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

## TL;DR

This study shows that a low neutrophil-to-lymphocyte ratio (NLR) at the start of pembrolizumab treatment is linked to a higher risk of developing hypothyroidism, suggesting NLR monitoring could help predict and manage this side effect.

## Contribution

The study introduces the use of baseline and longitudinal NLR trends as a predictive biomarker for pembrolizumab-induced hypothyroidism onset.

## Key findings

- Hypothyroidism occurred in 24% of patients treated with pembrolizumab.
- A lower baseline NLR and longer time to treatment failure were significantly associated with hypothyroidism onset.
- A maximum NLR cutoff of 4.3 predicted early-onset hypothyroidism with 77% accuracy.

## Abstract

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.