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

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 particularly 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 Although initial symptoms may appear indolent or subtle, the potential for rapid clinical deterioration to adrenal crisis emphasizes the importance of early recognition and appropriate glucocorticoid therapy.⁶ Current guidelines from the National Comprehensive Cancer Network, the American Society of Clinical Oncology, 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). This case highlights the diagnostic challenge posed by an indolent clinical presentation and illustrates a structured approach to distinguishing central from primary etiologies. Furthermore, it reinforces key considerations for pharmacists and clinicians managing the long-term sequelae of immunotherapy.

Case

A woman aged 67 years 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.

In April 2024, she was diagnosed with NSCLC. She underwent left lower lobectomy in June 2024 and was subsequently recommended for adjuvant chemotherapy with cisplatin 75 mg/m² and pemetrexed 500 mg/m² administered every 3 weeks for 4 planned cycles, followed by adjuvant pembrolizumab 200 mg every 3 weeks for 1 year. She received 3 of the 4 planned cycles of cisplatin and pemetrexed beginning in August 2024. The fourth cycle was omitted due to dose-limiting fatigue, nausea, and anxiety.

In November 2024, she initiated adjuvant pembrolizumab 200 mg every 3 weeks. After completing the first 3 cycles of pembrolizumab, she began to experience persistent fatigue and nausea, which worsened over the following 2 to 3 weeks. One week after receiving her fourth cycle of pembrolizumab (approximately 10 weeks after initiating immunotherapy), she presented to the emergency department in early January 2025 with progressive generalized weakness, nausea, and poor oral intake.

On presentation, she appeared mildly dehydrated. Blood pressure was 172/84 mm Hg and remained stable throughout her evaluation; her heart rate was 85 beats per minute, respiratory rate 18 breaths per minute, temperature 36.4 °C (97.5 °F), and oxygen saturation 98% on room air. Laboratory studies revealed hyponatremia with a serum sodium of 125 mmol/L (reference range, 137-145 mmol/L). Serum potassium was 4.2 mmol/L (reference range, 3.5-5.3 mmol/L), and the patient was euglycemic, findings that did not suggest mineralocorticoid deficiency. A morning serum cortisol level was 0.03 µg/dL (reference range, 4.5-22.7 µg/dL), and corticotropin (ACTH) was less than 5 pg/mL (reference range, 7.2-63.3 pg/mL), consistent with central (secondary) adrenal insufficiency.

Thyroid-stimulating hormone (TSH) was 1.17 mIU/L (reference range, 0.465-4.68 mIU/L) and free thyroxine was 1.44 ng/dL (reference range, 0.78-2.19 ng/dL). These findings indicated adequate thyroid hormone replacement and ruled out uncontrolled hypothyroidism as the etiology of her symptoms. Structural causes were also excluded; an adrenal PET scan performed for oncologic assessment was negative for metastases or structural adrenal disease, making primary adrenal pathology unlikely.

Her hyponatremia was attributed, in part, to volume depletion, and she received a 1000-mL bolus of intravenous normal saline for volume resuscitation. For confirmed adrenal insufficiency, she was given dexamethasone 4 mg intravenously per recommendation of the consulting oncologist and was subsequently tapered to dexamethasone 0.5 mg daily pending outpatient evaluation. Her home levothyroxine and other chronic medications were continued. She was discharged with plans for close follow-up in the oncology clinic within 3 to 6 weeks, with repeat complete blood count, comprehensive metabolic panel, TSH, and morning cortisol levels to guide further management.

At subsequent follow-up, in the context of persistent biochemical evidence of central adrenal insufficiency and suspected pembrolizumab-related immune-mediated toxicity, the multidisciplinary team elected to permanently discontinue pembrolizumab. Although current guidelines generally allow continuation of ICIs once endocrine irAEs are controlled with hormone replacement, a critical risk–benefit assessment in the adjuvant setting favored discontinuation.^7-9 Given that the patient was clinically free of cancer, the burden of a permanent, life-altering toxicity like adrenal insufficiency was weighed against the statistical goal of reducing the risk of future recurrence. This balance, combined with the patient's prior chemotherapy intolerance and the severity of her presentation, supported the cessation of immunotherapy. She was transitioned from dexamethasone to physiologic glucocorticoid replacement with hydrocortisone 10 mg twice daily and was prescribed a hydrocortisone 100-mg intramuscular emergency injection kit for use in the event of adrenal crisis.

