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.