ArticlesSurrogate endpoints for overall survival in metastatic melanoma: a meta-analysis of randomised controlled trials
Introduction
Substantial advances have been made in the treatment of metastatic melanoma on the basis of insights gained into the unique molecular biology of this disease and the mechanisms by which immune effector cells are silenced. The identification of activating BRAF mutations in about 50% of advanced melanomas in 2002 was a watershed event that pointed the specialty toward a molecularly targeted treatment approach.1 In addition, identification of CTLA4 and PD1 as negative regulators of effector T-cell function that could be countered with monoclonal antibodies has made the prospect of reversal of immune tolerance a tractable therapeutic approach.2, 3
Two BRAF inhibitors, vemurafenib and dabrafenib, and a MEK inhibitor, trametinib, have all proven superior to dacarbazine—the only cytotoxic chemotherapy approved by the US Food and Drug Administration for melanoma—in randomised phase 3 trials.4, 5, 6 Ipilimumab was superior to an investigational vaccine in patients refractory to chemotherapy and to dacarbazine alone when combined with dacarbazine in the first-line metastatic setting,2, 7 and nab-paclitaxel improved progression-free survival (PFS) compared with dacarbazine.8 Numerous randomised trials that have compared investigational therapies with dacarbazine in recent years have failed to show a significant improvement in overall survival.9, 10, 11, 12, 13, 14, 15
As melanoma researchers continue to develop new treatment approaches to extend the effects of molecularly targeted treatments and immunotherapies, the next generation of investigational melanoma therapies will undergo definitive, randomised trials in an environment in which patients will have access to therapies with known effects on overall survival. Furthermore, targeted therapy or immunotherapy control arms are increasingly incorporated into such trials. Provided that patients remain on protocol-assigned therapy until disease progression, PFS is not confounded by post-protocol therapy in the same way that overall survival can be. If a strong correlation between treatment effects for PFS and overall survival can be established from analysis of previous randomised trials in metastatic melanoma, a significant improvement in progression-free survival noted in a future trial could be regarded as definitive evidence of clinical benefit. Establishment of such surrogacy would permit the next generation of experimental therapies in melanoma to be judged on their individual merits and diminish the risk that a potentially effective therapy is deemed ineffective because overall survival endpoints are affected by post-protocol therapy with other effective drugs. Similar analyses have been done for metastatic breast cancer and colorectal cancer. In both cases, the observed correlations between PFS and overall survival were regarded as sufficiently robust to support PFS as a surrogate endpoint in definitive phase 3 trials.16, 17
Whether improved PFS can be regarded as a predictor of improved overall survival in metastatic melanoma needs to be understood. In several cancer types, including melanoma, PFS has been adopted as the primary endpoint in definitive phase 3 trials without supporting evidence in those cancers that an effect on PFS is a reliable predictor of overall survival. Therefore, we aimed to assess correlation between PFS and overall survival in randomised, dacarbazine-controlled trials of treatments for metastatic melanoma.
Section snippets
Search strategy and selection criteria
In September, 2013, we systematically searched Medline, Embase, the Cochrane Database of Systematic Review, Cochrane Central Register of Controlled Trials, Database of Abstracts of Reviews of Effects, the National Health Service Economic Evaluation Database, and International Network of Agencies for Health Technology Assessment Database. The appendix contains full details of the search terms. We hand-searched conference abstracts to retrieve the latest studies, which had not been published in
Results
After screening of 1649 reports and meeting abstracts, we identified 12 trials4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 that were eligible for inclusion (figure 1, table 1). One study included three comparisons between experimental therapy and control arms, so overall we included 14 comparisons (table 2). We did not require trials to be done in the first-line metastatic setting, but the requirement that dacarbazine be the control arm led to inclusion of only first-line trials.
Eight comparisons
Discussion
In our analysis of randomised, dacarbazine-controlled trials of metastatic melanoma, we noted a strong correlation between PFS and overall survival (correlation coefficients ranging from 0·55 to 0·96), irrespective of the weighting strategy applied. Randomised trials that permitted crossover to experimental therapy after disease progression on dacarbazine had the greatest effect on the correlation coefficients. Restriction of our analysis to those trials without crossover yielded a nearly
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