PD-L1 expression and immune profiling cannot predict osimertinib efficacy in lung cancer with EGFR T790 M mutation: A translational study

Background: PD-L1 is associated with poor efficacy of first- or second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in untreated EGFR-mutant non-small-cell lung cancer (NSCLC). Whether PD-L1 is also predictive of osimertinib efficacy in pre-treated patients with an acquired EGFR T790 M mutation is unclear.

Patients and methods: PD-L1 expression and tumor microenvironments were evaluated in tumors from EGFR-mutant T790 M + NSCLC patients treated with osimertinib. In vitro and in vivo experiments were also performed to examine the effect of PD-L1 overexpression on osimertinib susceptibility in EGFR T790 M + cells.

Results: A total of 134 pre-treated EGFR T790 M + patients were enrolled, of whom 72 had del19, 58 had L858R, and 4 had G719X as initial EGFR mutation subtype. Positive PD-L1 expression (TC ≥ 1%) was found in 21 of 134 (15.7%) patients. PD-L1 expression did not differ across different biopsied sites and among different EGFR mutation subgroups. Kaplan-Meier estimate revealed no significant difference in progression-free survival (PFS) in PD-L1-positive versus PD-L1-negative patients. Multivariate analysis using the Cox proportional hazard model found that older age and L858R mutation were independent predictive factors. Multiplex IHC showed that immune cell infiltration was not associated with PD-L1 expression or osimertinib treatment response. By overexpressing PD-L1 in EGFR T790 M + cells, we found that PD-L1 did not result in osimertinib resistance in in vitro and xenograft models.

Conclusions: PD-L1 expression in pre-treated EGFR T790 M + lung adenocarcinoma is not predictive of osimertinib efficacy, as demonstrated by in vitro, xenograft, and clinical case studies.