Progression-Free Survival as a Surrogate Endpoint of Overall Survival in Patients with Locally Advanced Non-Small Cell Lung Cancer Treated with Chemoradiotherapy: Trial-Level Meta-Analysis and Individual-Level Analysis of NRG/RTOG 0617 and PROCLAIM

Abstract

Overall Survival (OS) is the gold standard endpoint in randomized clinical trials (RCTs) of Locally Advanced Non-Small Cell Lung Cancer (LA-NSCLC). Intermediate endpoints that can be observed at earlier time points and predict OS would improve trial efficiency and expedite the adoption of proven interventions. Atrial-level meta-analysis was conducted using a weighted regression analysis to quantify the correlation between PFS and OS hazard ratios (HRs). Large (n≥ 100) contemporary RCTs in LA-NSCLC that used platinum-based chemoradiation were included. An individual-level surrogacy analysis based on Prentice criteria was performed to evaluate if PFS could reliably predict OS using NRG/RTOG 0617 (NCT00533949), a phase III RCT of dose escalated CRT. The individual-level correlation between PFS and OS was validated using PROCLAIM (NCT00686959) control arm. Nineteen RCTs comprising a total of 5525 patients (pts) were included in the trial-level meta-analysis. A moderately high correlation was observed between PFS HR and OS HR (R2 = 0.68, 95% CI = 0.42-0.94). Individual-level analysis of NRG/RTOG 0617 showed that, as reported, RT dose was associated with OS (HR = 1.28, 95% CI = 1.04-1.58, p = 0.02) and PFS (HR = 1.21, 95% CI = 0.99-1.46, p = 0.06). Progressive disease (PD) was highly associated with OS, where pts having PD within 6mo or 12mo had a significantly higher mortality risk than those not having PD within 6mo or 12 mo, respectively, in landmark analysis (PD within 6mo: HR = 2.56, 95% CI = 1.82-3.59, p<0.0001; PD within 12mo: HR = 3.18, 95% CI = 2.45-4.12, p<0.0001). Accounting for PD moderately reduced RT dose effect on OS (HR = 1.21, 95% CI = 0.98-1.49), suggesting RT dose effect on OS may be mediated partially through PD. The association between OS and PD occurrence within 6mo or 12mo was similar in PROCLAIM control arm (PD within 6mo: HR = 2.06, 95% CI = 1.48-2.86, p<0.0001; PD within 12mo: HR = 2.02, 95% CI = 1.38-2.95, p<0.0001). A moderately high trial-level surrogacy between PFS and OS was identified in trial-level meta-analysis. PD occurrence also reliably predicted OS at the individual patient level in both NRG/RTOG 0617 and PROCLAIM. These results support the use of PFS as a valid endpoint in clinical trials of LA-NSCLC.