Over the following months, with continued corticosteroid replacement, her generalized symptoms of fatigue, weakness, and nausea improved, and her biochemical parameters gradually trended upward. By 8 months post presentation (September 2025), her morning serum cortisol had increased from its nadir of 0.03 µg/dL to 1.5 µg/dL (reference range 4.5-22.7 µg/dL); however, a repeat ACTH level remained suppressed at 5 pg/mL, confirming the persistent nature of her central adrenal insufficiency. Concurrently, her serum sodium levels had improved toward the normal range. Thyroid function remained stable on her home dose of levothyroxine (TSH 1.87 mIU/L). At the time of last follow-up, she remained clinically stable on hydrocortisone replacement and was scheduled for reevaluation of adrenal function in 3 months.

Discussion

This case illustrates several important considerations in the recognition and management of ICI-associated central adrenal insufficiency. The patient developed progressive fatigue, nausea, and generalized weakness shortly after initiating adjuvant pembrolizumab, ultimately presenting to the emergency department with hyponatremia and biochemical evidence of central adrenal insufficiency. This clinical presentation overlaps significantly with cancer-related fatigue and prior chemotherapy adverse effects, which can delay recognition of endocrine irAEs if adrenal insufficiency is not actively considered in the differential diagnosis.

The timing and pattern of toxicity in this case are noteworthy. Hypophysitis is classically associated with CTLA-4 inhibitors such as ipilimumab (Yervoy; Bristol Myers Squibb), with reported incidences up to 17% in some series, whereas PD-1 monotherapy (eg, pembrolizumab) carries a substantially lower overall risk, typically reported at less than 1%.^5,10,11 Prior analyses report a median onset of adrenal insufficiency around 8 months, although onset varies widely across studies.^1,6,12 By contrast, our patient developed central adrenal insufficiency after only 4 cycles (roughly 10 weeks) of pembrolizumab. Furthermore, although pharmacovigilance data frequently identify older males as the predominant demographic for this toxicity, likely reflecting the underlying prevalence of lung cancer and melanoma in studied populations, our patient was female.¹³ Additionally, she was receiving pembrolizumab monotherapy, which, like other PD-1 inhibitors, appears to confer a relatively low risk of adrenal insufficiency (approximately 1%) compared with CTLA-4–containing or combination ICI regimens.^3,5,8,10-12 This case therefore underscores that ICI-related adrenal insufficiency can present early and should remain on the differential regardless of patient demographics or perceived lower-risk monotherapy regimens.

The diagnostic evaluation in this case illustrates a structured approach to distinguishing central from primary adrenal insufficiency and excluding alternative etiologies. The patient’s hyponatremia was attributed to a combination of reduced oral intake, a common confounder in oncology patients, and cortisol deficiency, which increases antidiuretic hormone secretion and impairs free-water excretion. However, the hormonal profile provided the definitive distinction: the combination of a profoundly reduced morning cortisol (0.03 µg/dL) with a suppressed ACTH (< 5 pg/mL) was diagnostic for a central etiology. Given the unequivocally low morning cortisol and suppressed ACTH, confirmatory testing with cosyntropin stimulation was not required to establish the diagnosis.

Clinical evaluation did not suggest mineralocorticoid deficiency. The presence of normokalemia (potassium 4.2 mmol/L) and the absence of hypotension on presentation strongly argued against a primary etiology. This preservation of mineralocorticoid function is a key feature distinguishing central from primary adrenal insufficiency, which classically presents with hyperkalemia and hemodynamic instability. Importantly, although the absence of hypotension helped distinguish central from primary adrenal insufficiency, it should not dissuade clinicians from considering the diagnosis, as life-threatening adrenal insufficiency can present without hemodynamic collapse. Finally, a negative adrenal PET scan supported the absence of adrenal metastases, further narrowing the differential to a central etiology.

