Immunotherapy combined with chemotherapy versus chemotherapy alone as the first-line treatment of PD-L1-negative and driver-gene-negative advanced nonsquamous non-small-cell lung cancer: An updated systematic review and meta-analysis

Abstract

Background: This meta-analysis aimed to compare the efficacy of immunotherapy combined with chemotherapy versus chemotherapy alone as the first-line therapy for patients with programmed death ligand-1 (PD-L1)-negative and driver-gene-negative advanced nonsquamous non-small-cell lung cancer (NSCLC).

Patients and methods: Eligible randomized trials were identified following the systematic search of PubMed, Cochrane Library, Embase, Web of Science, Wanfang Data, and China Knowledge Resource Integrated Database from January 2000 to June 2022.

Results: Seven trials involving 1132 patients with PD-L1-negative and driver-gene-negative advanced nonsquamous NSCLC were included. Immunotherapy combined with chemotherapy showed significantly superior objective response rate (ORR) compared with chemotherapy alone (odds ratio 2.81, 95% confidence interval [CI] 1.69-4.65). Immunotherapy combined with chemotherapy also significantly prolonged the progression-free survival (PFS) (hazard ratio [HR] 0.63, 95% CI 0.55-0.74, p < 0.001) and overall survival (OS) (HR 0.68, 95% CI 0.56-0.82, p < 0.001) of patients with PD-L1-negative and driver-gene-negative advanced nonsquamous NSCLC compared to chemotherapy alone. In terms of ≥3 treatment-related adverse events, patients receiving immunotherapy combined with chemotherapy were at higher risk than chemotherapy alone (OR 1.73, 95% CI 1.47-2.05).

Conclusions: This meta-analysis suggested that immunotherapy combined with chemotherapy yielded a better ORR, PFS, and OS, and a higher incidence of treatment-related adverse events as the first-line therapy for patients with PD-L1-negative and driver-gene-negative nonsquamous advanced NSCLC in comparison to chemotherapy alone. A rational treatment protocol should be selected according to the individual condition of the patients.

Keywords: immune checkpoint inhibitor; immunotherapy; meta-analysis; nonsquamous non-small cell lung cancer; programmed death ligand-1.

FIGURE 1

Flow‐chart of the literature search

FIGURE 2

Quality assessment: risk of bias according to Cochrane Collaboration's tool. (a) Methodological quality graph: authors' judgment about each methodological quality item presented as percentages across all included studies. (b) Methodological quality summary. Remarks: authors' judgment about each methodological quality item for each included study. +, low risk of bias; ?, unclear risk of bias; −, high risk of bias

FIGURE 3

Forest plot for ORR (a), PFS (b), and OS (c) of PD‐L1‐negative and driver‐gene‐negative nonsquamous NSCLC patients treated with immunotherapy versus chemotherapy. Remarks: outcomes with hazard ratio <1 would suggest better survival outcomes with immunotherapy, while ORR outcomes with odds ratio >1 would suggest better efficacies. NSCLC, non‐small‐cell lung cancer; ORR, overall response rate; OS, overall survival; PD‐L1, programmed death ligand‐1; PFS, progression‐free survival

FIGURE 4

Forest plot for ≥3 TRAEs of driver‐gene‐negative nonsquamous NSCLC patients treated with immunotherapy versus chemotherapy. Remarks: outcomes with odds ratio >1 would suggest higher incidence of adverse events with immunotherapy. NSCLC, non‐small‐cell lung cancer; PD‐L1, programmed death ligand‐1; TRAEs, treatment‐related adverse events