Severe Hypercalcemia Following Pembrolizumab Therapy: A Case Report and A Literature Review

Immune checkpoint inhibitors (ICIs) play a central role in advanced cancer treatment, but they are associated with immune-related adverse events (irAEs) that include two cases of hypercalcemia induced by the programmed death-1 (PD-1) inhibitor, pembrolizumab. We report a unique case of a colon cancer patient treated with pembrolizumab who acutely developed life-threatening hypercalcemia.

This case presents a seventy-five-year-old woman suffering from colon adenocarcinoma with liver metastasis undergoing pembrolizumab therapy. Shortly after its second administration, she developed severe hypercalcemia (21 mg/dL) with acute kidney failure. Serum intact parathyroid hormone (PTH), parathyroid hormone-related peptide (PTHrP), 25-OH vitamin D, and 1,25-OH vitamin D were suppressed while computerized tomography (CT) imaging ruled out relevant osteolytic or granulomatous lesions. Treatment included hydration, infusion of zoledronic acid, and high-dose glucocorticoids. The patient's serum calcium levels normalized, and her condition improved. Primary hyperparathyroidism, ectopic PTHrP secretion, and ectopic 25(OH) D-1-hydroxylase expression were ruled out by clinical and laboratory data. Notably, experimental models of PD-1/PD-L1 inhibition have demonstrated increased bone resorption. Although the absence of specific bone turnover markers and a recent 18FDG-PET/CT scan partly limits the understanding of the pathophysiological mechanism, immune-mediated osteoclast activation represents a potential pathophysiological mechanism of acute reversible hypercalcemia.

The present case is unique due to its early onset, absence of calcitriol and PTHrP elevation, and rapid response to corticosteroids. Serum calcium should be assessed both before each ICI’s dose administration and throughout treatment in case of symptoms suspicious for hypercalcemia to prevent the onset and progression of this rare but critical irAE.