Although a pituitary MRI was not performed because it was not expected to alter management in the absence of mass effect symptoms, the constellation of findings (including low cortisol, suppressed ACTH, and negative adrenal imaging) strongly supported a diagnosis of ICI-induced hypophysitis. Although hypophysitis often affects multiple pituitary axes, the preservation of thyroid function in this case suggests an isolated corticotroph deficiency. This specific pattern of isolated ACTH failure is a well-documented presentation of PD-1 inhibitor toxicity, contrasting with the pan-hypopituitarism more commonly seen with CTLA-4 inhibitors.^11,14 Accordingly, the biochemical profile alone was sufficient to support pembrolizumab as the most likely etiology.

Management in this case is consistent with contemporary guideline-based recommendations for ICI-related adrenal insufficiency, which emphasize prompt glucocorticoid administration, fluid resuscitation, transition to physiologic hydrocortisone replacement, and patient education on stress dosing and emergency injections.^7-9 Dexamethasone is often preferred when diagnostic testing is needed because it minimally interferes with cortisol assays. Our patient received intravenous dexamethasone and normal saline in the emergency department, followed by a taper to physiologic glucocorticoid replacement. She was ultimately transitioned to hydrocortisone 10 mg twice daily and prescribed a hydrocortisone intramuscular emergency kit, consistent with guideline recommendations for long-term management of central adrenal insufficiency and prevention of adrenal crisis.^7-9 Because this was central adrenal insufficiency, mineralocorticoid replacement was not required.

Despite discontinuation of pembrolizumab, the patient's morning cortisol remained subnormal at follow-up (1.5 µg/dL), with persistently suppressed ACTH (5 pg/mL), confirming the persistent nature of her central adrenal insufficiency. This finding aligns with prior reports suggesting that ICI-induced central adrenal insufficiency is often permanent, and long-term or lifelong glucocorticoid replacement is typically required.¹⁵ Accordingly, ongoing education regarding stress dosing and sick-day rules remains essential. Pharmacists are well positioned to lead this effort by providing comprehensive counseling on dose adjustments during acute illness and ensuring patients can confidently demonstrate the technique for administering their emergency hydrocortisone injection. Beyond education, pharmacists play a crucial role in performing medication reconciliation to screen for drug interactions with glucocorticoids (eg, CYP3A4 inducers that may accelerate steroid metabolism) and in facilitating access to these life-sustaining therapies.

Taken together, this case highlights several important lessons for clinicians. First, even nonspecific symptoms such as fatigue, anorexia, and nausea in patients receiving ICIs should prompt consideration of endocrine irAEs, particularly when accompanied by hyponatremia or other electrolyte abnormalities. Second, early, structured evaluation with morning cortisol and ACTH is critical to differentiate central from primary adrenal insufficiency, whereas thyroid function tests and appropriate imaging help exclude alternative etiologies such as adrenal metastases or hypothyroidism. Third, timely initiation of glucocorticoid replacement and adherence to guideline-based management strategies can prevent progression to adrenal crisis and improve patient outcomes. As the use of ICIs continues to expand, increased awareness of ICI-associated adrenal insufficiency among oncologists, pharmacists, and the broader oncology care team is essential to ensure early detection and optimal management of this potentially life-threatening complication.

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. This case reinforces the need for clinicians to maintain a high index of suspicion, pursue a structured diagnostic workup (including timely evaluation of cortisol, ACTH, and electrolyte abnormalities), and promptly initiate guideline-directed glucocorticoid replacement to prevent adrenal crisis.

Continued vigilance, interdisciplinary communication, and patient education are essential to ensuring safe and effective care for individuals receiving these widely used immune-modulating agents. The early onset observed during adjuvant PD-1 monotherapy highlights the necessity of rapid recognition even when the patient appears clinically stable. As medication experts, pharmacists are central to this mission, driving patient education on sick-day management and emergency hydrocortisone use, while ensuring safe and effective long-term monitoring.

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