- Design
- Systematic review and meta-analysis of randomised trials (surrogate endpoint analysis)
- Population
- 62 trials, 24,518 patients with metastatic renal cell carcinoma
- Primary outcome
- Correlation of treatment effects on PFS and ORR with overall survival
- Effect
- PFS-OS r=0.52 (95% CI 0.38 to 0.66); ORR-OS r=-0.59 (-0.72 to -0.45)
A meta-analysis of 62 randomised trials with 24,518 patients assessed whether treatment effects on progression-free survival (PFS) and objective response rate (ORR) predict effects on overall survival (OS) in metastatic renal cell carcinoma.
Trial-level correlations were moderate: PFS with OS r=0.52 (95% CI 0.38 to 0.66) and ORR with OS r=-0.59 (-0.72 to -0.45). The surrogate threshold effect for PFS was a hazard ratio of 0.92 (0.79 to 1.09), whose interval spans 1, so no reliable PFS threshold predicting OS benefit was shown. Subgroups by treatment class and line of therapy were often imprecise, and non-clear-cell histology was too sparse to analyse.
The authors conclude that surrogacy is context-dependent and that overall survival should remain the reference. For a clinician reading a trial that reports a PFS gain, the point is to ask whether overall survival data exist and how mature they are.
- Moderate correlations mean a PFS gain does not reliably predict an overall survival gain.
- Look for overall survival and quality of life data before changing practice.
- Surrogate performance varied by treatment class and line of therapy.
- Non-clear-cell renal cancer was too sparse to draw conclusions.
Why it matters
It cautions against reading early endpoint wins as survival gains in a fast-moving drug field.
Don't overread it
Trial-level surrogacy does not tell you what happens to an individual patient, and heterogeneity was substantial.
The statistics, in plain English
A correlation of 0.5 means treatment effects on PFS explain only about a quarter of the variation in treatment effects on survival across trials. A surrogate threshold whose interval crosses 1 means no reliable cut-off was found.
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