Evaluation of disease-free survival as surrogate endpoint for overall survival using two individual patient data meta-analyses of adjuvant chemotherapy in operable non-small cell lung cancer

Abstract

BACKGROUND: The gold standard endpoint in clinical trials of adjuvant chemotherapy (CT) in lung cancer is overall survival (OS), which while a reliant and simple-to-measure outcome, takes a long time to observe in this setting. This study aimed to evaluate disease-free survival (DFS) as a potential surrogate endpoint for OS in adjuvant CT trials, which could lead to more rapid conclusion of trials. METHODS: This analysis was based on individual patient data of 7,626 patients (pts) and 25 randomized trials from two large meta-analyses of adjuvant CT: surgery alone versus surgery + CT and surgery + radiotherapy (RT) versus surgery + RT + CT. DFS was defined as the time from randomization to the first event (local or distant recurrence or death from any cause). A correlation approach was used to assess individual and trial level surrogacy: at the individual level, to estimate association between distributions of DFS and OS ( ), and at trial level, to estimate association between treatment effects on DFS and OS (R). Values of and R closer to 1.0 would indicate strong surrogacy. RESULTS: Analysis 1 (without RT) included 18 trials (5,379 pts, 2,525 DFS events and 2,163 deaths); analysis 2 (with RT) included 7 trials (2,247 pts, 1,673 DFS events and 1,566 deaths). 79% and 84% of DFS events, respectively, occurred in the first three years. Correlations between DFS and OS were very strong, both at the individual ( =0.91 in trials without RT and 0.93 in trials with RT) and trial level (R=0.96, 95% confidence interval [0.92-1.00] and 0.99 [0.98-1.00], respectively). Considering only events occurring in the first three years and deaths in the first five years, trial-level correlation remained strong (R=0.94 [0.88-1.00] and 0.98 [0.95-1.01] respectively). CONCLUSIONS: Our large database provides good evidence that disease-free survival is a valid surrogate endpoint for overall survival in operable non-small cell lung cancer in the adjuvant CT setting. Supported by French Cancer League, PHRC and British Medical Research Council.