Progression-Free Survival Can Be Used as Surrogate for Overall Survival in Metastatic Melanoma Trials With Dacarbazine Control Group
In a meta-analysis reported in The Lancet Oncology, Flaherty et al found that progression-free survival is a reliable surrogate for overall survival in clinical trials in metastatic melanoma that include dacarbazine as control treatment.
Study Details
In the analysis, 1,649 reports and meeting abstracts published before September 8, 2013, were screened to identify randomized trials comparing treatment regimens in metastatic melanoma that included dacarbazine as the control treatment and that reported both progression-free survival and overall survival with a standard hazard ratio. A total of 12 first-line treatment trials that enrolled 4,416 patients were included in the meta-analysis. Hazard ratios for overall survival and progression-free survival were correlated with weighting by sample size or precision of the hazard ratio estimate.
Correlations in All Trials
Of the total of 14 comparisons in the 12 trials, 8 reported an improvement in progression-free survival and 4 reported an improvement in overall survival with the experimental treatment vs dacarbazine. A strong correlation between treatment effects for progression-free and overall survival, which appeared to be independent of type of treatment, was observed irrespective of weighting strategy.
With weighting for sample size, the Pearson correlation coefficient for correlation between progression-free survival and overall survival was 0.89 (95% confidence interval [CI] = 0.68–0.97). The correlation was weakened somewhat using a fixed-effect model that assumed no differences between type of therapy and effect on progression-free and overall survival (0.85, 95% CI = 0.59–0.95) and further weakened in a random-effects model allowing different types of therapy to have different effects on progression-free and overall survival (0.71, 95% CI = 0.29–0.90).
Correlations in Trials With Minimal Crossover
For the nine trials that did not include treatment crossover, the correlation coefficient was 0.96 (95% CI = 0.81–0.99); the correlation coefficient decreased somewhat to 0.93 (95% CI = 0.74–0.98) when two additional trials with less than 50% crossover were included in the analysis. Analysis including mature follow-up data after at least 50% crossover (which occurred in phase III trials of vemurafenib [Zelboraf] and dabrafenib [Tafinlar]) showed a weakened correlation (0.55, 95% CI = 0.03–0.84). In analysis including trials with little or no crossover and the random-effects assumption allowing different effects of different therapies on progression-free and overall survival, the correlation coefficient was 0.85 (95% CI = 0.51–0.96).
The investigators concluded, “[Progression-free survival] can be regarded as a robust surrogate for overall survival in dacarbazine-controlled randomized 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.”
They further noted, “The most important outcomes of our analysis would be an evolution in the regulatory standards by which new melanoma therapies are considered and approved, and in the weight of evidence given to [progression-free survival] by other bodies that set treatment guidelines. A move towards a clinical trial design standard in which [progression-free survival] is used as the primary endpoint would allow small randomised trials to be done and allow for more efficient vetting of new treatment regimens. Furthermore, this approach would minimize the risk of abandoning potentially effective new treatments when overall survival endpoints are contaminated by post-protocol therapy with other effective drugs.”
Dirk Schadendorf, MD, of University Hospital Essen, Germany, is the corresponding author for The Lancet Oncology article.
This study was designed by Keith T. Flaherty, MD, Sandra J. Lee, PhD, and Dirk Schadendorf, MD, in collaboration with GlaxoSmithKline’s Department of Biostatistics (Michael Hennig, PhD) without funding. For full disclosures of the study authors, visit www.thelancet.com.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
