Adjuvant ipilimumab versus placebo after complete resection of high-risk XXXX (EORTC 18071): a randomised, double-blind, phase 3 trial.

@entity1 @entity344 @entity177 @entity1960 @entity2744 @entity5011 @entity3 @entity9910 @entity2401 @entity320
BACKGROUND: Ipilimumab is an approved treatment for @entity1 with advanced @entity320 . We aimed to assess ipilimumab as adjuvant therapy for @entity1 with completely resected @entity9910 at high risk of recurrence. METHODS: We did a double-blind, phase 3 trial in @entity1 with stage III @entity320 (excluding lymph node @entity3  <=1 mm or in-transit @entity3 ) with adequate resection of lymph nodes (ie, the primary @entity320 must have been completely excised with adequate surgical margins) who had not received previous systemic therapy for @entity320 from 91 hospitals located in 19 countries. @entity1 were randomly assigned (1:1), centrally by an interactive voice response system, to receive intravenous infusions of 10 mg/kg ipilimumab or placebo every 3 weeks for four doses, then every 3 months for up to 3 years. Using a minimisation technique, randomisation was stratified by disease stage and geographical region. The primary endpoint was recurrence-free survival, assessed by an independent review committee, and analysed by intention to treat. Enrollment is complete but the study is ongoing for follow-up for analysis of secondary endpoints. This trial is registered with EudraCT, number 2007-001974-10, and ClinicalTrials.gov, number NCT00636168. FINDINGS: Between July 10, 2008, and Aug 1, 2011, 951 @entity1 were randomly assigned to ipilimumab (n=475) or placebo (n=476), all of whom were included in the intention-to-treat analyses. At a median follow-up of 2  74 years (IQR 2  28-3  22), there were 528 recurrence-free survival events (234 in the ipilimumab group vs 294 in the placebo group). Median recurrence-free survival was 26  1 months (95% CI 19  3-39  3) in the ipilimumab group versus 17  1 months (95% CI 13  4-21  6) in the placebo group (hazard ratio 0  75; 95% CI 0  64-0  90; p=0  0013); 3-year recurrence-free survival was 46  5% (95% CI 41  5-51  3) in the ipilimumab group versus 34  8% (30  1-39  5) in the placebo group. The most common grade 3-4 immune-related adverse events in the ipilimumab group were gastrointestinal (75 [16%] vs four [<1%] in the placebo group), hepatic (50 [11%] vs one [<1%]), and endocrine (40 [8%] vs none). Adverse events led to discontinuation of treatment in 245 (52%) of 471 @entity1 who started ipilimumab (182 [39%] during the initial treatment period of four doses). Five @entity1 (1%) died due to drug-related adverse events. Five (1%) @entity1 died because of drug-related adverse events in the ipilimumab group; three @entity1 died because of @entity1960 (two with @entity344 ), one @entity1 because of @entity2401 , and one @entity1 because of @entity177 with @entity5011 . INTERPRETATION: Adjuvant ipilimumab significantly improved recurrence-free survival for @entity1 with completely resected high-risk @entity9910 . The adverse event profile was consistent with that observed in advanced @entity320 , but at higher incidences in particular for @entity2744 . The risk-benefit ratio of adjuvant ipilimumab at this dose and schedule requires additional assessment based on distant @entity3 -free survival and overall survival endpoints to define its definitive value. FUNDING: Bristol-Myers Squibb.
