The association of PD-L1 expression with the efficacy of anti-PD-1/PD-L1 immunotherapy and survival of non-small cell lung cancer patients: a meta-analysis of randomized controlled trials

Abstract

Background: We conducted a meta-analysis to evaluate the efficacy of anti-programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) monotherapy or immunotherapy combined with chemotherapy and further estimated the value of PD-L1 expression in predicting the response from anti-PD-1/PD-L1 treatments as monotherapy or in combination with chemotherapy.

Methods: Clinical trial data were searched from electronic databases, which evaluated PD-1/PD-L1 inhibitors in non-small cell lung cancer (NSCLC) and correlated with PD-L1 expression levels.

Results: Fifteen randomized-controlled trials involving 10,074 patients were identified. Comparing anti-PD-1/PD-L1 monotherapy to chemotherapy, the pooled HR for overall survival (OS) was 0.77 (95% CI: 0.69-0.85, P<0.00001). Subgroup analyses revealed that patients had longer OS at ≥1%, ≥5%, ≥10% and ≥50% PD-L1 expression levels. Patients with higher PD-L1 expression may get increased benefit from PD-1/PD-L1 inhibitors. Moreover, patients with PD-L1 ≥50% had an objective response rate (ORR) improvement from anti-PD-1/PD-L1 therapy (RR =1.87, 95% CI: 1.27-2.75, P=0.001), but no ORR benefits were observed in patients with PD-L1 expression <1% (RR =0.82, 95% CI: 0.56-1.22, P=0.33) or 1-49% (RR =0.80, 95% CI: 0.64-0.98, P=0.03). OS was significantly better in patients receiving second-or-third line treatments (P<0.00001) with PD-L1 ≥1%. The efficacy of PD-1 inhibitors was similar to that of PD-L1 inhibitors, with no significant difference (P=0.63, I²=0%). Furthermore, immunotherapy combined with chemotherapy had better OS (HR =0.64, 95% CI: 0.48-0.84, P=0.001) than chemotherapy alone. Subgroup analyses showed that patients benefited from the combined chemo-IO treatment in the first-line setting regardless of PD-L1 expression level.

Conclusions: PD-L1 expression may be a valuable predictor of the efficacy of anti-PD-1/PD-L1 monotherapy in certain NSCLC patients. However, the combination of chemotherapy plus immunotherapy significantly improved survival regardless of the PD-L1 expression level in the first-line treatment of NSCLC.

Keywords: Immunotherapy; meta-analysis; non-small cell lung cancer (NSCLC); programmed cell death ligand 1 (PD-L1).

Figure 1

Flowchart of study selection procedure.

Figure 2

Forest plots of HR of OS for PD-1/PD-L1 inhibitors in the intention-to-treat population. HR, hazard ratio; OS, overall survival; PD-1, programmed cell death 1; PD-L1, programmed cell death ligand-1.

Figure 3

Forest plot for the subgroup analyses of RR of ORR by PD-L1 expression for PD-1/PD-L1 inhibitors. RR, risk ratio; ORR, objective response rate; PD-1, programmed cell death 1; PD-L1, programmed cell death ligand-1.

Figure 4

Forest plot for the subgroup analyses of HR of OS by tumor histology for the PD-L1 ≥1% population in second-or-third line treatment. HR, hazard ratio; OS, overall survival; PD-L1, programmed cell death ligand-1.

Figure 5

Forest plot for the subgroup analyses of HR of OS by the line of treatment for the PD-L1 ≥1% population. HR, hazard ratio; OS, overall survival; PD-L1, programmed cell death ligand-1.

Figure 6

Forest plot for the subgroup analyses of HR of OS by the inhibitors used in anti-PD-1/PD-L1 monotherapy. HR, hazard ratio; OS, overall survival; PD-1, programmed cell death 1; PD-L1, programmed cell death ligand-1.

Figure 7

Forest plots of HR of OS for the combined immunotherapy in the intention-to-treat population. HR, hazard ratio; OS, overall survival.

Figure 8

Forest plot for the subgroup analyses of HR of OS by PD-L1 expression for the combined immunotherapy. HR, hazard ratio; OS, overall survival; PD-L1, programmed cell death ligand-1.

Figure 9

Risk of bias graph.

Figure 10

Funnel plot for publication bias.

Figure S1

Forest plots of HR of PFS for PD-1/PD-L1 inhibitors in the intention-to-treat population. HR, hazard ratio; PFS, progression free survival; PD-1, programmed cell death 1; PD-L1, programmed cell death ligand-1.

Figure S2

Forest plots of RR of ORR for PD-1/PD-L1 inhibitors in the intention-to-treat population. RR, risk ratio; ORR, objective response rate; PD-1, programmed cell death 1; PD-L1, programmed cell death ligand-1.

Figure S3

Forest plot for the subgroup analyses of HR of PFS by PD-L1 expression for PD-1/PD-L1 inhibitors. (A) PD-L1 expression <1% vs. PD-L1 expression ≥1%; (B) PD-L1 expression <5% vs. PD-L1 expression ≥5%; (C) PD-L1 expression <10% vs. PD-L1 expression ≥10%; (D) PD-L1 expression ≥50%. HR, hazard ratio; PFS, progression free survival; PD-1, programmed cell death 1; PD-L1, programmed cell death ligand-1.

Figure S4

Forest plot for the subgroup analyses of HR of OS by the line of treatment for the PD-L1 ≥50% population. HR, hazard ratio; OS, overall survival; PD-L1, programmed cell death ligand-1.

Figure S5

Forest plots of HR of PFS for the combined immunotherapy in the intention-to-treat population. HR, hazard ratio; PFS, progression free survival.

Figure S6

Forest plots of RR of ORR for the combined immunotherapy in the intention-to-treat population. RR, risk ratio; ORR, objective response rate.

Figure S7

Forest plot for the subgroup analyses of HR of PFS by PD-L1 expression for the combined immunotherapy. HR, hazard ratio; PFS, progression free survival; PD-L1, programmed cell death ligand-1.