The Predictive Value of Clinical and Molecular Characteristics or Immunotherapy in Non-Small Cell Lung Cancer: A Meta-Analysis of Randomized Controlled Trials

Abstract

Background: This meta-analysis aimed to investigate the efficacy of immune checkpoint inhibitor (ICI)-based therapy in non-small cell lung cancer (NSCLC) patients with different clinical and molecular characteristics such as age, sex, histological type, performance status (PS), smoking status, driver mutations, metastatic site, region and number of prior systemic regimens.

Methods: A systematic literature search was conducted in PubMed, Embase, and the Cochrane library databases to identify qualified randomized controlled trials (RCTs). The primary endpoint was overall survival (OS), and the secondary endpoint was progression-free survival (PFS).

Results: A total of 19 RCTs were included in this meta-analysis. ICI-based therapy significantly improved OS compared with non-ICI therapy in patients aged <65 years (HR, 0.74; P<0.00001), 65-74 years (HR, 0.73; P<0.00001), receiving first-line (HR, 0.75; P<0.00001) or second-line (HR, 0.72; P<0.00001) treatment, current or previous smokers (HR, 0.76; P<0.00001), and EGFR wild-type patients (HR, 0.76; P<0.00001), but not in patients aged ≥75 years (HR, 0.91; P=0.50), receiving third-line treatment (HR, 0.93; P=0.55), never smokers (HR, 0.84; P=0.10), or EGFR mutant patients (HR, 0.99; P=0.92). No statistical OS improvement was observed in KRAS mutant (HR, 0.68; P=0.05) or KRAS wild-type (HR, 0.95; P=0.65) patients. Immunotherapy improved OS in NSCLC patients, regardless of sex (male or female), histological type (squamous or non-squamous NSCLC), PS (0 or 1), metastatic site (brain or liver metastases), and region (East Asia or America/Europe) (all P<0.05). Subgroup analysis showed that the survival benefit of ICIs in patients with brain metastases was observed in first-line combination therapy (P<0.05), but not in second or more line monotherapy (P>0.05). Programmed death-1 (PD-1) inhibitors significantly prolonged OS in patients with liver metastases compared with non-ICI therapy (P=0.0007), but PD-L1 inhibitors did not (P=0.35). Similar results were observed in the combined analysis of PFS.

Conclusions: Age, smoking status, EGFR mutation status, and number of prior systemic regimens predicted the efficacy of immunotherapy. While sex, histological type, PS 0 or 1, KRAS mutation status and region were not associated with the efficacy of ICIs. Patients with liver metastases benefited from anti-PD-1-based therapy, and those with brain metastases benefited from first-line ICI-based combination therapy.

Systematic review registration: http://www.crd.york.ac.uk/prospero, identifier CRD42020206062.

Keywords: efficacy; immune checkpoint inhibitor; meta-analysis; non-small cell lung cancer; predictor.