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.

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

Pharmacy Practice in Focus: Oncology · February 2026

Authors: Zachery Halford, PharmD, BCOP, BCPPS; Jamie Stewart, PharmD Candidate; George DeMaagd, PharmD, BCPS

Fact‑checked by: Ron Panarotti

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Key Takeaways

• Nonspecific fatigue, nausea, anorexia, and weakness during PD‑1 therapy warrant endocrine irAE evaluation, especially when persistent or accompanied by hyponatremia despite radiographic absence of disease.

• Biochemical confirmation of central adrenal insufficiency hinges on a very low morning cortisol with inappropriately low ACTH; normokalemia and preserved hemodynamics argue against primary adrenal failure.

• Early central adrenal insufficiency can occur within weeks of pembrolizumab monotherapy, despite a low reported incidence compared with CTLA‑4 or combination regimens and despite atypical demographics.

• Guideline‑concordant care includes immediate glucocorticoids and fluids, conversion to physiologic hydrocortisone, stress‑dosing education, and an emergency IM hydrocortisone kit; mineralocorticoids are unnecessary in central disease.

• Persistent ACTH suppression months after presentation supports frequent permanence of PD‑1–associated isolated corticotroph deficiency, informing long‑term monitoring and adjuvant risk–benefit decisions regarding ICI continuation.

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Introduction

Pembrolizumab in adjuvant NSCLC therapy can trigger central adrenal insufficiency with vague fatigue, nausea, and hyponatremia.

The rapid expansion of immune checkpoint inhibitors (ICIs) continues to transform oncology practice, yet it confronts clinicians with a distinct challenge: recognizing and managing immune‑related adverse events (irAEs) that can mimic common symptoms related to cancer progression or concurrent therapies.¹,²

Among these, endocrine toxicities such as thyroid dysfunction, hypophysitis, and adrenal insufficiency are particularly challenging because they often manifest with vague, constitutional complaints. Consequently, even mild or nonspecific symptoms such as fatigue or anorexia should prompt consideration of endocrine irAEs in patients receiving immunotherapy, particularly when symptoms are persistent or otherwise unexplained. This challenge is especially relevant in the adjuvant setting, where patients may be radiographically free of disease yet still at risk for serious, life‑altering irAEs.³,⁴

ICIs targeting CTLA‑4, PD‑1, and PD‑L1, including pembrolizumab (Keytruda; Merck), are now widely used in metastatic and adjuvant settings to improve survival.²‑⁴ However, by releasing inhibitory brakes on T‑cell activity, these agents can trigger off‑target immune responses against normal tissues, including the endocrine glands.¹,² ICI‑associated adrenal insufficiency may be primary, due to direct adrenal gland destruction, or central (secondary/tertiary), typically arising from hypophysitis with impaired corticotropin (ACTH) secretion.¹ If unrecognized, adrenal insufficiency can progress to adrenal crisis, a life‑threatening emergency with significant morbidity and mortality.⁵

The onset of ICI‑associated adrenal insufficiency is highly variable.¹ Although data suggest a median time to onset of approximately 8 months (range 3.8‑15.2 months), cases have been reported throughout the treatment course and even months after discontinuation.¹,⁶ Early recognition and appropriate glucocorticoid therapy are essential to prevent rapid clinical deterioration. Current guidelines from the National Comprehensive Cancer Network (NCCN), the American Society of Clinical Oncology (ASCO), and the Society for Endocrinology provide recommendations for the evaluation and management of ICI‑related endocrinopathies, including adrenal insufficiency.⁷‑⁹

This report details a case of pembrolizumab‑associated central adrenal insufficiency in a patient receiving adjuvant therapy for non‑small cell lung carcinoma (NSCLC). The case highlights the diagnostic challenge posed by an indolent clinical presentation and illustrates a structured approach to distinguishing central from primary etiologies. It also reinforces key considerations for pharmacists and clinicians managing the long‑term sequelae of immunotherapy.

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Case

A 67‑year‑old woman with stage IIB adenocarcinoma of the left lower lobe developed adrenal insufficiency while receiving adjuvant pembrolizumab. Her medical history was notable for hypothyroidism, for which she was maintained on levothyroxine (Synthroid; AbbVie); her other chronic medications were unchanged throughout treatment.

• April 2024: Diagnosed with NSCLC.

• June 2024: Left lower lobectomy.

• August 2024: Began adjuvant chemotherapy (cisplatin 75 mg/m² + pemetrexed 500 mg/m²) every 3 weeks; completed 3 of 4 planned cycles. The fourth cycle was omitted due to dose‑limiting fatigue, nausea, and anxiety.

• November 2024: Initiated adjuvant pembrolizumab 200 mg every 3 weeks. After the first three cycles she experienced persistent fatigue and nausea, which worsened over the next 2‑3 weeks.

Presentation (early January 2025): One week after her fourth pembrolizumab dose (≈10 weeks after starting immunotherapy) she presented to the emergency department with progressive generalized weakness, nausea, and poor oral intake.

• Vitals: BP 172/84 mm Hg (stable), HR 85 bpm, RR 18 /min, Temp 36.4 °C, SpO₂ 98 % on room air.

