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

Keith T Flaherty, Michael Hennig, Sandra J Lee, Paolo A Ascierto, Reinhard Dummer, Alexander M M Eggermont, Axel Hauschild, Richard Kefford, John M Kirkwood, Georgina V Long, Paul Lorigan, Andreas Mackensen, Grant McArthur, Steven O'Day, Poulam M Patel,

The Lancet Oncology, Volume 15, Issue 3, Pages 297 - 304, March 2014

Editor's comments:
Since decades, overall survival was the one and only primary endpoint of important multicenter randomized trial investigating the treatment outcome for metastatic melanoma. Prof. Schadendorf, Flaherty and co-workers have now provided a systematic analysis of many randomized controlled trials including more than 4000 patients that have used the cover sign in the control arm. The careful analysis of this large dataset revealed that progression-free survival is a powerful surrogate marker for overall survival. This is particularly true for studies investigating targeted therapy. It holds also true for immunotherapy. Within the evolving landscapes of treatment options for advanced melanoma, this analysis is extremely helpful in order to justify progression-free survival as a primary endpoint in the next generation of clinical trials.

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.