Can Keytruda (pembrolizumab) cause hypopituitarism?

From the Guidelines

Keytruda (pembrolizumab) is associated with a risk of hypopituitarism, although the exact incidence is not well-defined in the provided studies, which primarily focus on ipilimumab and combination therapies 1.

Clinical Presentation and Diagnosis

Hypopituitarism related to immune checkpoint inhibitors like Keytruda can present with symptoms such as fatigue, weakness, low blood pressure, nausea, headache, and hormonal deficiencies. Diagnosis requires a high index of suspicion, particularly in patients undergoing treatment with immune checkpoint inhibitors. Blood tests to evaluate pituitary hormone levels, including thyroid function tests (TSH, free T4), adrenal function tests (ACTH, cortisol or 1 mcg cosyntropin stimulation test), and gonadal hormones, are essential for diagnosis 1. MRI of the sella with pituitary cuts can also aid in diagnosis by showing pituitary enlargement or other abnormalities.

Management

Management of hypopituitarism includes replacement of deficient hormones, with strict attention to the order of replacement to avoid adrenal crisis, particularly starting with physiologic doses of steroids before initiating thyroid hormone replacement 1.

• Hormone replacement therapy may include corticosteroids, thyroid hormone, sex hormones, and sometimes growth hormone, depending on the hormonal axes affected.
• Severe cases may necessitate temporary discontinuation of Keytruda and the use of high-dose corticosteroids.
• Patients on Keytruda should be regularly monitored for endocrine abnormalities through symptom assessment and hormone level testing to facilitate early detection and treatment of hypopituitarism, thereby preventing serious complications.

Prognosis and Follow-Up

Pituitary dysfunction due to immune checkpoint inhibitors is often not reversible, and prolonged physiological replacement therapy may be required 1. Therefore, it is crucial to instruct patients, especially those with adrenal insufficiency, to obtain and carry a medical alert bracelet and to be aware of the signs of adrenal crisis and other endocrine emergencies. Regular follow-up with both oncology and endocrinology specialists is recommended to manage the condition effectively and adjust hormone replacement therapy as needed.

From the FDA Drug Label

KEYTRUDA can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism. Hypophysitis occurred in 0.6% (17/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (0. 2%) adverse reactions.

Hypopituitarism caused by KEYTRUDA is a result of immune-mediated hypophysitis. The symptoms of hypophysitis can include headache, photophobia, or visual field defects, and it can lead to hypopituitarism.

• Incidence: Hypophysitis occurred in 0.6% of patients receiving KEYTRUDA.
• Severity: Including Grade 4, Grade 3, and Grade 2 adverse reactions.
• Management: Initiate hormone replacement as indicated, and withhold or permanently discontinue KEYTRUDA depending on severity 2.

From the Research

Keytruda and Hypopituitarism

• Keytruda, also known as pembrolizumab, is an immune checkpoint inhibitor that can cause immune-related adverse events, including hypopituitarism 3, 4, 5.
• Hypopituitarism is a condition where the pituitary gland does not produce one or more of its hormones, which can lead to a range of symptoms, including fatigue, weakness, and hormonal imbalances.
• Studies have shown that pembrolizumab can cause hypopituitarism, as well as other endocrinopathies, such as hypothyroidism 3, 4, 5.
• In one case report, a patient developed hypopituitarism and hypothyroidism after treatment with pembrolizumab for non-small-cell lung cancer 3.
• Another study reported a case of a patient who developed hypothyroidism and hypopituitarism after receiving lenvatinib plus pembrolizumab therapy for gastric cancer 5.
• The exact mechanism of how pembrolizumab causes hypopituitarism is not fully understood, but it is thought to be related to the drug's immune checkpoint inhibiting effects, which can lead to an autoimmune response against the pituitary gland 4.

Diagnosis and Treatment

• Diagnosis of hypopituitarism caused by Keytruda typically involves laboratory tests to measure hormone levels, as well as imaging studies to rule out other causes of pituitary dysfunction 3, 5.
• Treatment of hypopituitarism caused by Keytruda usually involves replacement therapy with hormones, such as hydrocortisone and levothyroxine 3, 5, 6.
• In some cases, treatment with Keytruda may need to be discontinued or modified to manage the hypopituitarism 4, 5.
• Monitoring of thyroid and pituitary function is important in patients receiving Keytruda, as hypopituitarism can occur at any time during treatment 3, 4, 5.