Design-Outcome Concordance in Targeted-Therapy trials in Non-Small cell lung cancer: a Meta-Research study

In biomarker-selected non-small cell lung cancer (NSCLC) targeted therapies often produce substantial improvements in survival outcomes. We conducted a systematic review of phase III randomized controlled trials (RCTs) in oncogene-driven NSCLC to evaluate the concordance between design assumptions and observed treatment effects.

MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials were searched for phase III RCTs published between January 1, 2005, and February 1, 2025, enrolling patients with metastatic or locally advanced, biomarker-selected NSCLC, comparing targeted agents versus standard regimens in a superiority design. Hazard ratios (HRs) for progression-free survival were considered. Statistical analyses included meta-analyses with meta-regression; retrodesign analysis of power, type S error, and exaggeration ratios; design-outcome concordance; and restricted mean survival time (RMST).

1987 records were screened, and 45 studies included. Progression-free survival was the primary outcome in all RCTs. Median expected HR was 0.64 (IQR 0.61-0.67). Pooled observed HR was 0.47 (95% CI 0.40-0.54), studies with higher standard errors were associated with larger treatment effects (P<.001). Statistically significant results were reported in 38 (84%) RCTs. Under original assumptions, median retrodesign power was 0.78 (IQR 0.72-0.88), and using the observed HR, median power was 1.00 (IQR 0.98-1.00). Pooled observed-to-expected HR ratio was 0.76 (95%CI 0.66-0.87). In Bayesian analyses, 17 (41%) trials had <1% probability of exceeding planned HR. Proportional hazards (PH) assumption was violated in 8 trials (19%). Pooled HR/RMST ratio was 1.40 (95% CI 1.29-1.52).

Our work supports reporting retrodesign metrics, the minimal clinically important difference alongside the anticipated effect size, and systematic inclusion of RMST.