Immune-checkpoint inhibitor plus chemotherapy versus conventional chemotherapy for first-line treatment in advanced non-small cell lung carcinoma: a systematic review and meta-analysis

Abstract

Background: Immune-checkpoint inhibitors plus chemotherapy are emerging as effective first-line treatment in advanced non-small-cell lung carcinoma (NSCLC), but little is known about the magnitude of benefits and potential clinical predictors.

Methods: We performed a meta-analysis of randomized trials that compared PD-1/PD-L1 inhibitor plus chemotherapy with chemotherapy in first line of treatment for advanced NSCLC. The outcomes included progression-free survival (PFS), overall survival (OS), objective response rate (ORR) and treatment-related adverse events (AEs). A fixed-effect or random-effects model was adopted depending on between-study heterogeneity.

Results: Six trials involving 3144 patients were included. PD-1/PD-L1 inhibitor plus chemotherapy was significantly associated with improvement of PFS (hazards ratio [HR], 0.62; 95% CI 0.57-0.67; P < .001), OS (HR, 0.68; 95% CI 0.53-0.87; P = .002) and ORR (relative ratio [RR], 1.56; 95% CI 1.29-1.89; P < .001), irrespective of PD-L1 expression level. The significant predictor(s) for treatment benefit with combination therapy versus chemotherapy alone were PD-L1 expression level for PFS (P < .001); types of checkpoint inhibitor for ORR (P < .001); histology (P = .025), age (P = .038), gender (P < .001), and types of checkpoint inhibitor (P < .001) for OS. In safety analyses, PD-1/PD-L1 inhibitor plus chemotherapy had significantly higher incidence of adverse events (AEs) of grade 3 or higher (RR, 1.14; P = .007), AEs leading to treatment discontinuation (RR, 1.29; P = .022), serious AEs (RR 1.70; P = .006), immune mediated AEs of any grade (RR, 2.37; P < .001), and immune mediated AEs of grade 3 or higher (RR, 3.71; P < .001).

Conclusions: PD-1/PD-L1 inhibitor plus chemotherapy, compared with chemotherapy, is associated with significantly improved PFS, ORR, and OS in first-line therapy in NSCLC, at the expense of increased treatment-related AEs.

Keywords: Chemotherapy; Immune checkpoint inhibitor; Non-small cell lung carcinoma; Predict; Programmed death 1; Programmed death 1 ligand 1.

Fig. 1

Forest plot of hazard ratios and risk ratios comparing (a) progression-free survival, (b) overall survival, and (c) objective response rate in patients who received IO-Chemotherapy vs Chemotherapy alone. Squares represent study-specific effect size (HR or RR). The area of square is inversely proportional to the standard error of the study (and therefore indirectly to the sample size) and larger area indicates greater weight in the calculation of the pooled effect size. The horizontal line crossing the square represents the 95% CI. The diamonds represent the estimated overall effect, based on the meta-analysis. HR, hazard ratio; RR, relative risk; CI, confidence interval

Fig. 2

Forest plot of hazard ratios in subgroup-analyses comparing overall survival in patients who received IO-Chemotherapy vs Chemotherapy alone. The horizontal line crossing the dot represents the 95%CI of the pooled hazard ratio in each subgroup-analysis. No. of trials refers to the number of trials included in each subgroup-analysis. I² (P) shows the heterogeneity in each subgroup meta-analysis. P (subgroups) demonstrates the significance of differences between the subgroups. HR, hazard ratio; CI, confidence interval; ECOG PS, Eastern Cooperative Oncology Group performance status; EGFR, epidermal growth factor receptor; ALK, Anaplastic lymphoma kinase; PD-1, programmed cell death 1; PD-L1, programmed cell death 1 ligand 1; IO, Immuno-oncology

Fig. 3

Forest plot of hazard ratios by PD-L1 expression comparing progression-free survival in patients who received IO-Chemotherapy vs Chemotherapy alone. Squares represent study-specific effect size (HR or RR). The area of square is inversely proportional to the standard error of the study and larger area indicates greater weight in the calculation of the pooled effect size. The horizontal line crossing the square represents the 95% CI. The diamonds represent the estimated overall effect, based on the meta-analysis. HR, hazard ratio; IO, Immuno-oncology; CI, confidence interval; PD-L1, programmed cell death 1 ligand 1

Fig. 4

Forest plot of risk ratios comparing treatment-related adverse events in patients who received IO-Chemotherapy vs Chemotherapy alone. The horizontal line crossing the dot represents the 95%CI of the pooled risk ratio in each subgroup-analysis. No. of trials refers to the number of trials included in each subgroup-analysis. I² (P) shows the heterogeneity in each subgroup meta-analysis. ^aData provided in KEYNOTE-189 and KEYNOTE-407 were all-cause adverse events, regardless of attribution to any treatment. CI, confidence interval; RR, risk ratio; AEs, adverse events; IO, Immuno-oncology