1089PD - Relapse-free survival (RFS) as a surrogate endpoint for overall survival (OS) in adjuvant Interferon trials in patients (pts) with resectable cutan...

Date 29 September 2014
Event ESMO 2014
Session Melanoma and other skin tumours
Topics Immunotherapy
Skin Cancers
Presenter Stefan Suciu
Citation Annals of Oncology (2014) 25 (suppl_4): iv374-iv393. 10.1093/annonc/mdu344
Authors S. Suciu1, A.M.M. Eggermont2, P. Lorigan3, J. Kirkwood4, S. Markovic5, C. Garbe6, D. Cameron7, S. Kotapati8, C. Konto9, T. Chen10, K. Wheatley11, N. Ives11, G. De Schaetzen12, A. Efendi1, M. Buyse13
  • 1Biostatistics, EORTC Headquarters, 1200 - Brussels/BE
  • 2-, Institut Gustave Roussy, 94805 - Villejuif/FR
  • 3Medical Oncology, The Christie NHS Foundation Trust, M20 4BX - Manchester/GB
  • 4Department Of Medicine, University of Pittsburgh Cancer Institute, Pittsburgh/US
  • 5Hematology And Oncology, Mayo Clinic, Rochester/US
  • 6Dermatology, University of Tubingen, Tubingen/DE
  • 7Oncology, University of Edinburgh, Edinburgh/GB
  • 8Health Economics And Outcome Research, BMS, Wallingford/US
  • 9Global Clinical Research Oncology, BMS, Wallingford/US
  • 10Global Biometric Sciences, BMS, Wallingford/US
  • 11Birmingham Clinical Trials Unit, University of Birmingham, Birmingham/GB
  • 12Project Management, EORTC Headquarters, 1200 - Brussels/BE
  • 13Biostatistics, IDDI-International Drug Development Institute, BE-1340 - Louvain-la-Neuve/BE




We aimed to assess whether RFS is a valid surrogate for OS for high risk stage I-III melanoma through a meta-analysis of randomized controlled trials.


All trials with available IPD on RFS (time until recurrence/death) and OS were collected from high risk stage I-III pts enrolled in 11 randomized adjuvant trials (N = 5826) comparing interferon (IFN) to observation: EORTC (18871, 18952, 18991), ECOG (1684, 1690), MRC (AIMHIGH), WHO-16, NCCTG (83-7052), DKG 80-1, DeCOG and Scottish group. In addition IPD from ECOG 1694 trial, IFN vs GMK vaccine (N = 842), and ECOG 2696, IFN administered concomitantly/sequentially with GMK vaccine vs GMK vaccine (N = 107) were added. We applied a two-level modeling approach assessing Spearman's individual-level correlation of RFS and OS (rho) and the trial-level coefficient of determination (R2) of the treatment effect on RFS and on OS.


At a 7-yr median follow-up, a consistent advantage of IFN vs No IFN was observed for RFS and OS (see table). R2 could not reliably be estimated when all trials were considered. A proper R2 estimate was obtained after exclusion of ECOG 2696 trial, which was an outlier [HR(RFS) = 0.72 vs HR(OS) = 1.11]. As a sensitivity analysis, the model was also fitted after excluding the other vaccine comparator trial (ECOG 1694). In these two analyses, RFS and OS were strongly correlated and the surrogate threshold effect (STE) was estimated to be a HR of 0.774 and 0.786, respectively. The leave-one-out cross-validation showed consistently good model accuracy.

All pts (N = 6815) All but ECOG2696(N = 6708) No vaccine trials (N = 5826)
5-yr RFS 35.2% 38.8% .87 35.2% 38.8% .88 34.0% 38.0% .88
5-yr OS 47.2% 50.3% .91 47.0% 50.2% .91 45.4% 49.0% .91
rho** .887 .887 .887
R2** - .906 .924
STE** - .774 .786

*Forest plots; **Plackett copula.


We found that both individual-level and trial-level correlations are close to 1, suggesting a valid surrogacy of RFS for OS. If, in a future trial, the treatment effect HR on RFS were less than 0.774, one would expect this trial to also show a treatment effect on OS.


A.M.M. Eggermont: Member of advisory board: AMGEN, BMS, GSK, MedImmune, MSD; P. Lorigan: Advisory board member: BMS, Celgene, GSK, Merck, Novartis, Roche. Other supportive relationships: Support for travel BMS, Merck, Roche; J. Kirkwood: Consultancy: BMS, Celgene, MSD, Prometheus, Vical, Ziopharma; C. Garbe: Member of advisory board: BMS, GSK, MSD, Novartis, Philogen, Roche Corporate sponsore research: BMS, GSK, Roche; D. Cameron: Member of advisory board (compensated to employer): Roche Corporate sponsored research (paid to another institution): Roche; S. Kotapati: Stock ownership: BMS Corporate sponsored research: BMS; C. Konto: Stock ownership: BMS Corporate sponsored research: BMS Other: employee of BMS; T. Chen: Stock ownership: BMS Corporate sponsored research: BMS; M. Buyse: Stock ownership: IDDI. All other authors have declared no conflicts of interest.