Progression-Free Survival as a Surrogate Endpoint for Median Overall Survival in Metastatic Colorectal Cancer: Literature-Based Analysis from 50 Randomized First-Line Trials

Purpose: To evaluate progression-free survival (PFS) as a potential surrogate endpoint (SEP) for overall survival (OS) in metastatic colorectal cancer (mCRC) with a focus on applicability to trials containing targeted therapy with anti-VEGF- or anti-EGF receptor (EGFR)-directed monoclonal antibodies. Experimental Design: A systematic literature search of randomized trials of first-line chemotherapy for mCRC reported from January 2000 to January 2012 was conducted. Adjusted weighted linear regression was used to calculate correlations within PFS and OS (endpoints; R-EP) and between treatment effects on PFS and on OS (treatment effects; R-TE). Results: Fifty trials reflecting 22,736 patients met the inclusion criteria. Correlation between treatment effects on PFS and OS and between the endpoints PFS and OS was high across all studies (R-TE = 0.87, R-EP = 0.86). This was also observed in chemotherapy-only trials (R-TE = 0.93, R-EP = 0.81) but less so for trials containing monoclonal antibodies (R-TE = 0.47; R-EP = 0.52). Limiting the analysis to bevacizumab-based studies (11 trials, 3,310 patients) again yielded high correlations between treatment effects on PFS and on OS (R-TE = 0.84), whereas correlation within PFS and OS was low (R-EP = 0.45). In 7 trials (1,335 patients) investigating cetuximab- or panitumumab-based studies, contrasting correlations with very wide confidence intervals were observed (R-TE = 0.28; R-EP = 0.96). Conclusions: PFS showed consistently high correlation with OS of an order that would justify its use as an SEP in chemotherapy regimens. For validation of surrogacy in anti-VEGF and anti-EGFR-directed therapies, further research and a larger set of trials is needed. Clin Cancer Res; 19(1); 225-35. (c) 2012 AACR.