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

Abstract

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 ¼ 0.87, R EP ¼ 0.86). This was also observed in chemotherapy-only trials (R TE ¼ 0.93, R EP ¼ 0.81) but less so for trials containing monoclonal antibodies (R TE ¼ 0.47; R EP ¼ 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 ¼ 0.84), whereas correlation within PFS and OS was low (R EP ¼ 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 ¼ 0.28; R EP ¼ 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.

Evaluation of Progression-Free Survival as a Surrogate Endpoint for Survival in Chemotherapy and Targeted Agent Metastatic Colorectal Cancer Trials

“…Consistent with recent findings (29), our data suggest that in current mCRC treatment regimens, PFS remains strongly correlated with OS. Regardless of this, PFS may reflect clinical benefit on its own, has many intrinsic advantages, and, therefore, should be considered a true primary endpoint in mCRC (30)(31)(32).…”

Relationship between Treatment Effects on Progression-Free Survival and Overall Survival in Multiple Myeloma: A Systematic Review and Meta-Analysis of Published Clinical Trial Data

“…Using PFS instead of OS as a primary endpoint has accelerated the reporting of results, thus accelerating the introduction of new drugs. Researchers have investigated PFS as a surrogate endpoint for OS with other cancers, validating its use with metastatic colorectal cancer [43,44,45] and breast cancer [44], while questioning its role in trials of molecular targeted agents (e.g., tyrosine kinase inhibitors (TKIs)) [46,47]. PFS has not been fully validated as a surrogate endpoint for OS in MM, and due to the ongoing debate about surrogate endpoints, establishing the usefulness of PFS in predicting OS aids in the rationale for its use as a primary endpoint in clinical trials.…”

‘Deepness of Response' Is Associated with Overall Survival in Standard Systemic Chemotherapy for Metastatic Colorectal Cancer

“…The objective response rate was previously shown to represent a surrogate end point for OS in mCRC [11]; PFS has therefore been widely employed as a primary end point in clinical trials, especially those involving first-line treatments [12,13]. However, a recent comprehensive review demonstrated a weaker correlation between PFS and OS in first-line chemotherapies that involved cetuximab or panutumumab rather than bevacizumab-based or biologic-free regimens [14]. Therefore, novel biomarkers associated with OS are still awaited in the era of molecular targeting therapy for mCRC.…”