Biomarkers and outcomes in checkpoint inhibitor-associated diabetes and hyperglycemia
Studies on immune checkpoint inhibitor therapy found pretreatment biomarkers strongly predicted checkpoint inhibitor-associated autoimmune diabetes, while hyperglycemia during treatment was common and did not worsen disease progression.
Checkpoint inhibitor–associated autoimmune diabetes mellitus is a rare but life-altering complication of immune checkpoint inhibitor therapy, while ICI-related hyperglycemia occurs more commonly during treatment. In a prospective biobank analysis, pretreatment pancreatic volume, anti–glutamic acid decarboxylase autoantibody titers, and baseline immune flow profile were highly predictive of CIADM development, with an AUC of greater than 0.96.
From a prospective biobank, 14 patients with CIADM who had metastatic melanoma treated with anti–PD-1 with or without anti-CTLA4 were identified, and controls were selected from the same biobank, matched 2:1. Before treatment, patients with CIADM had smaller pancreatic volume, with a 27% reduction (P = 0.044), and higher anti-GAD titers, with a median 2.9 versus 0 (P = 0.01). They also had significantly higher baseline proportions of Th17 cells (P = 0.03), higher CD4+ central memory cells (P = 0.04), and lower naive CD4+ T cells (P = 0.01). With ICI treatment, greater declines in pancreatic volume were seen in patients with CIADM (P < 0.0001).
The study found that people who develop CIADM are immunologically predisposed and have antecedent pancreatic and immunological changes that accurately predict disease with excellent sensitivity. The biomarkers could be used to guide ICI use, particularly when planning treatment for low-risk tumors.
ICIs are recommended as a first-line treatment option for advanced or metastatic non–small cell lung cancer in those without targetable driver mutations, either alone or in combination with cytotoxic chemotherapy. Although hypophysitis and thyroiditis are the most documented endocrine immune-related adverse events, ICI-induced adrenal insufficiency and type 1 diabetes have also been noted. ICI-induced type 1 diabetes occurs in an estimated 0.2% to 1.4% of those receiving ICIs for the treatment of solid tumors, while ICI-related hyperglycemia, without the presence of ICI-induced type 1 diabetes, occurs in up to 27% of patients, regardless of tumor type, and is multifactorial in its geneses.
Hyperglycemia is common in patients with non–small cell lung cancer receiving ICIs, particularly those with preexisting diabetes or receiving chemotherapy. Routine glucose monitoring before and during ICI treatment is critical, especially in patients with risk factors such as type 2 diabetes or baseline hyperglycemia. Multidisciplinary management of hyperglycemia using dietary interventions, glucose-lowering medications, and potentially insulin may mitigate complications and optimize patient outcomes.
Evidence summarized in patients with NSCLC found that hyperglycemia does not negatively impact disease progression and may lead to longer time to disease progression in those with hyperglycemia and/or immune-related adverse events. In prior data cited for ICI-induced type 1 diabetes, a Canadian study examined 34 patients with heterogeneous cancer diagnoses, of whom 4 had NSCLC, and noted that patients with ICI-induced type 1 diabetes, although irreversible and requiring long-term dependence on insulin, had a high tumor response rate and may have prolonged survival. Among 11 patients with cutaneous melanoma, researchers found a 73% partial or complete response rate for patients continuing ICI treatment after ICI-induced type 1 diabetes.