Immunotherapy Endocrine Side Effects

Checkpoint inhibitors work by releasing brakes on the immune system. When that release affects a hormone-producing gland, the result is an endocrinopathy — a gland that stops working properly, or briefly works too hard.

The FDA label for pembrolizumab (Keytruda) groups these under one heading. It calls them immune-mediated endocrinopathies. It then reports how often each occurred in a safety group of 2,799 patients. Those figures set expectations well, because they come from a defined denominator.

Two thyroid problems dominate the list, and they are not equally likely.

Hypothyroidism, an underactive thyroid, occurred in 8% of patients, or 237 of 2,799. Most cases were mild to moderate. Grade 2 accounted for 6.2%, and grade 3 for 0.1%. The label states that most patients with hypothyroidism needed long-term thyroid hormone replacement.

Hyperthyroidism, an overactive thyroid, occurred in 3.4%, or 96 of 2,799, with grade 2 at 0.8% and grade 3 at 0.1%.

Thyroiditis, meaning inflammation of the gland, occurred in 0.6%, or 16 of 2,799. The label notes thyroiditis can appear with or without a hormone problem. It also says an underactive thyroid can follow an overactive one.

That last sentence explains a confusing sequence some people experience. A period of feeling hot, shaky, and fast-hearted can be followed weeks later by the opposite.

This is the detail most summaries miss, and the label is explicit about it.

New or worsening hypothyroidism ran higher in specific groups. Among 1,185 patients with head and neck squamous cell carcinoma, it occurred in 16%. Among 389 patients with classical Hodgkin lymphoma, it occurred in 17%. Among 580 patients with resected non-small cell lung cancer on adjuvant treatment, it occurred in 22%.

Hyperthyroidism followed the same pattern in that lung cancer group, occurring in 11% rather than the overall 3.4%.

So a general figure of 8% is not the right expectation for everyone. Asking for the rate in the specific setting is a fair question.

Thyroid problems are common and usually manageable. Two rarer ones carry more urgency.

Adrenal insufficiency occurred in 0.8% of patients, or 22 of 2,799, with grade 3 at 0.3% and grade 4 in under 0.1%. The label says systemic corticosteroids were required in 77% of those cases, 17 of 22, and that the majority remained on them.

Hypophysitis, inflammation of the pituitary gland, occurred in 0.6%, or 17 of 2,799, again with grade 3 at 0.3%. Systemic corticosteroids were required in 94% of those cases, 16 of 17.

The label describes how hypophysitis announces itself. That description is worth knowing in advance. It can bring sudden symptoms from mass effect. Those include headache, photophobia, meaning light hurting the eyes, and visual field defects. It can also cause hypopituitarism. That means the pituitary underproduces several hormones at once.

Because the pituitary directs other glands, a pituitary problem can produce adrenal failure downstream. That is why headache with vision changes during checkpoint inhibitor treatment is not treated as an ordinary headache.

Type 1 diabetes mellitus occurred in 0.2% of patients, or 6 of 2,799.

Two facts make that small number matter more than it looks. The label heading names how it can arrive: type 1 diabetes mellitus, which can present with diabetic ketoacidosis. And it states that all patients who developed it required long-term insulin therapy.

The label's monitoring instruction is short. Monitor patients for hyperglycemia, meaning high blood sugar, or other signs and symptoms of diabetes. Start insulin as clinically indicated.

This is the reassuring part of the label, and it is stated repeatedly.

Adrenal insufficiency led to permanent discontinuation in under 0.1% of patients, and to treatment being withheld in 0.3%. Every patient whose treatment was withheld restarted after symptoms improved.

The same sentence appears for hypophysitis, hyperthyroidism, hypothyroidism, and type 1 diabetes. In each case, all patients who had treatment withheld reinitiated it after symptom improvement.

So an endocrine side effect usually means a pause and a hormone prescription, not the end of immunotherapy.

The management steps are brief and specific, which makes them easy to ask about.

For grade 2 or higher adrenal insufficiency, start treatment for the symptoms. That includes hormone replacement as clinically indicated. And withhold the drug depending on severity.

For hypophysitis, start hormone replacement as indicated. Then withhold or permanently stop the drug, depending on severity.

For thyroid disorders, start hormone replacement for an underactive gland. For an overactive one, manage it medically. Either way, withhold or stop the drug depending on severity.

Two of these are lifelong in most cases. The label says the majority with hypothyroidism needed long-term thyroid replacement, and all with type 1 diabetes needed long-term insulin.

There is no temperature, blood sugar reading, or symptom duration in this label that triggers a call. The instructions are written for clinicians and say "monitor," "initiate," and "withhold ... depending on severity."

That absence is worth naming rather than filling in. The numbers that decide when to call come from the discharge or start-of-treatment instructions for the specific regimen, and they are worth asking for in writing before the first dose.

What the label does supply is the monitoring frame. It directs monitoring for hyperglycemia and other signs of diabetes, and management of thyroid, adrenal, and pituitary problems by severity grade. Grades are assigned by a clinician from labs and symptoms, not self-assessed.

Endocrine symptoms are famously vague, which is why the label leans on blood tests. But some patterns point somewhere.

• Cold intolerance, weight gain, slowed thinking, and deep fatigue fit an underactive thyroid.
• Heat intolerance, weight loss, tremor, and a racing heart fit an overactive one.
• Headache, light sensitivity, and changes in the visual field fit hypophysitis.
• Increased thirst and urination fit high blood sugar.

Dizziness and profound fatigue can belong to several of these. That overlap is the reason blood tests, not symptom lists, settle the question.

• Call 911 or go to an emergency department if you have signs of an adrenal crisis: severe weakness with dizziness or fainting, belly or flank pain, vomiting, a racing heart, confusion, or a high fever. MedlinePlus says to call 911 or go to the emergency room for symptoms of acute adrenal crisis. This is the reason a low adrenal result is treated urgently rather than at the next visit.
• Call 911 or go to an emergency department if you have signs of diabetic ketoacidosis: deep or labored breathing, breath that smells fruity, repeated vomiting, or reduced alertness. MedlinePlus lists decreased consciousness, fruity breath, nausea with vomiting, and trouble breathing as reasons to call 911 in someone with diabetes.
• Call your care team the same day if a new or unusual headache arrives with light hurting your eyes or with gaps in your side vision. That combination points at the pituitary rather than an ordinary headache, and it is not something to sleep on.
• Call your care team the same day if thirst and urination climb sharply over a day or so, which is how high blood sugar tends to announce itself.
• Call your care team within a day or two if you notice the slower thyroid patterns: creeping cold intolerance, weight gain, foggy thinking, or fatigue that rest does not touch. Do the same for the opposite set — heat intolerance, weight loss, tremor, or a heart that keeps racing. Blood tests, not the symptom list, will settle which gland is involved.

The broader family of these reactions is covered in immune-related side effects. Two other organ-specific versions are covered elsewhere. One is immunotherapy colitis. The other is immunotherapy pneumonitis.

• DailyMed: Keytruda label
• MedlinePlus: Acute adrenal crisis
• MedlinePlus: Diabetic ketoacidosis