Relapse-free survival as a surrogate for overall survival in the evaluation of stage II-III melanoma adjuvant therapy

Stefan Suciu, Alexander M. Eggermont, Paul Lorigan, John M. Kirkwood, Svetomir Markovic, Claus Garbe, David Cameron, Srividya Kotapati, Tai-Tsang Chen, Keith Wheatley, Natalie Ives, Gaetan de Schaetzen, Achmad Efendi, M Buyse

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43 Citations (Scopus)


Background: We assessed whether relapse free survival (RFS) (time until recurrence/death) is a valid surrogate for overall survival (OS) among resected stage II-III melanoma patients through a meta-analysis of randomized controlled trials.
Methods: Individual patient data (IPD) on RFS and OS were collected from 5826 patients enrolled in 11 randomized adjuvant trials comparing interferon (IFN) to observation. In addition, IPD from two studies comparing IFN and vaccination in 989 patients were included. A two-level modeling approach was used for assessing Spearman’s patient-level correlation (rho) of RFS and OS and the trial-level coefficient of determination (R²) of the treatment effects on RFS and on OS. The results were validated externally in 13 adjuvant studies without available IPD. We then tested the results on the EORTC 18071 double-blind trial comparing ipilimumab 10 mg/kg versus placebo, which showed a statistically significant impact of the checkpoint inhibitor on RFS and OS. All statistical tests were two-sided. 
Results: With a median follow-up of 7 years, 12 of 13 trials showed a consistency between the IFN vs No IFN differences regarding RFS (HRRFS=0.88) and OS (HROS=0.91), but, the small trial, ECOG 2696, was an outlier (HRRFS=0.72 vs HROS=1.11). Therefore, even if rho was high, R² was low and could not reliably be estimated. Based on the 12 trials, rho remained high (0.89), and hazard ratios for RFS and OS were strongly correlated (R²=0.91). The surrogate threshold effect for RFS was estimated to be 0.77. For the EORTC 18071 trial, the HRRFS was 0.75, predicting an effect of ipilimumab on OS. This was subsequently confirmed (HROS=0.72, 95.1% CI=0.58-0.88; P=0.001). 
Conclusions: In high-risk stage II-III melanoma, RFS appeared to be a valid surrogate endpoint for OS for adjuvant randomized studies assessing interferon or a checkpoint inhibitor. In future similar adjuvant studies, a HRRFS of < 0.77 would predict a treatment impact on OS.
Original languageEnglish
JournalJournal of the National Cancer Institute
Issue number1
Early online date22 Aug 2017
Publication statusPublished - 1 Jan 2018


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