Targeted agents combined with immune checkpoint inhibitors in advanced non-small cell lung cancer: a systematic review and externally anchored Bayesian network meta-analysis

Targeted agents combined with PD-1 or PD-L1 blockade have been investigated in advanced non-small cell lung cancer (NSCLC), but the evidence is dominated by small single-arm studies in clinically distinct populations. We evaluated class-level activity, safety, and progression-free survival using an explicit external chemotherapy benchmark. We conducted a systematic review and exploratory externally anchored, arm-based Bayesian network meta-analysis. PubMed, Embase, and the Cochrane Library were searched through 30 March 2025 and updated through 26 July 2026. Eligible studies evaluated an epidermal growth factor receptor inhibitor (EGFRi) plus PD-1 blockade, EGFRi plus PD-L1 blockade, or a multitarget tyrosine kinase inhibitor (MTKI) plus an immune checkpoint inhibitor (ICI). Objective response rate (ORR) was primary; disease control rate, grade 3 or higher treatment-related adverse events, and median progression-free survival (PFS) were secondary or exploratory. Three randomized platinum-chemotherapy control arms informed the external anchor. Nineteen independent intervention studies involving 730 patients were included; the chemotherapy anchor comprised 530 randomized patients. Model-based absolute ORRs were 23.1% for EGFRi plus PD-1, 64.1% for EGFRi plus PD-L1, 34.1% for MTKI plus ICI, and 30.6% for chemotherapy. Odds ratios versus chemotherapy were 0.67 (95% credible interval [CrI], 0.21–2.01), 3.97 (1.68–9.78), and 1.17 (0.62–2.18), respectively. Common heterogeneity was 0.43 (0.18–0.74). The grade 3 or higher toxicity estimate for MTKI plus ICI was 26.1%. Exploratory median-PFS ratios versus chemotherapy were 1.82 for EGFRi plus PD-L1 and 1.15 for MTKI plus ICI. Eighteen studies were at serious overall risk of bias and one at critical risk. EGFRi plus PD-L1 had a numerically high response signal, whereas the other combinations did not show clearly different ORR from chemotherapy. Confounding, nonexchangeability, sparse evidence, and historical-control dependence make all findings hypothesis-generating and unsuitable for treatment ranking. Systematic review registration: PROSPERO CRD420261461056.