The researchers from the Massachusetts General Hospital in Boston, MA, US led by assistant professor Meghan Sise, published on 18 May 2021 in the Annals of Oncology the results of a large analysis examining whether the immune checkpoint inhibitors (ICIs) induced thyroiditis is associated with prolonged survival in a retrospective cohort of adults treated with ICIs between 2010 and 2019. The study team showed a 20% reduction in the adjusted hazard ratio (aHR) for death in patients who developed ICI induced thyroiditis. The association between thyroiditis and overall survival (OS) varied by tumour type, but was strongest in patients with lung cancer, possibly related to the shared developmental origin of thyroid and lung epithelia.
The authors wrote in the background that it has been hypothesised that immune-related adverse events (irAEs) are a biomarker for treatment effect and a positive prognostic indicator in patients receiving ICIs. The ICI induced thyroiditis is a common irAE that has been associated with improved survival. They investigated whether the prolonged survival associated with ICI induced thyroiditis was a result of immortal time bias.
The researchers identified 9,419 patients receiving ICIs, but after exclusions, 6,596 were included in this analysis. Mean age was 64 years, 57% were male and 89% white, non-Hispanic. Patients were followed for a median of 9.6 months. Thyroiditis was developed in 1,155 patients (17%). Median time to thyroiditis was 3.1 months.
Multivariable models were adjusted for age, sex, race, cancer type, ICI class, pre-existing rheumatologic disease, and Charlson comorbidity score. The ICI induced thyroiditis was independently associated with a large improvement in OS in the time-independent model (aHR 0.47, 95% confidence interval [CI] 0.44-0.53, p < 0.001). The association with improved survival remained consistent, albeit with a lower effect estimate with time-varying Cox models (aHR 0.80, 95% CI 0.71-0.89, p < 0.001).
In the survival analysis, without applying a conditional landmark, thyroiditis was associated with a large reduction in death (HR 0.44 p <0.001). When a 6-month landmark was applied, a weaker, but statistically significant improvement in OS was found, HR for death 0.76 (95% CI 0.65–0.88, p < 0.001). Applying a 3-month landmark yielded a very similar result of HR 0.78 (95% CI 0.67–0.92, p = 0.002).
A 6-month landmark analysis was used to determine the association between thyroid dysfunction and OS in each cancer type. Patients with lung cancer demonstrated the strongest relationship between thyroiditis and OS (HR for death 0.56, 95% CI 0.40-0.79, p < 0.001). The relationship was least in breast, melanoma and genitourinary tumours.
The authors wrote that their study demonstrates the large effect of immortal time bias. Future studies with large cohorts are needed to examine the association of other irAEs with survival.
Street S, Chute D, Strohbehn I, et al. The positive effect of immune checkpoint inhibitor-induced thyroiditis on overall survival accounting for immortal time bias: a retrospective cohort study of 6,596 patients. Annals of Oncology; Published online 18 May 2021. DOI: https://doi.org/10.1016/j.annonc.2021.05.357