What is the treatment for Keytruda (pembrolizumab)-induced hypothyroidism?

Treatment of Pembrolizumab (Keytruda)-Induced Hypothyroidism

For Keytruda-induced hypothyroidism, thyroid hormone replacement with levothyroxine is the standard treatment, and patients can generally continue immunotherapy while managing this side effect. 1

Diagnosis and Evaluation

Before initiating treatment, confirm the diagnosis with appropriate testing:

• Check TSH and Free T4 levels
  • Primary hypothyroidism: Elevated TSH with low Free T4
  • Central hypothyroidism: Low/normal TSH with low Free T4 (evaluate for hypophysitis)
• Consider thyroid antibody testing, though only ~30% of patients with pembrolizumab-induced hypothyroidism have positive antibodies 2
• Monitor for diffuse increased uptake on FDG-PET, which is present in 64% of cases and suggests inflammatory thyroiditis 1, 2

Clinical Course of Pembrolizumab-Induced Thyroid Dysfunction

Pembrolizumab-induced hypothyroidism typically follows one of two patterns:

1. Thyroiditis with biphasic pattern (most common):

   • Initial transient thyrotoxicosis phase (often subclinical)
   • Followed by permanent hypothyroidism
   • Occurs early in treatment course (median 42 days after starting pembrolizumab) 3

2. Direct hypothyroidism:

   • Development of hypothyroidism without preceding thyrotoxicosis

Treatment Algorithm

1. For Subclinical Hypothyroidism (TSH >10 with normal FT4)

• Initiate levothyroxine even if asymptomatic 1
• Starting dose: 0.5-1.5 μg/kg/day based on ideal body weight 4
• Lower starting dose (25-50 mcg/day) for elderly or those with cardiac conditions 4, 5

2. For Overt Hypothyroidism (Low FT4 with elevated TSH)

• Initiate levothyroxine replacement therapy 1
• Dosing as above, adjusted for age and comorbidities
• Target TSH range: 0.5-2.0 mIU/L for most patients 4
• For elderly patients: Consider a slightly higher target TSH (1.0-4.0 mIU/L) 4

3. Monitoring and Dose Adjustments

• Check TSH and Free T4 after 6-8 weeks of treatment 4
• Adjust dose in increments of 12.5-25 mcg based on TSH results 4
• Continue pembrolizumab therapy while managing hypothyroidism 1
• Monitor thyroid function before every pembrolizumab infusion for first 3 months, then every second cycle thereafter 1

Special Considerations

• Transient thyrotoxicosis phase: If present, manage with beta-blockers (propranolol or atenolol) for symptomatic relief 1
• Painful thyroiditis: Consider prednisolone 0.5 mg/kg with taper 1
• Severe symptoms: Temporarily withhold pembrolizumab until symptoms are controlled 1
• Diabetes: Monitor glycemic control closely as levothyroxine may worsen glycemic control in diabetic patients 5
• Cardiovascular disease: Use lower initial doses in elderly patients or those with cardiac conditions 4, 5
• Medication interactions: Administer levothyroxine at least 4 hours before or after drugs that interfere with absorption 5

Prognosis and Follow-up

• Thyroid hormone replacement is usually lifelong 2, 6
• Some evidence suggests that patients who develop thyroid dysfunction may have improved survival outcomes with pembrolizumab therapy 3
• Continue to monitor thyroid function regularly as late endocrine dysfunction can occur 1

Common Pitfalls to Avoid

1. Failing to monitor thyroid function regularly during pembrolizumab therapy
2. Misinterpreting transient thyrotoxicosis as hyperthyroidism requiring anti-thyroid medications
3. Overlooking central hypothyroidism (low TSH with low FT4), which may indicate hypophysitis
4. Discontinuing pembrolizumab unnecessarily - most patients can continue immunotherapy while managing hypothyroidism
5. Not recognizing that elevated creatinine may be due to hypothyroidism rather than nephritis 7

Remember that thyroid dysfunction is one of the most common immune-related adverse events with pembrolizumab, occurring in 5-10% of patients receiving anti-PD-1 therapy alone and up to 20% with combination immunotherapy 1.