Endocrine Abstracts

JOINT784

Background.: Immune checkpoint inhibitors (ICIs) have dramatically changed cancer therapy by enhancing anti-tumor immunity. Their use, however, is potentially associated with a variety of immune-related adverse events (irAEs) that include rare cases of hypercalcemia. A single case of hypercalcemia induced by the programmed death-1 (PD-1) inhibitor pembrolizumab is currently reported. Severity, timing of occurrence, and pathophysiological mechanisms remain scarcely defined.

Case report: Seventy-year-old woman suffering from KRAS mutant, MSI-H colon adenocarcinoma with liver metastasis undergoing pembrolizumab as first line therapy. Shortly after its second administration, she developed severe, life-threatening, hypercalcemia (20 mg/dl) with acute kidney failure. Serum levels of intact parathyroid hormone (PTH), parathyroid hormone-related peptide (PTHrP), 25-OH vitamin D, and 1,25-OH vitamin D were suppressed, thus allowing the exclusion of primary hyperparathyroidism, ectopic PTHrP secretion and ectopic 25(OH)D-1-hydroxylase expression. Cross-sectional imaging ruled out the presence of osteolytic lesions or granulomatous disease. Immediate intravenous treatment included aggressive hydration and the infusion of zoledronic acid and high-dose glucocorticoids followed by pembrolizumab withdrawal. During the subsequent week, serum calcium levels gradually normalized and the patient’s overall condition improved.

Discussion: The occurrence of hypercalcemia in cancer patients receiving ICIs requires a careful differential diagnosis between malignancy-associated and immune-mediated causes. Notably, the interference of pembrolizumab on the PD-1 pathway may enhance osteoclast differentiation and activity through a RANKL/OPG imbalance and the production of pro-inflammatory cytokines, like TNF-α and IL-6. Accordingly, experimental models of PD-1/PD-L1 inhibition have demonstrated increased bone resorption. Thus, based on the clinical and instrumental evidence, the immune-mediated PD-1 pathway disruption may be postulated as the main cause of this case of pembrolizumab-induced hypercalcemia.

Conclusions.: In patients receiving ICIs, monitoring of serum calcium and its assessment before each dose administration appear advisable. Early recognition and immediate management of hypercalcemia mitigate its morbidity and allow for the maintenance of immunotherapy. Further research into the interplay between PD-1 inhibition and bone homeostasis is warranted to improve the prevention and management of this rare but potentially critical irAE.