Biomarker role of thyroid irAE and PD-L1 positivity in predicting PD-1 blockade efficacy in patients with non-small cell lung cancer

Abstract

Thyroid immune-related adverse events (irAEs) are associated with programmed cell death protein 1 (PD-1) blockade efficacy in non-small cell lung cancer (NSCLC). However, their independence from PD-L1 expression and quantitative impact on predicting PD-1 blockade efficacy remain unexplored. This multicenter, retrospective, longitudinal study from Korea included 71 metastatic NSCLC patients who underwent PD-L1 expression and thyroid function testing during PD-1 blockade. Disease progression by the Response Evaluation Criteria for Solid Tumors was the main outcome. Three-stage analyses were performed: (1) multivariate Cox regression models adjusted for PD-L1 expression according to thyroid irAEs; (2) subgroup analyses; (3) regrouping and comparing predictivity of current and alternative staging. Patients with thyroid irAE + exhibited a longer progression-free survival [7/20 vs. 34/51, adjusted HR 0.19 (0.07-0.47); P < 0.001] than those with thyroid irAE-, independent of PD-L1 expression; the results remained across most subgroups without interaction. The three groups showed different adjusted HR for disease progression (Group 1: PD L1 + and thyroid irAE + ; Group 2: PD-L1 + or thyroid irAE + : 5.08 [1.48-17.34]; Group 3: PD-L1- and thyroid irAE- : 30.49 [6.60-140.78]). Alternative staging (Group 1 in stage IVB → stage IVA; Group 3 in stage IVA → stage IVB) improved the prognostic value (PVE: 21.7% vs. 6.44%; C-index: 0.706 vs. 0.617) compared with the 8th Tumor-Node-Metastasis staging. Our study suggests thyroid irAEs and PD-L1 expression are independent biomarkers that improve predicting PD-1 blockade efficacy in NSCLC. Thyroid irAEs would be helpful to identify NSCLC patients who benefit from PD-1 blockade in early course of treatment.

Keywords: Immune-related adverse event; Non-small cell lung cancer; PD-1 blockade; PD-L1 expression; Predictivity; Thyroid.

Fig. 1

Effect of thyroid immune-related adverse events on progression-free survival according to subgroups using interaction analysis

Fig. 2

Changes in the classification of patients with stage IV non-small cell lung cancer who received programmed cell death protein 1 blockade by incorporating programmed death–‍ligand 1 expression and thyroid immune-related adverse events into the current staging system

Fig. 3

Kaplan–Meier curves with proportion of variance explained and C-index for disease progression according to a the 8th Tumor–Node–Metastasis staging and b alternative staging for patients with stage IV non-small cell lung cancer who received programmed cell death protein 1 blockade