ObjectivePembrolizumab has become an integral first line therapeutic agent for non-small cell lung cancer (NSCLC), but its potential predictive role in clinical and molecular characteristics remains to be clarified. Accordingly, we performed a systematic review and meta-analysis to evaluate the clinical benefit of pembrolizumab in treatment of first line NSCLC and to select individuals with the greatest potential benefit from pembrolizumab therapy, in order to obtain a more accurate treatment of NSCLC in immunotherapy.MethodsMainstream oncology datasets and conferences were searched for randomized clinical trials (RCTs) published before August 2022. RCTs involved individuals with first line NSCLC treated with pembrolizumab monotherapy or in combination with chemotherapy. Two authors independently selected the studies, extracted data, and assessed the risk of bias. The basic characteristics of the included studies were recorded, along with 95 percent confidence intervals (CI) and hazard ratios (HR) for all patients and subgroups. The primary endpoint was overall survival (OS), and secondary endpoints was progression-free survival (PFS). Pooled treatment data were estimated using the inverse variance-weighted method.ResultsFive RCTs involving 2,877 individuals were included in the study. Pembrolizumab-based therapy significantly improved OS (HR 0.66; CI 95%, 0.55–0.79;p< 0.00001) and PFS (HR 0.60; CI 95%, 0.40–0.91;p= 0.02) compared with chemotherapy. OS was substantially enhanced in individuals aged < 65 years (HR 0.59; CI 95%, 0.42–0.82;p= 0.002), males (HR 0.74; CI 95%, 0.65–0.83;p< 0.00001), with a smoking history (HR 0.65; CI 95%, 0.52–0.82;p= 0.0003), with PD-L1 tumor proportion score (TPS) < 1% (HR 0.55; CI 95%, 0.41–0.73;p< 0.0001) and TPS ≥ 50% (HR 0.66; CI 95%, 0.56–0.76;p< 0.00001), but not in individuals aged ≥ 75 years (HR 0.82; CI 95%, 0.56–1.21;p= 0.32), females (HR 0.57; CI 95%, 0.31–1.06;p= 0.08), never smokers (HR 0.57; CI 95%, 0.18–1.80;p= 0.34), or with TPS 1–49% (HR 0.72; CI 95%, 0.52–1.01;p= 0.06). Pembrolizumab significantly prolonged OS in NSCLC patients, regardless of histology type (squamous or non-squamous NSCLC), performance status (PS) (0 or 1), and brain metastatic status (allp< 0.05). Subgroup analysis revealed that pembrolizumab combined with chemotherapy had more favorable HR values than pembrolizumab monotherapy in improving the OS of individuals with different clinical and molecular features.ConclusionPembrolizumab-based therapy is a valuable option for first line treating advanced or metastatic NSCLC. Age, sex, smoking history and PD-L1 expression status can be used to predict the clinical benefit of pembrolizumab. Cautiousness was needed when using pembrolizumab in NSCLC patients aged ≥ 75 years, females, never smokers, or in patients with TPS 1–49%. Furthermore, pembrolizumab in combination with chemotherapy may be a more effective treatment regimen.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12885-023-10959-3.