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BackgroundDespite disappointing outcomes from immuno-monotherapy, studies reported that NSCLC patients with EGFR mutation may possibly benefit from combined immunotherapy. Whether the response to prior EGFR-TKI has association with the outcomes of subsequent immunotherapy remains unclear.Patients and MethodsAdvanced NSCLC patients with resistance to EGFR-TKIs and received ICI treatment from January 2016 to June 2019 were retrospectively analyzed. Single cell sequencing and flow cytometry were conducted to explore the difference of cell components in tumor microenvironments (TME). A 1:3 matched case–control study was conducted to compare the clinical effects of combined immunotherapy with standard chemotherapy as second-line treatment.ResultsFifty-eight patients treated with anti-PD-1/PD-L1 based immunotherapy behind EGFR-TKI treatment were enrolled. Correlation analysis showed TKI-PFS had a significantly negative association with corresponding IO-PFS (r = −0.35, p = 0.006). TKI-PFS cutoff 10 months had the most significant predictive function for posterior immunotherapy and was validated to be an independent predictor by uni- and multivariate analyses. Kaplan–Meier analysis showed that patients with TKI-PFS less than 10 months had significantly prolonged IO-PFS and higher ORR than those with long (median PFS, 15.1 vs 3.8 months; HR, 0.26, p = 0.0002; ORR, 31.8 versus 10%, p = 0.04). Single cell RNA-seq revealed that the cell components were varied among patients after treatment with EGFR-TKI. Patients with short TKI-PFS demonstrated a relatively higher proportion of CD8 effector cells and lower ratio of M2 like macrophage to M1 like macrophages, which was validated by flow cytometry. Case–control study demonstrated that combined immunotherapy achieved significantly longer PFS (HR, 0.51, 95% CI: 0.31–0.85, p = 0.02), longer OS (HR, 0.48, 95% CI: 0.26–0.89, p = 0.05) and higher ORR (33.3 vs 10.0%, p = 0.02) than traditional chemotherapy for patients with short TKI-PFS.ConclusionPatients with short TKI-PFS conferred better response to immunotherapy than those with long. The status of TME were different among those two populations. Combined ICI treatment could promisingly be a better choice than classical chemotherapy in second-line setting for patients with short TKI-PFS and no T790M mutation. Underlying mechanisms need to be further explored.

Programmed cell death ligand 1 (PD-L1) expressed on tumor tissues is a vital molecule for immune suppression and its impact on the response to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) has been reported. The significance of soluble PD-L1 (sPD-L1) for lung cancer patients remains unknown. This study investigated whether sPD-L1 could predict the response of EGFR-mutated non-small cell lung cancer (NSCLC) to EGFR-targeted therapy. We retrospectively evaluated patients who received first-line treatment with EGFR-TKIs for advanced NSCLC with EGFR mutations. Pre-treatment plasma concentrations of PD-L1 and on-treatment (1 month after treatment initiation) plasma concentrations of PD-L1 were measured using the R-plex Human PD-L1 assay. The association between the sPD-L1 level and the clinical outcome was analyzed. Among 66 patients who were eligible for the study, patients with high pre-treatment or on-treatment sPD-L1 levels had decreased objective response rate (ORR) compared with that of patients with low sPD-L1 levels (39.4 vs. 66.7%, p = 0.026 for pre-treatment sPD-L1 level, and 43.5 vs. 73.9%, p = 0.025 for on-treatment sPD-L1 level). A high baseline sPD-L1 level was associated with a shortened progression-free survival (PFS) rate (9.9 vs. 16.1 months, p = 0.005). Both univariate and multivariate analyses showed that a high baseline sPD-L1 level was an independent factor associated with the PFS (hazard ratio [HR] 2.56, p = 0.011). Our study revealed that the sPD-L1 level was strongly related to the outcome of EGFR-TKIs in NSCLC patients harboring EGFR mutations.