• Laboratory findings:

  • Hyponatremia: Na⁺ 125 mmol/L (ref 137‑145)

  • K⁺ 4.2 mmol/L (ref 3.5‑5.3) – normokalemia

  • Euglycemia

  • Morning cortisol 0.03 µg/dL (ref 4.5‑22.7)

  • ACTH < 5 pg/mL (ref 7.2‑63.3)

These results were consistent with central (secondary) adrenal insufficiency.

Additional endocrine evaluation:

• TSH 1.17 mIU/L (ref 0.465‑4.68) and free T4 1.44 ng/dL (ref 0.78‑2.19) indicated adequate thyroid hormone replacement.

• Adrenal PET scan was negative for metastases or structural adrenal disease, making primary adrenal pathology unlikely.

Acute management:

• 1 L IV normal saline bolus for volume resuscitation.

• IV dexamethasone 4 mg (per consulting oncologist), tapered to dexamethasone 0.5 mg daily pending outpatient evaluation.

• Continuation of home levothyroxine and other chronic medications.

She was discharged with close oncology follow‑up (3‑6 weeks) for repeat CBC, CMP, TSH, and morning cortisol.

Follow‑up & longer‑term management:

• Persistent biochemical evidence of central adrenal insufficiency prompted permanent discontinuation of pembrolizumab after multidisciplinary risk‑benefit assessment (patient clinically cancer‑free, severe endocrine toxicity).

• Transitioned from dexamethasone to physiologic hydrocortisone 10 mg twice daily and prescribed a 100‑mg IM hydrocortisone emergency kit.

• Over the next months, fatigue, weakness, and nausea improved; morning cortisol rose to 1.5 µg/dL by September 2025 (still subnormal), while ACTH remained suppressed at 5 pg/mL, confirming persistent central insufficiency.

• Thyroid function remained stable (TSH 1.87 mIU/L).

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Discussion

This case illustrates several important considerations in the recognition and management of ICI‑associated central adrenal insufficiency.

1. Nonspecific presentation: Fatigue, nausea, and weakness overlap with cancer‑related fatigue and chemotherapy side effects, potentially delaying diagnosis. Early endocrine evaluation is essential when such symptoms persist.

2. Incidence and timing: Hypophysitis is classically linked to CTLA‑4 inhibitors (e.g., ipilimumab) with reported incidences up to 17 %. PD‑1 monotherapy (e.g., pembrolizumab) carries a substantially lower overall risk (< 1 %).¹⁰,¹¹ Nevertheless, our patient developed central adrenal insufficiency after only ~10 weeks of pembrolizumab, underscoring that early onset is possible even with monotherapy and in demographics (female, older) not typically highlighted in pharmacovigilance data.¹³

3. Diagnostic work‑up:

   • Hyponatremia in this setting reflects cortisol deficiency‑driven ADH excess and volume depletion.

   • Hormonal profile (morning cortisol 0.03 µg/dL with ACTH < 5 pg/mL) definitively indicates a central etiology; cosyntropin stimulation is unnecessary when cortisol is profoundly low.

   • Mineralocorticoid function is preserved (normokalemia, stable BP), distinguishing central from primary adrenal failure.

   • Imaging: Negative adrenal PET and absence of pituitary mass on MRI (not performed because it would not alter management) support ICI‑induced hypophysitis with isolated corticotroph deficiency.

4. Management: Prompt glucocorticoid replacement (initial IV dexamethasone, then physiologic hydrocortisone) and fluid resuscitation align with NCCN, ASCO, and Society for Endocrinology guidelines.⁷‑⁹ Dexamethasone is preferred for acute treatment because it minimally interferes with cortisol assays. Long‑term therapy includes physiologic hydrocortisone dosing, patient education on stress dosing, and provision of an emergency IM hydrocortisone kit. Mineralocorticoid replacement is unnecessary in central disease.

5. Prognosis: Persistent ACTH suppression months after presentation suggests that ICI‑induced central adrenal insufficiency is often permanent, requiring lifelong glucocorticoid replacement and ongoing sick‑day counseling.¹⁵ Pharmacists play a pivotal role in education, medication reconciliation (e.g., avoiding CYP3A4 inducers that accelerate steroid metabolism), and ensuring access to emergency kits.

6. Therapeutic decision‑making: Although guidelines generally allow continuation of ICIs after endocrine irAEs are controlled, the adjuvant setting warrants a nuanced risk‑benefit analysis. In a patient who is cancer‑free, the permanent nature of adrenal insufficiency tipped the balance toward discontinuation of pembrolizumab.

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Conclusion

ICI‑induced central adrenal insufficiency is an uncommon but clinically significant complication that may present with subtle constitutional symptoms often mistaken for cancer‑ or treatment‑related sequelae. Clinicians must maintain a high index of suspicion, pursue a structured diagnostic work‑up (including timely cortisol, ACTH, and electrolyte assessment), and promptly initiate guideline‑directed glucocorticoid replacement to prevent adrenal crisis. Ongoing vigilance, interdisciplinary communication, and patient education are essential for safe, effective care of individuals receiving immune‑modulating agents.

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