OBJECTIVES: To determine whether treatment’s mechanism of action affects the surrogate relationship between progression free survival (PFS) and overall survival (OS) for metastatic colorectal cancer (mCRC) patients.

METHODS: A systematic literature review was conducted to identify randomised controlled trials (RCTs) of pharmacological therapies for mCRC published between January 2003 and April 2020 (PROSPERO: CRD42020167075). Trials included reported treatment effects on PFS and OS. The surrogate relationship between PFS and OS was evaluated in an overall analyses including all RCTs. Trials were then classified by the mechanism of action of the experimental arm. To evaluate the surrogate relationship between PFS and OS according to the mechanism of action a subgroup analyses of data within each class and a hierarchical method combining all data were used.

RESULTS: 63 RCTs were identified for the analysis. The surrogate relationship between treatment effects on PFS and OS including all RCTs was strong: intercept -0.01 (95% CrI: -0.05, 0.03), slope 0.38 (95% CrI: 0.30, 0.47), conditional variance 0.05 (95% CrI: 0.00, 0.10). Seven different treatment combinations were classified; Chemotherapy (eight RCTs), EGFR + Chemotherapy (23 RCTs), VEGF (four RCTs), VEGF + Chemotherapy (ten RCTs), VEGF + EGFR + Chemotherapy (three RCTs), EGFR (four RCTs), VEGF + EGFR (three RCTS), and eight RCTs remained unclassified. The surrogate relationship between the treatment effects on PFS and OS was strongest for the EGFR + Chemotherapy group (hierarchical method results): intercept -0.03 (95% CrI: -0.08, 0.03), slope 0.38 (95% CrI: 0.23, 0.55), conditional variance 0.01 (95% CrI: 0.00, 0.02). For those treatment classes with eight or more trials, PFS as a surrogate for OS appeared to have a stronger surrogate relationship than for all data combined.

CONCLUSIONS: There may be some impact of the mechanism of action on the surrogacy patterns in mCRC for PFS as a surrogate for OS.