Surrogate endpoints for overall survival in metastatic melanoma: a meta-analysis of randomised controlled trials

Abstract

Background: Recent phase 3 trials have shown an overall survival benefit in metastatic melanoma. We aimed to assess whether progression-free survival (PFS) could be regarded as a reliable surrogate for overall survival through a meta-analysis of randomised trials.

Methods: We systematically reviewed randomised trials comparing treatment regimens in metastatic melanoma that included dacarbazine as the control arm, and which reported both PFS and overall survival with a standard hazard ratio (HR). We correlated HRs for overall survival and PFS, weighted by sample size or by precision of the HR estimate, assuming fixed and random effects. We did sensitivity analyses according to presence of crossover, trial size, and dacarbazine dose.

Findings: After screening 1649 reports and meeting abstracts published before Sept 8, 2013, we identified 12 eligible randomised trials that enrolled 4416 patients with metastatic melanoma. Irrespective of weighting strategy, we noted a strong correlation between the treatment effects for PFS and overall survival, which seemed independent of treatment type. Pearson correlation coefficients were 0·71 (95% CI 0·29-0·90) with a random-effects assumption, 0·85 (0·59-0·95) with a fixed-effects assumption, and 0·89 (0·68-0·97) with sample-size weighting. For nine trials without crossover, the correlation coefficient was 0·96 (0·81-0·99), which decreased to 0·93 (0·74-0·98) when two additional trials with less than 50% crossover were included. Inclusion of mature follow-up data after at least 50% crossover (in vemurafenib and dabrafenib phase 3 trials) weakened the PFS to overall survival correlation (0·55, 0·03-0·84). Inclusion of trials with no or little crossover with the random-effects assumption yielded a conservative statement of the PFS to overall survival correlation of 0·85 (0·51-0·96).

Interpretation: PFS can be regarded as a robust surrogate for overall survival in dacarbazine-controlled randomised trials of metastatic melanoma; we postulate that this association will hold as treatment standards evolve and are adopted as the control arm in future trials.

Funding: None.

Figure 1. Study flow chart

*Details of these six trials are in the discussion section. CDSR=Cochrane Database of Systematic Reviews. CDAR=Cochrane Database of Abstracts of Reviews of Effects. CCTR=Cochrane Central Register of Controlled Trials. NHSEED=National Health Service Economic Evaluation Database. INHATA=International Network of Agencies for Health Technology Assessment. ASCO=American Society of Clinical Oncology. SMR=Society for Melanoma Research. ESMO=European Society for Medical Oncology. HR=hazard ratio. PFS=progression-free survival.

Figure 2. Correlation between treatment effects on overall survival and progression-free survival (PFS)

Size of circles is proportional to sample size. The regression equation can be used to predict the overall survival effect on the basis of an observed PFS effect; eg, an observed HR for PFS of 0.5 leads to an estimated HR for overall survival of 0.625.