Surrogate endpoints for overall survival in loco-regionally advanced nasopharyngeal carcinoma: Results from the individual patient data meta-analysis MAC-NPC2

Abstract

Background: Our objective was to evaluate progression-free survival (PFS) and distant metastasis-free survival (DMFS) as surrogate endpoints for overall survival (OS) in randomized trials of chemotherapy in loco-regionally advanced nasopharyngeal carcinomas (LANPC). Methods: Individual patient data were obtained from 19 trials of the updated Meta-Analysis of Chemotherapy in Nasopharyngeal Carcinoma (MAC-NPC) plus one additional trial (total: 5 144 patients). Surrogacy was evaluated at the individual level using a rank correlation coefficient ρ and at the trial level using a correlation coefficient R2 between treatment effects on the surrogate endpoint and OS. A sensitivity analysis was performed with 2-year PFS/DMFS and 5-year OS. Results: PFS was strongly correlated with OS at the individual level (ρ = 0.93, 95% Confidence Interval [CI]: 0.93-0.94) and at the trial level (R2 = 0.95, 95% CI: 0.47- 1.00). For DMFS, too, the individual-level correlation with OS was strong (ρ = 0.98, 95% CI: 0.98-0.98); at trial level, the correlation was high but the regression adjusted for measurement error could not be computed (unadjusted R2 = 0.96, 95% CI: 0.94-0.99). In the sensitivity analysis, 2-year PFS was highly correlated with 5-year OS at the individual level (ρ = 0.89, 95% CI: 0.88-0.90) and at the trial level (R2 = 0.85, 95% CI: 0.46-1.00); 2-year DMFS was highly correlated with 5-year OS at the individual level (ρ = 0.95, 95% CI: 0.94-0.95) and r at trial level (R2 = 0.78, 95% CI: 0.33-1.00). Conclusions: PFS and DMFS are valid surrogate endpoints for OS to assess treatment effect of chemotherapy in LANPC and PFS can be measured earlier.