Do crossover and post-progression treatments bias the relationship between surrogate endpoints and overall survival?
In two recent studies, we looked at evidence from 317 trials (78,644 patients) in first-line NSCLC setting (study 1 here) and 146 trials (43,061 patients) in further-line NSCLC setting (study 2 here). The relationship between surrogate endpoints, progression-free survival (PFS) and objective response rate (ORR), and overall survival (OS) was sequentially assessed in predefined subsets based on crossover and balance of post-progression therapies. In all trials analysis, ORR and PFS had weak (R<0.4) association, respectively, with OS. However, within trials that did not allow crossover and reported balanced post-progression treatments, ORR and PFS had moderate (R = 0.574, 95% CI: 0.396-0.710) and strong (R = 0.690, 95% CI: 0.503-0.816) relationships, association, with OS.
Based on this study, we may conclude that surrogacy of ORR and PFS for OS can be better estimated in trials that do not allow crossover and report balanced post-progression treatments. Further investigation of our methodology in other tumor types and settings is warranted.
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