A systematic review of surrogate endpoints (SEPs) for overall survival (OS) in metastatic colorectal cancer (mCRC).

Abstract

e18206 Background: Although progression free survival (PFS) and overall response rate (ORR) are common endpoints in mCRC trials, validation of these as SEPs for OS across the evolving landscape of systemic treatment in mCRC, with novel therapeutics and expanding lines of treatment, is limited. We aimed to evaluate the potential surrogacy of PFS and RR for OS and explore variations across trial factors. Methods: We identified phase 3 randomized trials of systemic therapy in mCRC between 1986 - 2016 from 4 electronic databases. Data regarding endpoints and trial variables were extracted from published reports. Spearman’s coefficient (r) and linear regression were used to evaluate rank correlations between A) PFS and ORR with OS of both treatment and control arms (arm level analysis); B) net improvement in outcomes using hazard ratio (HR) for PFS and relative risk (RR) for ORR with HR for OS (trial level analysis). Results: A total of 128 trials containing 233 and 230 arms reporting on PFS and ORR, respectively, were identified. Arm level analysis revealed that correlation of PFS and ORR with OS was 0.69 (95%CI: 0.6 – 0.7) and 0.79 (95%CI: 0.7 – 0.8), respectively ( P < 0.001). Of 86 trials with reported HR for OS, PFS and ORR ratios were obtained for 84 and 74 trials, respectively. Trial level analysis revealed that correlation of PFS and ORR treatment effect with OS was 0.71 (95%CI: 0.6 – 0.8) and 0.58 (95%CI: 0.4 – 0.7), respectively ( P < 0.001). Level of correlation for PFS and ORR varied with line of therapy, type of therapy and trial size (Spearman r shown in table). Conclusions: Both ORR and PFS are appropriate SEPs for OS for systemic therapy in mCRC but their relative value varies notably with line/type of therapy and study size. Judicious use of these SEPs in clinical trials accordingly to supplant OS may help improve trial designs and performance.[Table: see text]