Evaluating surrogacy metrics and investigating approval decisions of progression-free survival (PFS) in metastatic renal cell cancer: a systematic review

There is no published support of validity of progression-free survival (PFS) in metastatic renal cell (mRCC) disease. We determine the surrogate threshold effect, the PFS difference needed to predict with 95% confidence an overall survival (OS) benefit in targeted therapy trials. A new such trial with a 3.9 month PFS difference can claim OS benefit. Regulatory use of PFS evidence in mRCC is reviewed. In metastatic renal cell cancer (mRCC) trials, progression-free survival (PFS) is increasingly used instead of overall survival (OS) as the approval end point. Unlike other solid tumors, there is no published demonstration of what PFS is needed across and by treatment class in mRCC. We determine this and evaluate drug approval decisions in mRCC targeted therapy. We identified all randomized, controlled trials reporting PFS and OS in mRCC. Surrogacy metrics were the coefficient of determination and surrogate threshold effect (STE)—the PFS difference needed to predict, with 95% confidence, an OS difference. Data from regulatory commentaries, briefing documents and transcripts were extracted. No exclusively chemotherapy trial met criteria. Of 30 qualifying trials, 11 trials (13 comparisons) used targeted therapy. The all-trials and immunotherapy-only trials analysis failed to demonstrate a STE. The targeted trials, using the more conservative regression analysis demonstrated an STE of 3.9 months and anR2 of 0.44. Crossover upon progression, control to active treatment, was common. Regulatory approval, accelerated or regular, labeling, interim analyses, and adjudication were context specific. A new targeted therapy trial showing a PFS difference of 3.9 months can claim an OS benefit in mRCC. PFS surrogacy for OS in metastatic renal cell is not generalizable across all drug classes.