Real-World Emulation of Landmark Lung Cancer Trials: A Registry-Based Reconstruction of KN189, KN407, IMpower133, and PACIFIC

Background: Checkpoint inhibitors (CPIs) improve the survival in advanced NSCLC and ES-SCLC, but reproducibility of randomized trial results in routine practice remains unclear. Target trial emulation enables approximation of randomized trial designs using observational data while reducing common biases. Methods: Using the Baden-Württemberg Cancer Registry, we emulated four pivotal trials: KEYNOTE-189 (eKN189), KEYNOTE-407 (eKN407), IMpower133 (eIMP133), and PACIFIC (ePACIFIC). The eligibility criteria, treatment strategies, and outcomes were aligned with the original trials as closely as possible within registry constraints. Time-zero was defined as the treatment initiation for systemic therapy cohorts (eKN189, eKN407, eIMP133) and as completion of chemoradiotherapy for ePACIFIC. The treatment groups were balanced using propensity-score-based inverse probability weighting. The outcomes included the overall survival (OS) and the objective response rate (ORR). Results: A total of 4015 patients were included (eKN189: 1762; eKN407: 467; eIMP133: 1190; ePACIFIC: 595). After weighting, the baseline covariates were well balanced. ICI-based regimens were associated with an improved survival: eKN189: HR—0.59 (95% CI: 0.52–0.66), 5-year OS—22.7% vs. 4.7%; eKN407: HR—0.69 (95% CI: 0.54–0.89), 5-year OS—11.8% vs. 6.6%; eIMP133: HR—0.7 (95% CI: 0.62–0.79), 5-year OS—12.8% vs. 5.3%; ePACIFIC: HR—0.51 (95% CI: 0.39–0.66), 5-year OS—47.3% vs. 23.4%. The OS curves demonstrated long-term plateaus across CPI-containing arms. The ORRs were consistently higher with CPI-containing regimens (eKN189: 41.6% vs. 29.6%; eKN407: 44.8% vs. 31.5%; eIMP133: 51.7% vs. 43.1%; ePACIFIC: 56.6% vs. 47.1%). Conclusions: This registry-based target trial emulation reproduced the survival patterns observed in four landmark lung cancer RCTs within trial-like real-world populations, supporting the external validity of pivotal immunotherapy trials while reinforcing the role of high-quality registries as a powerful complement to randomized trials in oncology.