Early Prediction of Pembrolizumab-Induced Hypothyroidism Based on the Neutrophil-to-Lymphocyte Ratio

Introduction Pembrolizumab, an immune checkpoint inhibitor targeting programmed death-1 (PD-1)/PD-1 ligand (PD-L1), has demonstrated antitumor effects but can cause immune-related adverse events (irAEs) such as hypothyroidism. The neutrophil-to-lymphocyte ratio (NLR) may be linked to pembrolizumab efficacy and irAE risk. This study investigated the relationship between NLR trends and hypothyroidism onset, assessing its predictive potential. Methods This retrospective study analyzed 136 patients with advanced or recurrent cancer treated with pembrolizumab at The Jikei University Hospital, Tokyo, Japan, from February 2017 to September 2023. Patients were categorized based on hypothyroidism development, and their baseline NLR and time to treatment failure (TTF) were compared. NLR trends before hypothyroidism onset were also evaluated. Patients were further stratified based on onset timing (<90 days vs. ≥90 days), and NLR parameters prior to onset were also compared. Results Hypothyroidism occurred in 33 of 136 patients (24%). The hypothyroidism group had a significantly lower baseline NLR (P = 0.006) and longer TTF (P = 0.006). No significant NLR changes were observed before hypothyroidism onset (P = 0.626). However, the maximum NLR until onset was significantly lower in patients with early-onset hypothyroidism (<90 days) (P = 0.016). In contrast, no significant differences were observed in the mean and minimum NLR. A receiver-operating characteristic (ROC) analysis identified a maximum NLR cutoff of 4.3 for predicting early-onset hypothyroidism (P = 0.002, area under the curve (AUC) = 0.770). Conclusions A low baseline NLR was associated with hypothyroidism onset, and a persistently low NLR may contribute to early onset. These findings suggest that continuous NLR monitoring during pembrolizumab treatment may aid in predicting the risk of hypothyroidism and facilitate its appropriate management.