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Individual- and trial-level surrogacy in colorectal cancer

¹ IDDI (International Drug Development Institute), Louvain-la-Neuve, Belgium and Center for Statistics, Hasselt University, Diepenbeek, Belgium,
² Center for Statistics, Hasselt University, Diepenbeek, Belgium,
³ Biostatistics and Epidemiology Unit, Institut Gustave Roussy, Villejuif, France
⁴ Oncology Therapy Area, Astra-Zeneca Research and Development, Macclesfield, UK

^* To whom correspondence should be addressed.

	Abstract

Two conditions must be fulfilled for an intermediate endpoint to be an acceptable surrogate for a true clinical endpoint: (1) there must be a strong association between the surrogate and the true endpoint, and (2) there must be a strong association between the effects of treatment on the surrogate and the true endpoint. We test whether these conditions are fulfilled for disease-free survival (DFS) and progression-free survival (PFS) on data from 20 clinical trials comparing experimental treatments with standard treatments for early and advanced colorectal cancer. The effects of treatment on DFS (or PFS in advanced disease) and OS were quantified through log hazard ratios (log HR), estimated through a Weibull model stratified for trial. The rank correlation coefficients between DFS and OS, and trial-specific treatment effects, were estimated using a bivariate copula distribution for these endpoints. A linear regression model between the estimated log hazard ratios was used to compute the "surrogate threshold effect", which is the minimum treatment effect on DFS required to predict a non-zero treatment effect on OS in a future trial. In early disease, the rank correlation coefficient between DFS and OS was equal to 0.96 (CI 0.95–0.97). The correlation coefficient between the log hazard ratios was equal to 0.94 (CI 0.87–1.01). The risk reductions were approximately 3% smaller on OS than on DFS, and the surrogate threshold effect corresponded to a DFS hazard ratio of 0.93. In advanced disease, the rank correlation coefficient between PFS and OS was equal to 0.82 (CI 0.82–0.83). The correlation coefficient between the log hazard ratios was equal to 0.99 (CI 0.94–1.04). The risk reductions were approximately 19% smaller on OS than on PFS, and the surrogate threshold effect corresponded to a PFS hazard ratio of 0.86. One trial with a large treatment effect on PFS and OS had a strong influence on the results in advanced disease. DFS (and PFS in advanced disease) are acceptable surrogates for OS in colorectal cancer.

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