OBJECTIVES: Use of valid SEs enables assessment of long-term efficacy of treatments in absence of OS from the RCTs. We evaluated RFS as an SE for OS in resected stage II/III melanoma using trial-level data.

METHODS: RCTs were searched in a targeted literature review of Embase (inception to October 2022). Treatment effects reported as hazard ratios (HRs) on RFS and OS in patients ≥12 years old were extracted. Bivariate random effects meta-analysis (BRMA) and weighted linear regression (WLR) by study sample size were employed for correlation estimation (95% CI) between HR_RFS and HR_OS. Validity and predictive performance of WLR were assessed using leave-one-out cross-validation (LOOCV). Sensitivity analyses excluding trials failing the proportional hazards assumption and adjusting for cancer stage (II or III) were explored.

RESULTS: Thirty RCTs (stage II/III: n=8/11; mixed: n=11) published between 1978 to 2022 (median: 2013) formed the evidence base. Trials included 45 to 1,670 patients (median: 519). Treatments studied in the RCTs involved mostly interferon-alfa (n=18), followed by other immunotherapy-containing regimens agents (n=11), immune checkpoint inhibitors (ICIs; n=3) and targeted therapies (n=2). Estimated correlations from BRMA and WLR were 0.70 (95% CI: 0.49-0.83) and 0.71 (95% CI: 0.43-0.87), respectively. The surrogacy equation estimated from WLR was log(HR_OS)=-0.02+0.69×log(HR_RFS) with a statistically significant slope coefficient (95% CI: 0.43-0.95). In LOOCV, 95% prediction intervals for HR_OS captured the observed HR_OS for 93.5% of the RCTs. Accounting for proportional hazards (n = 21) and disease staging (n = 23) showed modest impact on correlations (BRMA: 0.70-0.75; WLR: 0.66-0.73), and similar accuracy in LOOCV (89.3%-95.5%) compared with the primary analysis.

CONCLUSIONS: With considerable correlation between HR_RFS and HR_OS, surrogacy equation in this study can assist earlier predictions of OS benefit in resected stage II/III melanoma from reported RFS benefit with the caveat that most included trials were conducted prior to the pursuit of modern ICIs.