Immune checkpoint inhibitors (ICIs) targeting PD-1/PD-L1 have changed the management of advanced non-small cell lung cancer (NSCLC) but can cause immune-related adverse events (irAEs) that affect endocrine organs. Among endocrine irAEs, immune checkpoint inhibitor–induced diabetes mellitus (ICI-DM) is uncommon (reported incidence 0.2–1.4%) but clinically important due to its typically abrupt onset, frequent presentation with diabetic ketoacidosis (DKA), and usual permanence of insulin dependence. Lung cancer patients contribute a substantial proportion of reported cases, reflecting widespread ICI use in thoracic oncology. This report describes an elderly patient with metastatic lung adenocarcinoma who developed ICI-DM during pembrolizumab therapy, the diagnostic workup, multidisciplinary management decisions, and extended follow-up after immunotherapy discontinuation.
A 72-year-old man with hypertension, benign prostatic hyperplasia, prior pulmonary tuberculosis, and former heavy smoking underwent right upper lobectomy for lung adenocarcinoma in 2018 (pathological stage pT2a pN2, stage IIIA). Molecular testing was negative for EGFR, ALK, ROS1 and BRAF alterations; PD-L1 tumor proportion score was 80%. After adjuvant cisplatin plus vinorelbine and mediastinal radiotherapy, he developed brain and liver metastases in May 2020. The solitary brain lesion was treated with SBRT. Pembrolizumab 400 mg every 6 weeks was started in August 2020, and a sustained partial response of intracranial and hepatic lesions was observed.
In October 2021, after 10 cycles of pembrolizumab, the patient developed polyuria, polydipsia and weight loss. Initial outpatient glycemia was 459 mg/dL and emergency department labs confirmed severe hyperglycemia (690 mg/dL) with metabolic acidosis (pH 7.31, bicarbonate 18 mEq/L). He was hospitalized and treated with continuous insulin infusion and IV fluids, with potassium and other electrolytes monitored.
Laboratory evaluation during the acute episode showed low endogenous insulin and borderline C-peptide: serum insulin 2.5 microUI/mL (reference >2.6 microUI/mL) and C-peptide 1.1 ng/mL (reference >1.1 ng/mL). Islet autoantibodies—glutamic acid decarboxylase antibodies (GADA) and islet cell antibodies (ICA)—were negative. The report states that other causes of hyperglycemia were excluded, including infections, medications (for example systemic corticosteroids or atypical antipsychotics), other endocrinopathies, and pancreatic disease. HbA1c at presentation was not available in the case record, limiting assessment of chronic hyperglycemia prior to presentation.
The constellation of abrupt hyperglycemia, metabolic acidosis, impaired insulin secretion, and exclusion of alternative causes led the treating team to attribute the condition to ICI-DM related to pembrolizumab.
Acute management consisted of hospitalization, continuous insulin infusion, fluid resuscitation, and correction of acid–base and electrolyte disturbances. After stabilization, the patient was transitioned to a basal–bolus insulin regimen with progressive glycemic optimization and was discharged after five days in good clinical condition.
During follow-up the patient remained permanently insulin-dependent, with no recovery of endogenous insulin secretion reported. Glycemic control was maintained without further episodes of decompensation, including during a later course of dexamethasone used for intracranial disease prophylaxis.
The authors emphasize guideline-based components of care: baseline glucose and HbA1c assessment before ICI initiation, glucose monitoring at each cycle during the first 12 weeks with more frequent checks when values are borderline, rapid evaluation of symptoms consistent with hyperglycemia, and urgent endocrinology consultation when indicated. Patient education on symptoms (polyuria, polydipsia, nausea, fatigue, confusion), insulin administration, and lifestyle measures was also highlighted as essential.
A multidisciplinary team including medical oncologists and endocrinologists discussed potential restart of pembrolizumab. The treating clinicians opted for permanent discontinuation, citing advanced age, comorbidities, the severity of diabetes onset, and the perceived high risk of further glycemic decompensation. The report notes that current guidelines from ASCO, ESMO and SITC provide frameworks that generally allow for ICI rechallenge in selected patients once glycemic control is achieved, particularly when oncological benefit is significant, but also permit permanent discontinuation in frail patients or those at high metabolic risk. The authors underline that guideline recommendations on rechallenge vary slightly and decisions should be individualized.
After pembrolizumab discontinuation, systemic disease remained controlled on surveillance imaging through December 2025, when thoracic–abdominal CT showed no systemic progression but brain MRI detected a new intracranial lesion. The new brain metastasis was treated with SBRT. The patient remained clinically stable under combined oncological and endocrinological follow-up. The report highlights that durable oncological responses can persist after ICI interruption for irAEs in some cases, though causality between irAEs and sustained benefit cannot be established from a single case.
This case demonstrates several commonly reported features of ICI-DM: delayed onset after several months of therapy, rapid progression to insulin deficiency, frequent absence of islet autoantibodies, and permanence of insulin dependence. Detection rates of GADA in published series vary, and antibody negativity does not exclude the diagnosis. The pathophysiology is thought to involve T cell–mediated β-cell destruction triggered by PD-1/PD-L1 blockade.
Management priorities include early recognition, prompt metabolic stabilization (including DKA management), initiation of insulin replacement, and close endocrinology involvement. The literature and guideline bodies recommend baseline metabolic assessment and periodic monitoring, and they stress patient education. The choice to resume or permanently stop ICI requires individualized risk–benefit assessment considering patient frailty, severity of diabetes, oncological response to therapy, and the ability to maintain safe glycemic control.
ICI-DM is a rare but severe complication of PD-1/PD-L1 blockade that typically presents with abrupt insulin deficiency and often leads to lifelong insulin therapy. Early diagnosis, urgent metabolic stabilization and long-term endocrinological care are essential. Decisions about continuing or discontinuing immunotherapy should be individualized within a multidisciplinary team. This case adds real-world insight into long-term outcomes after ICI interruption and highlights the need for vigilance and collaborative management in patients receiving checkpoint inhibitors.