PD-L1 expression as a negative predictive biomarker in advanced esophageal squamous-cell cancer treated with chemotherapy alone

Abstract

Background

Programmed death-ligand 1 (PD-L1) expression is a well-established positive predictive biomarker for response to immunotherapy in advanced esophageal squamous-cell carcinoma (aESCC). However, the association between PD-L1 and response to chemotherapy alone remains unclear. This study aims to determine the prognostic significance of PD-L1 expression in patients treated with first-line chemotherapy alone in aESCC.

Materials and methods

First-line phase III randomized trials that included PD-L1 expression as a biomarker in aESCC were extracted after a systematic search. A graphical reconstructive algorithm was used to estimate time-to-event outcomes from reported Kaplan–Meier (KM) plots and, where unavailable, KMSubtraction was utilized to derive KM plots of unreported PD-L1 subgroups. Thereafter, an individual patient data meta-analysis was conducted. Survival analyses for overall survival (OS) and progression-free survival (PFS) were conducted with Cox proportional hazards models with a shared-frailty term incorporated to account for interstudy differences.

Results

Chemotherapy arms from five randomized phase III trials—CheckMate-648, ESCORT-1st, KEYNOTE-590, RATIONALE-306 and ORIENT-15—comprising 1517 patients were included in the OS analysis. Compared with PD-L1-low-expressing tumors, patients with PD-L1-high-expressing tumors were at a significantly higher risk of mortality [hazard ratio (HR) 1.153, 95% confidence interval (CI) 1.018-1.305, P = 0.025]. Three trials—CheckMate-648, ESCORT-1st and ORIENT-15—comprising 949 patients treated with chemotherapy alone were included in the PFS analysis. Patients with PD-L1-high-expressing tumors had a non-significant increased risk of tumor progression (HR 1.076, 95% CI 0.923 –1.253, P = 0.349).

Conclusions

Our study found PD-L1 expression is a negative predictor of OS in aESCC treated with first-line chemotherapy.