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Abstract
BackgroundImmune checkpoint inhibitors and targeted therapies are approved for adjuvant treatment of patients with resected melanoma; however, they have not been compared in randomized controlled trials (RCTs). We compared the efficacy and safety of adjuvant nivolumab with other approved treatments using available evidence from RCTs in a Bayesian network meta-analysis (NMA).MethodsA systematic literature review was conducted through May 2019 to identify relevant RCTs evaluating approved adjuvant treatments. Outcomes of interest included recurrence-free survival (RFS)/disease-free survival (DFS), distant metastasis-free survival (DMFS), all-cause grade 3/4 adverse events (AEs), discontinuations, and discontinuations due to AEs. Time-to-event outcomes (RFS/DFS and DMFS) were analyzed both assuming that hazard ratios (HRs) are constant over time and that they vary.ResultsOf 26 identified RCTs, 19 were included in the NMA following a feasibility assessment. Based on HRs for RFS/DFS, the risk of recurrence with nivolumab was similar to that of pembrolizumab and lower than that of ipilimumab 3 mg/kg, ipilimumab 10 mg/kg, or interferon. Risk of recurrence with nivolumab was similar to that of dabrafenib plus trametinib at 12 months, however, was lower beyond 12 months (HR [95% credible interval] at 24 months, 0.46 [0.27–0.78]; at 36 months, 0.28 [0.14–0.59]). Based on HRs for DMFS, the risk of developing distant metastases was lower with nivolumab than with ipilimumab 10 mg/kg or interferon and was similar to dabrafenib plus trametinib.ConclusionAdjuvant therapy with nivolumab provides an effective treatment option with a promising risk–benefit profile.
Highlights
Immune checkpoint inhibitors and targeted therapies are approved for adjuvant treatment of patients with resected melanoma; they have not been compared in randomized controlled trials (RCTs)
Evidence base An systematic literature review (SLR) conducted through May 2019 identified 11 new studies in addition to the 41 studies identified in an earlier SLR, generating an evidence base of 52 studies (Additional file 1: Appendix A, Fig. A.1)
Based on Hazard ratio (HR) for distant metastasis-free survival (DMFS), the risk of developing distant metastases was lower with nivolumab than with ipilimumab 10 mg/kg or IFN but was similar to that of dabrafenib plus trametinib (Table 4)
Summary
Immune checkpoint inhibitors and targeted therapies are approved for adjuvant treatment of patients with resected melanoma; they have not been compared in randomized controlled trials (RCTs). Since 2011, adjuvant treatment options have expanded to include biologic agents such as interferon (IFN)-alpha and immune checkpoint inhibitors, such as cytotoxic T-lymphocyte antigen 4 and programmed death (PD)-1 inhibitors [1, 2]. Most of the trials involving these agents utilized placebo rather than an active comparator as the control and reported that 70 to 88% of patients remained recurrence-free 1 year after initiating active adjuvant treatment [7,8,9]. Ipilimumab 10 mg/kg and nivolumab 3 mg/kg have been compared head to head in the phase III CheckMate 238 trial [15], efficacy and safety comparisons between nivolumab and other adjuvant treatments in clinical trials are lacking
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