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In 2011, ipilimumab was approved by the US Food and Drug Administration (FDA) for metastatic melanoma. Since its approval, numerous targeted therapies have been approved by the FDA. Population-based studies assessing the survival benefit from these agents are lacking. We therefore carried out this study to compare the 1-year, 2-year, and median overall survival (OS) among metastatic melanoma patients in pretargeted and post-targeted eras. This is a retrospective study that utilized the Surveillance, Epidemiology, and End Results (SEER-18) database, version 8.3.4 (22 March 2017). The patient groups were defined as the pretargeted era (2004–2010) and the post-targeted era (2011–2014) as ipilimumab was approved by the FDA in 2011. The database comprised of 5471 patients (3314 in the pretargeted era and 2157 in the post-targeted era). OS in the post-targeted era was found to be significantly better compared with the pretargeted era by Kaplan–Meier curve (1-year OS: 38.9 vs. 36.8%, 2-year OS: 28.3 vs. 23.5%, and median survival: 8 vs. 7 months, P=0.001 by the log-rank test). The survival was significantly better in the post-targeted era compared with the pretargeted era on multivariate analysis using a Cox proportional hazard model after adjusting for age, sex, race, and metasectomy status (adjusted hazard ratio of 0.889, 95% CI: of 0.832–0.951, P=0.001). There is significant survival benefit in metastatic melanoma patients since the introduction of immune checkpoint-blocking agents.