Pembrolizumab-Induced Adrenal Insufficiency: Recognizing and Managing a Diagnostic Challenge in Adjuvant NSCLC Therapy

Why It Matters

Central adrenal insufficiency can rapidly become life‑threatening, affecting patient safety and treatment continuity. Recognizing this irAE early ensures appropriate steroid replacement and informs decisions about continuing immune checkpoint therapy.

Key Takeaways

• Fatigue, nausea, hyponatremia signal adrenal insufficiency on pembrolizumab
• Very low cortisol with suppressed ACTH confirms central adrenal insufficiency
• Early glucocorticoid replacement prevents adrenal crisis and guides therapy
• Persistent ACTH suppression indicates likely permanent hormone deficiency
• Discontinue pembrolizumab in adjuvant setting after severe endocrine irAE

Pulse Analysis

The rapid expansion of immune checkpoint inhibitors has transformed oncology, yet endocrine immune‑related adverse events remain a hidden threat. Central adrenal insufficiency, though reported in less than 1% of patients on PD‑1 monotherapy, can masquerade as routine cancer‑related fatigue. Clinicians must maintain a high index of suspicion, especially in the adjuvant setting where patients are otherwise disease‑free. Early laboratory assessment—including morning cortisol and ACTH—provides a decisive diagnostic edge, allowing differentiation from primary adrenal failure and preventing delayed treatment.

Guideline‑driven evaluation emphasizes a structured work‑up: hyponatremia without hyperkalemia, profoundly low cortisol, and suppressed ACTH point to a central etiology. Imaging is often unnecessary once biochemical criteria are met, streamlining care. The NCCN, ASCO, and Society for Endocrinology protocols recommend immediate IV glucocorticoids—preferably dexamethasone for its minimal assay interference—followed by physiologic hydrocortisone dosing. Fluid resuscitation corrects volume depletion, while patient education on stress dosing and emergency intramuscular kits mitigates adrenal crisis risk.

Long‑term management shifts focus to chronic hormone replacement and interdisciplinary coordination. Persistent ACTH suppression suggests irreversible corticotroph damage, necessitating lifelong hydrocortisone and regular endocrine monitoring. Pharmacists play a pivotal role in counseling on dose timing, avoiding CYP3A4 inducers, and ensuring access to emergency kits. Moreover, the permanence of adrenal insufficiency influences therapeutic decisions; in adjuvant NSCLC, discontinuing pembrolizumab may be justified when the toxicity outweighs marginal survival benefit. This nuanced risk‑benefit calculus underscores the importance of integrating endocrine safety into immunotherapy protocols.