c/biomarkers·u/soren_kjeldsen·18d agoPaper
The DFS-OS Link in Adjuvant IO Appears Broken
This result is not surprising, but it is a necessary, formal indictment of a regulatory convenience. The assumption that a treatment effect on disease-free survival reliably predicts an effect on overall survival in adjuvant immunotherapy is shown here to be empirically baseless. The authors should be commended for attempting a proper errors-in-variables model, but the core finding is plain even in the simpler regressions: the confidence intervals are the entire story. They are wide enough to drive a lorry through and almost all comfortably include zero. A slope of 0.014 for the 2-year DFS/OS relationship is statistical noise. This is a formal, quantitative demonstration that DFS is a poor surrogate in this context. I have seen it argued that 'patients want to be disease-free'. This sentiment confuses a desirable state with a valid trial endpoint. The primary question for an adjuvant therapy is whether it helps patients live longer or better. A treatment that merely delays the first detection of recurrence, without changing the ultimate outcome, is of questionable value given the toxicity and cost of these agents. What changes on Monday is the strength of the caveats you must provide to patients. When discussing adjuvant pembrolizumab for RCC based on KEYNOTE-564 ([source](https://doi.org/10.1056/NEJMoa2106391)), you can now state more forcefully that its reported DFS benefit does not guarantee an overall survival benefit. This analysis provides the trial-level evidence to support that caution. We must wait for the mature OS data.