

Desai: What advice do you have for healthcare professionals who are treating patients with these kind of medications?

Shariff: I think the advice is different for oncologists and endocrinologists. When it is an oncologist treating these patients, certainly my common advice is to make sure you are interpreting fatigue in the context of thyroid labs and other labs, especially within the endocrine system.

It's important to not ignore symptoms, especially when patients have abnormal thyroid labs. It's also important to test them frequently, which they already tend to do, but also to test them post-treatment.

What often happens in the oncology world is that when patients are on active therapy, they get labs done every 3-6 weeks. Once the treatment is complete and they're in the surveillance phase, the immune system continues to be ramped up and it can still cause thyroid toxicities beyond the ending of the cancer treatment or beyond the last infusion.

What I often see is that patients get dropped in regard to monitoring their TFTs after treatment completion. That's the perspective for oncologists.

For endocrinologists, the common advice I give is to make sure you are interpreting the thyrotoxic phase correctly. If there is a doubt that the patient has the more rare thyroid abnormality, which is Graves disease, make sure you're confirming that before you put patients on methimazole.

That's a common thing I'll encounter, a case or two every month or other month, regarding a patient who truly has thyroiditis but presented with a completely suppressed TSH and a very high free T4.

It scared the clinician who was taking care of the patient because they're concerned about Graves disease, and they put the patient on methimazole without confirming that the patient had Graves disease. They should be getting thyrotropin receptor antibodies and thyroid-stimulating immunoglobulins to confirm this before they put patients on methimazole.

If they still have a clinical suspicion for Graves disease despite negative antibodies, they should consider doing an uptake scan, obviously taking into consideration when the patient received their last iodinated contrast, which is hard to find in the oncology patient population because they get so many imaging studies done and fairly frequently. Be careful when you're putting patients on methimazole. Be sure that you're treating the right disease.

What happens if someone with thyroiditis gets on methimazole is that, when they transition to being hypothyroid — which they will no matter what you do — it's hard to figure out whether it is the methimazole that's causing it or whether it's because the patient just transitioned to being hypothyroid. You have to stop methimazole for a couple of weeks to figure out where that trends out.

To avoid this diagnostic and treatment dilemma, it's always wise to get the antibody testing or the confirmatory testing for Graves disease before considering methimazole.

Desai: Thank you for providing both perspectives, the oncology perspective and the endocrinology perspective. Do you recommend that all of these patients, if they have confirmed abnormal TFTs, come see endocrinology, or is this something that oncology can manage and only few patients have to come see endocrinology?

Shariff: I think that's a great question. Ten years ago when I started doing this, I was seeing every patient with an abnormal TFT. It almost became like the troponins for cardiologists, right?

Now, as oncologists have become more and more comfortable managing thyroid disease and putting patients on levothyroxine, the common things that need an endocrinologist's weigh-in, or the common referrals that I now tend to get, are the ones where the oncologist requires frequent dose adjustment, which is what I was talking to you about earlier.

It's more anecdotal, where I tend to see patients requiring frequent dose adjustments. Those are the kind of patients that end up coming to endocrinology and should come to endocrinology.

The other ones are patients who have, say, colitis or any other thing that's going on that affects their absorption, and it requires more fine-tuning and a more refined approach to managing hypothyroidism or thyrotoxicosis in these patients. Those patients should come see us.

Patients who have persistent thyrotoxicosis or hyperthyroidism beyond the 6- to 8-week mark should see an endocrinologist exactly for the reason that I've told you, which is to identify whether this is Graves disease vs thyroiditis and the thyrotoxic phase that is just more extensive.

Even though the median time is about 5 weeks for resolution, it can range sometimes up to 20 weeks. You really want to make sure that you're treating the right animal when it comes to thyroid toxicity.

Desai: Speaking of that, because these medications have now been out for over a decade and we've seen some of the side effects — and oncologists and endocrinologists are much more comfortable managing them — where would you say future research is headed for these side effects related to the thyroid? Is there any more research being done, and what studies can be done to help us manage this?

Shariff: I think that's a great question. If you ask me, there are certainly many studies that need to be done in this space. We want to identify who's at risk or whether we can change the course of this disease.

If you ask me as a human being if I want to avoid taking a medication for the rest of my life, I'd say, "Absolutely." That's the way patients feel. Even though it seems like not much to do, taking a pill first thing in the morning every single day, if you had to take it for the rest of your life, it can certainly catch up with you.

There is much to be desired regarding understanding what thyroiditis is, what the pathophysiology is, and why is it so different from traditional thyroiditis, which can take weeks to months to move from hyper- to hypothyroidism. These patients move very quickly. Is there something we can do to intervene?

There was one study that was published in Science by Dr Lechner and her team from UCLA in mid-2023 that really sheds light on the mechanistic pathways or the mechanistic basis of this.

The study really compared phenotypes of thyroid-infiltrative cells from individuals with checkpoint-induced thyroid disease, patients with regular Hashimoto disease, and individuals with normal thyroid glands.

In their findings, checkpoint-induced thyroiditis was really characterized by IL-21–producing T-follicular helper cells and T-peripheral helper cells as well. That was the one that was found to drive the expansion and cytotoxic activity of thyroid-infiltrating effector CD8+ T cells.

Similar populations of cells were observed in a mouse model for immune checkpoint inhibitor–induced thyroiditis, suggesting that there is a translational relevance. Perhaps there's a relevance of this even in general thyroiditis. We don't know yet.

I think further studies are warranted to validate these findings and establish the efficacy of any therapeutic intervention that is developed around this.

Desai: Thank you. This has been very educational. Could you provide three main points for our listeners to take away about the thyroid-related side effects of these medications?

Shariff: Absolutely. Keep a low threshold for identifying and treating patients, when the patient is in the thyrotoxic phase. Sometimes doing less is more.

Often, we're causing more harm to patients when we try to fix things with methimazole. Watching that course sometimes is more important than actually jumping in and doing something.

For folks interested in endo-oncology or onco-endocrinology, which focuses on endocrine disease and cancer, I would suggest, as an endocrinologist, to reach out to your oncology colleagues and identify their needs, to understand how you can help them in these cases, because they need some help and we're there to help. It's really nice to have a very collaborative, multidisciplinary approach to managing these conditions.

Desai: Thank you. Thank you for joining us today on this podcast.

Shariff: It was my pleasure to be here. Thank you so much for inviting me.

Cite this: Managing Thyroid Adverse Events From Checkpoint Inhibitors - Medscape - May 07, 2024.