MON-305 - Timing of Thyroid Dysfunction and Its Association with Outcomes Following PD-1/PD-L1 Inhibitor Therapy in Lung Cancer

Immune checkpoint inhibitors (ICIs) targeting programmed cell death-1 (PD-1) and programmed death-ligand 1 (PD-L1) have become standard therapy for advanced lung cancer. Thyroid dysfunction is among the most frequent endocrine immune-related adverse events (irAE). The timing of thyroid irAE onset varies by type: thyroiditis emerges earliest at 5–8 weeks after exposure, followed by hyperthyroidism at 8–10 weeks, and hypothyroidism at 10–14 weeks. Timing of thyroid disease after PD-1/PD-L1 inhibitor initiation remains inadequately characterized, underscoring the need for real-world data to inform risk stratification and evidence-based surveillance strategies.

A retrospective cohort analysis was performed utilizing the TriNetX Research Network, which comprised 152, 775, 371 patients from 112 participating healthcare institutions. We identified individuals with lung cancer who received one of the four most frequently used PD-1/PD-L1 inhibitors—pembrolizumab, nivolumab, atezolizumab, or durvalumab—and subsequently developed thyroid dysfunction, namely thyroiditis, hyperthyroidism, or hypothyroidism. Temporal patterns were examined by classifying thyroid dysfunction as early-onset if it occurred within 90 days of treatment initiation and late-onset if diagnosed after. Overall survival (OS) was evaluated using the Kaplan–Meier method, and group comparisons were conducted using the log-rank test. Propensity score matching was applied to control for age, sex, comorbid conditions, and treatment lines.

Early thyroid dysfunction occurred in roughly half of patients across all agents, including pembrolizumab (52.9%), nivolumab (53.2%), atezolizumab (53.1%), and durvalumab (51.2%). Patients who experienced late-onset hypothyroidism after treatment with pembrolizumab and nivolumab demonstrated significantly improved survival outcomes. Among those treated with pembrolizumab, there were 2,996 deaths in the early-onset hypothyroidism cohort with a median OS of 852 days, compared to 3,218 deaths in the late-onset cohort with a median OS of 701 days (p < 0.0001). For nivolumab, patients with late-onset hypothyroidism exhibited a significantly longer OS (p < 0.0001), with a median OS of 823 days and 1,338 deaths, whereas the early-onset group had a median OS of 362 days with 1,527 deaths. The timing of immune-related hyperthyroidism or thyroiditis onset did not significantly affect overall survival across any of the immunotherapies evaluated.

Patients who remain on immune therapy long enough to develop delayed hypothyroidism may represent a particularly favorable immunologic subset with durable benefit. The association between delayed hypothyroidism following treatment and improved survival raises the possibility that late endocrine autoimmunity serves as a clinical correlate of sustained immune engagement and therapeutic benefit.

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