In metastatic kidney cancer, progression-free survival was an imperfect stand-in for overall survival

Design

Systematic review and trial-level surrogate endpoint meta-analysis of randomised trials

Population

62 randomised trials with 24,518 patients with metastatic renal cell carcinoma

Primary outcome

Correlation of treatment effects on progression-free survival and response rate with overall survival

Effect

PFS-OS r = 0.52 (95% CI 0.38 to 0.66), surrogate threshold HR 0.92 (95% CI 0.79 to 1.09); ORR-OS r = -0.59

This meta-analysis used 62 randomised trials of metastatic renal cell carcinoma with 24,518 patients to ask whether treatment effects on progression-free survival or response rate predict effects on overall survival, which matters because new drugs are often approved on the earlier endpoints.

The trial-level correlation between effects on progression-free survival and overall survival was moderate (r = 0.52, 95% CI 0.38 to 0.66), with a surrogate threshold effect hazard ratio of 0.92 (95% CI 0.79 to 1.09). For objective response rate, the correlation was moderate (r = -0.59, 95% CI -0.72 to -0.45), with a threshold odds ratio of 1.40 (0.99 to 1.89). Subgroup results by treatment class, line of therapy and histology varied and were often imprecise, and non-clear cell cancers were too few for conclusions.

The authors judge that neither endpoint showed consistent enough surrogacy to predict a survival benefit reliably, and they support continued reliance on overall survival. For clinicians, it is a reminder that a drug approved for delaying progression may not be proven to extend life, and the size and certainty of that benefit need to be discussed with patients.

• Ask whether a new kidney cancer drug has shown an overall survival benefit, not only a progression-free benefit.
• Discuss both the delay in progression and the uncertainty about survival with patients.
• Weigh toxicity against benefit, particularly where overall survival data are immature.
• Refer to a tumour board for decisions on sequencing treatments.

Why it matters

It tests the assumption behind many approvals that delaying progression means living longer.

Don't overread it

Trial-level correlations come from heterogeneous trials and do not tell you what will happen for an individual patient or a specific drug.

The statistics, in plain English

A correlation of 0.52 means that trials with bigger progression-free benefits tended to have bigger survival benefits, but with a lot of scatter, so a given trial's progression result is only a rough guide to its survival result. A surrogate threshold effect is the smallest endpoint benefit that would reliably predict survival benefit; here the intervals for it cross 1, so none could be set with confidence.

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